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Objective To investigate the impact of human leukocyte antigen (HLA) functional epitope mismatch (EM) on the efficacy of platelet transfusion in patients with hematological diseases. Methods HLA genotyping was performed on platelet donors and patients with hematological diseases who applied for platelet serological cross-matching and HLA antigen matching from June 2021 to June 2023 by PCR-SBT method. HLA platelet matching was based on the principle of CREG to select donors for patients. HLA Matchmaker 4.0 software was used to analyze donor-recipient HLA EM information. The expression level and gene distribution of related HLA functional epitope (Eplet) were searched from the international HLA Epitope registry website (www.Epregistry.com.br). Retrospective analysis was conducted on clinical platelet transfusion data to evaluate the impact of HLA EM on platelet transfusion effectiveness. Results Platelet transfusion efficacy showed no correlation with gender and age, but it was associated with platelet matching strategy. When the total number of HLA EMs was less than 20, a lower total number of donor-recipient HLA EMs resulted in higher platelet transfusion efficiency (χ2=19.311, P=0.001) and higher average value of 24 h corrected count increment (CCI)(F=7.737, P

Abstract Coronavirus disease 2019 (COVID‐19) pandemic has caused millions of deaths. The risk of COVID‐19 spreading still exists after the deconfinement act, Omicron became the dominant variant. Although N6‐methyladenosine (m6A) regulators has been reported to affect the pathogenicity of COVID‐19, their mechanism in the progression of lung injury in COVID‐19 patients remain elusive. Here we show the landscape and specific mechanisms of m6A regulators in lung tissues through single‐nucleus RNA sequencing (snRNA‐Seq) data sets of 116,252 cells, and the external validation was performed using data from another snRNA‐Seq data. The m6A reader IGF2BP2 was specifically upregulated in alveolar type I (AT1) cells, resulting in impaired lung regeneration. ALKBH5 expression upregulation in macrophages, impairing immune responses. Moreover, WTAP markedly upregulated in fibroblasts, leading to pulmonary fibrosis. In addition, m6A regulators dysregulation induced aberrant cell–cell communication in pulmonary tissue and mediated ligand–receptor interactions across diverse cell types in lung tissues by activating the TGF‐β signaling pathway. Overall, these results indicated that the upregulation of m6A regulators in alveolar cells, myeloid cells, and fibroblasts may induce pulmonary injury in patients. The development of m6A‐regulator inhibitors could be as one potential antifibrotic drugs for COVID‐19.

Abstract Background The diagnosis of primary small intestinal lymphoma (PSIL) is difficult. This study aimed to evaluate the clinical, radiological and endoscopic characteristics of PSIL and provide clue for diagnosis. Methods A total of 30 patients diagnosed with PSIL who underwent double balloon endoscopy (DBE) in the First Affiliated Hospital of Zhejiang University were retrospectively analyzed. Clinical, radiological and endoscopic data were collected. Univariate analysis was used to determine significant indicators for differentiating three main subtypes of PSIL. Cox regression analysis was performed to assess the risk factors for survival. Results In this study, 10 patients were pathologically diagnosed as diffuse large B-cell lymphoma (DLBCL), 11 were indolent B-cell lymphoma (BCL) and 9 were T-cell lymphoma (TCL). Compared with DLBCL patients, the body mass index (BMI) of TCL patients was significantly lower (p = 0.004). Meanwhile, compared with patients with DLBCL, the patients with indolent BCL had lower levels of C-reactive protein, lactate dehydrogenase (LDH), fibrinogen and D-Dimer (p = 0.004, p = 0.004, p = 0.006, and p = 0.002, respectively), and lower proportion of thicker intestinal wall and aneurysmal dilation in CT scan (p = 0.003 and p = 0.020, respectively). In terms of ulcer morphology, patients with DLBCL had significantly higher proportion of deep ulcers than patients with indolent BCL (p = 0.020, respectively). Cox regression analysis showed that drink (p = 0.034), concomitant colonic ulcers (p = 0.034) and elevated LDH (p = 0.043) are risk factors for mortality in patients with PSIL. Conclusions This study provides clinical characteristics of patients with PSIL. Thicker intestinal wall and aneurismal dilation detected on CT scan and deeper ulcer on DBE examination helps to establish a diagnosis of DLBCL.

