A physical wiring diagram for the human immune system.

The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes1. Despite their therapeutic potential2, our map of these surface interactions remains incomplete3,4. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention.

PHF2 regulates genome topology and DNA replication in neural stem cells via cohesin.

Cohesin plays a crucial role in the organization of topologically-associated domains (TADs), which influence gene expression and DNA replication timing. Whether epigenetic regulators may affect TADs via cohesin to mediate DNA replication remains elusive. Here, we discover that the histone demethylase PHF2 associates with RAD21, a core subunit of cohesin, to regulate DNA replication in mouse neural stem cells (NSC). PHF2 loss impairs DNA replication due to the activation of dormant replication origins in NSC. Notably, the PHF2/RAD21 co-bound genomic regions are characterized by CTCF enrichment and epigenomic features that resemble efficient, active replication origins, and can act as boundaries to separate adjacent domains. Accordingly, PHF2 loss weakens TADs and chromatin loops at the co-bound loci due to reduced RAD21 occupancy. The observed topological and DNA replication defects in PHF2 KO NSC support a cohesin-dependent mechanism. Furthermore, we demonstrate that the PHF2/RAD21 complex exerts little effect on gene regulation, and that PHF2's histone-demethylase activity is dispensable for normal DNA replication and proliferation of NSC. We propose that PHF2 may serve as a topological accessory to cohesin for cohesin localization to TADs and chromatin loops, where cohesin represses dormant replication origins directly or indirectly, to sustain DNA replication in NSC.

Molecular regulatory mechanisms of staminate strobilus development and dehiscence in Torreya grandis.

Gymnosperms are mostly dioecious, and their staminate strobili undergo a longer developmental period than those of angiosperms. However, the underlying molecular mechanisms remain unclear. This study aimed to identify key genes and pathways involved in staminate strobilus development and dehiscence in Torreya grandis. Through weighted gene co-expression network analysis (WGCNA), we identified fast elongation-related genes enriched in carbon metabolism and auxin signal transduction, whereas dehiscence-related genes were abundant in alpha-linolenic acid metabolism and the phenylpropanoid pathway. Based on WGCNA, we also identified PHYTOCHROME-INTERACTING FACTOR4 (TgPIF4) as a potential regulator for fast elongation of staminate strobilus and 2 WRKY proteins (TgWRKY3 and TgWRKY31) as potential regulators for staminate strobilus dehiscence. Multiple protein-DNA interaction analyses showed that TgPIF4 directly activates the expression of TRANSPORT INHIBITOR RESPONSE2 (TgTIR2) and NADP-MALIC ENZYME (TgNADP-ME). Overexpression of TgPIF4 significantly promoted staminate strobilus elongation by elevating auxin signal transduction and pyruvate content. TgWRKY3 and TgWRKY31 bind to the promoters of the lignin biosynthesis gene PHENYLALANINE AMMONIA-LYASE (TgPAL) and jasmonic acid metabolism gene JASMONATE O-METHYLTRANSFERASE (TgJMT), respectively, and directly activate their transcription. Overexpression of TgWRKY3 and TgWRKY31 in the staminate strobilus led to early dehiscence, accompanied by increased lignin and methyl jasmonate levels, respectively. Collectively, our findings offer a perspective for understanding the growth of staminate strobili in gymnosperms.

Unveiling the protective effects of BMSCs/anti-miR-124-3p exosomes on LPS-induced endometrial injury.

Researchers have reported that miR-124-3p is highly expressed in patients with chronic endometritis. However, the underlying mechanism of miR-124-3p in the development of endometritis remains unclear. This study constructed an in vitro endometrial cell injury model by treating HEECs with 2 µg/mL LPS for 48 h. Then, 1 mg/kg LPS was injected into both sides of the mouse uterus to construct an in vivo endometrial injury model. The expression of miR-124-3p in human endometrial epithelial cells (HEECs) was assessed using RT‒qPCR. Exosomes were separated from bone marrow-derived mesenchymal stem cells (BMSCs) and cocultured with HEECs. A dual-luciferase reporter assay was performed to confirm the relationship between miR-124-3p and DUSP6. The results indicated that LPS inhibited HEEC viability in a time- and dose-dependent manner. The miR-124-3p inhibitor reversed the LPS-induced apoptosis and inhibition of HEEC viability. In addition, miR-124-3p could be transferred from BMSCs to HEECs by exosomes. Exosomes were derived from BMSCs treated with an NC inhibitor (BMSCs/NC Exo) or miR-124-3p inhibitor (BMSCs/anti-miR-124-3p Exo). In addition, BMSCs/anti-miR-124-3p Exo abolished the LPS-induced inhibition of HEEC viability and proliferation by inducing HEEC apoptosis. Moreover, BMSCs/anti-miR-124-3p Exo alleviated the LPS-induced inflammation of HEECs by upregulating DUSP6 and downregulating p-p65 and p-ERK. Furthermore, in an LPS-induced in vivo endometrial injury model, BMSCs/anti-miR-124-3p Exo increased the expression level of DUSP6 and decreased the expression levels of p-p65 and p-ERK. BMSCs/anti-miR-124-3p Exo protected against LPS-induced endometrial damage in vitro and in vivo by upregulating DUSP6 and downregulating p-p65 and p-ERK1/2. This study showed that BMSCs/anti-miR-124-3p Exo might be a potential alternative for the treatment of endometritis.

