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Background: Although the pathogenesis of essential hypertension is not clear, a large number of studies have shown that oxidative stress plays an important role in the occurrence and development of hypertension and target organ damage. Purpose: This paper systematically summarizes the relationship between oxidative stress and hypertension, and explores the potential mechanisms of Chinese herbal medicine (CHM) in the regulation of oxidative stress in hypertension, aiming to establish a scientific basis for the treatment of hypertension with CHM. Methods: To review the efficacy and mechanism by which CHM treat hypertension through targeting oxidative stress, data were searched from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the Chinese National Knowledge Infrastructure, the VIP Information Database, the Chinese Biomedical Literature Database, and the Wanfang Database from their inception up to January 2024. NPs were classified and summarized by their mechanisms of action. Results: In hypertension, the oxidative stress pathway of the body is abnormally activated, and the antioxidant system is inhibited, leading to the imbalance between the oxidative and antioxidative capacity. Meanwhile, excessive production of reactive oxygen species can lead to endothelial damage and vascular dysfunction, resulting in inflammation and immune response, thereby promoting the development of hypertension and damaging the heart, brain, kidneys, blood vessels, and other target organs. Numerous studies suggested that inhibiting oxidative stress may be the potential therapeutic target for hypertension. In recent years, the clinical advantages of traditional Chinese medicine (TCM) in the treatment of hypertension have gradually attracted attention. TCM, including active ingredients of CHM, single Chinese herb, TCM classic formula and traditional Chinese patent medicine, can not only reduce blood pressure, improve clinical symptoms, but also improve oxidative stress, thus extensively affect vascular endothelium, renin–angiotensin–aldosterone system, sympathetic nervous system, target organ damage, as well as insulin resistance, hyperlipidemia, hyperhomocysteinemia and other pathological mechanisms and hypertension related risk factors. Conclusions: CHM display a beneficial multi-target, multi-component, overall and comprehensive regulation characteristics, and have potential value for clinical application in the treatment of hypertension by regulating the level of oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Delirium affects 50–85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes. Methods: Microglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4–9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes. Results: Frontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p < 0.01, p < 0.01, respectively). These structural changes were accompanied by worse delirium-like behaviors in microglia depleted VILI mice compared to vehicle controls. Specifically, microglia depleted VILI mice demonstrated: (1) significantly increased time in the periphery of the Open Field (p = 0.01), (2) significantly increased coefficient of variation (p = 0.02), (3) trend towards reduced time in the open arms of the Elevated Plus Maze (p = 0.09), and (4) significantly decreased spontaneous alternations on Y-maze (p < 0.01). There was a significant inverse correlation between frontal CC3 and percent spontaneous alternations (R2 = 0.51, p < 0.01). Microglia repopulation showed a near-complete return to vehicle levels of delirium like-behaviors. Conclusions: This study demonstrates that microglia depletion exacerbates structural and functional delirium-like phenotypes after VILI, while subsequent repopulation of microglia restores these phenotypes. These findings suggest a neuroprotective role for microglia in ameliorating neuronal and functional delirium-like phenotypes and call for consideration of interventions that leverage endogenous microglia physiology to mitigate delirium. [ABSTRACT FROM AUTHOR]

Bovine mastitis is one of the main inflammatory diseases that can affect the udder during lactation. Somatic cell counts and sometimes microbiological tests are routinely adopted during monitoring diagnostics in dairy herds. However, subclinical mastitis is challenging to identify, reducing the possibility of early treatments. The main aim of this study was to investigate the miRNome profile of extracellular vesicles isolated from milk as potential biomarkers of subclinical mastitis. Milk samples were collected from a total of 60 dairy cows during routine monitoring tests. Small RNA sequencing technology was applied to extracellular vesicles of milk samples collected from cows classified according to the somatic cell count to identify differences in the miRNome between mastitic and healthy cows. A total of 1997 miRNAs were differentially expressed between both groups. Among them, 68 miRNAs whose FDRs were < 0.05 were mostly downregulated, with only one upregulated miRNA (i.e., miR-361). Functional analysis revealed that miR-455-3p, miR-503-3p, miR-1301-3p and miR-361-5p are involved in the regulation of several biological processes related to mastitis, including immune system-related processes. This study suggests the involvement of extracellular vesicle-derived miRNAs in the regulation of mastitis. Moreover, these findings provide evidence that miRNAs from milk extracellular vesicles can be used to identify biomarkers of mastitis. However, further studies must be conducted to validate these miRNAs, especially for subclinical diagnosis. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to describe the clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles (CFEOM), and to evaluate the phenotype–genotype correlations in these patients. Methods: This was a retrospective study. Patients with CFEOM underwent detailed ophthalmic examinations and magnetic resonance imaging (MRI). Panel-based next-generation sequencing was performed to identify pathogenic variants of disease-causing genes. Results: Sixty-two patients with CFEOM were recruited into this study. Thirty-nine patients were diagnosed with CFEOM1 and 23 with CFEOM3. Forty-nine of the 62 patients with CFEOM carried either KIF21A (41/49) or TUBB3 variants (8/49). Six known missense variants in the KIF21A and TUBB3 genes, and a novel variant (c.3906T > A, p.D1302E) in the KIF21A gene were detected. Most patients with CFEOM1 carrying the KIF21A mutation displayed isolated CFEOM, whereas patients with CFEOM3 carrying the TUBB3 mutation had a wide range of clinical manifestations, either CFEOM alone or syndromes. Nystagmus was also present in 12 patients with CFEOM. Furthermore, the MRI findings varied, ranging from attenuation of the extraocular muscles to dysgenesis of the cranial nerves and brain structure. Conclusions: The novel variants identified in this study will further expand the spectrum of pathogenic variants in CFEOM-related genes. However, no phenotype–genotype correlations were established because of the diversity of the clinical characteristics of these patients. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke elicits a complex and sustained immune response in the brain. Immunomodulatory treatments have long held promise for improving stroke outcomes, yet none have succeeded in the clinical setting. This lack of success is largely due to our incomplete understanding of how immune cells respond to stroke. The objective of the current study was to dissect the effect of permanent stroke on microglia, the resident immune cells within the brain parenchyma. Methods: A permanent middle cerebral artery occlusion (pMCAO) model was used to induce ischemic stroke in young male and female mice. Microglia were sorted from fluorescence reporter mice after pMCAO or sham surgery and then subjected to single-cell RNA sequencing analysis. Various methods, including flow cytometry, RNA in situ hybridization, immunohistochemistry, whole-brain imaging, and bone marrow transplantation, were also employed to dissect the microglial response to stroke. Stroke outcomes were evaluated by infarct size and behavioral tests. Results: First, we showed the morphologic and spatial changes in microglia after stroke. We then performed single-cell RNA sequencing analysis on microglia isolated from sham and stroke mice of both sexes. The data indicate no major sexual dimorphism in the microglial response to permanent stroke. Notably, we identified seven potential stroke-associated microglial clusters, including four major clusters characterized by a disease-associated microglia-like signature, a highly proliferative state, a macrophage-like profile, and an interferon (IFN) response signature, respectively. Importantly, we provided evidence that the macrophage-like cluster may represent the long-sought stroke-induced microglia subpopulation with increased CD45 expression. Lastly, given that the IFN-responsive subset constitutes the most prominent microglial population in the stroke brain, we used fludarabine to pharmacologically target STAT1 signaling and found that fludarabine treatment improved long-term stroke outcome. Conclusions: Our findings shed new light on microglia heterogeneity in stroke pathology and underscore the potential of targeting specific microglial populations for effective stroke therapies. [ABSTRACT FROM AUTHOR]

Background: Intramammary infection is the result of invasion and multiplication of microorganisms in the mammary gland and commonly leads to mastitis in dairy animals. Although much has been done to improve cows' udder health, mastitis remains a significant and costly health issue for dairy farmers, especially if subclinical. In this study, quarter milk samples from clinically healthy cows were harvested to detect pathogens via quantitative PCR (qPCR) and evaluate changes in individual milk traits according to the number of quarters infected and the type of microorganism(s). A commercial qPCR kit was used for detection of Mycoplasma bovis, Mycoplasma spp., Staphylococcus aureus, coagulase-negative staphylococci (CNS), Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus uberis, Prototheca spp., Escherichia coli, Klebsiella spp., Enterococcus spp. and Lactococcus lactis ssp. lactis. Quarter and pooled milk information of 383 Holstein, 132 Simmental, 129 Rendena, and 112 Jersey cows in 9 Italian single-breed herds was available. Results: Among the cows with pathogen(s) present in at least 1 quarter, CNS was the most commonly detected DNA, followed by Streptococcus uberis, Mycoplasma bovis, and Streptococcus agalactiae. Cows negative to qPCR were 206 and had the lowest milk somatic cell count. Viceversa, cows with DNA isolated in ≥ 3 quarters were those with the highest somatic cell count. Moreover, when major pathogens were isolated in ≥ 3 quarters, milk had the lowest casein index and lactose content. In animals with pathogen(s) DNA isolated, the extent with whom milk yield and major solids were impaired did not significantly differ between major and minor pathogens. Conclusions: The effect of the number of affected quarters on the pool milk quality traits was investigated in clinically healthy cows using a commercial kit. Results remark the important negative effect of subclinical udder inflammations on milk yield and quality, but more efforts should be made to investigate the presence of untargeted microorganisms, as they may be potentially dangerous for cows. For a smarter use of antimicrobials, analysis of milk via qPCR is advisable – especially in cows at dry off - to identify quarters at high risk of inflammation and thus apply a targeted/tailored treatment. [ABSTRACT FROM AUTHOR]