Depression is a prevalent psychiatric disorder with accumulating evidence implicating dysregulation of extracellular adenosine triphosphate (ATP) levels in the medial prefrontal cortex (mPFC). It remains unclear whether facilitating endogenous ATP production and subsequently increasing extracellular ATP level in the mPFC can exert a prophylactic effect against chronic social defeat stress (CSDS)-induced depressive-like behaviors and enhance stress resilience. Here, we found that nicotinamide mononucleotide (NMN) treatment effectively elevated nicotinamide adenine dinucleotide (NAD+) biosynthesis and extracellular ATP levels in the mPFC. Moreover, both the 2-week intraperitoneal (i.p.) injection and 3-week oral gavage of NMN prior to exposure to CSDS effectively prevented the development of depressive-like behavior in mice. These protective effects were accompanied with the preservation of both NAD+ biosynthesis and extracellular ATP level in the mPFC. Furthermore, catalyzing ATP hydrolysis by mPFC injection of the ATPase apyrase negated the prophylactic effects of NMN on CSDS-induced depressive-like behaviors. Prophylactic NMN treatment also prevented the reduction in GABAergic inhibition and the increase in excitability in mPFC neurons projecting to the lateral habenula (LHb). Collectively, these findings demonstrate that the prophylactic effects of NMN on depressive-like behaviors are mediated by preventing extracellular ATP loss in the mPFC, which highlights the potential of NMN supplementation as a novel approach for protecting and preventing stress-induced depression in susceptible individuals.

In this paper, a new flexible stab-resistant composite material was prepared by growing ZnO nanowires on aramid plain fabric by the hydrothermal method. Through SEM, FTIR, and XRD characterization, it is proved that ZnO nanowires have been grown on aramid fabric and the surfaces of aramid filaments become much rougher. Moreover, the inter-filament friction and breaking strength of aramid fabric with nanowires are increased significantly, especially the inter-filament friction, which has been increased by more than 4 times after ZnO nanowires growth. Stab tests were conducted on the bare aramid fabric sample and aramid fabric sample with ZnO nanowires based on the test standard of GA 68–2019. Both of the two samples are 43 layers and are subject to 5 stabs of D1 knife, 3 stabs of D2 knife and 3 stabs of D3 knife. The stab resistance of aramid fabric grown with nanowires is significantly enhanced, and the average penetration depth under the D1 knife impact is decreased by 49.7%. The reason may be that the inter-filament friction increases dramatically with the nanowires and thus the friction energy consumption increases. The flexibility test results show that the softness characteristics of the single aramid fabric and the 43-layer fabric with the nanowires are still maintained. In addition, although the growth of nanowires will lead to smaller voids and a decrease of air permeability of the fabric, the moisture permeability has been slightly improved because ZnO nanowires have the ability to bind with water.

PURPOSEThe aim of this meta-analysis is to summarize the diagnostic accuracies of point shear wave elas- tography (pSWE) and two-dimensional (2D) SWE for esophageal varices (EV) and varices needing treatment (VNT).METHODSWe conducted a systematic review and meta-analysis of diagnostic accuracy studies. We searched for studies reporting the EV and VNT diagnostic accuracy of pSWE and 2D SWE using PubMed Cen- tral, SCOPUS, MEDLINE, Embase, and Cochrane databases. STATA software“Midas”package was used for meta-analysis.RESULTSA total of 24 studies with 3867 patients were included in the review. Pooled score sensitivities of pSWE were 91% (95% CI, 80%-96%) for EV, and 94% (95% CI, 86%-97%) for VNT. Pooled score sensi- tivities of 2D SWE were 78% (95% CI, 69%-85%) for EV, and 79% (95% CI, 72%-85%) for VNT. Pooled score specificities of pSWE were 70% (95% CI, 60%-78%) for EV, and 59% (95% CI, 40%-75%) for VNT. Pooled score specificities of 2D SWE for EV were 79% (95% CI, 72%-85%) 72% (95% CI, 66%-77%) for VNT. We found significant heterogeneity for all the elastography-based measurements with the chi- square test results and an I2 statistic >75%.CONCLUSIONBoth pSWE and 2D SWE can diagnose EV and VNT with moderate diagnostic accuracy. Further large- scale setting-specific longitudinal studies are required to establish the best modality.

