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Background: Endometriosis (EMs) results in approximately 50% of reproductive-age women facing infertility. Currently, no precise model is available to predict successful postoperative pregnancy. Methods: This study involved 81 patients with severe EMs (stages III and IV) and 38 controls with benign gynecological conditions, matched by age and BMI, diagnosis at Fujian Maternity and Child Health Hospital from January 2018 to December 2019. Relative expression levels of ERRβ and ERRγ mRNA in ectopic and ectopic endometrial tissues were measured using fluorescence quantitative PCR. Serum levels of ERRβ, ERRγ, and fertility-related hormones (AMH, FSH, LH, CA125) were assessed. Correlations were analyzed, and the predictive value of ERRγ for postoperative pregnancy was evaluated using a nomogram based on LASSO and multivariate logistic regression. Internal validation using bootstrapping techniques assessed the nomograms performance, including calibration and DCA. Results: ERRβ and ERRγ mRNA levels from ectopic tissues were significantly reduced in patients with severe EMs compared to controls. High serum CA125 correlated with increased ERRγ mRNA expression in ectopic tissues. ERRγ mRNA expression in ectopic endometrial tissues was negatively correlated with age, BMI, and FSH levels, and positively with AMH and LH/FSH ratio. ERRγ mRNA and FSH were significant predictors of postoperative pregnancy, with the nomogram model showing a Brier score of 0.175 and a consistency statistic of 0.811. Conclusions: ERRβ and ERRγ are downregulated in ectopic tissues from severe EMs. Elevated ERRγ mRNA expression and lower FSH levels are predictive factors for successful postoperative pregnancy. [ABSTRACT FROM AUTHOR]

CDK8 is an important member of the cyclin-dependent kinase family associated with transcription and acts as a key "molecular switch" in the Mediator complex. CDK8 regulates gene expression by phosphorylating transcription factors and can control the transcription process through Mediator complex. Previous studies confirmed that CDK8 is an important oncogenic factor, making it a potential tumor biomarker and a promising target for tumor therapy. However, CDK8 has also been confirmed to be a tumor suppressor, indicating that it not only promotes the development of tumors but may also be involved in tumor suppression. Therefore, the dual role of CDK8 in the process of tumor development is worth further exploration and summary. This comprehensive review delves into the intricate involvement of CDK8 in transcription-related processes, as well as its role in signaling pathways related to tumorigenesis, with a focus on its critical part in driving cancer progression. [ABSTRACT FROM AUTHOR]

Trichosanthis fruit (TF) is a classic medicinal material obtained from Shandong, China. The peel of this fruit (Trichosanthis pericarpium, TP) is known to exert antithrombotic effects. However, the anti-thrombotic active components and mechanisms of TP have yet to be fully elucidated. Combined with zebrafish models and high-performance liquid chromatography (HPLC), this study evaluated the endogenous anti-thrombotic effects with the combination of three compounds from TP. First, we used HPLC to investigate the components in the water extract of TP. Next, we used the zebrafish model to investigate the anti-thrombotic activity of the three compound combinations by evaluating a range of indicators. Finally, the expression of related genes was detected by real-time quantitative polymerase chain reaction (qPCR). HPLC detected a total of eight components in TP water extract, with high levels of paeonol (Pae), diosmetin-7-O-β-D-glucopyranoside (diosmetin-7- O-glucoside), and 5-hydroxymethylfurfural (5-HMF). The most significant antithrombotic activity was detected when the Pae: diosmetin-7-O-glucoside:5- HMF ratio was 4:3:3. qPCR analysis revealed that the abnormal expression levels of f2, fga, fgb, vwf, ptgs1, and tbxas1 induced by arachidonic acid (AA) were improved. The combination of Pae, diosmetin-7-O-glucoside, and 5-HMF may alleviate AA-induced thrombosis by inhibiting the inflammatory reaction, coagulation cascade reaction, and arachidonic acid metabolism pathways. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), Alzheimer's disease (AD), and epilepsy share proposed mechanisms of injury, including neuronal excitotoxicity, cascade signaling, and activation of protein biomarkers such as tau. Although tau is typically present intracellularly, in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, the latter leading to decreased neuronal stability and neurofibrillary tangles (NFTs). Tau cleavage at particular sites increases susceptibility to hyper-phosphorylation, NFT formation, and eventual cell death. The relationship between tau and inflammation, however, is unknown. In this review, we present evidence for an imbalanced endoplasmic reticulum (ER) stress response and inflammatory signaling pathways resulting in atypical p-tau, hp-tau and NFT formation. Further, we propose tau as a biomarker for neuronal injury severity in TBI, AD, and epilepsy. We present a hypothesis of tau phosphorylation as an initial acute neuroprotective response to seizures/TBI. However, if the underlying seizure pathology or TBI recurrence is not effectively treated, and the pathway becomes chronically activated, we propose a "tipping point" hypothesis that identifies a transition of tau phosphorylation from neuroprotective to injurious. We outline the role of amyloid beta (Aβ) as a "last ditch effort" to revert the cell to programmed death signaling, that, when fails, transitions the mechanism from injurious to neurodegenerative. Lastly, we discuss targets along these pathways for therapeutic intervention in AD, TBI, and epilepsy. [ABSTRACT FROM AUTHOR]

