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Abstract Background Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. Methods To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335). Results The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335 R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (−43 ± 18% and −23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335 R1092W allele(s) exhibited a significantly blunted LDL statin response. Conclusions Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.

The ongoing high occurrence of harmful infectious diseases significantly threatens human health. Existing methods used to control such diseases primarily involve targeting the pathogens, usually neglecting the vital role of host factors in disease advancement. Gamma delta (γδ) T cells act as a bridge between innate and adaptive immunity, playing a crucial role in combating pathogen invasion. Among these γδT cell subsets, which are categorized based on T cell receptor delta variable expression patterns, V delta (δ) 1+ T cells possess unique recognition abilities and regulatory characteristics and actively engage in various immune responses. The differentiation, development, and immune reactivity of Vδ1+ T cells are closely associated with the initial and progressive stages of infectious diseases. This article provides an overview of the classification, distribution, differentiation, and development of Vδ1+ T cells and their mechanisms in combating pathogenic infections, offering new insights for disease diagnosis and treatment.

Abstract Alzheimer’s disease (AD) has a complex pathogenesis, and multiple studies have indicated that histone post-translational modifications, especially acetylation, play a significant role in it. With the development of mass spectrometry and proteomics, an increasing number of novel HPTMs, including lactoylation, crotonylation, β-hydroxybutyrylation, 2-hydroxyisobutyrylation, succinylation, and malonylation, have been identified. These novel HPTMs closely link substance metabolism to gene regulation, and an increasing number of relevant studies on the relationship between novel HPTMs and AD have become available. This review summarizes the current advances and implications of novel HPTMs in AD, providing insight into the deeper pathogenesis of AD and the development of novel drugs.

Background: Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates. Methods: A total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity. Results: MSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits. Conclusions: Our findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.

Rice, a critical staple on a global scale, faces escalating challenges in yield preservation due to the rising prevalence of abiotic and biotic stressors, exacerbated by frequent climatic fluctuations in recent years. Moreover, the scorching climate prevalent in the rice-growing regions of South China poses obstacles to the cultivation of good-quality, heavy-grain varieties. Addressing this dilemma requires the development of resilient varieties capable of withstanding multiple stress factors. To achieve this objective, our study employed the broad-spectrum blast-resistant line Digu, the brown planthopper (BPH)-resistant line ASD7, and the heavy-grain backbone restorer lines Fuhui838 (FH838) and Shuhui527 (SH527) as parental materials for hybridization and multiple crossings. The incorporation of molecular markers facilitated the rapid pyramiding of six target genes (Pi5, Pita, Pid2, Pid3, Bph2, and Wxb). Through a comprehensive evaluation encompassing blast resistance, BPH resistance, cold tolerance, grain appearance, and quality, alongside agronomic trait selection, a promising restorer line, Guihui5501 (GH5501), was successfully developed. It demonstrated broad-spectrum resistance to blast, exhibiting a resistance frequency of 77.33% against 75 artificially inoculated isolates, moderate resistance to BPH (3.78 grade), strong cold tolerance during the seedling stage (1.80 grade), and characteristics of heavy grains (1,000-grain weight reaching 35.64 g) with good grain quality. The primary rice quality parameters for GH5501, with the exception of alkali spreading value, either met or exceeded the second-grade national standard for premium edible rice varieties, signifying a significant advancement in the production of good-quality heavy-grain varieties in the southern rice-growing regions. Utilizing GH5501, a hybrid combination named Nayou5501, characterized by high yield, good quality, and resistance to multiple stresses, was bred and received approval as a rice variety in Guangxi in 2021. Furthermore, genomic analysis with gene chips revealed that GH5501 possessed an additional 20 exceptional alleles, such as NRT1.1B for efficient nitrogen utilization, SKC1 for salt tolerance, and STV11 for resistance to rice stripe virus. Consequently, the restorer line GH5501 could serve as a valuable resource for the subsequent breeding of high-yielding, good-quality, and stress-tolerant hybrid rice varieties.

Abstract With the rapid development of the economy, people have increasingly higher requirements for the comfort of living spaces, and the result is the sharp increase in building energy consumption. Several design parameters influence living space comfort and building energy efficiency. Since the same design standard can include different design parameter combinations, synergic relationships may exist between these criteria for one case. Identifying these synergic relationships requires an inverse problem approach. This paper established a model by combining an improved genetic algorithm (IGA) and numerical calculation to determine the synergic design parameter relationships (e.g. the thermophysical building material properties and energy-saving factors). For $${{\text{I}}}_{{\text{sum}}}= {0} $$ I sum = 0 , the shading coefficient significantly influenced the linear function between the thermal conductivity and insulation thickness. In this case, the insulation thickness was exponentially related to the shading coefficient, while the thermal conductivity of the insulation material significantly impacted the synergic relationship. For $${\text{ESR}}{=65}\%$$ ESR = 65 % , the insulation thickness was a segmented function of the shading coefficient. The results verified that the proposed model was efficient and reliable for identifying the synergic relationships between energy-saving parameters. In engineering applications, designers can select the optimal design parameter combination based on the relationship curve between the parameters in this paper according to the local market conditions and specific design requirements.

Mapping and monitoring the spatial–temporal evolution of thermokarst lakes on the Tibetan Plateau can significantly contribute to the estimation of climate change impacts on permafrost degradation. Remote sensing-based methods have been developed to monitor the interannual changes of thermokarst lakes. However, the seasonal changes, which are vital for understanding thermokarst lake dynamics, are commonly overlooked. This paper developed automatic methods which integrated the normalized difference water index (NDWI), modified normalized difference water index (MNDWI), principal component analysis (PCA), and independent component analysis (ICA) with Markov random field (MRF) for rapid mapping of thermokarst lakes in different physical states characterized by season changes. To validate the effectiveness, the proposed methods were applied to map thermokarst lakes on the central Tibetan Plateau, using four Sentinel-2 images representing different evolutionary states. Specifically, the area-to-point regression kriging (ATPRK) method was employed to downscale the 20-m short-wave infrared (SWIR) band to 10 m. Using manually digitized lakes as a reference, the proposed methods achieved an average Kappa coefficient of 0.79, significantly outperforming the water index thresholding method that merely attained 0.44. The results corroborate that the proposed methods can be robustly applied in mapping thermokarst lake dynamics with both interannual and seasonal trends on the Tibetan Plateau.

Obesity impairs the health and regeneration of skeletal muscle. Astaxanthin (AX) possesses antioxidant and anti-obesity properties, making it possible to improve obesity-associated damages. 42 male C57BL/6J mice were fed a control diet, a high-fat diet (HFD) or a HFD with 0.02 %AX for 16 weeks. Mice were either immediately euthanized (experiment one) or given intramuscular injections of cardiotoxin (CTX) and euthanized on the seventh day (experiment two). The experiment one showed that AX improved grip strength and motor function with reduced fat deposition and elevated SOD in skeletal muscle. The experiment two found that AX increased the expression of proteins related to muscle regeneration and mitochondrial biogenesis. The in vitro experiment of interfering C2C12 myogenic cells with AX suggested that AX promoted myoblast differentiation and mitochondrial biogenesis. In conclusion, astaxanthin improves skeletal muscle health and regeneration in obese mice induced by HFD.