Abstract Background It is widely accepted that there exist microbiota communities in urinary tract of healthy individuals. Imbalance in the urinary microbiome plays important roles in the development of various benign urological conditions including lower urinary track symptoms (LUTS) and overactive bladder (OAB). However, whether alteration in urinary microbiome exerts influence on the severity of OAB symptom has yet to be elucidated. The purpose of this study is to examine the correlation between urinary microbiome and the severity of OAB. Methods A total of 70 OAB patients were recruited to finish overactive bladder symptom score (OABSS) questionnaires. Catheterized urine samples were obtained for 16S rRNA gene sequencing. The species richness and evenness were evaluated by α diversity, and the difference in urinary microbiome between patients with mild or moderate/severe severity was evaluated by β diversity. The relationship between urinary microbiome and the severity of OAB symptom was evaluated using Pearson’s correlation analysis. Results Mild patients (OABSS ≤ 5, n = 17) had lower bacterial diversity (Simpson index, P = 0.024) and richness (Chao1, P = 0.023) than those with moderate/severe symptom (OABSS > 5, n = 53). Beta-diversity of urinary microbiome between two groups were significantly different. Furthermore, the score of OABSS was positively correlated with the richness index (Chao1, P = 0.002) and diversity index (Shannon index, P = 0.044) of urinary microbiome. Certain bacterial genera (e.g., Porphyromona and Prevotella) were significantly correlated with severity of OAB sub-symptoms. Conclusion This study demonstrated that urinary microbiome was intimately correlated with the severity of OAB symptom and the increase of the diversity and richness of urinary microbiome was accompanied by more severe OAB symptoms, indicating that urinary dysbiosis may play pivotal roles in the deterioration of functional bladder diseases.

Abstract Background Urogenital microbiota may be associated with the recurrence of bladder cancer, but the underlying mechanism remains unclear. The notion that microbiota can upregulate PD-L1 expression in certain epithelial tumors to promote immune escape has been demonstrated. Thus, we hypothesized that the urogenital microbiota may be involved in the recurrence and progression of non-muscle invasive bladder cancer (NMIBC) by upregulating the PD-L1 expression. To test this hypothesis, we investigated the relationship between urogenital microbial community and PD-L1 expression in male patients with NMIBC. Results 16S rRNA gene sequencing was performed to analyse the composition of urogenital microbiota, and the expression of PD-L1 in cancerous tissues was detected by immunohistochemistry. The subjects (aged 43–79 years) were divided into PD-L1-positive group (Group P, n = 9) and PD-L1-negative group (Group N, n = 19) respectively based on their PD-L1 immunohistochemical results. No statistically significant differences were found in the demographic characteristics between group P and N. We observed that group P exhibited higher species richness (based on Observed species and Ace index, both P < 0.05). Furthermore, subgroup analysis showed that the increase in number of PD-L1 positive cells was accompanied by increased richness of urogenital microbiota. Significantly different composition of urogenital microbiota was found between group P and group N (based on weighted Unifrac and unweighted Unifrac distances metric, both P < 0.05). Enrichment of some bacterial genera (e.g., Leptotrichia, Roseomonas, and Propionibacterium) and decrease of some bacterial genera (e.g., Prevotella and Massilia) were observed in group P as compared with group N. These findings indicated that these genera may affect the expression of PD-L1 through some mechanisms to be studied. Conclusion Our study provided for the first time an overview of the association between urogenital microbiota and PD-L1 expression in male patients with NMIBC, indicating that urogenital microbiota was an important determinant of PD-L1 expression in male NMIBC patients.

The interpretation of the variability and determinants of erythrocyte oxygenation is complicated by multiple interacting factors manifesting gaseous and fluidic microenvironments during microcirculation. In this paper, a multifunctional microdevice was developed for quantitatively extracting the dominant role of RBC concentration, local oxygen (O2), and fluid dynamics in an ex vivo setting. Serial dilution of RBCs was achieved by repeated splitting and mixing of the source RBC suspension solutions in the bifurcating serpentine microchannels. O2 perfusion of buried microchannels in a gas-permeable polydimethylsiloxane membrane allowed for exposing RBCs to a spatial linear O2 gradient along with the blood flow direction. Taking the variability in the optically relevant properties of erythrocytes and their oxygenation status, an optical-fiber-based measurement system was integrated with the microfluidic device to capture the characteristic spectroscopic features of RBCs covering the visible to near-infrared range. The spectroscopic analysis provided a linear regression model of oxygen saturation with variables containing RBC concentrations, O2 levels, and blood flow velocity, which agreed well with numerical simulation results. This systematic experimental approach could be applicable as an in vitro microcirculatory model system while adding a dimension to a wide range of blood processing and analysis.