Crimean-Congo hemorrhagic fever virus (CCHFV; family Nairoviridae) is a tick-borne pathogen that frequently causes lethal disease in humans. CCHFV has a wide geographic distribution, and cases have been reported in Africa, Asia, the Middle East, and Europe. Availability of a safe and efficacious vaccine is critical for restricting outbreaks and preventing disease in endemic countries. We previously developed a virus-like replicon particle (VRP) vaccine that provides complete protection against homologous and heterologous lethal CCHFV challenge in mice after a single dose. However, the immune responses induced by this vaccine are not well characterized, and correlates of protection remain unknown. Here we comprehensively characterized the kinetics of cell-mediated and humoral immune responses in VRP-vaccinated mice, and demonstrate that they predominantly target the nucleoprotein (NP). NP antibodies are not associated with protection through neutralizing activity, but VRP vaccination results in NP antibodies possessing Fc-mediated antibody effector functions, such as complement activation (ADCD) and antibody-mediated cellular phagocytosis (ADCP). This suggests that Fc-mediated effector functions may contribute to this vaccine'sefficacy. [ABSTRACT FROM AUTHOR]

Introduction: Lumbar disc herniation (LDH) is one of the most common conditions associated with functional disability, affecting patients’ quality of life (QOL). Disability can be affected by cognitive factors, such as pain catastrophizing. Similarly, unfulfilled basic psychological needs (i.e., autonomy, competence, relatedness) are associated with biases in pain perception and QOL. Using the fear-avoidance model and the self-determination theory, this study investigates: (1) the separate contribution of pain-related variables and basic psychological needs satisfaction in predicting QOL in patients proposed for LDH surgery; (2) pre- and post-surgical differences in pain catastrophizing and basic psychological needs satisfaction. Methods: First, we used hierarchical regression on 193 patients (Mage = 46.10, SDage = 11.40) to identify predictors of QOL. Second, we performed paired ttests on 55 patients to investigate pre- and post-surgical differences in pain catastrophizing and basic psychological needs satisfaction. Results: Hierarchical regression showed that the model predicts 27% of the variance in QOL; medium pain level, age, pain catastrophizing, and basic psychological needs satisfaction were significant predictors. Also, pain catastrophizing significantly decreased after surgery [t (54) = 6.07, p < 0.001, Cohen’s d = 0.81], but basic psychological needs satisfaction did not modify significantly. Discussion: This research confirms the importance of pain perception and pain catastrophizing for LDH patients’ QOL and broadens the applicability of the selfdetermination theory for spinal patients. [ABSTRACT FROM AUTHOR]

The interplay between platelets and tumors has long been studied. It has been widely accepted that platelets could promote tumor metastasis. However, the precise interactions between platelets and tumor cells have not been thoroughly investigated. Although platelets may play complex roles in multiple steps of tumor development, most studies focus on the platelets in the circulation of tumor patients. Platelets in the primary tumor microenvironment, in addition to platelets in the circulation during tumor cell dissemination, have recently been studied. Their effects on tumor biology are gradually figured out. According to updated cancer hallmarks, we reviewed the biological effects of platelets on tumors, including regulating tumor proliferation and growth, promoting cancer invasion and metastasis, inducing vasculature, avoiding immune destruction, and mediating tumor metabolism and inflammation. [ABSTRACT FROM AUTHOR]