Abstract Background This study’s objective was to investigate the predictors for severe anemia, severe leukopenia, and severe thrombocytopenia when amphotericin B deoxycholate-based induction therapy is used in HIV-infected patients with talaromycosis. Methods A total of 170 HIV-infected patients with talaromycosis were enrolled from January 1st, 2019, to September 30th, 2020. Results Approximately 42.9%, 20.6%, and 10.6% of the enrolled patients developed severe anemia, severe leukopenia, and severe thrombocytopenia, respectively. Baseline hemoglobin level 73.4 µmol/L (OR = 2.573, 95% CI: 1.157 ~ 5.723), AST/ALT ratio > 1.6 (OR = 2.479, 95% CI: 1.167 ~ 5.266), sodium level ≤ 136 mmol/liter (OR = 4.342, 95% CI: 1.747 ~ 10.789), and a dose of amphotericin B deoxycholate > 0.58 mg/kg/d (OR = 2.504, 95% CI:1.066 ~ 5.882) were observed to be independent risk factors associated with the development of severe anemia. Co-infection with tuberculosis (OR = 3.307, 95% CI: 1.050 ~ 10.420), and platelet level (per 10 × 109 /L) (OR = 0.952, 95% CI: 0.911 ~ 0.996) were shown to be independent risk factors associated with the development of severe leukopenia. Platelet level

Mapping and monitoring thermokarst lakes are crucial to understanding the impact of climate change on permafrost regions and quantifying permafrost-related carbon emissions. Several automatic methods based on remote sensing images have been developed for thermokarst lake mapping. However, mixed pixels containing both land and water characteristics in the lakeshore zones pose a significant challenge to the accuracy of these methods. Furthermore, few approaches were able to fully automate the identification of thermokarst lakes without the manual training sample selection or parameter tuning. In this study, we present a fully automatic framework for thermokarst lake mapping using moderate-resolution Sentinel-2 images. The proposed method combines multidimensional hierarchical clustering and sub-pixel mapping (SPM) based on the radial basis function (RBF) interpolation and Markov random field (MRF) (referred to as RBF-then-MRF SPM), so as to achieve thermokarst lake mapping at a spatial resolution of 3.3 m. We apply the proposed method to two representative thermokarst lake distribution regions in the Northern Hemisphere and achieve a mean Kappa coefficient of 0.89 and 0.99, and a mean Quality of 89.86% and 96.60% on the central Tibetan Plateau and the northern Seward Peninsula, respectively. The results demonstrate that the proposed method significantly improves the accuracy of mixed pixel extraction, and the automatic thermokarst lake mapping is applicable to diverse permafrost regions.

Large industrial estates for electrical and electronic waste (e-waste) mechanical dismantling and recycling are gradually replacing outmoded small factories and intensive domestic workshops for e-waste manual and chemical dismantling. However, the air pollution and health risks of persistent organic pollutants during the modern mechanical processing of e-waste, especially obsolete electrical equipment, still remain unclear. Here, unexpectedly high levels (409.3 ng/m3) and health risks of airborne polychlorinated biphenyls (PCBs) were found during the mechanical processing of obsolete electric equipment or parts in a large integrated dismantling industrial estate, which is comparable to or a dozen times higher than those reported during chemical processing. In contrast, the levels (936.0 pg/m3) and health risks of particulate polybrominated diphenyl ethers (PBDEs) were all lower than those of previous studies. PCB emissions (44.9–3300.5 ng/m3) varied significantly across six mechanical dismantling places specifically treating waste motors, electrical appliances, hardware, transformers, and metals, respectively. The high PCB content and mass processing number of obsolete electrical equipment probably result in the highest PCB emissions from the mechanical dismantling of obsolete motors, followed by waste electrical appliances and metals. The PCB non-cancer and cancer risks associated with inhalation and dermal exposure in different mechanical dismantling places were all above the given potential risk limits. In particular, the health risks of dismantling obsolete motor exceeded the definite risk levels. Little difference in PCB emissions and health risks between working and non-working time suggested the importance of PCB volatilization from most e-waste. Such high PCB emissions and health risks of PCBs undoubtedly posed a severe threat to frontline workers, but fortunately, they decreased significantly with the increasing distance from the industrial estate. We highlight that PCB emissions and associated health risks from obsolete electrical equipment with high PCB content during mechanical dismantling activities should be of great concern.

PurposeTo investigate the effective connectivity (EC) changes after multisite repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG).MethodWe selected 51 patients with mild or moderate Alzheimer's disease (AD) and delivered 10 Hz rTMS over the left dorsal lateral prefrontal cortex (DLPFC) and the lateral temporal lobe (LTL) combined with COG or sham stimulation for 4 weeks. The selected AD patients were divided into real (real rTMS+COG, n = 11) or sham (sham rTMS+COG, n = 8) groups to undergo neuropsychological assessment, resting-state fMRI, and 3D brain structural imaging before (T0), immediately at the end of treatment (T4), and 4 weeks after treatment (T8). A 2 × 3 factorial design with “time” as the within-subjects factor (three levels: T0, T4, and T8) and “group” as the between-subjects factor (two levels: real and sham) was used to investigate the EC changes related to the stimulation targets in the rest of the brain, as well as the causal interactions among seven resting-state networks based on Granger causality analysis (GCA).ResultsAt the voxel level, the EC changes from the left DLPFC out to the left inferior parietal lobe and the left superior frontal gyrus, as well as from the left LTL out to the left orbital frontal cortex, had a significant group × time interaction effect. At the network level, a significant interaction effect was identified in the increase in EC from the limbic network out to the default mode network. The decrease in EC at the voxel level and the increase in EC at the network level were both associated with the improved ability to perform activities of daily living and cognitive function.ConclusionMultisite rTMS combined with cognitive training can modulate effective connectivity in patients with AD, resulting in improved ability to perform activities of daily living and cognitive function.

Histone lysine crotonylation was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of histone and nonhistone crotonylation in reproduction, development, and disease. Although the regulatory enzyme systems and targets of crotonylation partially overlap with those of acetylation, the peculiar CC bond structure of crotonylation suggests that crotonylation may have specific biological functions. In this review, we summarize the latest research progress regarding crotonylation, especially its regulatory factors and relationship with diseases, which suggest further research directions for crotonylation and provide new ideas for developing disease intervention and treatment regimens.

Abstract. Background:. A more comprehensive understanding of the trends of incidence, prevalence, and mortality in human immunodeficiency virus (HIV), and their complex interrelationships, may provide important evidence for decision-making related to HIV prevention and control. The variances in these indices between different population groups, genders, and ages are critical to decipher evolving patterns of the HIV epidemic in specific populations. Methods:. A secondary analysis of relevant data was conducted using data extracted from the Global Burden of Disease study of 2019. HIV/acquired immune deficiency syndrome (AIDS) incidence, prevalence, AIDS-related mortality, and mortality-to-prevalence ratio (MPR) for annual percentage change, average annual percentage change (AAPC), and corresponding 95% confidence intervals (CIs) were calculated using joinpoint regression statistical analysis. Results:. The AAPC of HIV/AIDS incidence, prevalence, AIDS-related mortality rate, and MPR were –1.4 (95% CI: –1.6, –1.2), 4.1 (95% CI: 4.0, 4.3), 2.0 (95% CI: 1.7, 2.3), and –2.1 (95% CI: –2.3, –1.8) between 1990 and 2019 globally, and were 3.5 (95% CI: 2.2, 4.8), 6.9 (95% CI: 6.8, 7.0), 8.1 (95% CI: 7.1, 9.1), and 1.2 (95% CI: 0.1, 2.3) in China during the same period. In terms of differences in the preceding indicators by gender, we observed a similar pattern of trends for male and female genders both globally and in China during the entire study period. Each specific age group exhibits a distinct pattern in terms of incidence, prevalence, mortality rate, and MPR both globally and in China. Conclusions:. Prevalence and mortality rates of HIV/AIDS have increased between 1990 and 2019 globally and in China. While the incidence rate and MPR have declined globally over the past three decades, these two indicators are observed to present an increasing trend in China. There is a high HIV burden among young and middle-aged adults globally; however, the elderly have a high HIV burden in China. HIV screening at older age should be scaled up, and patients with advanced HIV disease should be provided early with additional care and health resources.