Background: In dairy cattle, mastitis causes high financial losses and impairs animal well-being. Genetic selection is used to breed cows with reduced mastitis susceptibility. Techniques such as milk cell flow cytometry may improve early mastitis diagnosis. In a highly standardized in vivo infection model, 36 half-sib cows were selected for divergent paternal Bos taurus chromosome 18 haplotypes (Q vs. q) and challenged with Escherichia coli for 24 h or Staphylococcus aureus for 96 h, after which the samples were analyzed at 12 h intervals. Vaginal temperature (VT) was recorded every three minutes. The objective of this study was to compare the differential milk cell count (DMCC), milk parameters (fat %, protein %, lactose %, pH) and VT between favorable (Q) and unfavorable (q) haplotype cows using Bayesian models to evaluate their potential as improved early indicators of differential susceptibility to mastitis. Results: After S. aureus challenge, compared to the Q half-sibship cows, the milk of the q cows exhibited higher PMN levels according to the DMCC (24 h, p < 0.001), a higher SCC (24 h, p < 0.01 and 36 h, p < 0.05), large cells (24 h, p < 0.05) and more dead (36 h, p < 0.001) and live cells (24 h, p < 0.01). The protein % was greater in Q milk than in q milk at 0 h (p = 0.025). In the S. aureus group, Q cows had a greater protein % (60 h, p = 0.048) and fat % (84 h, p = 0.022) than q cows. Initially, the greater VT of S. aureus-challenged q cows (0 and 12–24 h, p < 0.05) reversed to a lower VT in q cows than in Q cows (48–60 h, p < 0.05). Additionally, the following findings emphasized the validity of the model: in the S. aureus group all DMCC subpopulations (24 h-96 h, p < 0.001) and in the E. coli group nearly all DMCC subpopulations (12 h-24 h, p < 0.001) were higher in challenged quarters than in unchallenged quarters. The lactose % was lower in the milk samples of E. coli-challenged quarters than in those of S. aureus-challenged quarters (24 h, p < 0.001). Between 12 and 18 h, the VT was greater in cows challenged with E. coli than in those challenged with S. aureus (3-h interval approach, p < 0.001). Conclusion: This in vivo infection model confirmed specific differences between Q and q cows with respect to the DMCC, milk component analysis results and VT results after S. aureus inoculation but not after E. coli challenge. However, compared with conventional milk cell analysis monitoring, e.g., the global SCC, the DMCC analysis did not provide refined phenotyping of the pathogen response. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms. Main content: Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron–glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics. Conclusion: Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research. [ABSTRACT FROM AUTHOR]

Purpose: String indexes such as the suffix array (sa) and the closely related longest common prefix (lcp) array are fundamental objects in bioinformatics and have a wide variety of applications. Despite their importance in practice, few scalable parallel algorithms for constructing these are known, and the existing algorithms can be highly non-trivial to implement and parallelize. Methods: In this paper we present caps-sa, a simple and scalable parallel algorithm for constructing these string indexes inspired by samplesort and utilizing an LCP-informed mergesort. Due to its design, caps-sa has excellent memory-locality and thus incurs fewer cache misses and achieves strong performance on modern multicore systems with deep cache hierarchies. Results: We show that despite its simple design, caps-sa outperforms existing state-of-the-art parallel sa and lcp-array construction algorithms on modern hardware. Finally, motivated by applications in modern aligners where the query strings have bounded lengths, we introduce the notion of a bounded-context sa and show that caps-sa can easily be extended to exploit this structure to obtain further speedups. We make our code publicly available at https://github.com/jamshed/CaPS-SA. [ABSTRACT FROM AUTHOR]

Microglia are sexually dimorphic, yet, this critical aspect is often overlooked in neuroscientific studies. Decades of research have revealed the dynamic nature of microglial-neuronal interactions, but seldom consider how this dynamism varies with microglial sex differences, leaving a significant gap in our knowledge. This study focuses on P2RY12, a highly expressed microglial signature gene that mediates microglial-neuronal interactions, we show that adult females have a significantly higher expression of the receptor than adult male microglia. We further demonstrate that a genetic deletion of P2RY12 induces sex-specific cellular perturbations with microglia and neurons in females more significantly affected. Correspondingly, female mice lacking P2RY12 exhibit unique behavioral anomalies not observed in male counterparts. These findings underscore the critical, sex-specific roles of P2RY12 in microglial-neuronal interactions, offering new insights into basal interactions and potential implications for CNS disease mechanisms. Highlights: Microglial P2RY12 shows a greater protein expression in adult females than adult males Microglial P2RY12 deficiency triggers morphological perturbations, especially in females Microglial P2RY12 deficiency triggers sex-specific dendritic spine alterations Microglial P2RY12 deficiency triggers sexually dimorphic behavioral anomalies [ABSTRACT FROM AUTHOR]

Background: Horizontal gene transfer inference approaches are usually based on gene sequences: parametric methods search for patterns that deviate from a particular genomic signature, while phylogenetic methods use sequences to reconstruct the gene and species trees. However, it is well-known that sequences have difficulty identifying ancient transfers since mutations have enough time to erase all evidence of such events. In this work, we ask whether character-based methods can predict gene transfers. Their advantage over sequences is that homologous genes can have low DNA similarity, but still have retained enough important common motifs that allow them to have common character traits, for instance the same functional or expression profile. A phylogeny that has two separate clades that acquired the same character independently might indicate the presence of a transfer even in the absence of sequence similarity. Our contributions: We introduce perfect transfer networks, which are phylogenetic networks that can explain the character diversity of a set of taxa under the assumption that characters have unique births, and that once a character is gained it is rarely lost. Examples of such traits include transposable elements, biochemical markers and emergence of organelles, just to name a few. We study the differences between our model and two similar models: perfect phylogenetic networks and ancestral recombination networks. Our goals are to initiate a study on the structural and algorithmic properties of perfect transfer networks. We then show that in polynomial time, one can decide whether a given network is a valid explanation for a set of taxa, and show how, for a given tree, one can add transfer edges to it so that it explains a set of taxa. We finally provide lower and upper bounds on the number of transfers required to explain a set of taxa, in the worst case. [ABSTRACT FROM AUTHOR]

Objective: This study aims to assess the effectiveness of traditional Chinese exercise therapy in alleviating pain, improving sleep quality, and reducing symptoms of anxiety and depression among fibromyalgia patients. Methods: We conducted a comprehensive search across various databases, including PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge, VIP database, and Wanfang, to identify randomized controlled trials (RCTs) examining the impact of Traditional Chinese Exercise (TCE) interventions on fibromyalgia. Two independent authors extracted data from the selected studies based on predefined inclusion and exclusion criteria. Meta-analyses were performed using RevMan 5.3. Results: The analysis encompassed 15 RCTs, comprising 936 participants. The meta-analysis revealed that TCE significantly surpassed the control group in reducing pain scores for fibromyalgia patients, as evidenced by improvements in FIQ [MD = -3.30, 95% CI (− 5.37, − 0.69), z = 2.53, p = 0.01] and VAS [MD = -1.87, 95% CI (− 2.12, − 1.61), z = 6.98, p < 0.00001]. Additionally, TCE demonstrated notable enhancements in sleep quality (PSQI) [MD = -2.23, 95% CI (− 2.86, − 1.61), z = 6.98, p < 0.0001], as well as in alleviating symptoms of anxiety and depression [MD = − 0.59, 95% CI (− 0.80, − 0.39), z = 5.63, p < 0.0001]. Conclusion: Traditional Chinese Exercise (TCE) exhibits significant efficacy in ameliorating pain, enhancing sleep quality, and alleviating symptoms of anxiety and depression in fibromyalgia patients. [ABSTRACT FROM AUTHOR]

Background: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia; it disproportionally affects women in terms of both incidence rates and severity of progression. The cellular and molecular mechanisms underlying this clinical phenomenon remain elusive and ill-defined. Methods: In-depth analyses were performed with multiple human LOAD single-nucleus transcriptome datasets to thoroughly characterize cell populations in the cerebral cortex. ROSMAP bulk human brain tissue transcriptome and DNA methylome datasets were also included for validation. Detailed assessments of microglial cell subpopulations and their relevance to sex-biased changes at the tissue level were performed. Clinical trait associations, cell evolutionary trajectories, and transcription regulon analyses were conducted. Results: The relative numbers of functionally defective microglia were aberrantly increased uniquely among affected females. Substratification of the microglia into different subtypes according to their transcriptomic signatures identified a group of female-enriched and disease-associated microglia (FDAMic), the numbers of which were positively associated with disease severity. Phenotypically, these cells exhibit transcriptomic signatures that support active proliferation, MHC class II autoantigen presentation and amyloid-β binding, but they are also likely defective in phagocytosis. FDAMic are likely evolved from female activated response microglia (ARMic) with an APOE4 background and compromised estrogen receptor (ER) signaling that is deemed to be active among most subtypes of microglia. Conclusion: This study offered important insights at both the cellular and molecular levels into how ER signaling affects microglial heterogeneity and function. FDAMic are associated with more advanced pathologies and severe trends of cognitive decline. Their emergence could, at least in part, explain the phenomenon of greater penetrance of the APOE4 genotype found in females. The biases of FDAMic emergence toward female sex and APOE4 status may also explain why hormone replacement therapy is more effective in APOE4 carriers. The pathologic nature of FDAMic suggests that selective modulations of these cells may help to regain brain neuroimmune homeostasis, serving as a new target for future drug development. [ABSTRACT FROM AUTHOR]