Background: Little research addressed deprescribing-focused medication optimization interventions while utilizing implementation science. This study aimed to develop a pharmacist-led medication review service with a deprescribing focus in a care facility serving patients of low income receiving medications for free in Lebanon followed by an assessment of the recommendations' acceptance by prescribing physicians. As a secondary aim, the study evaluates the impact of this intervention on satisfaction compared to satisfaction associated with receiving routine care. Methods: The Consolidated Framework for Implementation Research (CFIR) was used to address implementation barriers and facilitators by mapping its constructs to the intervention implementation determinants at the study site. After filling medications and receiving routine pharmacy service at the facility, patients 65 years or older and taking 5 or more medications, were assigned into two groups. Both groups of patients received the intervention. Patient satisfaction was assessed right after receiving the intervention (intervention group) or just before the intervention (control group). The intervention consisted of an assessment of patient medication profiles before addressing recommendations with attending physicians at the facility. Patient satisfaction with the service was assessed using a validated translated version of the Medication Management Patient Satisfaction Survey (MMPSS). Descriptive statistics provided data on drug-related problems, the nature and the number of recommendations as well as physicians' responses to recommendations. Independent sample t-tests were used to assess the intervention's impact on patient satisfaction. Results: Of 157 patients meeting the inclusion criteria, 143 patients were enrolled: 72 in the control group and 71 in the experimental group. Of 143 patients, 83% presented drug-related problems (DRPs). Further, 66% of the screened DRPs met the STOPP/START criteria (77%, and 23% respectively). The intervention pharmacist provided 221 recommendations to physicians, of which 52% were to discontinue one or more medications. Patients in the intervention group showed significantly higher satisfaction compared to the ones in the control group (p < 0.001, effect size = 1.75). Of those recommendations, 30% were accepted by the physicians. Conclusion: Patients showed significantly higher satisfaction with the intervention they received compared to routine care. Future work should assess how specific CFIR constructs contribute to the outcomes of deprescribing-focused interventions. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is a major cerebrovascular illness that causes substantial neurological sequelae and dysfunction caused by secondary brain injury (SBI), and there are no effective therapies to mitigate the disability. Microglia, the brain-resident macrophage, participates in the primary inflammatory response, and activation of microglia to an M1-like phenotype largely takes place in the acute phase following ICH. A growing body of research suggests that the pathophysiology of SBI after ICH is mediated by an inflammatory response mediated by microglial-pyroptotic inflammasomes, while inhibiting the activation of microglial pyroptosis could suppress the inflammatory cascade reaction, thus attenuating the brain injury after ICH. Pyroptosis is characterized by rapid plasma membrane disruption, followed by the release of cellular contents and pro-inflammatory mediators. In this review, we outline the molecular mechanism of microglial pyroptosis and summarize the up-to-date evidence of its involvement in the pathological process of ICH, and highlight microglial pyroptosis-targeted strategies that have the potential to cure intracerebral hemorrhage. This review contributes to a better understanding of the function of microglial pyroptosis in ICH and assesses it as a possible therapeutic target. [ABSTRACT FROM AUTHOR]

This study investigates the reliability of phytolith assemblage analysis for characterizing subtropical vegetation and explores the potential for using these modern phytolith–vegetation relationships for paleoenvironmental interpretation in southeastern China. The samples were collected from five common subtropical vegetation communities in the Daiyun Mountains, southeastern China, with the above-ground vegetation recorded at each plot. Constrained ordination analysis was used to determine the most important factor governing the variations in phytolith assemblages that could be quantitatively reconstructed with weighted averaging partial least squares regression (WAPLS). The relationship between modern phytolith assemblages and the parent vegetation, as well as production, dispersal, and taphonomic processes, was discussed. Results demonstrated that the main subtropical biomes in southeastern China could be well distinguished by soil phytolith assemblages. In particular, the overall amount of tree coverage was well represented by topsoil phytolith assemblages. Grass silica short cell phytoliths (GSSCP) tended to occur in higher proportions in open habitats (shrub-meadow) at higher elevations, whereas non-grass phytolith morphotypes attained higher frequencies under mixed and broadleaf forests at lower elevations. Human-induced deforestation might increase the frequency of GSSCP within the bulk phytolith assemblage. Our results constitute the primary phytolith reference data for the subtropical zone in southeastern Asia where vegetation change during the Holocene period, particularly forest shifts, anthropogenic deforestation, and early agriculture are poorly documented. [ABSTRACT FROM AUTHOR]

WU polyomavirus (WUPyV) is a novel member of the family Polyomaviridae recently detected in respiratory tract specimens. So far, it has not been proven whether WUPyV is a real causative agent for respiratory diseases. In this study, we described two patients with fatal infection who had WUPyV detected in their nasopharyngeal swabs. Furthermore, we conducted a multicentre study in six hospitals from different districts of China. WUPyV was detected by real-time polymerase chain reaction assays, and the clinical and molecular epidemiological characteristics of WUPyV strains among hospitalized children with acute lower respiratory tract infections all around China from 2017 to 2019 were analysed. Two complete WUPyV genome sequences were assembled from fatal patients' airway specimens. Phylogenetic tree analysis revealed that they were most closely related to strains derived from Fujian and Chongqing, China, in 2008 and 2013, respectively. In 2017–2019, a total of 1,812 samples from children with acute lower respiratory tract infections were detected for WUPyV, of which 11 (0.6%) were positive. Children aged ≤5 were more susceptible to WUPyV infection. A total of 81.8% of WUPyV-positive patients were coinfected with other viruses, of which rhinovirus enjoyed the highest frequency. The main clinical symptoms of infected patients include fever, coughing and sputum expectoration. Most patients were diagnosed with pneumonia, followed by bronchial surgery. Three patients manifested severe infection, and all patients improved and were discharged. Our results show that WUPyV persistently circulates in China. Further investigations on the clinical role and pathogenicity of WUPyV are necessary. [ABSTRACT FROM AUTHOR]