Abstract Background Cytomegalovirus (CMV) infection can significantly complicate and worsen the condition of acute severe ulcerative colitis (UC) patients. We aimed to explore the predictive risk factors to prevent and identify CMV infection at an early stage in acute UC patients. Methods A total of 115 moderate-to-severe active UC patients from 17 hospitals throughout China were enrolled. Active CMV infection was diagnosed by one of the following: CMV pp65 antigens, CMV IgM antibodies or CMV DNA. We identified the independent risk factors by multivariate analyses. Results A total of 64 of 115 active UC patients had active CMV infection. Compared to the non-CMV-infected patients, the CMV-infected patients had a tendency to be male and to exhibit abdominal pain; fever; oral ulcers; eosinopenia; low albumin, immunoglobulin (Ig) A, IgM, and IgG levels; increased high-sensitivity C-reactive protein (hsCRP) levels; hyponatremia; pancolonic lesions; initial onset type; severe activity; and glucocorticoid (high-dose) and immunosuppressive agent use (P

Helicobacter pylori (H. pylori) is proved to be the main pathogenic agent of various diseases, including chronic gastritis, gastric ulcer, duodenal ulcer, and gastric cancer. In addition, chronic cholecystitis and cholelithiasis are common worldwide, which are supposed to increase the total mortality of patients. Epidemiologic evidence on the relationship between H. pylori infection of the gallbladder and chronic cholecystitis/cholelithiasis still remains unclear. We conducted a systematic review and meta-analysis of overall studies to investigate the relationship between H. pylori infection of the gallbladder and chronic cholecystitis/cholelithiasis. Two researchers searched PubMed, Embase, and Cochrane Library databases to obtain all related and eligible studies published before July 2020. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by the random-effects model. Subgroup analysis, heterogeneity, publication bias, and sensitivity analysis were also conducted. Twenty studies were included in the meta-analysis, involving 1735 participants and 1197 patients with chronic cholecystitis/cholelithiasis. Helicobacter species infection of the gallbladder was positively correlated with increased risk of chronic cholecystitis and cholelithiasis, especially H. pylori (OR = 3.05; 95% CI, 1.81–5.14; I2 = 23.5%). Besides, country-based subgroup analysis also showed a positive correlation between the gallbladder H. pylori positivity and chronic cholecystitis/cholelithiasis risk. For Asian and non-Asian country studies, the ORs were 4.30 (95% CI, 1.76–10.50; I2 = 37.4%) and 2.13 (95% CI, 1.23–3.70; I2 = 0.0%), respectively. The association was more obvious using the bile sample and urease gene primer. In conclusion, this meta-analysis provided evidence that there is a positive correlation between H. pylori infection in the gallbladder and increased risk of chronic cholecystitis and cholelithiasis.

Numerous studies indicate that resident microbiome exists in urine of healthy individuals and dysbiosis of the urobiome (urinary microbiome) may be associated with pathological conditions. This study was performed to characterize the alterations in urobiome and explore its implications of clinical outcome in male patients with bladder cancer. 62 male patients with bladder cancer and 19 non-neoplastic controls were recruited. The follow-up study cohort included 40 patients who were diagnosed with non-muscle invasive bladder cancer (NMIBC) and underwent transurethral resection of bladder tumor (TURBT). Mid-stream urine samples were collected from all the participants the day before cystoscopy. DNA was extracted from urine pellet samples and processed for high throughput 16S rRNA amplicon sequencing of the V4 region using Illumina MiSeq. Sequencing reads were filtered using QIIME and clustered using UPARSE. We found bacterial richness indices (Observed Species index, Chao1 index, Ace index; all P < 0.01) increased in cancer group when compared with non-neoplastic group, while there were no differences in Shannon and Simpson index between two groups. During a median follow-up time of 12 (5.25–25) months, 5/40 (12.5%)of the patients developed recurrence and no patient suffered from progression to muscle-invasive disease. Species diversity of the microbiome was significantly higher in the recurrence group compared with non-recurrence group in patients with NMIBC after TURBT. The LEfSe analysis demonstrated that 9 genera were increased (e.g., Micrococcus and Brachybacterium) in recurrence group. To our knowledge we report the relative comprehensive study to date of the male bladder cancer urinary microbiome and its relationship to pathogenesis and clinical outcomes. Given our preliminary data, additional studies evaluating the urine microbiome in relation to clinical outcomes are warranted to improve our understanding of tumor recurrence after TURBT.