The energy content of secondary batteries is often limited by the charge carriers available in the system. Here, the authors employed an anion acceptor cathode for simultaneous use of electrolyte anions and cations as effective charge carriers in solid polymer electrolytes for lithium-based batteries.

Background and purposeHypoperfusion of the posterior cingulate cortex (PCC) and precuneus has consistently been reported in patients with Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG) is effective in alleviating the symptoms of patients with mild AD. This study investigated the effects of rTMS-COG therapy on cerebral blood flow (CBF), with a special interest in the PCC/precuneus, and whether observed CBF changes are associated with changes in neuropsychological assessments in AD.Materials and methodsTwenty-one patients with mild or moderate AD were randomly divided into real rTMS (n = 11) and sham treatment (n = 10) groups, both combined with COG. Neuro-navigated 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks in the real rTMS group. All patients with AD underwent neuropsychological assessment, pseudo-continuous arterial spin labeling, and structural 3D T1-weighted MRI before treatment (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). CBF in the precuneus, PCC, and stimulation targets at the region-of-interest (ROI) level, as well as whole-brain CBF changes at the voxel level, were compared between the two groups at three timepoints.ResultsrTMS-COG therapy revealed significant group × time interactions for the Mini-Mental State Examination (F = 5.339, p = 0.023, η2 = 0.433) and activities of daily living (F = 5.409, p = 0.039, η2 = 0.436) scores. The regional CBF in the precuneus showed a significant group × time interaction (F = 5.833, p = 0.027, η2 = 0.593). For voxel-level analysis, a significant group main effect was found in the left limbic lobe cluster, with the maximal peak in the left parahippocampus (p < 0.001, uncorrected, peak at [−16 −8 −24]). Simple effects analysis indicated that rTMS-COG therapy induced a decrease in CBF in the precuneus at T1 (p = 0.007) and an increase in the left parahippocampus at T2 (p=0.008). CBF decrease in the precuneus was correlated with better cognitive function immediately after treatment (T1) (r =−0.732, p=0.025).ConclusionNeuropsychological assessments showed immediate and long-term effects on cognitive function and activities of daily living after rTMS-COG therapy. CBF changes induced by high-frequency rTMS-COG therapy are region-dependent, showing immediate effects in the precuneus and long-term effects in the left parahippocampus. These results provide imaging evidence to understand the underlying neurobiological mechanism for the application of rTMS-COG in AD.

Abstract Thermally activated delayed fluorescence (TADF)-sensitized fluorescence is a promising strategy to maintain the advantage of TADF materials and fluorescent materials. Nevertheless, the delayed lifetime of the TADF sensitizer is still relatively long, which causes heavy efficiency roll-off. Here we reported a valid tactic to construct fluorescent devices with low-efficiency roll-off by utilizing the TADF sensitizer with a reduced delayed lifetime. By the construction of the sensitization system, the energy transfer efficiency can reach up to 90%. The high-energy transfer efficiency and the TADFʼs short delayed lifetime result in high sensitization over 95% and the maximum external quantum efficiency of 16.2%. Meanwhile, the TADF-sensitized fluorescent devices exhibit reduced efficiency roll-off with an “onset” current density of 23 mA · cm−2. Our results provide an effective strategy to reduce the efficiency roll-off of the TADF sensitization system.

BackgroundHIV self-testing (HIVST) is recommended by the World Health Organization as a valid approach to routine HIV testing services. The scale of HIVST use has gradually been expanded in China over the past 5 years. To take a closer look at the role of HIVST in China, we reviewed the promotion and application of HIVST within China. ObjectiveThe main objective of this study was to systematically analyze the proportion of past use and actual uptake of HIVST within China. Moreover, we aimed to quantify the effect of HIVST on HIV prevention and treatment. MethodsIn all, 5 medical databases and 2 registration systems, including PubMed, Web of Science, MEDLINE, WanFang, China National Knowledge Internet, ClinicalTrials.gov, and the Chinese Clinical Trial Registry were systematically searched for studies reporting the prevalence of HIVST use from January 1, 2010, to December 25, 2021. Meta-analyses of the pooled proportion estimates were carried out by the meta-package in R software (version 4.1.2). Statistical heterogeneity among the studies was estimated using Cochran Q test and the inconsistency index (I2). ResultsA total of 50 studies were included in our systematic review. The estimated pooled prevalence of HIVST use in China was 29.9% (95% CI 22.5%-37.9%). Among individuals who have ever used HIVST, 47.5% (95% CI 37.2%-57.8%) were tested for HIV for the first time. The pooled reactive rate of HIVST was 4.2% (95% CI 3.1%-5.8%). When HIVST revealed a reactive result, 81.3% (95% CI 70.9%-91.6%) of individuals sought medical care. ConclusionsIn recent times, HIVST has become a valuable tool for HIV prevention in China. The widespread use of HIVST in non–men who have sex with men populations needs to be endorsed and promoted. The long-term applications of HIVST and the potential consequences of self-financing of HIVST in China have yet to be explored. Trial RegistrationPROSPERO CRD42022304846; https://tinyurl.com/54d9pxy8

Recently, biomaterials for cartilage regeneration has been intensively investigated. However, the development of scaffolds that capture regenerated cartilage with biomechanical and structural recovery has rarely been reported. To address this challenge, platelet-rich plasma (PRP)-based cartilage constructs with a well-orchestrated symphony of cellular, biochemical and biomechanical elements were prepared by simultaneously employing chondrogenic progenitor cells (CPCs) as a cell source, optimizing platelet concentration, and adding an enzyme-ion activator. It was shown that this triple-optimized PRP + CPC construct possessed increased biomechanical properties and suitable biochemical signals. The following in vitro study demonstrated that the triple-optimized PRP + CPC constructs generated cartilage-like tissue with higher expression levels of chondrogenic-specific markers, more deposition of cartilage-specific extracellular matrix (ECM), and greater biomechanical values than those of the other constructs. Twelve weeks after the construct was implanted in a cartilage defect in vivo, histological analysis, qPCR, and biomechanical tests collectively showed that the triple-optimized constructs yielded a more chondrocyte-like cell phenotype with a higher synthesis of Col-II and aggrecan. More importantly, the triple-optimized constructs facilitated cartilage regeneration with better biomechanical recovery than that of the other constructs. These results demonstrate the efficacy of the triple-optimization strategy and highlight the simplicity and potency of this PRP + CPC construct for cartilage regeneration.