Enhanced nutrient supply promotes mutualistic interactions between cyanobacteria and bacteria in oligotrophic ocean.

Cyanobacteria can form complex interactions with heterotrophic microorganisms, but this relationship is susceptible to nutrient concentrations. Disentangling the cyanobacteria-bacteria interactions in relation to nutrient supply is essential to understanding their roles in geochemical cycles under global change. We hypothesize that enhanced nutrient supply in oligotrophic oceans can promote interactions among cyanobacteria and bacteria. Therefore, we investigated the planktonic bacteria and their interactions with cyanobacteria in relation to elevated nutrients caused by enhanced upwelling around a shallow and a deep seamount in the tropical western Pacific Ocean. We found obviously higher complexity of network occurred with significantly more cyanobacteria in the deep chlorophyll maximum layer of the shallow seamount when compared with that of the deep seamount. Cyanobacteria can shape bacterial interaction and community evenness in response to relatively high nutrient concentrations. The effects of the nutrients on cyanobacteria-related networks were further estimated based on the Tara Oceans data. Statistical analyses further showed a facilitative effect of nitrate concentrations on cyanobacteria-bacteria mutualistic interactions in the global oligotrophic ocean. By analysing the Tara Ocean macrogenomic data, we detected functional genes related to cyanobacteria-bacteria interactions in all samples, indicating the existence of a mutualistic relationship. Our results reveal cyanobacteria-bacteria interaction in response to nutrient elevation in oligotrophic ocean and highlight the potentially negative effects of global change on the bacterial community from the view of the bio-interaction.

Serum matrix metalloproteinase-7 for discriminating biliary atresia: a diagnostic accuracy and validation study.

BACKGROUND: Prompt and precise differential diagnosis of biliary atresia (BA) among cholestatic patients is of great importance. Matrix metalloproteinase-7 (MMP-7) holds great promise as a diagnostic marker for BA. This study aimed to investigate the accuracy of age-specific serum MMP-7 for discriminating BA from other cholestatic pediatric patients. METHODS: This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases (n = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients (n = 318, with 172 BA) and validated in a prospective cohort (n = 687, including 395 BA). RESULTS: The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946-0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0-90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9-93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6-96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0-30 days, which was 86.4% (95% CI: 75.0-94.0%), 95.5% (95% CI: 77.2-99.9%), 98.1% (95% CI: 89.7-100%), and 72.4% (95% CI: 52.8-87.3%), respectively. CONCLUSIONS: The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.

Therapeutic progress in relapsed/refractory multiple myeloma.

Improvement in the therapeutics for multiple myeloma (MM) has been continuously developed owing to the application of novel drugs and technologies in the last 20 years. The standard first-line therapy for MM consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly. This study aimed to summarize and review the results of RRMM trials over the past 5 years to provide a holistic overview and insights for practitioners in related fields and to provide additional ideas for clinical trialists. This study shows that daratumumab and isatuximab continue to significantly advance as treatment options. Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes. However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment.

Effect of CVAI on the incidence of MASLD compared to BMI in populations with different body types: A prospective cohort study in China.