Background: Many reports describe statistical approaches for estimating interindividual differences in trainability and classifying individuals as "responders" or "non-responders." The extent to which studies in the exercise training literature have adopted these statistical approaches remains unclear. Objectives: This systematic review primarily sought to determine the extent to which studies in the exercise training literature have adopted sound statistical approaches for examining individual responses to exercise training. We also (1) investigated the existence of interindividual differences in trainability, and (2) tested the hypothesis that less conservative thresholds inflate response rates compared with thresholds that consider error and a smallest worthwhile change (SWC)/minimum clinically important difference (MCID). Methods: We searched six databases: AMED, CINAHL, EMBASE, Medline, PubMed, and SportDiscus. Our search spanned the aerobic, resistance, and clinical or rehabilitation training literature. Studies were included if they used human participants, employed standardized and supervised exercise training, and either: (1) stated that their exercise training intervention resulted in heterogenous responses, (2) statistically estimated interindividual differences in trainability, and/or (3) classified individual responses. We calculated effect sizes (ESIR) to examine the presence of interindividual differences in trainability. We also compared response rates (n = 614) across classification approaches that considered neither, one of, or both errors and an SWC or MCID. We then sorted response rates from studies that also reported mean changes and response thresholds (n = 435 response rates) into four quartiles to confirm our ancillary hypothesis that larger mean changes produce larger response rates. Results: Our search revealed 3,404 studies, and 149 were included in our systematic review. Few studies (n = 9) statistically estimated interindividual differences in trainability. The results from these few studies present a mixture of evidence for the presence of interindividual differences in trainability because several ESIR values lay above, below, or crossed zero. Zero-based thresholds and larger mean changes significantly (both p < 0.01) inflated response rates. Conclusion: Our findings provide evidence demonstrating why future studies should statistically estimate interindividual differences in trainability and consider error and an SWC or MCID when classifying individual responses to exercise training. Systematic Review Registration: [website], identifier [registration number]. [ABSTRACT FROM AUTHOR]

The human tau protein is implicated in a wide range of neurodegenerative "tauopathy" diseases, consisting of Alzheimer's disease (AD) and frontotemporal lobar degeneration which includes progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and FTLD-tau (frontotemporal dementia with parkinsonism caused by MAPT mutations). Tau gene transcripts in the human brain undergo alternative splicing to yield 6 different tau protein isoforms that are expressed in different ratios in neurodegeneration which result in tau pathology of paired-helical filaments, neurofibrillary tangles, and tau fibrillar aggregates with detrimental microtubule destabilization. Protease-mediated tau truncation is an important post-translational modification (PTM) which drives neurodegeneration in a tau fragment-dependent manner. While numerous tau fragments have been identified, knowledge of the proteolytic steps that convert each parent tau isoform into specific truncated tau fragments has not yet been fully defined. An improved understanding of the relationships between tau isoforms and their proteolytic processing to generate neurotoxic tau fragments is important to the field. This review evaluates tau isoform expression patterns including PTMs and mutations that influence proteolysis of tau to generate toxic fragments that drive cognitive deficits in AD and other tauopathy models. This assessment identifies the gap in the field on understanding the details of proteolytic steps used to convert each tau isoform into fragments. Knowledge of the processing mechanisms of tau isoforms can lead to new protease targeted drug strategies to prevent the formation of toxic tau fragments in tauopathy neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Although platelets are critically involved in thrombosis and hemostasis, experimental and clinical evidence indicate that platelets promote tumor progression and metastasis through a wide range of physical and functional interactions between platelets and cancer cells. Thrombotic and thromboembolic events are frequent complications in patients with solid tumors. Hence, cancer modulates platelet function by directly inducing platelet-tumor aggregates and triggering platelet granule release and altering platelet turnover. Also, platelets enhance tumor cell dissemination by activating endothelial cell function and recruiting immune cells to primary and metastatic tumor sites. In this review, we summarize current knowledge on the complex interactions between platelets and tumor cells and the host microenvironment. We also critically discuss the potential of anti-platelet agents for cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood. In 90% of AD cases, Aβ deposition around the brain vasculature, known as cerebral amyloid angiopathy (CAA), alters blood brain barrier (BBB) essential functions. While the effects of vascular Aβ accumulation are better documented, the scientific community has only recently started to consider the impact of tau on neurovascular pathology in AD. Emerging compelling evidence points to transmission of neuronal tau to different brain cells, including astrocytes, as well as to the release of tau into brain interstitial fluids, which may lead to perivascular neurofibrillar tau accumulation and toxicity, affecting vessel architecture, cerebral blood flow (CBF), and vascular permeability. BBB integrity and functionality may therefore be impacted by pathological tau, consequentially accelerating the progression of the disease. Tau aggregates have also been shown to induce mitochondrial damage: it is known that tau impairs mitochondrial localization, distribution and dynamics, alters ATP and reactive oxygen species production, and compromises oxidative phosphorylation systems. In light of this previous knowledge, we postulate that tau can initiate neurovascular pathology in AD through mitochondrial dysregulation. In this review, we will explore the literature investigating tau pathology contribution to the malfunction of the brain vasculature and neurovascular unit, and its association with mitochondrial alterations and caspase activation, in cellular, animal, and human studies of AD and tauopathies. [ABSTRACT FROM AUTHOR]