Background: Virtual Reality (VR) has already emerged as an effective instrument for simulating realistic interactions, across various domains. In the field of User Experience (UX), VR has been used to create prototypes of real-world products. Here, the question is to what extent the users' experience of a virtual prototype can be equivalent to that of its real counterpart (the real product). This issue particularly concerns the perceptual, cognitive and affective dimensions of users' experiences. Methods: This exploratory study aims to address this issue by comparing the users' experience of a well-known product, i.e., the Graziella bicycle, presented either in Sumerian or Sansar VR platform, or in a physical setting. Participants' Emotional Engagement, Sense of Presence, Immersion, and Perceived Product Quality were evaluated after being exposed to the product in all conditions (i.e., Sumerian, Sansar and Physical). Results: The findings indicated significantly higher levels of Engagement and Positive Affect in the virtual experiences when compared to their real-world counterparts. Additionally, the sole notable distinction among the VR platforms was observed in terms of Realism. Conclusions: This study suggests the feasibility and potential of immersive VR environments as UX evaluation tools and underscores their effectiveness in replicating genuine real-world experiences. [ABSTRACT FROM AUTHOR]

Background: Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloidosis and altered microglial phenotypes that are specific to male mice. The molecular events underlying microglial phenotypic transitions remain unclear. Here, by generating 'APPPS1-21-CD11br' reporter mice, we investigated the translational state of microglial/macrophage ribosomes during their phenotypic transition and in a sex-specific manner. Methods: Six groups of mice that included WT-CD11br, antibiotic (ABX) or vehicle-treated APPPS1-21-CD11br males and females were sacrificed at 7-weeks of age (n = 15/group) and used for immunoprecipitation of microglial/macrophage polysomes from cortical homogenates using anti-FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry and label-free quantification was used to identify newly synthesized peptides isolated from polysomes. Results: We show that ABX-treatment leads to decreased Aβ levels in male APPPS1-21-CD11br mice with no significant changes in females. We identified microglial/macrophage polypeptides involved in mitochondrial dysfunction and altered calcium signaling that are associated with Aβ-induced oxidative stress. Notably, female mice also showed downregulation of newly-synthesized ribosomal proteins. Furthermore, male mice showed an increase in newly-synthesized polypeptides involved in FcγR-mediated phagocytosis, while females showed an increase in newly-synthesized polypeptides responsible for actin organization associated with microglial activation. Next, we show that ABX-treatment resulted in substantial remodeling of the epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex-specific manner. While microglia in ABX-treated male mice exhibited a metabolic shift towards a neuroprotective phenotype that promotes Aβ clearance, microglia in ABX-treated female mice exhibited loss of energy homeostasis due to persistent mitochondrial dysfunction and impaired lysosomal clearance that was associated with inflammatory phenotypes. Conclusions: Our studies provide the first snapshot of the translational state of microglial/macrophage cells in a mouse model of Aβ amyloidosis that was subject to ABX treatment. ABX-mediated changes resulted in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance in a sex-specific manner. This microglial plasticity to support neuro-energetic homeostasis for its function based on sex paves the path for therapeutic modulation of immunometabolism for neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: The levels of synaptic markers synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) have been shown to increase early in the cerebrospinal fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD) and to have prognostic potential. However, no validation studies assessed these biomarkers' diagnostic and prognostic value in a large clinical setting cohort of rapidly progressive dementia. Methods: In this retrospective study, using commercially available immunoassays, we measured the levels of SNAP-25, Ng, 14–3-3, total-tau (t-tau), neurofilament light chain (NfL), and phospho-tau181 (p-tau) in CSF samples from consecutive patients with CJD (n = 220) or non-prion rapidly progressive dementia (np-RPD) (n = 213). We evaluated and compared the diagnostic accuracy of each CSF biomarker and biomarker combination by receiver operating characteristics curve (ROC) analyses, studied SNAP-25 and Ng CSF concentrations distribution across CJD subtypes, and estimated their association with survival using multivariable Cox regression analyses. Results: CSF SNAP-25 and Ng levels were higher in CJD than in np-RPD (SNAP-25: 582, 95% CI 240–1250 vs. 115, 95% CI 78–157 pg/ml, p < 0.0001; Ng: 841, 95% CI 411–1473 vs. 390, 95% CI 260–766 pg/ml, p < 0.001). SNAP-25 diagnostic accuracy (AUC 0.902, 95% CI 0.873–0.931) exceeded that of 14–3-3 (AUC 0.853, 95% CI 0.816–0.889), t-tau (AUC 0.878, 95% CI 0.845–0.901), and the t-tau/p-tau ratio (AUC 0.884, 95% CI 0.851–0.916). In contrast, Ng performed worse (AUC 0.697, 95% CI 0.626–0.767) than all other surrogate biomarkers, except for NfL (AUC 0.649, 95% CI 0.593–0.705). SNAP-25 maintained a relatively high diagnostic value even for atypical CJD subtypes (AUC 0.792, 95% CI 0.729–0.854). In Cox regression analyses, SNAP-25 levels were significantly associated with survival in CJD (hazard ratio [HR] 1.71 95% CI 1.40–2.09). Conversely, Ng was associated with survival only in the most rapidly progressive CJD subtypes (sCJD MM(V)1 and gCJD M1) (HR 1.81 95% CI 1.21–2.93). Conclusions: In the clinical setting, CSF SNAP-25 is a viable alternative to t-tau, 14–3-3, and the t-tau/p-tau ratio in discriminating the CJD subtypes from other RPDs. Additionally, SNAP-25 and, to a lesser extent, Ng predict survival in CJD, showing prognostic power in the range of CSF t-tau/14–3-3 and NfL, respectively. [ABSTRACT FROM AUTHOR]

Background: C-X-C motif chemokine ligand 9 (CXCL9), which is involved in the pathological processes of various human cancers, has become a hot topic in recent years. We developed a radiomic model to identify CXCL9 status in ovarian cancer (OC) and evaluated its prognostic significance. Methods: We analyzed enhanced CT scans, transcriptome sequencing data, and corresponding clinical characteristics of CXCL9 in OC using the TCIA and TCGA databases. We used the repeat least absolute shrinkage (LASSO) and recursive feature elimination(RFE) methods to determine radiomic features after extraction and normalization. We constructed a radiomic model for CXCL9 prediction based on logistic regression and internal tenfold cross-validation. Finally, a 60-month overall survival (OS) nomogram was established to analyze survival data based on Cox regression. Results: CXCL9 mRNA levels and several other genes involving in T-cell infiltration were significantly relevant to OS in OC patients. The radiomic score (rad_score) of our radiomic model was calculated based on the five features for CXCL9 prediction. The areas under receiver operating characteristic (ROC) curves (AUC-ROC) for the training cohort was 0.781, while that for the validation cohort was 0.743. Patients with a high rad_score had better overall survival (P < 0.001). In addition, calibration curves and decision curve analysis (DCA) showed good consistency between the prediction and actual observations, demonstrating the clinical utility of our model. Conclusion: In patients with OC, the radiomics signature(RS) of CT scans can distinguish the level of CXCL9 expression and predict prognosis, potentially fulfilling the ultimate purpose of precision medicine. [ABSTRACT FROM AUTHOR]

Background: MUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on the surface of natural killer cells (NK cells), B cells, and monocytes. However, the role of MUC16 on neutrophils in the tumor microenvironment remains to be further explored. Methods: The correlation between the proportion and count of peripheral blood cells, serum inflammatory-related factors and serum MUC16 (CA125) level in patients was constructed based on clinical samples. RNAseq data was obtained from TCGA and sequencing of ovarian cancer tissues, followed by TIMER immune cell infiltration and correlation analysis. Ovarian cancer organoid was constructed to stimulate neutrophils with immunophenotype identification by qPCR and flow cytometry. MUC16 protein stimulation to neutrophils validated the role of MUC16 under the analysis of RNA sequencing and inhibition of NK cytotoxicity in vitro. Results: The serum MUC16 level was positively correlated with the proportion and count of peripheral blood neutrophils, neutrophil-to-lymphocyte ratio (NLR) and inflammatory factors IL-6, IL-8, IL-10 and IL-2R. Siglec-9, the receptor of MUC16, was expressed on neutrophils and was positively correlated to neutrophil infiltration in ovarian cancer. After the stimulation of ovarian cancer organoids and MUC16 respectively, the proportions of CD11b+, CD66b+, and ICAM-1+ neutrophils were significantly increased, while the proportion of CXCR4+ neutrophils was slightly decreased, with increasing of of inflammatory factors MMP9, IL-8, OSM, IL-1β, TNF-α, CXCL3, and ROS. RNA-sequencing analysis revealed that inflammatory response, TNFA signaling pathway, and IL6-related pathway were upregulated in MUC16-stimulated neutrophils, accompanied by high expression of immunosuppression-related factors HHLA2, IL-6, TNFRSF9, ADORA2A, CD274 (PD-L1), and IDO1. NK cytotoxicity was decreased when treated by supernanant of MUC16-stimulated neutrophils in vitro. Conclusion: MUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: The interaction between bacteriophages and their hosts is intricate and highly specific. Receptor-binding proteins (RBPs) of phages such as tail fibers and tailspikes initiate the infection process. These RBPs bind to diverse outer membrane structures, including the O-antigen, which is a serogroup-specific sugar-based component of the outer lipopolysaccharide layer of Gram-negative bacteria. Among the most virulent Escherichia coli strains is the Shiga toxin-producing E. coli (STEC) pathotype dominated by a subset of O-antigen serogroups. Methods: Extensive phylogenetic and structural analyses were used to identify and validate specificity correlations between phage RBP subtypes and STEC O-antigen serogroups, relying on the principle of horizontal gene transfer as main driver for RBP evolution. Results: We identified O-antigen specific RBP subtypes for seven out of nine most prevalent STEC serogroups (O26, O45, O103, O104, O111, O145 and O157) and seven additional E. coli serogroups (O2, O8, O16, O18, 4s/O22, O77 and O78). Eight phage genera (Gamaleya-, Justusliebig-, Kaguna-, Kayfuna-, Kutter-, Lederberg-, Nouzilly- and Uetakeviruses) emerged for their high proportion of serogroup-specific RBPs. Additionally, we reveal sequence motifs in the RBP region, potentially serving as recombination hotspots between lytic phages. Conclusion: The results contribute to a better understanding of mosaicism of phage RBPs, but also demonstrate a method to identify and validate new RBP subtypes for current and future emerging serogroups. [ABSTRACT FROM AUTHOR]