BACKGROUND AND AIMS: To explore the relationship between body mass index (BMI), chinese visceral adiposity index (CVAI) and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in populations with different body types defined by BMI. METHODS AND RESULTS: 24 191 participants from the Jinchang cohort were involved in the prospective cohort study with a 2.3-year follow-up. Information from epidemiological investigations, comprehensive health examinations and biochemical examinations was collected. MASLD was assessed by abdominal ultrasonography. BMI and CVAI were calculated using recognized formulas. Cox regressions, Restricted cubic spline (RCS) and Receiver operating characteristic (ROC) analysis were performed. The risk of MASLD increased with the increase in BMI and CVAI (Ptrend <0.001), and there was a nonlinear dose-response relationship. In the total population, BMI and CVAI increased the risk of MASLD with adjusted HR (95%CI) of 1.097 (1.091-1.104) and 1.024 (1.023-1.026), respectively. The results were similar in the lean and overweight/obese groups. There was also a nonlinear relationship between CVAI and MASLD (Pnon-linearity<0.001), no matter in which group. The area under the curve of CVAI was significantly higher than that of BMI in females with different body types, and the areas in the whole females were 0.802 (95%CI: 0.787-0.818) and 0.764 (95%CI: 0.747-0.780), respectively. There was no significant difference in the ability of BMI and CVAI to predict MASLD in all-sex and males, either in lean or overweight/obese groups. CONCLUSIONS: CVAI and BMI were independently associated with the risk of MASLD regardless of body types defined by BMI, and CVAI showed better diagnostic ability for MASLD in females.

Association between urinary polycyclic aromatic hydrocarbons and risk of metabolic associated fatty liver disease.

OBJECTIVE: To investigate the effect of urinary PAHs on MAFLD. METHODS: The study included 3,136 adults from the National Health and Nutrition Examination Survey (NHANES) conducted between 2009 and 2016. Among them, 1,056 participants were diagnosed with MAFLD and were designated as the case group. The analysis of the relationship between monohydroxy metabolites of seven PAHs in urine and MAFLD was carried out using logistic regression and Bayesian kernel regression (BKMR) models. RESULTS: In single-pollutant models, the concentration of 2-hydroxynaphthalene (2-OHNAP) was positively correlated with MAFLD (OR = 1.47, 95% CI 1.18, 1.84), whereas 3-hydroxyfluorene (3-OHFLU) and 1-hydroxypyrene (1-OHPYR) demonstrated a negative correlation with MAFLD (OR = 0.59, 95% CI 0.48 0.73; OR = 0.70, 95% CI 0.55, 0.89). Conversely, in multi-pollutant models, 2-OHNAP, 2-hydroxyfluorene (2-OHFLU), 2-hydroxyphenanthrene, and 3-hydroxyphenanthrene (2&3-OHPHE) displayed positive correlations with MAFLD (OR = 6.17, 95% CI 3.15, 12.07; OR = 2.59, 95% CI 1.37, 4.89). However, 3-OHFLU and 1-OHPYR continued to exhibit negative correlations with MAFLD (OR = 0.09, 95% CI 0.05, 0.15; OR = 0.62, 95% CI 0.43, 0.88). Notably, the BKMR analysis mixtures approach did not indicate a significant joint effect of multiple PAHs on MAFLD, but identified interactions between 3-OHFLU and 2-OHFLU, 1-OHPYR and 2-OHFLU, and 1-OHPYR and 3-OHFLU. CONCLUSION: No significant association was found between mixed PAHs exposure and the risk of MAFLD. However, interactions were observed between 3-OHFLU and 2-OHFLU. Both 2-OHFLU and 2&3-OHPHE exposure are significant risk factors for MAFLD, whereas 3-OHFLU is a key protective factor for the disease.

Differentiation and immunosuppressive function of CD19+CD24hiCD27+ regulatory B cells are regulated through the miR-29a-3p/NFAT5 pathway.

BACKGROUND: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.

Exposure to PM2.5 and its five constituents is associated with the incidence of type 2 diabetes mellitus: a prospective cohort study in northwest China.