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information on potential and observed PTMs on tau provides an opportunity to better understand these modifications in the context of tau homeostasis, which becomes perturbed with aging and disease. Prevailing views regard tau as a protein that undergoes abnormal phosphorylation prior to its accumulation into the toxic aggregates implicated in Alzheimer's disease (AD) and other tauopathies. However, the phosphorylation of tau may, in fact, represent part of the normal but interrupted function and catabolism of the protein. In addition to phosphorylation, tau undergoes another forms of post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. A holistic appreciation of how these PTMs regulate tau during health and are potentially hijacked in disease remains elusive. Recent studies have reinforced the idea that PTMs play a critical role in tau localization, protein-protein interactions, maintenance of levels, and modifying aggregate structure. These studies also provide tantalizing clues into the possibility that neurons actively choose how tau is post-translationally modified, in potentially competitive and combinatorial ways, to achieve broad, cellular programs commensurate with the distinctive environmental conditions found during development, aging, stress, and disease. Here, we review tau PTMs and describe what is currently known about their functional impacts. In addition, we classify these PTMs from the perspectives of protein localization, electrostatics, and stability, which all contribute to normal tau function and homeostasis. Finally, we assess the potential impact of tau PTMs on tau solubility and aggregation. Tau occupies an undoubtedly important position in the biology of neurodegenerative diseases. This review aims to provide an integrated perspective of how post-translational modifications actively, purposefully, and dynamically remodel tau function, clearance, and aggregation. In doing so, we hope to enable a more comprehensive understanding of tau PTMs that will positively impact future studies. [ABSTRACT FROM AUTHOR]

Deficiencies of medium-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, isolated long-chain 3-hydroxyacyl-CoA dehydrogenase, and very long-chain acyl-CoA dehydrogenase activities are considered the most frequent fatty acid oxidation defects (FAOD). They are biochemically characterized by the accumulation of medium-chain, long-chain hydroxyl, and long-chain fatty acids and derivatives, respectively, in tissues and biological fluids of the affected patients. Clinical manifestations commonly include hypoglycemia, cardiomyopathy, and recurrent rhabdomyolysis. Although the pathogenesis of these diseases is still poorly understood, energy deprivation secondary to blockage of fatty acid degradation seems to play an important role. However, recent evidence indicates that the predominant fatty acids accumulating in these disorders disrupt mitochondrial functions and are involved in their pathophysiology, possibly explaining the lactic acidosis, mitochondrial morphological alterations, and altered mitochondrial biochemical parameters found in tissues and cultured fibroblasts from some affected patients and also in animal models of these diseases. In this review, we will update the present knowledge on disturbances of mitochondrial bioenergetics, calcium homeostasis, uncoupling of oxidative phosphorylation, and mitochondrial permeability transition induction provoked by the major fatty acids accumulating in prevalent FAOD. It is emphasized that further in vivo studies carried out in tissues from affected patients and from animal genetic models of these disorders are necessary to confirm the present evidence mostly achieved from in vitro experiments. [ABSTRACT FROM AUTHOR]