Background: Molecular phylogenetics studies the evolutionary relationships among the individuals of a population through their biological sequences. It may provide insights about the origin and the evolution of viral diseases, or highlight complex evolutionary trajectories. A key task is inferring phylogenetic trees from any type of sequencing data, including raw short reads. Yet, several tools require pre-processed input data e.g. from complex computational pipelines based on de novo assembly or from mappings against a reference genome. As sequencing technologies keep becoming cheaper, this puts increasing pressure on designing methods that perform analysis directly on their outputs. From this viewpoint, there is a growing interest in alignment-, assembly-, and reference-free methods that could work on several data including raw reads data. Results: We present phyBWT2, a newly improved version of phyBWT (Guerrini et al. in 22nd International Workshop on Algorithms in Bioinformatics (WABI) 242:23–12319, 2022). Both of them directly reconstruct phylogenetic trees bypassing both the alignment against a reference genome and de novo assembly. They exploit the combinatorial properties of the extended Burrows-Wheeler Transform (eBWT) and the corresponding eBWT positional clustering framework to detect relevant blocks of the longest shared substrings of varying length (unlike the k-mer-based approaches that need to fix the length k a priori). As a result, they provide novel alignment-, assembly-, and reference-free methods that build partition trees without relying on the pairwise comparison of sequences, thus avoiding to use a distance matrix to infer phylogeny. In addition, phyBWT2 outperforms phyBWT in terms of running time, as the former reconstructs phylogenetic trees step-by-step by considering multiple partitions, instead of just one partition at a time, as previously done by the latter. Conclusions: Based on the results of the experiments on sequencing data, we conclude that our method can produce trees of quality comparable to the benchmark phylogeny by handling datasets of different types (short reads, contigs, or entire genomes). Overall, the experiments confirm the effectiveness of phyBWT2 that improves the performance of its previous version phyBWT, while preserving the accuracy of the results. [ABSTRACT FROM AUTHOR]

Background: Recurring therapy resistant hives, accompanied by IgM-gammopathy, fever and joint pain can indicate Schnitzler syndrome, a rare autoimmune disorder. There is currently no approved treatment, but complete remission of symptoms can be induced with IL-1 antagonists. Case presentation: A patient with a history of chronic urticaria presented frequently at the outpatient clinic with severe hives and was treated unsuccessfully with antihistamines and omalizumab. After several years, additional symptoms such as joint pain, recurrent fever, and IgM-gammopathy developed. After the diagnostic criteria for Schnitzler syndrome were met, treatment with anakinra was initiated and resulted in an improvement of the symptoms. Shortly after the first injection, the patient developed large and painful erythematous lesions at the injection sites, leading to discontinuation of treatment and a rapid recurrence of symptoms. Subsequently, treatment with a longer-acting IL-1 antagonist (canakinumab) was initiated, resulting in a complete remission of symptoms. Conclusion: This case report demonstrates that patients with urticarial symptoms that are not relieved by typical treatments should prompt repeated reassessments of the diagnosis, even years later, because gammopathy and other diagnostic criteria for Schnitzler syndrome can occur with a delay. [ABSTRACT FROM AUTHOR]

Background: Rapidly progressive forms of Alzheimer's disease (rpAD) are increasingly recognized and may have a prevalence of up to 30% of patients among all patients with Alzheimer's disease (AD). However, insights about risk factors, underlying pathophysiological processes, and clinical characteristics of rpAD remain controversial. This study aimed to gain a comprehensive picture of rpAD and new insights into the clinical manifestation to enable a better interpretation of disease courses in clinical practice as well as in future clinical studies. Methods: Patients (n = 228) from a prospective observational study on AD were selected and categorized into rpAD (n = 67) and non-rpAD (n = 161) disease groups. Patients were recruited through the German Creutzfeldt-Jakob disease surveillance center and the memory outpatient clinic of the Göttingen University Medical Center, representing diverse phenotypes of the AD population. Biomarkers and clinical presentation were assessed using standardized protocols. A drop of ≥ MMSE 6 points within 12 months defined rapid progressors. Results: Lower CSF Amyloid beta 1–42 concentrations (p = 0.048), lower Amyloid beta 42/40 ratio (p = 0.038), and higher Tau/Amyloid-beta 1–42 ratio, as well as pTau/Amyloid-beta 1–42 ratio (each p = 0.004) were associated with rpAD. Analyzes in a subset of the cohort (rpAD: n = 12; non-rpAD: n = 31) showed higher CSF NfL levels in rpAD (p = 0.024). Clinically, rpAD showed earlier impairment of functional abilities (p < 0.001) and higher scores on the Unified Parkinson's Disease Rating Scale III (p < 0.001), indicating pronounced extrapyramidal motor symptoms. Furthermore, cognitive profiles (adjusted for overall cognitive performance) indicated marked deficits in semantic (p = 0.008) and phonematic (0.023) verbal fluency tests as well as word list learning (p = 0.007) in rpAD compared to non-rpAD. The distribution of APOE genotypes did not differ significantly between groups. Conclusions: Our results suggest that rpAD is associated with distinct cognitive profiles, earlier occurrence of non-cognitive symptoms, extrapyramidal motoric disturbance, and lower Amyloid-beta 1–42 concentrations in the CSF. The findings may help to characterize a distinct phenotype of rpAD and estimate prognosis based on clinical characteristics and biomarker results. However, an important future goal should be a unified definition for rpAD to enable targeted study designs and better comparability of the results. [ABSTRACT FROM AUTHOR]

Background: Nowadays, wearable sensors are widely used to quantify physical and motor activity during daily life, and they also represent innovative solutions for healthcare. In the clinical framework, the assessment of motor behaviour is entrusted to clinical scales, but they are dependent on operator experience. Thanks to their intrinsic objectivity, sensor data are extremely useful to provide support to clinicians. Moreover, wearable sensors are user-friendly and compliant to be used in an ecological environment (i.e., at home). This paper aims to propose an innovative approach useful to predict clinical assessment scores of infants' motor activity. Materials and methods: Starting from data acquired by accelerometers placed on infants' wrists and trunk during playtime, we exploit the method of functional data analysis to implement new models combining quantitative data and clinical scales. In particular, acceleration data, transformed into activity indexes and combined with baseline clinical data, represent the input dataset for functional linear models. Conclusions: Despite the small number of data samples available, results show correlation between clinical outcome and quantitative predictors, indicating that functional linear models could be able to predict the clinical evaluation. Future works will focus on a more refined and robust application of the proposed method, based on the acquisition of more data for validating the presented models. Trial registration number: ClincalTrials.gov; NCT03211533. Registered: July, 7th 2017. ClincalTrials.gov; NCT03234959. Registered: August, 1st 2017. [ABSTRACT FROM AUTHOR]