Studies have demonstrated that fine particulate matter (PM2.5) is an underlying risk factor for type 2 diabetes mellitus (T2DM), but evidence exploring the relationship between PM2.5 chemical components and T2DM was extremely limited, to investigate the effects of long-term exposure to PM2.5 and its five constituents (sulfate [SO42-], nitrate [NO3-], ammonium [NH4+]), organic matter [OM] and black carbon [BC]) on incidence of T2DM. Based on the "Jinchang Cohort" platform, a total of 19,884 participants were selected for analysis. Daily average concentrations of pollutants were gained from Tracking Air Pollution in China (TAP). Cox proportional hazards regression models were utilized to estimate the hazard ratios (HR) and 95% confidence interval (CI) in single-pollutant models, restricted cubic splines functions were used to examine the dose-response relationships, and quantile g-computation (QgC) was applied to evaluate the combined effect of PM2.5 compositions on T2DM. Stratification analysis was also considered. A total of 791 developed new cases of T2DM were observed during a follow-up period of 45254.16 person-years. The concentrations of PM2.5, NO3-, NH4+, OM and BC were significantly associated with incidence of T2DM (P-trend < 0.05), with the HRs in the highest quartiles of 2.16 (95% CI 1.79, 2.62), 1.43 (95% CI 1.16, 1.75), 1.75 (95% CI 1.45, 2.11), 1.31 (95% CI 1.08, 1.59) and 1.79 (95% CI 1.46, 2.21), respectively. Findings of QgC model showed a noticeably positive joint effect of one quartile increase in PM2.5 constituents on increased T2DM morbidity (HR 1.27, 95% CI 1.09, 1.49), and BC (32.7%) contributed the most to the overall effect. The drinkers, workers and subjects with hypertension, obesity, higher physical activity, and lower education and income were generally more susceptible to PM2.5 components hazards. Long-term exposure to PM2.5 and its components (i.e., NO3-, NH4+, OM, BC) was positively correlated with T2DM incidence. Moreover, BC may be the most responsible for the association between PM2.5 constituents and T2DM. In the future, more epidemiological and experimental studies are needed to identify the link and potential biological mechanisms.

Exposure to PM2.5 and its constituents is associated with metabolic dysfunction-associated fatty liver disease: a cohort study in Northwest of China.

Accumulating animal studies have demonstrated associations between ambient air pollution (AP) and metabolic dysfunction-associated fatty liver disease (MAFLD), but relevant epidemiological evidence is limited. We evaluated the association of long-term exposure to AP with the risk of incident MAFLD in Northwest China. The average AP concentration between baseline and follow-up was used to assess individual exposure levels. Cox proportional hazard models and restricted cubic spline functions (RCS) were used to estimate the association of PM2.5 and its constituents with the risk of MAFLD and the dose-response relationship. Quantile g-computation was used to assess the joint effects of mixed exposure to air pollutants on MAFLD and the weights of the various pollutants. We observed 1516 cases of new-onset MAFLD, with an incidence of 10.89%. Increased exposure to pollutants was significantly associated with increased odds of MAFLD, with hazard ratios (HRs) of 2.93 (95% CI: 1.22, 7.00), 2.86 (1.44, 5.66), 7.55 (3.39, 16.84), 4.83 (1.89, 12.38), 3.35 (1.35, 8.34), 1.89 (1.02, 1.62) for each interquartile range increase in PM2.5, SO42-, NO3-, NH4+, OM, and BC, respectively. Stratified analyses suggested that females, frequent exercisers and never-drinkers were more susceptible to MAFLD associated with ambient PM2.5 and its constituents. Mixed exposure to SO42-, NO3-, NH4+, OM and BC was associated with an increased risk of MAFLD, and the weight of BC had the strongest effect on MAFLD. Exposure to ambient PM2.5 and its constituents increased the risk of MAFLD.

Seasonal variation and human impacts of the river biofilm bacterial communities in the Shiting River in southeastern China.

Bacterial communities in epilithic biofilm plays an important role in biogeochemistry processes in freshwater ecosystems. Nevertheless, our understanding of the geographical and seasonal variations of the composition of bacterial communities in the biofilm of gravels on river bed is still limited. Various anthropogenic activities also influence the biofilm bacteria in gravel rivers. By taking the Shiting River in the upper Yangtze River basin in Sichuan Province as an example, we studied the geographical and seasonal variations of epilithic bacteria and the impacts of weirs and other human activities (e.g., sewage pollution). The river has experienced severe degradation since the Ms 8.0 Wenchuan Earthquake, and weirs were constructed to prevent bed erosion. We collected epilithic biofilms samples at 17 sites along ~ 30 km river reach of the Shiting River in the autumn of 2021 and the summer of 2022, respectively. We applied 16S rRNA gene high-throughput sequencing technology and Functional Annotation of Prokaryotic Taxa (FAPROTAX) to analyze the seasonal and biogeographic patterns and potential functions of the biofilm bacterial communities. The results showed that epilithic bacteria from the two surveys exhibited variation in community composition, bacterial diversity and potential functions. The bacteria samples collected in the autumn have much higher alpha diversity and richness than those collected in the summer. Bacterial richness and diversity were lower downstream of the weirs than upstream. Low diversity was observed at a sampling site influenced by sewage inflow, which contains high level of nitrogen-related chemicals.

Serum Metabolomic Signatures of Hirschsprung's Disease Based on GC-MS and LC-MS.