OBJECTIVES: Anemia and changes in platelets (PLT) are common in inflammatory bowel disease (IBD). In our study, we aimed to verify whether PLT count can independently reflect the severity of IBD. METHODS: In our hospital, 137 Crohn’s Disease (CD), 69 Ulcerative colitis (UC) patients, and 412 healthy controls were included to compare the differences in PLT count. In addition, the effect of anemia, C-reactive protein (CRP), age, CD activity index (CDAI) or Mayo on PLTs was also analyzed. If PLTs independently affected CD or UC, we used the receiver operating characteristic (ROC) curve to verify the diagnostic value and obtain the cut-off value of PLT. RESULTS: CD and UC patients had higher PLT than controls (p

Objective Intestinal permeability increases during the course of acute pancreatitis (AP). We assessed duodenal permeability alterations in patients with AP by confocal laser endomicroscopy (CLE). Methods Thirty patients with AP underwent CLE evaluation of the antral and duodenal mucosa. Images were graded based on the appearance of capillaries and the degree of fluorescein leakage. Results Patients with AP had increased duodenal mucosal permeability that could be detected by CLE. The mucosal permeability progressively increased in the gastric antrum, duodenal bulb, and descending duodenum. The CLE parameters in the antrum and duodenal bulb were not significantly different between patients with mild and severe AP. The CLE grades in the descending duodenum were higher in patients with severe than mild AP. The C-reactive protein level in AP was positively correlated with the permeability in the duodenal bulb and descending duodenum, while the computed tomography severity index score was positively correlated with the mucosal permeability in the duodenal bulb and descending duodenum. Conclusion CLE revealed increased duodenal permeability in patients with AP. Higher permeability in the descending duodenum was observed in severe than mild AP. Further large-scale studies are needed to confirm the relationship between altered duodenal permeability and the severity of AP.

We aim to examine the negative (relationship conflict) and positive (in-role job performance) outcomes of employees’ innovative behavior and explore the moderation effect of employees’ goal content and supervisors’ achievement goal orientation in these relationships. Data from 218 employees and their immediate supervisors were collected in companies in China and results show that employees’ innovative behaviors are positively related to their relationship conflict and in-role job performance, and employees’ extrinsic goals and supervisors’ performance goal moderate these relationships. Specifically, employees’ innovative behaviors were significantly and positively related to relationship conflict when either employees have high extrinsic goals or supervisor have high performance goals or both; and when supervisor have low level of performance goals, employees’ innovative behaviors were significantly and positively related to their in-role job performance. We contribute in showing when there are positive and negative outcomes of employees’ innovative behaviors and document the effect of moderating factors that may strengthen these benefits and lower the conflicts.

Broad-spectrum drugs appear to be more promising for the treatment of acute ischemic stroke. In our previous work, a new ligustrazine derivative (3,5,6-trimethylpyrazin-2-yl) methyl 3-methoxy-4-[(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoate (T-VA) showed neuroprotective effect on injured PC12 cells (EC50 = 4.249 µM). In the current study, we show that this beneficial effect was due to the modulation of nuclear transcription factor-κB/p65 (NF-κB/p65) and cyclooxygenase-2 (COX-2) expressions. We also show that T-VA exhibited neuroprotective effect in a rat model of ischemic stroke with concomitant improvement of motor functions. We propose that the protective effect observed in vivo is owing to increased vascular endothelial growth factor (VEGF) expression, decreased oxidative stress, and up-regulation of Ca2+–Mg2+ ATP enzyme activity. Altogether, our results warrant further studies on the utility of T-VA for the potential treatment of ischemic brain injuries, such as stroke.

A series of novel ligustrazine-benzoic acid derivatives were synthesized and evaluated for their protective effect against cobalt chloride-induced neurotoxicity in differentiated PC12 cells. Combining hematoxylin and eosin staining, we found compound that (3,5,6-trimethylpyrazin-2-yl)methyl 3-methoxy-4-[(3,5,6-trimethylpyrazin-2-yl)methoxy]benzoate (4a) displayed promising protective effect on the proliferation of the injured PC12 cells (EC50 = 4.249 µM). Structure-activity relationships are briefly discussed.