As an important predictor of adulthood psychopathology, self-reported childhood abuse appears heritable and is associated with brain abnormalities. However, the specific genetic mechanisms behind these brain alterations remain largely unknown. This study recruited young adults who reported different degrees of childhood abuse from the community. In order to fully understand the influence of genes on brain changes related to self-reported childhood abuse, various experiments were conducted in this study. Firstly, volume changes of gray matter and white matter related to childhood abuse were investigated by using advanced magnetic resonance imaging techniques. After sequencing the whole exons, we further investigated the relationship between polygenic risk score, brain volume alterations, and childhood abuse score. Furthermore, transcription-neuroimaging association analysis was used to identify risk genes whose expressions were associated with brain volume alterations. The gray matter volumes of left caudate and superior parietal lobule, and white matter volumes of left cerebellum and right temporal lobe-basal ganglia region were significantly correlated with the childhood abuse score. More importantly, brain volume changes mediated the influence of polygenic risk on self-reported childhood abuse. Additionally, transcription-neuroimaging association analysis reported 63 risk genes whose expression levels were significantly associated with childhood abuse-related brain volume changes. These genes are involved in multiple biological processes, such as nerve development, synaptic transmission, and cell construction. Combining data from multiple perspectives, our work provides evidence of brain abnormalities associated with childhood abuse, and further indicates that polygene genetic risk and risk gene expression may affect the occurrence of childhood abuse by brain regulation, which provides insights into the molecularpathology and neuromechanism of childhood adversity. Paying attention to the physical and mental health of high-risk children may be a fundamental way to prevent childhood abuse and promote lifelong mental health.

Grain shape is an important agronomic trait directly associated with yield in rice. In order to explore new genes related to rice grain shape, a high-density genetic map containing 2193 Bin markers (526957 SNP) was constructed by whole-genome resequencing of 208 recombinant inbred (RILs) derived from a cross between ZP37 and R8605, with a total genetic distance of 1542.27 cM. The average genetic distance between markers was 0.76 cM, and the physical distance was 201.29 kb. Quantitative trait locus (QTL) mapping was performed for six agronomic traits related to rice grain length, grain width, length-to-width ratio, thousand-grain weight, grain cross-sectional area, and grain perimeter under three different environments. A total of 39 QTLs were identified, with mapping intervals ranging from 8.1 kb to 1781.6 kb and an average physical distance of 517.5 kb. Among them, 15 QTLs were repeatedly detected in multiple environments. Analysis of the genetic effects of the identified QTLs revealed 14 stable genetic loci, including three loci that overlapped with previously reported gene positions, and the remaining 11 loci were newly identified loci associated with two or more environments or traits. Locus 1, Locus 3, Locus 10, and Locus 14 were novel loci exhibiting pleiotropic effects on at least three traits and were detected in multiple environments. Locus 14, with a contribution rate greater than 10%, influenced grain width, length-to-width ratio, and grain cross-sectional area. Furthermore, pyramiding effects analysis of three stable genetic loci showed that increasing the number of QTL could effectively improve the phenotypic value of grain shape. Collectively, our findings provided a theoretical basis and genetic resources for the cloning, functional analysis, and molecular breeding of genes related to rice grain shape.

Over half of the world’s population relies on rice as their staple food. The brown planthopper (Nilaparvata lugens Stål, BPH) is a significant insect pest that leads to global reductions in rice yields. Breeding rice varieties that are resistant to BPH has been acknowledged as the most cost-effective and efficient strategy to mitigate BPH infestation. Consequently, the exploration of BPH-resistant genes in rice and the development of resistant rice varieties have become focal points of interest and research for breeders. In this review, we summarized the latest advancements in the localization, cloning, molecular mechanisms, and breeding of BPH-resistant rice. Currently, a total of 70 BPH-resistant gene loci have been identified in rice, 64 out of 70 genes/QTLs were mapped on chromosomes 1, 2, 3, 4, 6, 8, 10, 11, and 12, respectively, with 17 of them successfully cloned. These genes primarily encode five types of proteins: lectin receptor kinase (LecRK), coiled-coil-nucleotide-binding-leucine-rich repeat (CC-NB-LRR), B3-DNA binding domain, leucine-rich repeat domain (LRD), and short consensus repeat (SCR). Through mediating plant hormone signaling, calcium ion signaling, protein kinase cascade activation of cell proliferation, transcription factors, and miRNA signaling pathways, these genes induce the deposition of callose and cell wall thickening in rice tissues, ultimately leading to the inhibition of BPH feeding and the formation of resistance mechanisms against BPH damage. Furthermore, we discussed the applications of these resistance genes in the genetic improvement and breeding of rice. Functional studies of these insect-resistant genes and the elucidation of their network mechanisms establish a strong theoretical foundation for investigating the interaction between rice and BPH. Furthermore, they provide ample genetic resources and technical support for achieving sustainable BPH control and developing innovative insect resistance strategies.

ObjectiveTo investigate the characteristics and mechanism of the dynamics of HBV infection with the progression of HIV disease and to explore the different responses of T lymphocytes to HBV in HIV patients in different stages of disease.MethodsWe compared the rates and characteristics of HBV coinfection between 372 early HIV-infected and 306 chronically HIV-infected men who have sex with men (MSM) in the Beijing Youan Hospital from October 2006 to November 2014. We further analysed IFN-γ-producing HBV-specific CD8+ T cells in 15 early HIV-infected individuals and 20 chronic HIV-infected individuals with HBV coinfection.ResultsTwenty-three HBsAg-positive cases were detected among the 372 early HIV-infected patients of this cohort, and the coinfection rate was 6.18%, while 35 HBsAg-positive cases were detected among the 306 chronically HIV-infected patients, with a coinfection rate of 11.44%. The coinfection rate of the chronically HIV-infected patients was significantly higher than that of the early-infected patients (p=0.0005). The median CD4+ T cell count in the early HIV infection patients was 445 cells/μL (196-1,030 cells/μL), which was higher than that in the chronic HIV infection patients [358 cells/μL (17-783 cells/μL)] (p

Metastatic brain tumors are the rare cause of intracerebral hemorrhage in the young. In this study, we present a case of a 24-year-old woman who suffered from brain and lung metastatic choriocarcinoma with intracerebral hemorrhage as initial presentation. Head computed tomography showed an irregular hematoma of the right frontal lobe and enlarged within 1 month. Chest X ray showed a mass in the right lung. This patient responded well with combined treatment with craniotomy for evacuation of hematoma, multidrug chemotherapy and lobectomy. This case report discusses a rare phenomenon of hemorrhage metastasis in the brain from choriocarcinoma. The better knowledge of this entity would facilitate earlier diagnosis and improve the outcome.