Hair cells are sensitive to many insults including environmental toxins such as heavy metals. We show here that cadmium can consistently kill hair cells of the zebrafish lateral line. Disrupting hair cell mechanotransduction genetically or pharmacologically significantly reduces the amount of hair cell death seen in response to cadmium, suggesting a role for mechanotransduction in this cell death process, possibly as a means for cadmium uptake into the cells. Likewise, when looking at multiple cilia-associated gene mutants that have previously been shown to be resistant to aminoglycoside-induced hair cell death, resistance to cadmium-induced hair cell death is only seen in those with mechanotransduction defects. In contrast to what was seen with mechanotransduction, significant protection was not consistently seen from other ions previously shown to compete for cadmium uptake into cells or tissue including zinc and copper. These results show that functional mechanotransduction activity is playing a significant role in cadmium-induced hair cell death. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by SFTS virus (SFTSV), which is a novel bunyavirus. SFTSV was first isolated from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction in China. Subsequently, it was found to be widely distributed in Southeast Asia (Korea, Japan, and Vietnam). SFTSV can be transmitted not only from ticks but also from domestic animals, companion animals, and humans. Because the case fatality rate of SFTS is high (6–30%), development of specific and effective treatment for SFTS is required. Studies of potential antiviral drugs for SFTS-specific therapy have been conducted on existing or newly discovered agents in vitro and in vivo , with ribavirin and favipiravir being the most promising candidates. While animal experiments and retrospective studies have demonstrated the limited efficacy of ribavirin, it was also speculated that ribavirin would be effective in patients with a viral load <1 × 106 copies/mL. Favipiravir showed higher efficacy than ribavirin against SFTSV in in vitro assays and greater efficacy in animal models, even administrated 3 days after the virus inoculation. Although clinical trials evaluating the efficacy of favipiravir in SFTS patients in Japan are underway, this has yet to be confirmed. Other drugs, including hexachlorophene, calcium channel blockers, 2′-fluoro-2′-deoxycytidine, caffeic acid, amodiaquine, and interferons, have also been evaluated for their inhibitory efficacy against SFTSV. Among them, calcium channel blockers are promising because in addition to their efficacy in vitro and in vivo , retrospective clinical data have indicated that nifedipine, one of the calcium channel blockers, reduced the case fatality rate by >5-fold. Although further research is necessary to develop SFTS-specific therapy, considerable progress has been achieved in this area. Here we summarize and discuss recent advances in antiviral drugs against SFTSV. [ABSTRACT FROM AUTHOR]

Ebolavirus (EBOV) life cycle involves interactions with numerous host factors, but it remains poorly understood, as does pathogenesis. Herein, we synthesized 65 siRNAs targeting host genes mostly connected with aspects of the negative-sense RNA virus life cycle (including viral entry, uncoating, fusion, replication, assembly, and budding). We produced EBOV transcription- and replication-competent virus-like particles (trVLPs) to mimic the EBOV life cycle. After screening host factors associated with the trVLP life cycle, we assessed interactions of host proteins with trVLP glycoprotein (GP), VP40, and RNA by co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP). The results demonstrate that RNAi silencing with 11 siRNAs (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) decreased the replication efficiency of trVLPs. Co-IP revealed nine candidate host proteins (FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) potentially interacting with trVLP GP, and four (ANXA5, GRP78, HSPA1A, and HSP90AB1) potentially interacting with trVLP VP40. Ch-IP identified nine candidate host proteins (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, MAPK11, MEK2, and NTRK1) interacting with trVLP RNA. This study was based on trVLP and could not replace live ebolavirus entirely; in particular, the interaction between trVLP RNA and host proteins cannot be assumed to be identical in live virus. However, the results provide valuable information for further studies and deepen our understanding of essential host factors involved in the EBOV life cycle. [ABSTRACT FROM AUTHOR]

The estrogen-related receptors (ERRs) are important members of nuclear receptors which contain three isoforms (α, β, and γ). ERRα is the best-characterized isoform expressed mainly in high-energy demanding tissues where it preferentially works in association with the peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α) and PGC-1β. ERRα together with its cofactors modulates cellular metabolism, supports the growth of rapidly dividing cells, directs metabolic programs required for cell differentiation and maintains cellular energy homeostasis in differentiated cells. In cancer cells, the functional association between ERRα and PGC-1s is further influenced by oncogenic signals and induces metabolic programs favoring cell growth and proliferation as well as tumor progression. Recently, cholesterol has been identified as a natural ERRα ligand using a combined biochemical strategy. This new finding highlighted some important physiological aspects related to the use of cholesterol-lowering drugs such as statins and bisphosphonates. Even more meaningful is the link between increased cholesterol levels and certain cancer phenotypes characterized by an overexpressed ERRα such as mammary, prostatic, and colorectal cancers, where the metabolic adaptation affects many cancer processes. Moreover, high-energy demanding cancer-related processes are strictly related to the cross-talk between tumor cells and some key players of tumor microenvironment, such as tumor-associated macrophage that fuels cancer progression. Some evidence suggests that high cholesterol content and ERRα activity favor the inflammatory environment by the production of different cytokines. In this review, starting from the most recent observations on the physiological role of the new signaling activated by the natural ligand of ERRα, we propose a new hypothesis on the suitability to control cholesterol levels as a chance in modulating ERRα activity in those tumors in which its expression and activity are increased. [ABSTRACT FROM AUTHOR]