Objective: To explore the difference in the protective effects of intraperitoneal injection of exogenous melatonin of daytime or nighttime on bone loss in ovariectomized (OVX) rats. Methods: After bilateral ovariectomy and sham surgery, 40 rats were randomly divided into four groups: sham operation group (Sham), ovariectomy (OVX), and daytime melatonin injection group (OVX + DMLT, 9:00, 30 mg/kg/d) and nighttime injection of melatonin (OVX + NMLT, 22:00, 30 mg/kg/d). After 12 weeks of treatment, the rats were sacrificed. The distal femur, blood and femoral marrow cavity contents were saved. The rest of the samples were tested by Micro-CT, histology, biomechanics and molecular biology. Blood was used for bone metabolism marker measurements. CCK-8, ROS, and Cell apoptosis are performed using MC3E3-T1 cells. Results: Compared with treatment at night, the bone mass of the OVX rats was significantly increased after the daytime administration. All microscopic parameters of trabecular bone increased, only Tb.Sp decreased. Histologically, the bone microarchitecture of the OVX + DMLT was also more dense than the bone microarchitecture of the OVX + LMLT. In the biomechanical experiment, the femur samples of the day treatment group were able to withstand greater loads and deformation. In molecular biology experiments, bone formation-related molecules increased, while bone resorption-related molecules decreased. After treatment with melatonin administration at night, the expression of MT-1β was significantly decreased. In cell experiments, the MC3E3-T1 cells treated with low-dose MLT had higher cell viability and greater efficiency in inhibiting ROS production than the MC3E3-T1 cells treated with high-dose MLT, which in turn more effectively inhibited apoptosis. Conclusion: Daytime administration of melatonin acquires better protective effects on bone loss than night in OVX rats. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency is associated with worse clinical outcomes after ischemic stroke; nevertheless, the pathophysiological mechanisms remain largely unexplored. In this study, we characterized the molecular mechanisms of how vitamin D signaling modulated stroke progression in male mouse ischemia–reperfusion stroke models. We found that vitamin D receptor (VDR) exhibited a predominant upregulation in peri-infarct microglia/macrophages following cerebral ischemia. Conditional Vdr inactivation in microglia/macrophages markedly augmented infarct volumes and neurological deficits. VDR-deficient microglia/macrophages exhibited a more primed proinflammatory phenotype with substantial secretion of TNF-α and IFN-γ. These inflammatory cytokines further enhanced CXCL10 release from endothelial cells and blood–brain barrier disruption, and ultimately infiltration of peripheral T lymphocytes. Notably, blocking TNF-α and IFN-γ significantly ameliorated stroke phenotypes in Vdr conditional knockout mice. Collectively, VDR signaling in microglia/macrophages plays a crucial role in restraining ischemia-elicited neuroinflammation and stroke progression. Our findings delineate a novel mechanism underlying the association between vitamin D deficiency and poor stroke outcomes, and underline the significance of maintaining a functional vitamin D signaling in the management of acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Aim: We aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG–PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated. Materials and methods: We analyzed metabolic networks measured by interregional correlation coefficients (ICCs) of FDG–PET scans in WT mice and in mice with mutations in progranulin (Grn) or triggering receptor expressed on myeloid cells 2 (Trem2) knockouts (−/−) as well as in double mutant Grn−/−/Trem2−/− mice. We selected those rodent models as they represent opposite microglial signatures with disease associated microglia in Grn−/− mice and microglia locked in a homeostatic state in Trem2−/− mice; however, both resulting in lower glucose uptake of the brain. The direct influence of microglia on metabolic networks was further determined by microglia depletion using a CSF1R inhibitor in WT mice at two different ages. Within maps of global mean scaled regional FDG uptake, 24 pre-established volumes of interest were applied and assigned to either cortical or subcortical networks. ICCs of all region pairs were calculated and z-transformed prior to group comparisons. FDG uptake of neurons, microglia, and astrocytes was determined in Grn−/− and WT mice via assessment of single cell tracer uptake (scRadiotracing). Results: Microglia depletion by CSF1R inhibition resulted in a strong decrease of metabolic connectivity defined by decrease of mean cortical ICCs in WT mice at both ages studied (6–7 m; p = 0.0148, 9–10 m; p = 0.0191), when compared to vehicle-treated age-matched WT mice. Grn−/−, Trem2−/− and Grn−/−/Trem2−/− mice all displayed reduced FDG–PET signals when compared to WT mice. However, when analyzing metabolic networks, a distinct increase of ICCs was observed in Grn−/− mice when compared to WT mice in cortical (p < 0.0001) and hippocampal (p < 0.0001) networks. In contrast, Trem2−/− mice did not show significant alterations in metabolic connectivity when compared to WT. Furthermore, the increased metabolic connectivity in Grn−/− mice was completely suppressed in Grn−/−/Trem2−/− mice. Grn−/− mice exhibited a severe loss of neuronal FDG uptake (− 61%, p < 0.0001) which shifted allocation of cellular brain FDG uptake to microglia (42% in Grn−/− vs. 22% in WT). Conclusions: Presence, absence, and activation of microglia have a strong impact on metabolic connectivity of the mouse brain. Enhanced metabolic connectivity is associated with increased microglial FDG allocation. Highlights: Microglial activation influences metabolic connectivity. Microglial depletion results in distinct decreases of metabolic connectivity. Metabolic connectivity increases in progranulin deficient mice. Cellular FDG allocation in progranulin deficient mice is shifted to microglia. [ABSTRACT FROM AUTHOR]

Background: Fractional Flow Reserve (FFR) is a widely applied invasive physiological assessment, endorsed by major guidelines to aid in the decision to perform or defer revascularisation. While a threshold of > 0.8 has been applied universally, clinical outcomes may be affected by numerous factors, including the presence of diabetes. This meta-analysis aims to investigate the outcomes of diabetic versus non-diabetic patients in whom revascularisation was deferred based on negative FFR. Methods: We performed a meta-analysis investigating the outcomes of diabetic and non-diabetic patients in whom revascularisation was deferred based on negative FFR. A search was performed on MEDLINE, PubMed and EMBASE, and peer-reviewed studies that reported MACE for diabetic and non-diabetic patients with deferred revascularisation based on FFR > 0.8 were included. The primary end point was MACE. Results: The meta-analysis included 7 studies in which 4275 patients had revascularisation deferred based on FFR > 0.8 (1250 diabetic). Follow up occurred over a mean of 3.2 years. Diabetes was associated with a higher odds of MACE (OR = 1.66, 95% CI 1.35–2.04, p = < 0.001), unplanned revascularisation (OR = 1.48, 95% CI 1.06–2.06, p = 0.02), all-cause mortality (OR = 1.74, 95% CI 1.20–2.52, p = 0.004) and cardiovascular mortality (OR = 2.08, 95% CI 1.07–4.05, p = 0.03). Conclusions: For patients with stable coronary syndromes and deferred revascularisation based on FFR > 0.8, the presence of diabetes portends an increased long-term risk of MACE compared to non-diabetic patients. Trail registration URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42022367312. [ABSTRACT FROM AUTHOR]

The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia–neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1–CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1, Tnf-α, Il-6, and Bdnf, essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K+ currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved. [ABSTRACT FROM AUTHOR]

Background: CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subforms of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype. To determine the impact of sex on CLN8 disease burden and progression, we utilized a Cln8mnd mouse model to measure the impact and progression of histopathological and behavioral outcomes between sexes. Results: Several notable sex differences were observed in the presentation of brain pathology, including Cln8mnd female mice consistently presenting with greater GFAP+ astrocytosis and CD68+ microgliosis in the somatosensory cortex, ventral posteromedial/ventral posterolateral nuclei of the thalamus, striatum, and hippocampus when compared to Cln8mnd male mice. Furthermore, sex differences in motor-behavioral assessments revealed Cln8mnd female mice experience poorer motor performance and earlier death than their male counterparts. Cln8mnd mice treated with an AAV9-mediated gene therapy were also examined to assess sex differences on therapeutics outcomes, which revealed no appreciable differences between the sexes when responding to the therapy. Conclusions: Taken together, our results provide further evidence of biologic sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact. [ABSTRACT FROM AUTHOR]

Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia-OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage and accelerated chronic phase of OL regeneration at 30 days post-TBI. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1-7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI. [ABSTRACT FROM AUTHOR]

Sex differences have been identified in many diseases associated with dysregulated immune responses, including Alzheimer's disease (AD), for which approximately two-thirds of patients are women. An accumulating body of research indicates that microglia may play a causal role in the pathogenesis of this disease. We hypothesised that sex differences in the transcriptome of human myeloid cells may contribute to the sex difference observed in AD prevalence. To explore this, we assessed bulk and single-nuclear RNA sequencing data sets generated from four human derived myeloid cell populations: post-mortem microglial nuclei, peripheral monocytes, monocyte-derived macrophages (MDMs) and induced pluripotent stem cell derived microglial-like cells (MGLs). We found that expression of AD risk genes, gene signatures associated with the inflammatory response in AD, and genes related to proinflammatory immune responses were enriched in microglial nuclei isolated from aged female donors without ante-mortem neurological disease, relative to those from males. In addition, these inflammation-associated gene sets were found to be enriched in peripheral monocytes isolated from postmenopausal women and in MDMs obtained from premenopausal individuals relative to age-matched males. Expression of these gene sets did not differ in MDMs derived from women whose blood was sampled across the menstrual cycle or in MGLs cultured with 17β-oestradiol. This suggests that the observed gene set enrichments in myeloid cells from women were not being driven by acute hormonal influences. Together, these data support the hypothesis that the increased prevalence of AD in women may be partly explained by a myeloid cell phenotype biased towards expression of biological processes relevant to AD. [ABSTRACT FROM AUTHOR]

Background: In myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), several areas of demyelination are detectable in mouse cerebral cortex, where neuroinflammation events are associated with scarce inflammatory infiltrates and blood–brain barrier (BBB) impairment. In this condition, the administration of mesenchymal stem cells (MSCs) controls neuroinflammation, attenuating astrogliosis and promoting the acquisition of stem cell traits by astrocytes. To contribute to the understanding of the mechanisms involved in the pathogenesis of EAE in gray matter and in the reverting effects of MSC treatment, the neocortex of EAE-affected mice was investigated by analyzing the cellular source(s) of chemokine CCL2, a molecule involved in immune cell recruitment and BBB-microvessel leakage. Methods: The study was carried out by immunohistochemistry (IHC) and dual RNAscope IHC/in situ hybridization methods, using astrocyte, NG2-glia, macrophage/microglia, and microglia elective markers combined with CCL2. Results: The results showed that in EAE-affected mice, hypertrophic microglia are the primary source of CCL2, surround the cortex neurons and the damaged BBB microvessels. In EAE-affected mice treated with MSCs, microgliosis appeared diminished very soon (6 h) after treatment, an observation that was long-lasting (tested after 10 days). This was associated with a reduced CCL2 expression and with apparently preserved/restored BBB features. In conclusion, the hallmark of EAE in the mouse neocortex is a condition of microgliosis characterized by high levels of CCL2 expression. Conclusions: This finding supports relevant pathogenetic and clinical aspects of the human disease, while the demonstrated early control of neuroinflammation and BBB permeability exerted by treatment with MSCs may have important therapeutic implications. [ABSTRACT FROM AUTHOR]