Abstract Purpose Anti‐CD19 chimeric antigen receptor T (CAR‐T) cell therapy has demonstrated remarkable efficacy for refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). However, this therapy failed in nearly 25% patients mainly due to antigen loss. The authors performed a phase Ⅱ trial by coadministration of anti‐CD19 and anti‐CD20 CAR‐T cells treatment for R/R DLBCL and evaluated its efficacy and toxicity. Methods Totally 21 patients with DLBCL were enrolled in this study. The patients were conditioned with fludarabine and cyclophosphamide before the infusion of anti‐CD19 and anti‐CD20 CAR‐T cells. Treatment response, toxicity, and persistence were monitored continuously. Results Of the 21 patients received the treatment, the objective response rate (ORR) is 81.0% (95% confidence interval [CI], 58.1%‐94.6%) with four cases of bulk (4/5) and one case of testis involvement; 52.4% (95% CI, 29.8%‐74.3%) had a complete response (CR). Peak levels of anti‐CD19 and anti‐CD20 CAR cells were associated with response (P = .007 and .002). Grade 3‐4 cytokine release syndrome (CRS) and neurologic events occurred in 28.5% and 9.5% patients, respectively. Median overall survival (OS) and progression‐free survival (PFS) were 8.1 and 5.0 months, respectively. The maximum standard uptake value (SUVmax) of CD4/CD8 ratio before and after infusion were associated with responses, and the total lesion glycolysis (TLG) before infusion correlates with cytokines level. Conclusions Coadministration of anti‐CD19 and CD20 CAR‐T cells therapy for DLBCL is feasible with manageable toxicity. Cytokine markers are related to toxicity and SUVmax could predict efficacy. This trial was registered at www.clinicaltrials.gov as NCT03207178.

Abstract Background Talaromyces marneffei (TM) is a dimorphic fungus mainly prevalent in Southeast Asian countries, which often causes disseminated life-threatening infection. TM infection often occurs in HIV/AIDS patients even in the antiretroviral therapy (ART) era. However, there has as yet, not been a systematic analysis of the prevalence of TM infection in HIV-infected populations in Asia. Methods In this study, we searched Pubmed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and WanFang from inception to 21 November 2018 for studies reporting TM infection in people living with HIV/AIDS (PLWHA). Our meta-analysis included studies investigating the prevalence of TM infection in PLWHA. Reviews, duplicate studies, and animal studies were excluded. A random effects model was used to estimate pooled prevalence, and meta-regression analysis was conducted to explore potential factors for heterogeneity. Results 159,064 patients with HIV infection in 33 eligible studies were included in our meta-analysis. The pooled prevalence of TM infection in PLWHA was 3.6%. Vietnam had the highest prevalence (6.4%), followed by Thailand (3.9%), China (3.3%), India (3.2%) and Malaysia (2.1%). In China, TM infection was most prevalent in South China (15.0%), while the burden in Southwest China was not very heavy (0.3%). CD4+ T-cell counts below 200 cells/mm3 contributed to the increased risk of TM infection in PLWHA (OR 12.68, 95%CI: 9.58–16.77). However, access to ART did not significantly decrease the risk of TM infection in PLWHA. Conclusions The burden of TM infection in Asia is heavy, and varies from region to region. PLWHA in lower latitude areas are more likely to suffer from TM infection. Optimization of diagnostic tools and universal screening for TM in vulnerable people to ensure early case detection and prompt antifungal treatment should be considered.

Abstract Background Current WHO guidelines (2018) recommend screening for cryptococcal antigen (CrAg) in HIV-infected persons with CD4+ T cell counts

Abstract Background Pneumocystis pneumonia (PCP) is a common acquired immune deficiency syndrome (AIDS)-related opportunistic infection. Recent reports estimate that more than 400,000 patients with human immunodeficiency virus (HIV) develop PCP each year globally. However, the timing of antiretroviral therapy (ART) initiation for HIV-infected patients with PCP is still controversial, and the benefits and risks of early initiation of ART are not completely clear. We thus designed this study in order to determine the optimal timing for ART initiation for HIV-positive patients with moderate to severe PCP. Methods This study will be an open-label, multi-centre, prospective randomised controlled trial. A total of 200 subjects will be randomly assigned to an early ART initiation group (≤14 days after PCP diagnosis) and a deferred ART initiation group (>14 days after PCP diagnosis) at a 1:1 ratio. All subjects will be followed up for 48 weeks after starting ART. The primary endpoint is incidence of disease progression (including new or relapsing opportunistic infections and death) at week 48. The secondary endpoints are the changes in CD4 counts from baseline at weeks 12, 24 and 48; the degree of virological suppression (HIV RNA

BACKGROUND After the initial surge in COVID-19 cases, large numbers of patients were discharged from a hospital without assessment of recovery. Now, an increasing number of patients report postacute neurological sequelae, known as “long COVID” — even those without specific neurological manifestations in the acute phase.METHODS Dynamic brain changes are crucial for a better understanding and early prevention of “long COVID.” Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge.RESULTS Overall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases.CONCLUSION Our study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of “long COVID” and early clinical guidance toward complete recovery.FUNDING National Natural Science Foundation of China.

As one of the most studied resting-state functional networks, default mode network (DMN) is related to pathogenesis in neuropsychiatry. However, it is unclear whether changed DMN connectivity is transformed into vulnerability to psychopathology in adults who experienced childhood trauma, and what is the underlying genetic basis. Exploring the effect of DMN on environment-behavior pathway and the related genetic modulation mechanisms could further a better understanding of psychiatric pathogenesis and early prevention strategy. Two hundred and sixteen young adults with varying levels of early trauma indexed by the Childhood Trauma Questionnaire (CTQ) were recruited from the community. Static and dynamic functional connectivity based on DMN seeds and independent component analysis based on whole-brain voxels were combined to explore DMN alterations related to the CTQ score. Relationships between CTQ score, DMN connectivity, and behavioral scores were confirmed by mediation effect analysis. Imaging-genomic correlations were further used to identify risk genes whose expression was associated with the DMN changes. Dysregulated DMN connectivity was found both in seed-level and voxel-level analyses. Moreover, the functional disruption in the left temporal pole, right parahippocampal gyrus, and frontoparietal connectivity mediated the effects of childhood trauma on emotional behavior. The serotonin transporter gene was identified and might suggest the biological underpinning of the relationship between childhood trauma, DMN, and emotion regulation. Changed DMN may be useful as biomarkers to provide a powerful supplement to psychological evaluation related to childhood trauma. Combined with gene expression profiles, our findings advance a more integrative understanding of DMN alterations induced by childhood trauma, and clarify its implications for psychiatric pathogenesis and early prevention strategies.

This study aimed to evaluate the difference in wall shear stress (WSS) (axial, circumferential, and 3D) between high-risk and low-risk plaques in patients with moderate carotid artery stenosis and to identify which time points and directions play the dominant roles in determining the risk associated with plaques. Forty carotid arteries in 30 patients were examined in this study. All patients underwent high-resolution vessel wall (HRVW) imaging, diffusion-weighted imaging (DWI), and 4D flow MRI; HRVW imaging and DWI were used to separate low- and high-risk plaque. Twenty-four high-risk plaques and 16 low-risk plaques were enrolled. An independent-sample t-test was used to compare WSS between low- and high-risk plaques in the whole cardiac cycle and at 20 different time points in the cardiac cycle. The study found that patients with high-risk plaques had higher WSS than those with low-risk plaques throughout the entire cardiac cycle (p < 0.05), but the changes varied at the 20 different time points. The number of non-significant differences (p > 0.05) was less in diastole than in systole across different time points. The axial WSS values were higher than the circumferential WSS values; the difference in axial WSS values between high- and low-risk plaques was more significant than the difference in circumferential WSS, whereas 3D WSS values best reflected the difference between high-risk and low-risk plaques because they showed significant differences at every time point. In conclusion, increased WSS, especially during the diastolic period and in the axial direction, may be a signal of a high-risk plaque and may cause cerebrovascular events in patients with moderate carotid artery stenosis. Additionally, WSS can provide hemodynamic information and help clinicians make more appropriate decisions for patients with plaques.

