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Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Cervical cancer remains a significant global public health concern, often exhibits cisplatin resistance in clinical settings. Hypoxia, a characteristic of cervical cancer, substantially contributes to cisplatin resistance. To evaluate the therapeutic efficacy of cisplatin in patients with cervical cancer and to identify potential effective drugs against cisplatin resistance, we established a hypoxia-inducible factor-1 (HIF-1)-related risk score (HRRS) model using clinical data from patients treated with cisplatin. Cox and LASSO regression analyses were used to stratify patient risks and prognosis. Through qRT-PCR, we validated nine potential prognostic HIF-1 genes that successfully predict cisplatin responsiveness in patients and cell lines. Subsequently, we identified fostamatinib, an FDA-approved spleen tyrosine kinase inhibitor, as a promising drug for targeting the HRRS-high group. We observed a positive correlation between the IC50 values of fostamatinib and HRRS in cervical cancer cell lines. Moreover, fostamatinib exhibited potent anticancer effects on high HRRS groups in vitro and in vivo. In summary, we developed a hypoxia-related gene signature that suggests cisplatin response prediction in cervical cancer and identified fostamatinib as a potential novel treatment approach for resistant cases.

Sustainable provision of lake ecosystem services is essential for maintaining regional, national, and even global ecological security patterns. Scholars have been conducting in-depth research on the concept, assessment models, impact mechanisms, trade-offs, and optimization of ecosystem services. Integrating management decisions and policy design still presents significant challenges in various aspects. It is necessary to design a spatial security pattern and develop a hierarchical and classified control and protection system. This study establishes an assessment system of the ecosystem service values of Chinese lakes using meta-analysis and evaluates the spatial distribution of ecosystem services. We propose a method to build the protection security patterns of Chinese lakes based on the value of lake ecosystem services and the degree of human threats and establish a framework for evaluating the protection levels of lake ecosystems. Based on the dominant ecological functions, this study further determines the distribution of low, medium, and high-level security patterns in each lake region. Lakes within a low-level security pattern mean that higher protection levels are needed. In different ecological security patterns, this study proposes to determine the management indicators and monitoring intensity based on the ecological function types and human pressure threat levels of each lake region, to promote the improvement and healthy development of lake ecosystems. This study assesses the ecosystem service values of lakes as an entry point and establishes a framework for evaluating the protection level of lake ecosystems considering their human threat levels. The evaluation framework helps establish a hierarchical and classified control and protection system, which is of positive significance to the scientific, quantitative assessment, and standardization of territorial spatial planning processes.

ObjectivePrevious studies have found that patients with Major Depressive Disorder (MDD) exhibit impaired visual motion perception capabilities, and multi-level abnormalities in the human middle temporal complex (MT+), a key brain area for processing visual motion information. However, the brain activity pattern of MDD patients during the perception of visual motion information is currently unclear. In order to study the effect of depression on the activity and functional connectivity (FC) of MT+ during the perception of visual motion information, we conducted a study combining task-state fMRI and psychophysical paradigm to compare MDD patients and healthy control (HC).MethodsDuration threshold was examined through a visual motion perception psychophysical experiment. In addition, a classic block-design grating motion task was utilized for fMRI scanning of 24 MDD patients and 25 HC. The grating moved randomly in one of eight directions. We examined the neural activation under visual stimulation conditions compared to the baseline and FC.ResultsCompared to HC group, MDD patients exhibited increased duration threshold. During the task, MDD patients showed decreased beta value and percent signal change in left and right MT+. In the sample comprising MDD and HC, there was a significant negative correlation between beta value in right MT+ and duration threshold. And in MDD group, activation in MT+ were significantly correlated with retardation score. Notably, no such differences in activation were observed in primary visual cortex (V1). Furthermore, when left MT+ served as the seed region, compared to the HC, MDD group showed increased FC with right calcarine fissure and surrounding cortex and decreased FC with left precuneus.ConclusionOverall, the findings of this study highlight that the visual motion perception function impairment in MDD patients relates to abnormal activation patterns in MT+, and task-related activity are significantly connected to the retardation symptoms of the disease. This not only provides insights into the potential neurobiological mechanisms behind visual motion perception disorder in MDD patients from the aspect of task-related brain activity, but also supports the importance of MT+ as a candidate biomarker region for MDD.