Accumulating proofs signify that pleiotropic effects of mesenchymal stromal cells (MSCs) are not allied to their differentiation competencies but rather are mediated mainly by the releases of soluble paracrine mediators, making them a reasonable therapeutic option to enable damaged tissue repair. Due to their unique immunomodulatory and regenerative attributes, the MSC-derived exosomes hold great potential to treat neurodegeneration-associated neurological diseases. Exosome treatment circumvents drawbacks regarding the direct administration of MSCs, such as tumor formation or reduced infiltration and migration to brain tissue. Noteworthy, MSCs-derived exosomes can cross the blood–brain barrier (BBB) and then efficiently deliver their cargo (e.g., protein, miRNAs, lipid, and mRNA) to damaged brain tissue. These biomolecules influence various biological processes (e.g., survival, proliferation, migration, etc.) in neurons, oligodendrocytes, and astrocytes. Various studies have shown that the systemic or local administration of MSCs-derived exosome could lead to the favored outcome in animals with neurodegeneration-associated disease mainly by supporting BBB integrity, eliciting pro-angiogenic effects, attenuating neuroinflammation, and promoting neurogenesis in vivo. In the present review, we will deliver an overview of the therapeutic benefits of MSCs-derived exosome therapy to ameliorate the pathological symptoms of acute and chronic neurodegenerative disease. Also, the underlying mechanism behind these favored effects has been elucidated. [ABSTRACT FROM AUTHOR]

Recently, mesenchymal stromal cell (MSC)-based therapy has become an appreciated therapeutic approach in the context of neurodegenerative disease therapy. Accordingly, a myriad of studies in animal models and also some clinical trials have evinced the safety, feasibility, and efficacy of MSC transplantation in neurodegenerative conditions, most importantly in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The MSC-mediated desired effect is mainly a result of secretion of immunomodulatory factors in association with release of various neurotrophic factors (NTFs), such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Thanks to the secretion of protein-degrading molecules, MSC therapy mainly brings about the degradation of pathogenic protein aggregates, which is a typical appearance of chronic neurodegenerative disease. Such molecules, in turn, diminish neuroinflammation and simultaneously enable neuroprotection, thereby alleviating disease pathological symptoms and leading to cognitive and functional recovery. Also, MSC differentiation into neural-like cells in vivo has partially been evidenced. Herein, we focus on the therapeutic merits of MSCs and also their derivative exosome as an innovative cell-free approach in AD, HD, PD, and ALS conditions. Also, we give a brief glimpse into novel approaches to potentiate MSC-induced therapeutic merits in such disorders, most importantly, administration of preconditioned MSCs. [ABSTRACT FROM AUTHOR]

Lymphoma is the second most common cancer affecting Golden Retrievers and is hypothesized to arise through a complex interaction of genetic and environmental factors. The aim of this nested case–control study was to investigate the association between potential environmental pollutant sources and lymphoma risk among Golden Retrievers participating in the Golden Retriever Lifetime Study. Forty-nine Golden Retrievers with non-cutaneous lymphoma and 98 Golden Retrievers without a history of cancer matched by age, sex and neuter status were selected from the Golden Retriever Lifetime Study cohort. Geographic proximity between each dog's primary residence and nine potential sources of environmental pollution was determined. In addition, the average annual ozone and airborne fine particulate matter levels for each dog's county of residence and owner-reported secondhand smoke exposure were evaluated. Environmental pollution sources of interest included chemical plants, municipal dumps, manufacturing plants, incineration plants, railroad embankment tracks, landfills, coal plants, high-voltage transmission lines, and nuclear power plants. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each exposure of interest. Subgroup analyses were conducted to evaluate whether associations differed among 1) dogs with multicentric lymphoma, 2) dogs with B-cell lymphoma, and 3) dogs with T-cell lymphoma. No variables reached statistical significance when evaluating all cases together. However, cumulative exposure burden (household proximity to 3 or more pollution sources) approached significance within the multicentric lymphoma subgroup (OR = 2.60, 95%CI 0.99–6.86, p-value = 0.053). Patterns emerged among B- and T-cell subgroups, but none reached statistical significance. Ongoing research is warranted to discern if different environmental mechanisms may be driving B- and T-cell lymphoma immunophenotypes, consistent with previously reported regional differences in subtype prevalence. Plain English Summary: Lymphoma is a common cancer affecting dogs, particularly Golden Retrievers. By identifying risk factors for lymphoma, work can be done to reduce harmful exposures or increase monitoring among dogs at a higher risk of disease. Using a subset of dogs from the Golden Retriever Lifetime Study, we sought to investigate whether dogs with lymphoma were more likely to live near certain environmental pollutant sources than dogs without lymphoma. Forty-nine Golden Retrievers with non-cutaneous lymphoma and 98 Golden Retrievers without a history of cancer were selected from the Golden Retriever Lifetime Study Cohort. We evaluated how close each dog lived to nine environmental pollutant sources: chemical plants, municipal dumps, manufacturing plants, incineration plants, railroad embankment tracks, landfills, coal plants, high-voltage transmission lines, and nuclear power plants. Additionally, we evaluated individual exposure to secondhand smoke, and average annual ozone and particulate matter exposure (as surrogate measures for air pollution) for each dog's county of residence. None of the exposures examined were associated with an increased lymphoma risk in this population. More research is needed, including direct biomonitoring, to determine whether specific environmental exposures are associated with lymphoma in the Golden Retriever breed. [ABSTRACT FROM AUTHOR]

Background: Systemic factors can strongly affect how tumour cells behave, grow, and communicate with other cells in breast cancer. Lipid metabolic reprogramming is a systemic process that tumour cells undergo; however, the formation and dynamics of lipids associated with the tumour immune microenvironment (TIME) remain unclear. The investigation of the sophisticated bidirectional crosstalk of tumour cells with cancer metabolism, gene expression, and TIME could have the potential to identify novel biomarkers for diagnosis, prognosis, and immunotherapy. This study aimed to construct a prognostic signature to detect the bicrosstalk between the lipid metabolic system and the TIME of breast cancer. Methods: To detect the expression of LRGs and execute GO/KEGG analysis, the R program was chosen. Considering the clinical information and pathological features, a prognostic gene signature was constructed by LASSO Cox regression analysis. TMB, MSI, and immune infiltration analyses were performed, and consensus cluster analysis of LRGs was also performed. Results: These 16 lipid metabolism-related genes (LRGs) were mainly involved in the process of lipid metabolism and fatty acid binding in breast cancer. Prognosis analysis identified the prognostic value of FABP7(Fatty acid binding protein 7) and NDUFAB1(NADH:ubiquinone oxidoreductase subunit AB1) in breast cancer patients. The prognostic gene signature constructed with FABP7 and NDUFAB1 was significantly related to immune cell infiltration and could predict the overall survival rate with above average correctness of breast cancer patients. FABP7 and NDUFAB1 were proven to have relevance in immune cell infiltration and tumour mutation burden (TMB). Consensus cluster analysis identified that the upregulated mRNAs were mostly related to the oncogenesis process, while the downregulated mRNAs were associated with immune-related signalling pathways. Conclusion: A comprehensive analysis was performed to evaluate the lipid metabolic system and identified a signature constructed by two prognostic genes for immunotherapies in breast cancer. The results also revealed evidence of vulnerabilities in the interplay between the lipid metabolic system and the TIME in breast cancer. Further data with clinical studies and experiments are warranted. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease is the leading cause of dementia worldwide. TAM receptor tyrosine kinases (Tyro3, Axl, MerTK) are known for their role in engagement of phagocytosis and modulation of inflammation, and recent evidence suggests a complex relationship between Axl, Mer, and microglial phagocytosis of amyloid plaques in AD. Gas6, the primary CNS TAM ligand, reduces neuroinflammation and improves outcomes in murine models of CNS disease. Therefore, we hypothesized that AAV-mediated overexpression of Gas6 would alleviate plaque pathology, reduce neuroinflammation, and improve behavior in the APP/PS1 model of Alzheimer's disease.Methods: Adeno-associated viral vectors were used to overexpress Gas6 in the APP/PS1 model of Alzheimer's disease. Nine-month-old male and female APP/PS1 and nontransgenic littermates received bilateral stereotactic hippocampal injections of AAV-Gas6 or AAV-control, which expresses a non-functional Gas6 protein. One month after injections, mice underwent a battery of behavioral tasks to assess cognitive function and brains were processed for immunohistochemical and transcriptional analyses.Results: Gas6 overexpression reduced plaque burden in male APP/PS1 mice. However, contrary to our hypothesis, Gas6 increased pro-inflammatory microglial gene expression and worsened contextual fear conditioning compared to control-treated mice. Gas6 overexpression appeared to have no effect on phagocytic mechanisms in vitro or in vivo as measured by CD68 immunohistochemistry, microglial methoxy-04 uptake, and primary microglial uptake of fluorescent fibrillar amyloid beta.Conclusion: Our data describes a triad of worsened behavior, reduced plaque number, and an increase in proinflammatory signaling in a sex-specific manner. While Gas6 has historically induced anti-inflammatory signatures in the peripheral nervous system, our data suggest an alternative, proinflammatory role in the context of Alzheimer's disease pathology. [ABSTRACT FROM AUTHOR]