PurposeThis study aimed to assess the spatiotemporal evolution of oxygen extraction fraction (OEF) in ischemic stroke with a newly developed cluster analysis of time evolution (CAT) for a combined quantitative susceptibility mapping and quantitative blood oxygen level-dependent model (QSM + qBOLD, QQ).MethodOne hundred and fifteen patients in different ischemic stroke phases were retrospectively collected for measurement of OEF of the infarcted area defined on diffusion-weighted imaging (DWI). Clinical severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Of the 115 patients, 11 underwent two longitudinal MRI scans, namely, three-dimensional (3D) multi-echo gradient recalled echo (mGRE) and 3D pseudo-continuous arterial spin labeling (pCASL), to evaluate the reversal region (RR) of the initial diffusion lesion (IDL) that did not overlap with the final infarct (FI). The temporal evolution of OEF and the cerebral blood flow (CBF) in the IDL, the RR, and the FI were assessed.ResultsCompared to the contralateral mirror area, the OEF of the infarcted region was decreased regardless of stroke phases (p < 0.05) and showed a declining tendency from the acute to the chronic phase (p = 0.022). Five of the 11 patients with longitudinal scans showed reversal of the IDL. Relative oxygen extraction fraction (rOEF, compared to the contralateral mirror area) of the RR increased from the first to the second MRI (p = 0.044). CBF was about 1.5-fold higher in the IDL than in the contralateral mirror area in the first MRI. Two patients showed penumbra according to the enlarged FI volume. The rOEF of the penumbra fluctuated around 1.0 at earlier scan times and then decreased, while the CBF decreased continuously.ConclusionThe spatiotemporal evolution of OEF and perfusion in ischemic lesions is heterogeneous, and the CAT-based QQ method is feasible to capture cerebral oxygen metabolic information.

Gibberellins (GAs) promote secondary cell wall (SCW) development in plants, but the underlying molecular mechanism is still to be elucidated. Here, we employed a new system, the first internode of cotton, and the virus-induced gene silencing method to address this problem. We found that knocking down major DELLA genes via VIGS phenocopied GA treatment and significantly enhanced SCW formation in the xylem and phloem of cotton stems. Cotton DELLA proteins were found to interact with a wide range of SCW-related NAC proteins, and virus-induced gene silencing of these NAC genes inhibited SCW development with downregulated biosynthesis and deposition of lignin. The findings indicated a framework for the GA regulation of SCW formation; that is, the interactions between DELLA and NAC proteins mediated GA signaling to regulate SCW formation in cotton stems.

Breast cancer has the highest incidence among cancers and is the most frequent cause of death in women worldwide. The detailed mechanism of the pathogenesis of breast cancer has not been fully elucidated, and there remains a lack of effective treatment methods for the disease. SUMOylation covalently conjugates a large amount of cellular proteins, and affects their cellular localization and biological activity to participate in numerous cellular processes. SUMOylation is an important process and imbalance of SUMOylation results in the progression of human diseases. Increasing evidence shows that numerous SUMOylated proteins are involved in the occurrence and development of breast cancer. This review summarizes a series of studies on protein SUMOylation in breast cancer in recent years. The study of SUMOylated proteins provides a comprehensive understanding of the pathophysiology of breast cancer and provides evolving therapeutic strategies for the treatment of breast cancer.

Leukemia is a malignant disease of hematopoietic tissue characterized by the differentiation arrest and malignant proliferation of immature hematopoietic precursor cells in bone marrow. ERG (ETS-related gene) is an important member of the E26 transformation-specific (ETS) transcription factor family that plays a crucial role in physiological and pathological processes. However, the role of ERG and its modification in leukemia remains underexplored. In the present study, we stably knocked down or overexpressed ERG in leukemia cells and observed that ERG significantly promotes the proliferation and inhibits the differentiation of AML (acute myeloid leukemia) cells. Further experiments showed that ERG was primarily modified by SUMO2, which was deconjugated by SENP2. PML promotes the SUMOylation of ERG, enhancing its stability. Arsenic trioxide decreased the expression level of ERG, further promoting cell differentiation. Furthermore, the mutation of SUMO sites in ERG inhibited its ability to promote the proliferation and inhibit the differentiation of leukemia cells. Our results demonstrated the crucial role of ERG SUMOylation in the development of AML, providing powerful targeted therapeutic strategies for the clinical treatment of AML.

Background: People living with HIV (PLWH) are aging worldwide, and different management strategies may be required for older and younger PLWH. However, demographic characteristics, illness distribution, mortality, and independent risk factors in the PLWH population in China are not yet fully understood, especially in patients aged 50 years or older.Methods: We conducted a retrospective analysis of 4445 HIV-positive Chinese inpatients in Chongqing, China.Results: The mortality rate in patients 50 years or older (the older group) was significantly higher than that in those under 50 years (the younger group) (p < 0.001). In the younger group, independent risk factors for death included: nadir CD4+ T-cell counts

Post-translational modification by SUMO (small ubiquitin-like modifier) proteins has been shown to regulate a variety of functions of proteins, including protein stability, chromatin organization, transcription, DNA repair, subcellular localization, protein–protein interactions, and protein homeostasis. SENP (sentrin/SUMO-specific protease) regulates precursor processing and deconjugation of SUMO to control cellular mechanisms. SENP3, which is one of the SENP family members, deconjugates target proteins to alter protein modification. The effect of modification via SUMO and SENP3 is crucial to maintain the balance of SUMOylation and guarantee normal protein function and cellular activities. SENP3 acts as an oxidative stress-responsive molecule under physiological conditions. Under pathological conditions, if the SUMOylation process of proteins is affected by variations in SENP3 levels, it will cause a cellular reaction and ultimately lead to abnormal cellular activities and the occurrence and development of human diseases, including cardiovascular diseases, neurological diseases, and various cancers. In this review, we summarized the most recent advances concerning the critical roles of SENP3 in normal physiological and pathological conditions as well as the potential clinical implications in various diseases. Targeting SENP3 alone or in combination with current therapies might provide powerful targeted therapeutic strategies for the treatment of these diseases.

AimsOur object was to find the most appropriate, most effective, and most readily available of four induction regimens for HIV-associated cryptococcal meningitis (CM) (Regimen A: 1 week of AmB plus 5-FC followed by 1 week of fluconazole, Regimen B: 1 week of AmB plus fluconazole followed by 1 week of fluconazole, Regimen C: 2 weeks of AmB plus 5-FC, Regimen D: 2 weeks of AmB plus fluconazole), given the vast differences between resource-limited and resource-abundant settings regarding therapeutic drug accessibility, availability, and affordability for HIV-associated (CM).MethodsWe conducted a network meta-analysis to compare the therapeutic efficacy and safety of four different induction treatment regimens.ResultsThe 10-week mortality of Regimen A was significantly lower than that of Regimen B and D, and the 2-week mortality of Regimen A was significantly lower than that of Regimen B. Furthermore, there were no statistically significant differences in 10-week mortality, 2-week mortality, as well as in effective fungicidal activity (EFA) over the first 2 weeks among Regimens B, C, and D. The statistical differences in adverse events between Regimen B and Regimen D, and Regimen C and Regimen D were not calculated to be significant.ConclusionsOur results indicate that, 1 week of AmB plus 5-FC followed by 1 week of fluconazole is superior to the three other studied regimens, and that when 5-FC is not available, accessible, or affordable, 2 weeks of AmB plus fluconazole or 1 week of AmB plus fluconazole followed by 1 week of fluconazole is an appropriate substitution for 2 weeks of AmB plus 5-FC.