BACKGROUND AND STUDY AIMS: Chronic abdominal pain is one of the most common chief complaints, but the underlying pathophysiology often remains unknown after routine clinical evaluation. Capsule endoscopy (CE) is a new technique for the visualization of the entire small bowel. The aim of this study was to evaluate the diagnostic efficacy of CE in patients with chronic abdominal pain of obscure origin. PATIENTS AND METHODS: Two hundred forty three patients with chronic abdominal pain with no significant lesions were enrolled in this study. CE was performed in all patients. RESULTS: A diagnosis was made in 23.0% of patients screened with CE. Of the 243 patients, 19 (7.8%) were diagnosed with Crohn's disease, 15 (6.2%) with enteritis, 11 (4.5%) with idiopathic intestinal lymphangiectasia, 5 (2.1%) with uncinariasis, and a number of other diagnoses including small bowel tumor, ascariasis, and anaphylactoid purpura. Five patients had abnormal transit time, and capsule retention occurred in two patients. CONCLUSIONS: In contrast to other previous studies, we found that CE is an effective diagnostic tool for patients with abdominal pain.

The authors wish to change the first author’s name “Guoling Li” to “Guoliang Li” on the Page of their paper published in the International Journal of Molecular Sciences [1]. [...]

Abstract Background Associations between perceived and actual risk of HIV infection and HIV prevention services uptake are inconclusive. This study aimed to evaluate the discrepancy between the perceived and actual HIV risk, and quantify the associations between perceived and actual risk of HIV infection and three HIV prevention services utilization among men who have sex with men (MSM) in Shandong province, China. Methods A cross-sectional study was conducted in Shandong province in June 2021. Participants were eligible if they were born biologically male, aged 18 years or older, had negative or unknown HIV status, and had sex with men in the past year. Participants were recruited online. The discrepancy between their perceived and actual risk of HIV infection was evaluated by calculating the Kappa value. Bayesian model averaging was used to assess the associations between perceived and actual risk of HIV infection and HIV prevention services uptake. Results A total of 1136 MSM were recruited, most of them were 30 years old or younger (59.9%), single (79.5%), with at least college education level (74.7%). Most participants (97.4%) perceived that they had low risk of HIV infection, and 14.1% were assessed with high actual risk. The discrepancy between their perceived and actual risk of HIV infection was evaluated with a Kappa value of 0.076 (P

Summary: Background: Tissue-specific analysis of the transcriptome is critical to elucidating the molecular basis of complex traits, but central tissues are often not accessible. We propose a methodology, Multi-mOdal-based framework to bridge the Transcriptome between PEripheral and Central tissues (MOTPEC). Methods: Multi-modal regulatory elements in peripheral blood are incorporated as features for gene expression prediction in 48 central tissues. To demonstrate the utility, we apply it to the identification of BMI-associated genes and compare the tissue-specific results with those derived directly from surrogate blood. Findings: MOTPEC models demonstrate superior performance compared with both baseline models in blood and existing models across the 48 central tissues. We identify a set of BMI-associated genes using the central tissue MOTPEC-predicted transcriptome data. The MOTPEC-based differential gene expression (DGE) analysis of BMI in the central tissues (including brain caudate basal ganglia and visceral omentum adipose tissue) identifies 378 genes overlapping the results from a TWAS of BMI, while only 162 overlapping genes are identified using gene expression in blood. Cellular perturbation analysis further supports the utility of MOTPEC for identifying trait-associated gene sets and narrowing the effect size divergence between peripheral blood and central tissues. Interpretation: The MOTPEC framework improves the gene expression prediction accuracy for central tissues and enhances the identification of tissue-specific trait-associated genes. Funding: This research is supported by the National Natural Science Foundation of China 82204118 (D.Z.), the seed funding of the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), the National Institutes of Health (NIH) Genomic Innovator Award R35HG010718 (E.R.G.), NIH/NHGRI R01HG011138 (E.R.G.), NIH/NIA R56AG068026 (E.R.G.), NIH Office of the Director U24OD035523 (E.R.G.), and NIH/NIGMS R01GM140287 (E.R.G.).