The present COVID-19 pandemic has revealed that several characteristics render patients especially prone to developing severe COVID-19 disease, i.e., the male sex, obesity, and old age. An explanation for the observed pattern of vulnerability has been proposed which is based on the concept of low sensitivity of the TLR7-signaling pathway at the time of infection as a common denominator of vulnerable patient groups. We will discuss whether the concept of established TLR-tolerance in macrophages and dendritic cells of the obese and elderly prior to infection can explain not only the vulnerability of these two demographic groups towards development of a severe infection with SARS-CoV-2, but also the observed cytokine response in these vulnerable patients, which is skewed towards pro-inflammatory cytokines with a missing interferon signature. [ABSTRACT FROM AUTHOR]

Background: Africa is an important watershed in the genetic history of domestic cattle, as two lineages of modern cattle, Bos taurus and B. indicus, form distinct admixed cattle populations. Despite the predominant B. indicus nuclear ancestry of African admixed cattle, B. indicus mitochondria have not been found on the continent. This discrepancy between the mitochondrial and nuclear genomes has been previously hypothesized to be driven by male-biased introgression of Asian B. indicus into ancestral African B. taurus. Given that this hypothesis mandates extreme demographic assumptions relying on random genetic drift, we propose a novel hypothesis of selection induced by mitonuclear incompatibility and assess these hypotheses with regard to the current genomic status of African admixed cattle. Results: By analyzing 494 mitochondrial and 235 nuclear genome sequences, we first confirmed the genotype discrepancy between mitochondrial and nuclear genome in African admixed cattle: the absence of B. indicus mitochondria and the predominant B. indicus autosomal ancestry. We applied approximate Bayesian computation (ABC) to assess the posterior probabilities of two selection hypotheses given this observation. The results of ABC indicated that the model assuming both male-biased B. indicus introgression and selection induced by mitonuclear incompatibility explains the current genomic discrepancy most accurately. Subsequently, we identified selection signatures at autosomal loci interacting with mitochondria that are responsible for integrity of the cellular respiration system. By contrast with B. indicus-enriched genome ancestry of African admixed cattle, local ancestries at these selection signatures were enriched with B. taurus alleles, concurring with the key expectation of selection induced by mitonuclear incompatibility. Conclusions: Our findings support the current genome status of African admixed cattle as a potential outcome of male-biased B. indicus introgression, where mitonuclear incompatibility exerted selection pressure against B. indicus mitochondria. This study provides a novel perspective on African cattle demography and supports the role of mitonuclear incompatibility in the hybridization of mammalian species. [ABSTRACT FROM AUTHOR]

Purpose: Tyro is a deep hypersaline anoxic basin (DHAB) located at the seafloor of the Eastern Mediterranean sea. Tyro hosts a stratified eukaryotic microbiome moving from seawater to the brine, but no reports are available on its prokaryotic community. We provide the first snapshot of the bacterial community structure in Tyro brine, seawater-brine interface, and the overlaying deep seawater. Methods: In this study, we combined the use of molecular analyses, i.e., DNA fingerprinting and 16S rRNA pyrosequencing for the description of the bacterial community structure and taxonomy. PiCRUST2 was used to infer information on the prokaryotes functional diversity. A culture-dependent approach was applied to enrich bacteria of interest for marine biotechnology. Results: Bacterial communities sharply clustered moving from the seawater to the Tyro brine, in agreement with the abrupt increase of salinity values. Moreover, specific taxonomic groups inhabited the seawater-brine interface compared to the overlaying seawater and their identification revealed converging taxonomy with other DHABs in the Eastern Mediterranean sea. Functional traits inferred from the prokaryote taxonomy in the upper interface and the overlaying seawater indicated metabolic pathways for the synthesis of osmoprotectants, likely involved in bacterial adaptation to the steep increasing salinity. Metabolic traits related to methane and methylated compounds and to hydrocarbon degradation were also revealed in the upper interface of Tyro. The overall capability of the Tyro microbiome for hydrocarbon metabolism was confirmed by the isolation of hydrocarbonoclastic bacteria in the sediments. Conclusions: Our results suggest that Tyro seawater-brine interface hosts a specific microbiome adapted to the polyextreme condition typical of DHABs with potential metabolic features that could be further explored for the characterization of the metabolic network connecting the brine with the deep seawater through the chemocline. Moreover, Tyro could be a reservoir of culturable microbes endowed with functionalities of interest for biotechnological applications like hydrocarbon bioremediation. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel diseases (IBD) are remitting and relapsing diseases that mainly interest the gastrointestinal tract. IBD is associated with a condition of psycho-social discomfort that deeply compromises the quality of life and the competence of patient to be fully engaged in their self-management. As a consequence, effective care of IBD patients should include not only medical but also psychological support in order to improve patients' wellbeing. Although this, to date there is no standardized approach to promote psychological wellbeing of IBD patients in order to improve the perception of the quality of the care. To fill this gap, a consensus conference has been organized in order to define the psychosocial needs of IBD patients and to promote their engagement in daily clinical practice. This paper describes the process implemented and illustrates the recommendations deriving from it, which focus on the importance of a multidisciplinary approach in IBD management. Results: The consensus conference has been organized in three phases: (1) literature review about life experiences, engagement, and psychosocial needs of IBD patients; (2) workshops with IBD experts and patients' representatives; (3) drafting of statements and voting. Seventy-three participants were involved in the consensus conference, and sixteen statements have been voted and approved during the consensus process. Conclusions: The main conclusion is the necessity of the early detection of – and, in case of need, intervention on- psycho-social needs of patients in order to achieve patient involvement in IBD care. [ABSTRACT FROM AUTHOR]

Background: There has been an increasing prevalence of parental separation in China due to divorce or migration for work in recent decades. However, few studies have compared the impacts of these two types of separation on children's mental health. This study aimed to investigate how parental divorce and parental migration impact children's mental health and self-injurious thoughts and behaviors (SITB), while considering positive factors, including parent-adolescent communication and psychological resilience. Methods: We randomly recruited participants in grades 5–8 from 18 schools in 2 counties in Anhui Province. A self-administered questionnaire was conducted to measure children's mental health, SITB, parent-adolescent communication, psychological resilience, and socio-demographic characteristics. Results: Data from 1026 children with both parents migrating (BLBC), 1322 children with one parent migrating (SLBC), 475 children living in a divorced family (DC) and 1160 children with non-migrating parents (NLBC) were included. Regression model results showed that, compared to the other three groups (BLBC, SLBC, NLBC), DC exhibited higher internalizing problems (p < 0.05), higher externalizing problems (p < 0.01), less prosocial behaviors (p < 0.05), and higher rates of suicidal ideation (SI) (p < 0.05) and non-suicidal self-injury (NSSI) behaviors (p < 0.05) when adjusting for social-demographic variables. However, when further adjusting for parent-adolescent communication and psychological resilience, DC no longer had higher levels of internalizing problems, externalizing problems, NSSI and SI than left-behind groups (BLBC, SLBC). Conclusions: The experience of separation from divorced parents had stronger negative effects on the mental health of children than was observed in LBC. The Chinese government should design special policy frameworks that provide support to DC. [ABSTRACT FROM AUTHOR]

Background: The objective was to investigate the individual effect and potential interactions of probable rapid eye movement sleep behavior disorder (pRBD) and sleep insufficiency on fall risk among a Chinese elderly population.Methods: Community-dwelling population aged 55 years or above were recruited from the Beijing Longitudinal Study on Aging II cohort from 2010 to 2011. Odds ratio (ORs) and 95% confidence intervals (CIs) were estimated using multivariate logistic regression models. Multiplicative and additive interactions between pRBD and sleep insufficiency were examined using likelihood ratio tests and relative excess risk due to interaction (RERI), respectively.Results: Among 6891 included participants, 479 experienced at least once fall. pRBD and sleep insufficiency were both independently associated with elevated fall risk. Compared to the elderly without pRBD or sleep insufficiency, pRBD and sleep insufficiency was each associated with a 2.57-fold (OR = 2.57, 95%CI: 1.46-4.31) and 1.45-fold (OR = 1.45, 95%CI: 1.11-1.88) risk of falls individually, while their coexistence was associated with a less-than-additive 17% (OR = 1.17, 95%CI: 0.43-2.63) increased risk of falls. The combination of these two factors demonstrated evidence of a negative interaction on both multiplicative (ratio of ORs = 0.31, 95%CI: 0.10, 0.86) and additive (RERI = - 1.85, 95%CI: - 3.61, - 0.09) scale.Conclusions: Our study has provided robust evidence for the adverse effect of pRBD and sleep insufficiency, as well as their negative interaction on increasing fall risk in a Chinese elderly population. [ABSTRACT FROM AUTHOR]