Objective: To evaluate the antiobesity effect and underlying mechanism of Andrias davidianus peptide (ADP) supplementation combined with treadmill exercise. Methods: A mouse model of obesity was established by feeding mice a high-fat diet (HFD), and the obese mice were randomly divided into four groups: model, treadmill exercise (Ex), ADP and ADP combined with treadmill exercise (ADP + Ex). The rats in the Ex group were subjected to a six-week treadmill exercise training. The rates in the ADP group were gavaged with ADP for six weeks. The rats in the ADP + Ex group were treated with ADP supplementation combined with treadmill exercise training. Normal Sprague Dawley (SD) rats were used as the control (CN) group. Body mass and food intake were recorded each week, and the serum levels of glucagon-like peptide-1 (GLP-1), neuropeptide Y (NPY), irisin, leptin, triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) were investigated by enzyme-linked immunosorbent assay (ELISA). Western blot was used to detect the expression of appetite-regulated proteins (NPY and proopiomelanocortin (POMC)) and energy metabolism-related proteins. Results: Body mass, inguinal and epididymal fat accumulation, food intake, and serum TG, TC and LDL levels significantly decreased in the ADP + Ex group compared with the model group. In addition, ELISA results revealed that combination of ADP supplementation with treadmill exercise reduced the serum levels of NPY and leptin but increased the serum concentrations of GLP-1 and irisin in obese rats. Western blot analysis showed that ADP supplementation combined with treadmill exercise greatly up-regulated the expression of POMC and energy metabolism related proteins (irisin, phospho-adenosine monophosphate-activated protein kinase, peroxisome proliferator-activated receptor γ co-activated factor-1α, and fibronectin type III domain containing protein 5), but down-regulated the expression of NPY. Conclusion: The combination of ADP with aerobic exercise can effectively alleviate HFD-induced obesity, thereby providing a new promising strategy to alleviate HFD-induced obesity.

Sacral sore is a common problem in patients with spinal cord injury. It leads to prolonged hospitalization and recurrent infections which might require repeated surgery to treat. Flap reconstruction allows soft tissue coverage of sacral sore under the premise of infection-free wound base. Maggot debridement therapy (MDT) has been described as an alternative non-surgical management as opposed to the traditional surgical debridement in case of infected sore, reducing number of surgeries under anaesthesia. However, MDT and surgery are not mutually exclusive. In this article we describe a hybrid approach combining MDT and flap reconstruction with multi-disciplinary effort in management of sacral sore, which accelerates wound healing and prevents morbidities, while lowering the risks associated with repeated surgical debridement at the same time.

Abstract Deficit schizophrenia (DS) is a subtype of schizophrenia (SCZ). The polygenic effects on the neuroimaging alterations in DS still remain unknown. This study aims to calculate the polygenic risk scores for schizophrenia (PRS-SCZ) in DS, and further explores the potential associations with functional features of brain. PRS-SCZ was calculated according to the Whole Exome sequencing and Genome-wide association studies (GWAS). Resting-state fMRI, as well as biochemical features and neurocognitive data were obtained from 33 DS, 47 NDS and 41 HCs, and association studies of genetic risk with neuroimaging were performed in this sample. The analyses of amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and functional connectivity (FC) were performed to detect the functional alterations between DS and NDS. In addition, correlation analysis was used to investigate the relationships between functional features (ALFF, ReHo, FC) and PRS-SCZ. The PRS-SCZ of DS was significantly lower than that in NDS and HC. Compared to NDS, there was a significant increase in the ALFF of left inferior temporal gyrus (ITG.L) and left inferior frontal gyrus (IFG.L) and a significant decrease in the ALFF of right precuneus (PCUN.R) and ReHo of right middle frontal gyrus (MFG.R) in DS. FCs were widely changed between DS and NDS, mainly concentrated in default mode network, including ITG, PCUN and angular gyrus (ANG). Correlation analysis revealed that the ALFF of left ITG, the ReHo of right middle frontal gyrus, the FC value between insula and ANG, left ITG and right corpus callosum, left ITG and right PCUN, as well as the scores of Trail Making Test-B, were associated with PRS-SCZ in DS. The present study demonstrated the differential polygenic effects on functional changes of brain in DS and NDS, providing a potential neuroimaging-genetic perspective for the pathogenesis of schizophrenia.

Abstract The shotgun proteomic analysis is currently the most promising single-cell protein sequencing technology, however its identification level of ~1000 proteins per cell is still insufficient for practical applications. Here, we develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep identification capable of quantifying up to 3000 protein groups in a mammalian cell using the label-free quantitative method. The PiSPA workflow is specially established for single-cell samples mainly based on a nanoliter-scale microfluidic liquid handling robot, capable of achieving single-cell capture, pretreatment and injection under the pick-up operation strategy. Using this customized workflow with remarkable improvement in protein identification, 2449–3500, 2278–3257 and 1621–2904 protein groups are quantified in single A549 cells (n = 37), HeLa cells (n = 44) and U2OS cells (n = 27) under the DIA (MBR) mode, respectively. Benefiting from the flexible cell picking-up ability, we study HeLa cell migration at the single cell proteome level, demonstrating the potential in practical biological research from single-cell insight.