Forest regeneration is a key element in achieving sustainable forest management. Partial harvest methods have been used extensively in temperate broadleaf and mixedwood ecosystems to promote regeneration on poorly stocked sites and to maintain forest composition and productivity. However, their effectiveness in promoting conifer establishment has yet to be demonstrated in unmanaged boreal forests, especially those dominated by black spruce (Picea mariana (Mill.) BSP) where constraints for regeneration differ from those found in more meridional regions. We aimed to evaluate conifer seedling density and dimensions, 10 years after the onset of a gradient of silvicultural treatments varying in harvesting intensities, and to identify the critical factors driving the regeneration process. Study blocks of even-aged black spruce stands in the eastern Canadian boreal forest were submitted to three variants of shelterwood harvesting: a seed-tree harvest, a clear-cut and an untreated control. Shelterwood and seed-tree harvesting were combined with spot scarification to promote regeneration. Shelterwood and seed-tree harvesting produced a density of conifer regeneration sufficient to maintain forest productivity, but they did not promote seedling growth. Black spruce was the predominant species in terms of regeneration density, with proportions 3–5× higher than that for balsam fir (Abies balsamea (L.) Mill.). Ten years after treatment, seed-origin black spruce seedlings were abundant in skidding trails, while layers dominated the residual strips. Balsam fir density was not influenced by treatment nor by tree position relative to skidding trails. Balsam fir and black spruce had different responses to treatment in terms of height and diameter, the former exhibiting a better growth performance and larger diameter in the residual strips. Spot scarification created micro-sites that had a significant impact on the regeneration process. Overall, our results support that shelterwood and seed-tree harvesting combined with scarification enable adequate regeneration in black spruce stands, confirming these treatments as viable silvicultural alternatives to clear-cutting when required by sustainable forest management objectives. [ABSTRACT FROM AUTHOR]

Introduction: Genito-pelvic pain/penetration disorder (GPPPD) not only adversely affects women's sexuality and sexual satisfaction but is also associated with a wide range of psychosocial consequences such as reduced quality of life and well-being, mental health comorbidities, and relationship distress. Evidence for effective treatment options is scarce. Aim: This article describes the rationale, treatment protocol, and study design for a randomized controlled trial examining the efficacy of an Internet-based guided intervention for GPPPD. Method: Two hundred women who meet the criteria for GPPPD and have not been able to experience sexual intercourse for at least the last 6 months will be recruited and randomly assigned either to the intervention group (IG) or a 6-month waitlist control group. Assessments take place at baseline (T1), peritreatment after completion of Session 5 in IG (T2), after completion of Session 8 or 12 weeks after randomization (T3), and after 6 months (T4). Data will be analyzed on an intention-to-treat and a completer basis. Main outcome measures: The primary outcome will be sexual intercourse involving the insertion of the partner's penis at posttreatment. Secondary outcomes include, e.g., improved non-intercourse penetration, sexual functioning, dyadic stress coping, reduced fear of sexuality and negative penetration-related cognitions. Fear of sexuality, penetration-related cognitions, and exercise intensity will be assessed as mediators of intercourse in the IG. Sexual dysfunctions of partners will be measured at baseline (T1) and investigated as a potential moderator of the primary treatment outcome. Discussion: Given the burden associated with GPPPD and the need for specialized treatment, there is a surprising lack of evidence-based treatment options. This study aims to assess whether Internet-based interventions could contribute to closing this treatment gap. [ABSTRACT FROM AUTHOR]