Background: Catechins are crucial in determining the flavour and health benefits of tea, but it remains unclear that how the light intensity regulates catechins biosynthesis. Therefore, we cultivated tea plants in a phytotron to elucidate the response mechanism of catechins biosynthesis to light intensity changes. Results: In the 250 μmol·m− 2·s− 1 treatment, the contents of epigallocatechin, epigallocatechin gallate and total catechins were increased by 98.94, 14.5 and 13.0% respectively, compared with those in the 550 μmol·m− 2·s− 1 treatment. Meanwhile, the photosynthetic capacity was enhanced in the 250 μmol·m− 2·s− 1 treatment, including the electron transport rate, net photosynthetic rate, transpiration rate and expression of related genes (such as CspsbA, CspsbB, CspsbC, CspsbD, CsPsbR and CsGLK1). In contrast, the extremely low or high light intensity decreased the catechins accumulation and photosynthetic capacity of the tea plants. The comprehensive analysis revealed that the response of catechins biosynthesis to the light intensity was mediated by the photosynthetic capacity of the tea plants. Appropriately high light upregulated the expression of genes related to photosynthetic capacity to improve the net photosynthetic rate (Pn), transpiration rate (Tr), and electron transfer rate (ETR), which enhanced the contents of substrates for non-esterified catechins biosynthesis (such as EGC). Meanwhile, these photosynthetic capacity-related genes and gallic acid (GA) biosynthesis-related genes (CsaroB, CsaroDE1, CsaroDE2 and CsaroDE3) co-regulated the response of GA accumulation to light intensity. Eventually, the epigallocatechin gallate content was enhanced by the increased contents of its precursors (EGC and GA) and the upregulation of the CsSCPL gene. Conclusions: In this study, the catechin content and photosynthetic capacity of tea plants increased under appropriately high light intensities (250 μmol·m− 2·s− 1 and 350 μmol·m− 2·s− 1) but decreased under extremely low or high light intensities (150 μmol·m− 2·s− 1 or 550 μmol·m− 2·s− 1). We found that the control of catechin accumulation by light intensity in tea plants is mediated by the plant photosynthetic capacity. The research provided useful information for improving catechins content and its light-intensity regulation mechanism in tea plant. [ABSTRACT FROM AUTHOR]

Sex differences in the rates of affective disorders have been recognized for decades. Studies of physiologic sex-related differences in animals and humans, however, have generally yielded little in terms of explaining these differences. Furthermore, the significance of these findings is difficult to interpret given the dynamic, integrative, and highly context-dependent nature of human physiology. In this article, we provide an overview of the current literature on sex differences as they relate to mood disorders, organizing existing findings into five levels at which sex differences conceivably influence physiology relevant to affective states. These levels include the following: brain structure, network connectivity, signal transduction, transcription/translation, and epigenesis. We then evaluate the importance and limitations of this body of work, as well as offer perspectives on the future of research into sex differences. In creating this overview, we attempt to bring perspective to a body of research that is complex, poorly synthesized, and far from complete, as well as provide a theoretical framework for thinking about the role that sex differences ultimately play in affective regulation. Despite the overall gaps regarding both the underlying pathogenesis of affective illness and the role of sex-related factors in the development of affective disorders, it is evident that sex should be considered as an important contributor to alterations in neural function giving rise to susceptibility to and expression of depression. [ABSTRACT FROM AUTHOR]

Salmonella enterica ssp. enterica serovars Enteritidis (SE) and Gallinarum (SG) cause different diseases in chickens. However, both are able to reach the blood stream where heterophils and monocytes are potentially able to phagocytose and kill the pathogens. Using an ex vivo chicken whole blood infection model, we compared the complex interactions of the differentially host-adapted SE and SG with immune cells in blood samples of two White Leghorn chicken lines showing different laying performance (WLA: high producer; R11: low producer). In order to examine the dynamic interaction between peripheral blood leucocytes and the Salmonella serovars, we performed flow cytometric analyses and survival assays measuring (i) leucocyte numbers, (ii) pathogen association with immune cells, (iii) Salmonella viability and (iv) immune gene transcription in infected whole blood over a four-hour co-culture period. Inoculation of blood from the two chicken lines with Salmonella led primarily to an interaction of the bacteria with monocytes, followed by heterophils and thrombocytes. We found higher proportions of monocytes associated with SE than with SG. In blood samples of high producing chickens, a decrease in the numbers of both heterophils and Salmonella was observed. The Salmonella challenge induced transcription of interleukin-8 (IL-8) which was more pronounced in SG- than SE-inoculated blood of R11. In conclusion, the stronger interaction of monocytes with SE than SG and the better survivability of Salmonella in blood of low-producer chickens shows that the host–pathogen interaction and the strength of the immune defence depend on both the Salmonella serovar and the chicken line. [ABSTRACT FROM AUTHOR]

Background: Homozygotic mutations in the GBA gene cause Gaucher's disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson's disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher's disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported.Methods: We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice.Results: Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins.Conclusion: This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication. [ABSTRACT FROM AUTHOR]

Tea should be perceived more as a cultural product than a fast-moving consumer good with its roots deep in different cultures across nations. Nevertheless, consumer demands on tea have not been explored sufficiently from a cultural perspective. This research aims to examine motives that are driving Chinese tea consumption on two usage occasions, under the influence of the Chinese renqing, mianzi, collectivism, and man-nature unity culture. Linkage was established between Chinese culture and consumer motives. The factor analysis on 280 respondents identified five consumer psychological motives. Further logistic regression analysis suggested consumer motives and usage situations were related. The contribution of the findings is summarized. On one hand, this study adds to the limited understandings on consumer motives of tea in an emerging country from the cultural aspect. On the other hand, deep understandings of brand chasing, sustainability, and pragmatism motives should businesses to better serve consumers. [ABSTRACT FROM AUTHOR]

Background: Bone tissue engineering is a new concept bringing hope for the repair of large bone defects, which remains a major clinical challenge. The formation of vascularized bone is key for bone tissue engineering. Growth of specialized blood vessels termed type H is associated with bone formation. In vivo and in vitro studies have shown that low level laser therapy (LLLT) promotes angiogenesis, fracture healing, and osteogenic differentiation of stem cells by increasing reactive oxygen species (ROS). However, whether LLLT can couple angiogenesis and osteogenesis, and the underlying mechanisms during bone formation, remains largely unknown. Methods: Mouse bone marrow mesenchymal stem cells (BMSCs) combined with biphasic calcium phosphate (BCP) grafts were implanted into C57BL/6 mice to evaluate the effects of LLLT on the specialized vessel subtypes and bone regeneration in vivo. Furthermore, human BMSCs and human umbilical vein endothelial cells (HUVECs) were co-cultured in vitro. The effects of LLLT on cell proliferation, angiogenesis, and osteogenesis were assessed. Results: LLLT promoted the formation of blood vessels, collagen fibers, and bone tissue and also increased CD31hiEMCNhi-expressing type H vessels in mBMSC/BCP grafts implanted in mice. LLLT significantly increased both osteogenesis and angiogenesis, as well as related gene expression (HIF-1α, VEGF, TGF-β) of grafts in vivo and of co-cultured BMSCs/HUVECs in vitro. An increase or decrease of ROS induced by H2O2 or Vitamin C, respectively, resulted in an increase or decrease of HIF-1α, and a subsequent increase and decrease of VEGF and TGF-β in the co-culture system. The ROS accumulation induced by LLLT in the co-culture system was significantly decreased when HIF-1α was inhibited with DMBPA and was followed by decreased expression of VEGF and TGF-β. Conclusions: LLLT enhanced vascularized bone regeneration by coupling angiogenesis and osteogenesis. ROS/HIF-1α was necessary for these effects of LLLT. LLLT triggered a ROS-dependent increase of HIF-1α, VEGF, and TGF-β and resulted in subsequent formation of type H vessels and osteogenic differentiation of mesenchymal stem cells. As ROS also was a target of HIF-1α, there may be a positive feedback loop between ROS and HIF-1α, which further amplified HIF-1α induction via the LLLT-mediated ROS increase. This study provided new insight into the effects of LLLT on vascularization and bone regeneration in bone tissue engineering. [ABSTRACT FROM AUTHOR]

Background: The efficient management of relational competences in healthcare professionals is crucial to ensuring that a patient's treatment and care process is conducted positively. Empathy is a major component of the relational skills expected of health professionals. Knowledge of undergraduate healthcare students' empathic abilities is important for educators in designing specific and efficient educational programmes aimed at supporting or enhancing such competences. In this study, we measured first-year undergraduate nursing students' attitudes towards professional empathy in clinical encounters. The students' motivations for entering nursing education were also evaluated. This study takes a multi-method approach based on the use of qualitative and quantitative tools to examine the association between students' positive attitudes towards the value of empathy in health professionals and their prosocial and altruistic motivations in choosing to engage in nursing studies. Methods: A multi-method study was performed with 77 first-year nursing students. The Jefferson Scale of Empathy (JSE) – Health Professions Student Version was administered. Students' motivations for choosing nursing studies were detected through an open question and thematically analysed. Using explorative factor analysis and principal component analysis, a dimensional reduction was conducted to identify subjects with prosocial and altruistic motivations. Finally, linear models were tested to examine specific associations between motivation and empathy. Results: Seven distinct themes distinguishing internal and external motivational factors were identified through a thematic analysis of students' answers regarding their decision to enter a nursing degree course. Female students gained higher scores on the empathy scale than male ones. When students' age was considered, this difference was only observed for younger students, with young females' total scores being higher than young males'. High empathy scores were positively associated with altruistic motivational factors. A negative correlation was found between external motivational factors and the scores of the Compassionate Care subscale of the JSE. Conclusions: Knowing the level of nursing students' empathy and their motivational factors for entering nursing studies is important for educators to implement training paths that enhance students' relational attitudes and skills and promote the positive motivational aspects that are central to this profession. [ABSTRACT FROM AUTHOR]