Abnormal structural connectivity of cerebral small-vessel disease (CSVD) is associated with cognitive impairment. But the different characteristics of structural connectivity have not been elucidated in early CSVD patients. The current study aimed to investigate the potential differences of structural connectivity in CSVD patients with mild cognitive impairment (MCI) and CSVD patients with normal cognition. Twenty-two CSVD patients with MCI, 34 CSVD patients with normal cognition, and 35 controls, who were age, sex, and education matched underwent diffusion tensor imaging and high resolution T1-weighted imaging. Clinical characteristics, lacunar infarct volume, white matter hyperintensity (WMH) volume, and global atrophy were quantitatively evaluated. Maps of fiber connectivity density (FiCD) were constructed and compared across groups in vertex levels. Pearson correlation was used to estimate the imaging–clinical relationships with control of general characteristics. CSVD patients with MCI had higher lesion load of WMH and lacunar infarcts, and correspondingly lower global FiCD value than CSVD patients with normal cognition (P < 0.01). Lacunar infarct (r = −0.318, P < 0.01) and WMH (r = −0.400, P < 0.01), but not global atrophy, age, or sex, were significantly correlated with the global FiCD value. CSVD patients with normal cognition showed decreased FiCD value mainly in the prefrontal areas (P < 0.01 with Monte Carlo correction). Compared with CSVD patients with normal cognition, CSVD patients with MCI showed significantly decreased FiCD value in enlarged frontal and parietal areas (P < 0.01 with Monte Carlo correction). Inter-group comparisons showed regional enhanced impairment of connectivity density in CSVD patients with MCI in the left superior frontal gyrus, the left precuneus, and the orbital part of the right inferior frontal gyrus (P < 0.01 with Monte Carlo correction). Regional FiCD value of frontal and parietal areas was associated with the cognitive function (P < 0.01). In conclusion, cognitively normal CSVD patients already have disruptions of structural connectivity. The extent and intensity of connectivity disruptions in frontal and parietal areas may underlie the mechanism of cognitive impairment in CSVD. Fiber connectivity density measurements may be helpful for quantitative description of structural cortical connectivity.

Abstract Chemotherapy resistance of breast cancer poses a great challenge to the survival of patients. During breast cancer treatment, the development of intrinsic and acquired drug resistance tends to further induce adverse prognosis, such as metastasis. In recent years, the progress of research on cytokine-modulated tumor microenvironment and breast cancer stem cells (BCSCs) has shed light on defining the mechanisms of drug resistance gradually. In this review, we have discussed cytokine regulation on breast cancer chemoresistance. Cytokines can affect tumor cell behavior or reprogram tumor niche through specific signaling pathways, thereby regulating the progress of drug resistance. In addition, we summarized the mutually regulatory networks between cytokines and BCSCs in mediating chemoresistance. Cytokines in the tumor microenvironment can regulate the self-renewal and survival of BCSCs in a variety of ways, sequentially promoting chemotherapeutic resistance. Therefore, the combinational treatment of BCSC targeting and cytokine blockade may have a positive effect on the clinical treatment of breast cancer.

Background/Aims: Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder resulting from mutations in SLC19A2, and is mainly characterized by megaloblastic anemia, diabetes, and progressive sensorineural hearing loss. Methods: We study a Chinese Zhuang ethnicity family with thiamine-responsive megaloblastic anemia. The proband of the study presented with anemia and diabetes, similar to his late brother, as well as visual impairment. All clinical manifestations were corrected with thiamine (30 mg/d) supplementation for 1–3 months, except for visual impairment, which was irreversible. The presence of mutations in all exons and the flanking sequences of the SLC19A2 gene were analyzed in this family based on the proband’s and his brother’s clinical data. Computer analysis and prediction of the protein conformation of mutant THTR-1. The relative concentration of thiamine pyrophosphate in the proband’s whole blood before and after initiation of thiamine supplement was measured by high performance liquid chromatography (HPLC). Results: Gene sequencing showed a homozygous mutation in exon 6 of the SLC19A2 gene (c.1409insT) in the proband. His parents and sister were diagnosed as heterozygous carriers of the c.1409insT mutation. Computer simulation showed that the mutations caused a change in protein conformation. HPLC results suggested that the relative concentration of thiamine pyrophosphate in the proband’s whole blood after thiamine supplement was significantly different (P=0.016) from that at baseline. Conclusions: This novel homozygous mutation (c.1409insT) caused the onset of thiamine-responsive megaloblastic anemia in the proband.

Abstract Background Perimenopausal insomnia is one of the core symptoms of the menopausal transition. Acupuncture is considered to exert a positive effect on restoring the normal sleep–wake cycle. However, there is little intuitive evidence besides evaluation using clinical effectiveness scales. We therefore designed this study, aiming to use more intuitive and reliable detection techniques such as functional magnetic resonance imaging before and after applying acupuncture to provide neuroimaging evidence, as well as to verify the effectiveness with other curative effect indicators. Methods/Design This study is a randomized, assessor–statistician-blinded, positive medicine controlled trial involving 40 participants. A total of 40 eligible patients with perimenopausal insomnia will be randomly assigned to two groups in a 1:1 ratio as an intervention group using acupuncture and a control group taking estazolam. Participants in the intervention group will receive six acupuncture treatment sessions per week for 4 consecutive weeks, for a total of 24 sessions during the study. Meanwhile, the medicine control group will be prescribed estazolam 1–2 mg/day to be taken 30 minutes before sleep for 4 weeks. The primary outcome is the Pittsburgh Sleep Quality Index. Secondary outcomes are the micro-movement sensitive mattress-type sleep monitoring system, the Hamilton Depression Scale, and the Hamilton Anxiety Scale. All outcomes will be evaluated before and after treatment. The safety of interventions will be assessed at every visit. Discussion The results of this trial, which will be available in 2018, will investigate the impact of acupuncture treating perimenopausal insomnia from assessment of the sleep architecture, hormone level, and emotional-circuit neurological function, and will uncover the effective mechanism of acupuncture regulating the emotional center integrated effect. Trial registration Chinese Clinical Trials Register, ChCTR-IPC-16007832 . Registered on 26 January 2016.