Antibodies have proven their high value in antitumor therapy over the last two decades. They are currently being used as the first-choice to treat some of the most frequent metastatic cancers, like HER2+ breast cancers or colorectal cancers, currently treated with trastuzumab (Herceptin) and bevacizumab (Avastin), respectively. The impressive therapeutic success of antibodies inhibiting immune checkpoints has extended the use of therapeutic antibodies to previously unanticipated tumor types. These anti-immune checkpoint antibodies allowed the cure of patients devoid of other therapeutic options, through the recovery of the patient's own immune response against the tumor. In this review, we describe how the antibody-based therapies will evolve, including the use of antibodies in combinations, their main characteristics, advantages, and how they could contribute to significantly increase the chances of success in cancer therapy. Indeed, novel combinations will consist of mixtures of antibodies against either different epitopes of the same molecule or different targets on the same tumor cell; bispecific or multispecific antibodies able of simultaneously binding tumor cells, immune cells or extracellular molecules; immunomodulatory antibodies; antibody-based molecules, including fusion proteins between a ligand or a receptor domain and the IgG Fab or Fc fragments; autologous or heterologous cells; and different formats of vaccines. Through complementary mechanisms of action, these combinations could contribute to elude the current limitations of a single antibody which recognizes only one particular epitope. These combinations may allow the simultaneous attack of the cancer cells by using the help of the own immune cells and exerting wider therapeutic effects, based on a more specific, fast, and robust response, trying to mimic the action of the immune system. [ABSTRACT FROM AUTHOR]

Estrogen-signaling pathways are implicated in the development of breast cancer and prostate cancer. Various studies have focused on additional signaling pathways, mediated by estrogen-related receptors (ERRs). ERRs are constitutively active receptors that share a high degree of homology with the classical estrogen receptors (ERs). However, they do not bind to estrogen, while ERs do. ERRs are involved in the development of alternative pathways that lead to the development of cancer and are regarded as potential therapeutic targets for the treatment of breast cancer and prostate cancer that do not respond to conventional therapies. In this review, we first present general structural features of ERRs. Then, we focus on breast cancer and prostate cancer, which are primarily hormone-dependent cancers, and summarizes recent progress in elucidating the involvement of each ERR in these two types of malignancies. [ABSTRACT FROM AUTHOR]

Preterm birth (PTB; birth before 37 completed weeks of gestation) remains the major cause of neonatal morbidity and mortality. The current generation of biomarkers predictive of PTB have limited utility. In pregnancy, the human cervicovaginal fluid (CVF) proteome is a reflection of the local biochemical milieu and is influenced by the physical changes occurring in the vagina, cervix and adjacent overlying fetal membranes. Term and preterm labor (PTL) share common pathways of cervical ripening, myometrial activation and fetal membranes rupture leading to birth. We therefore hypothesize that CVF biomarkers predictive of labor may be similar in both the term and preterm labor setting. In this review, we summarize some of the existing published literature as well as our team's breadth of work utilizing the CVF for the discovery and validation of putative CVF biomarkers predictive of human labor. Our team established an efficient method for collecting serial CVF samples for optimal 2-dimensional gel electrophoresis resolution and analysis. We first embarked on CVF biomarker discovery for the prediction of spontaneous onset of term labor using 2D-electrophoresis and solution array multiple analyte profiling. 2D-electrophoretic analyses were subsequently performed on CVF samples associated with PTB. Several proteins have been successfully validated and demonstrate that these biomarkers are associated with term and PTL and may be predictive of both term and PTL. In addition, the measurement of these putative biomarkers was found to be robust to the influences of vaginal microflora and/or semen. The future development of a multiple biomarker bed-side test would help improve the prediction of PTB and the clinical management of patients. [ABSTRACT FROM AUTHOR]

In normal adult brain the microtubule associated protein (MAP) tau contains 2-3 phosphates per mol of the protein and at this level of phosphorylation it is a soluble cytosolic protein. The normal brain tau interacts with tubulin and promotes its assembly into microtubules and stabilizes these fibrils. In Alzheimer disease (AD) brain tau is three to fourfold hyperphosphorylated. The abnormally hyperphosphorylated tau binds to normal tau instead of the tubulin and this binding leads to the formation of tau oligomers. The tau oligomers can be sedimented at 200,000×g whereas the normal tau under these conditions remains in the supernatant. The abnormally hyperphosphorylated tau is capable of sequestering not only normal tau but also MAP MAP1 and MAP2 and causing disruption of the microtubule network promoted by these proteins. Unlike Ab and prion protein (PrP) oligomers, tau oligomerization in AD and related tauopathies is hyperphosphorylation-dependent; in vitro dephosphorylation of AD P-tau with protein phosphatase 2A (PP2A) inhibits and rehyper-phosphorylation of the PP2A-AD P-tau with more than one combination of tau protein kinases promotes its oligomerization. In physiological assembly conditions the AD P-tau readily self-assembles into paired helical filaments. Missense tau mutations found in frontotemporal dementia apparently lead to tau oligomerization and neurofibrillary pathology by promoting its abnormal hyperphosphorylation. Dysregulation of the alternative splicing of tau that alters the 1:1 ratio of the 3-repeat: 4-repeat taus such as in Down syndrome, Pick disease, and progressive supranuclear palsy leads to the abnormal hyperphosphorylation of tau. [ABSTRACT FROM AUTHOR]