ObjectiveThe aim of this study was to explore the risk factors for different metabolic status in patients with schizophrenia.MethodsA total of 968 hospitalized patients with schizophrenia were recruited. Fasting blood glucose (GLU) and lipid profile, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) were measured. Schizophrenia patients were divided into four groups: normal metabolism and weight (NMNW), abnormal metabolism and normal weight (AMNW), normal metabolism and overweight/obesity (NMO), and abnormal metabolism and overweight/obesity (AMO).ResultsOur results showed that NMNW, AMNW, NMO, and AMO accounted for 25.3%, 12.7%, 25.4%, and 36.6%, respectively. There were significant differences in age, disease duration, body mass index (BMI), waist circumference, chronic disease, systolic blood pressure (SBP), diastolic blood pressure (DBP), GLU, TG, TC, HDL-C, and LDL-C among these four groups (all p < 0.05). With the NMNW group as the reference, the disordered multiple classification regression analysis showed that chronic disease was a significant risk factor for AMNW (OR = 5.271, 95% CI = 3.165 to 8.780, p < 0.001) and AMO (OR = 3.245, 95% CI = 2.004 to 5.254, p < 0.001), age was an important protective factor for NMO (OR = 0.968, 95% CI = 0.943 to 0.994, p = 0.015) and AMO (OR = 0.973, 95% CI = 0.948 to 0.999, p < 0.042), waist circumference was a significant risk factor for NMO (OR = 1.218, 95% CI = 1.180 to 1.257, p < 0.001) and AMO (OR = 1.252, 95% CI = 1.212 to 1.291, p < 0.001), and college education was an obvious protective factor for AMO (OR = 0.343, 95% CI = 0.123 to 0.953, p < 0.040) among patients with schizophrenia.ConclusionThe findings of our study underscored the importance of factors such as age, education level, chronic disease, and waist circumference when exploring the influencing factors and biological mechanisms of obesity-related metabolic problems in schizophrenia patients.

In-depth analysis of asteroid samples will provide a key scientific basis for understanding its evolution history, resource utilization, and life origin. Obtaining rock samples from asteroids is getting more and more attention. However, successful sampling in asteroid is difficult due to extremely complex environmental conditions. In this paper, the dynamic processes of rock failure by sampling device are investigated by a continuum-discontinuum element method (CDEM) to instruct the rock sampling in asteroid. The deformation and failure of rock samples under different conditions (impact speeds, impact positions, rock cut-slot numbers, cut-slot spacings, cut-slot depths and cut-slot widths, etc.) are analyzed, and the relationships between the rock failure and hammer impact method are obtained. The results show that the cut-slot formed by grinding wheel increases the free surface of rock sample, which is beneficial to impact fracture and asteroid sampling. The relative distance between cut-slot free surface and impact position significantly affects the rock fracture under impact loading. The fracture degree of rock with single cut-slot is obviously smaller than that of rock with double cut-slots, the cut-slot scheme of double grinding wheels is more suitable for asteroid sampling. Under the impact loading, the rock fracture is negatively correlated with the cut-slot spacing formed by double grinding wheel cutting, the effective spacing of double cut-slots is 12 mm. The fracture unit number of rock varies nonlinearly with an increase of the depth from impact position, there is an optimal cut-slot depth corresponding to a certain impact velocity, and the rock crushing efficiency of asteroid sampling can be improved as the cut-slot depth matches the crack propagation depth.

Background: The Calcium-sensing receptor (CaSR) participates in the regulation of gastrointestinal (GI) motility under normal conditions and might be involved in the regulation of GI dysmotility in patients with Parkinson's disease (PD). Methods: CaSR antagonist-NPS-2143 was applied in in vivo and ex vivo experiments to study the effect and underlying mechanisms of CaSR inhibition on GI dysmotility in the MPTP-induced PD mouse model. Findings: Oral intake of NPS-2143 promoted GI motility in PD mice as shown by the increased gastric emptying rate and shortened whole gut transit time together with improved weight and water content in the feces of PD mice, and the lack of influence on normal mice. Meanwhile, the number of cholinergic neurons, the proportion of serotonergic neurons, as well as the levels of acetylcholine and serotonin increased, but the numbers of nitrergic and tyrosine hydroxylase immunoreactive neurons, and the levels of nitric oxide synthase and dopamine decreased in the myenteric plexus in the gastric antrum and colon of PD mice in response to NPS-2143 treatment. Furthermore, the numbers of c-fos positive neurons in the nucleus tractus solitarius (NTS) and cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) increased in NPS-2143 treated PD mice, suggesting the involvement of both the enteric (ENS) and central (CNS) nervous systems. However, ex vivo results showed that NPS-2143 directly inhibited the contractility of antral and colonic strips in PD mice via a non-ENS mediated mechanism. Further studies revealed that NPS-2143 directly inhibited the voltage gated Ca2+ channels, which might, at least in part, explain its direct inhibitory effects on the GI muscle strips. Interpretation: CaSR inhibition by its antagonist ameliorated GI dysmotility in PD mice via coordinated neuronal regulation by both ENS and CNS in vivo, although the direct effects of CaSR inhibition on GI muscle strips were suppressive.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.