Nonalcoholic fatty liver disease (NAFLD) is one of the common diseases in the world, and it can progress from simple lipid accumulation to sustained inflammation. The present study was designed to investigate the effects and underlying mechanisms of ginsenoside Rg1 (G-Rg1) treatment on NAFLD in vitro. HepG2 cells were treated with palmitic acid (PA) to induce steatosis and inflammation and then successively incubated with G-Rg1. Lipids accumulation was analyzed by Oil Red O staining and intracellular triglyceride (TG) quantification. Inflammatory conditions were examined by quantifying the levels of cell supernatant alanine transaminase/aspartate aminotransferase (ALT/AST) and secretory proinflammatory cytokines, including IL-1β, IL-6, and TNF-α in the cell supernatants. Quantitative RT-PCR and western blotting were used to measure the expressions of genes and proteins associated with lipogenic synthesis and inflammation, including AMP-activated protein kinase (AMPK) and nuclear factor-kappa B (NF-κB) pathways. HepG2 cells were pretreated with an AMPK inhibitor; then, Oil Red O staining and TG quantification were performed to study the lipid deposition. Phospho-AMPK (Thr172) (p-AMPK) and phospho-acetyl-CoA carboxylase (Ser79) (p-ACCα) were quantified by immunoblotting. Immunofluorescence was performed to demonstrate the nuclear translocation of NF-κB P65. The present study showed that PA markedly increased the intracellular lipid droplets accumulation and TG levels, but decreased AMPK phosphorylation and the expressions of its downstream lipogenic genes. However, G-Rg1 alleviated hepatic steatosis and reduced the intracellular TG content; these changes were accompanied by the activation of the AMPK pathway. In addition, blocking AMPK by using the AMPK inhibitor markedly abolished the G-Rg1-mediated protection against PA-induced lipid deposition in HepG2 cells. Furthermore, G-Rg1 reduced the ALT/AST levels and proinflammatory cytokines release, which were all enhanced by PA. These effects were correlated with the inactivation of the NF-κB pathway and translocation of P65 from the cytoplasm to the nucleus. Overall, these results suggest that G-Rg1 effectively ameliorates hepatic steatosis and inflammation, which might be associated with the AMPK/NF-κB pathway.

Objective: A novel approach to regulate obesity-associated adipose inflammation may be through metabolic reprogramming of macrophages (MΦs). Broadly speaking, MΦs dependent on glucose are pro-inflammatory, classically activated MΦs (CAM), which contribute to adipose inflammation and insulin resistance. In contrast, MΦs that primarily metabolize fatty acids are alternatively activated MΦs (AAM) and maintain tissue insulin sensitivity. In actuality, there is much flexibility and overlap in the CAM-AAM spectrum in vivo dependent upon various stimuli in the microenvironment. We hypothesized that specific lipid trafficking proteins, e.g. fatty acid transport protein 1 (FATP1), would direct MΦ fatty acid transport and metabolism to limit inflammation and contribute to the maintenance of adipose tissue homeostasis. Methods: Bone marrow derived MΦs (BMDMs) from Fatp1−/− and Fatp1+/+ mice were used to investigate FATP1-dependent substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. We also generated C57BL/6J chimeric mice by bone marrow transplant specifically lacking hematopoetic FATP1 (Fatp1B−/−) and controls Fatp1B+/+. Mice were challenged by high fat diet (HFD) or low fat diet (LFD) and analyses including MRI, glucose and insulin tolerance tests, flow cytometric, histologic, and protein quantification assays were conducted. Finally, an FATP1-overexpressing RAW 264.7 MΦ cell line (FATP1-OE) and empty vector control (FATP1-EV) were developed as a gain of function model to test effects on substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. Results: Fatp1 is downregulated with pro-inflammatory stimulation of MΦs. Fatp1−/− BMDMs and FATP1-OE RAW 264.7 MΦs demonstrated that FATP1 reciprocally controled metabolic flexibility, i.e. lipid and glucose metabolism, which was associated with inflammatory response. Supporting our previous work demonstrating the positive relationship between glucose metabolism and inflammation, loss of FATP1 enhanced glucose metabolism and exaggerated the pro-inflammatory CAM phenotype. Fatp1B−/− chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1B+/+ controls. Adipose tissue macrophages displayed a CAM-like phenotype in the absence of Fatp1. Conversely, functional overexpression of FATP1 decreased many aspects of glucose metabolism and diminished CAM-stimulated inflammation in vitro. FATP1 displayed acyl-CoA synthetase activity for long chain fatty acids in MΦs and modulated lipid mediator metabolism in MΦs. Conclusion: Our findings provide evidence that FATP1 is a novel regulator of MΦ activation through control of substrate metabolism. Absence of FATP1 exacerbated pro-inflammatory activation in vitro and increased local and systemic components of the metabolic syndrome in HFD-fed Fatp1B−/− mice. In contrast, gain of FATP1 activity in MΦs suggested that Fatp1-mediated activation of fatty acids, substrate switch to glucose, oxidative stress, and lipid mediator synthesis are potential mechanisms. We demonstrate for the first time that FATP1 provides a unique mechanism by which the inflammatory tone of adipose and systemic metabolism may be regulated. Keywords: Adipose tissue macrophage, M2 macrophage, Obesity, Glycolysis, Crown-like structures, Mitochondria

Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.

Machine learning techniques, along with imaging markers extracted from structural magnetic resonance images, have been shown to increase the accuracy to differentiate patients with Alzheimer's disease (AD) from normal elderly controls. Several forms of anatomical features, such as cortical volume, shape, and thickness, have demonstrated discriminative capability. These approaches rely on accurate non-linear image transformation, which could invite several nuisance factors, such as dependency on transformation parameters and the degree of anatomical abnormality, and an unpredictable influence of residual registration errors. In this study, we tested a simple method to extract disease-related anatomical features, which is suitable for initial stratification of the heterogeneous patient populations often encountered in clinical data. The method employed gray-level invariant features, which were extracted from linearly transformed images, to characterize AD-specific anatomical features. The intensity information from a disease-specific spatial masking, which was linearly registered to each patient, was used to capture the anatomical features. We implemented a two-step feature selection for anatomic recognition. First, a statistic-based feature selection was implemented to extract AD-related anatomical features while excluding non-significant features. Then, seven knowledge-based ROIs were used to capture the local discriminative powers of selected voxels within areas that were sensitive to AD or mild cognitive impairment (MCI). The discriminative capability of the proposed feature was measured by its performance in differentiating AD or MCI from normal elderly controls (NC) using a support vector machine. The statistic-based feature selection, together with the knowledge-based masks, provided a promising solution for capturing anatomical features of the brain efficiently. For the analysis of clinical populations, which are inherently heterogeneous, this approach could stratify the large amount of data rapidly and could be combined with more detailed subsequent analyses based on non-linear transformation.

The purpose of this study is to explore the changes in functional brain networks of AD patients using complex network theory. In this study, resting-state fMRI datasets of 10 AD patients and 11 healthy controls were collected. Time series of 90 brain regions were extracted from the fMRI datasets after preprocessing. Pearson correlation method was used to calculate the correlation coefficient between any two time series. Then, a wide threshold range was selected to transform the adjacency matrix to a binary matrix under a different threshold. The topology parameters of each binary network were calculated, and all of them were then averaged within a group. During the evolution, node betweenness and the Euclidean distance between the nodes were set as control factors. Each binary network of healthy controls underwent evolution of 100 steps in accordance with the evolution rules. Then, the topology parameters of the evolution network were calculated. Finally, support vector machine (SVM) was used to classify the network topology parameters of the evolution network and to determine whether evolution results matched the datasets from AD patients. We found there were differing degrees of decline in global efficiency, clustering coefficient, number of edges and transitivity in AD patients compared with healthy controls. The topology parameters of the evolution network tended toward those of the AD group. The results of SVM classification of the evolution network show that the evolution network had a greater probability to be classified as an AD patients group. A new biological marker for diagnosis of AD was provided through comparison of topology parameters between AD patients and healthy controls. The study of network evolution strategies enriched the method of brain network evolution. The use of SVM to classify the results of network evolution provides an objective criteria for determining evolution results.