Hirschsprung's disease (HSCR) is a congenital digestive tract malformation characterized by the absence of intramural ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. Although the improvement of surgical methods has allowed great progress in the treatment of HSCR, its incidence and postoperative prognosis are still not ideal. The pathogenesis of HSCR remains unclear to date. In this study, metabolomic profiling of HSCR serum samples was performed by an integrated analysis of gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) as well as multivariate statistical analyses. Based on the random forest algorithm and receiver operator characteristic analysis, 21 biomarkers related to HSCR were optimized. Several amino acid metabolism pathways were identified as important disordered pathways of HSCR, among which tryptophan metabolism was crucial. To our knowledge, this is the first serum metabolomics study focusing on HSCR, and it provides a new perspective for explaining the mechanism of HSCR.

Two Metastable Endohedral Metallofullerenes Sc2C2@C1(39656)-C82 and Sc2C2@C1(51383)-C84: Direct-C2-Insertion Products from Their Most Stable Precursors.

Endohedral metallofullerenes (EMFs) are sub-nano carbon materials with diverse applications, yet their formation mechanism, particularly for metastable isomers, remains ambiguous. The current theoretical methods focus mainly on the most stable isomers, leading to limited predictability of metastable ones due to their low stabilities and yields. Herein, we report the successful isolation and characterization of two metastable EMFs, Sc2C2@C1(39656)-C82 and Sc2C2@C1(51383)-C84, which violate the isolated pentagon rule (IPR). These two non-IPR EMFs exhibit a rare case of planar and pennant-like Sc2C2 clusters, which can be considered hybrids of the common butterfly-shaped and linear configurations. More importantly, the theoretical results reveal that despite being metastable, these two non-IPR EMFs survived as the products from their most stable precursors, Sc2C2@C2v(5)-C80 and Sc2C2@Cs(6)-C82, via a C2 insertion during the post-formation annealing stages. We propose a systematic theoretical method for predicting metastable EMFs during the post-formation stages. The unambiguous molecular-level structural evidence, combined with the theoretical calculation results, provides valuable insights into the formation mechanisms of EMFs, shedding light on the potential of post-formation mechanisms as a promising approach for EMF synthesis.

Single-cell RNA sequencing of solid pseudopapillary neoplasms of the pancreas in children.

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare pancreatic tumor in children. Its origin remains elusive, along with its pathogenesis. Heterogeneity within SPN has not been previously described. In addition, low malignant but recurrent cases have occasionally been reported. To comprehensively unravel these profiles, single-cell RNA sequencing was performed using surgical specimens. We identified the cell types and suggested the origin of pancreatic endocrine progenitors. The Wnt/ß-catenin pathway may be involved in tumorigenesis, while the epithelial-to-mesenchymal transition may be responsible for SPN recurrence. Furthermore, NOV, DCN were nominated as primary and S100A10, MGP as recurrent SPN marker genes, respectively. Our results provide insight into the pathogenesis of SPN.

Effect of Adjuvant Steroid Therapy in Type 3 Biliary Atresia: A Single-Center, Open-Label, Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy and side effects of additional postoperative steroid therapy for type 3 BA versus the current routine care. SUMMARY BACKGROUND DATA: Whether steroid therapy post-Kasai portoen-terostomy improves the outcomes of BA remains controversial. Clinical evidence from 2 randomized trials in the UK and USA do not support the routine use of steroid in the treatment of BA. METHODS: In this open-label randomized controlled trial, patients with type 3 BA were randomized to routine postoperative treatment with or without 10 to 12 weeks of adjuvant steroid treatment. The primary outcome was the postoperative jaundice clearance rate with native liver at 6 months. The secondary outcomes included postoperative jaundice clearance rate at 3, 12, and 24 months, survival with native liver at 12 and 24 months, and SAEs within 3 months. RESULTS: Overall, 200 participants were randomized and allocated into either steroid or control group (n = 100/group). The proportion of participants that are jaundice free without liver transplantation was significantly higher in the steroid group than in the control group at 6 months (54.1% vs 31.0%, P = 0.0015). The native liver survival rate was higher postoperatively in the steroid group than in the control group at 12 (66.3% vs 50.0%, P = 0.02) and 24 (57.1% vs 40.0%, P = 0.02) months. The survival time with native liver was significantly longer in the steroid group than in the control group (median survival, steroid vs control: not reached vs 1.21 years, P = 0.02). There were no significant differences between the 2 groups in the mean occurrence of SAEs within 3 months (steroid vs control: 0.63 vs 0.45, P = 0.20). CONCLUSIONS: Postoperative adjuvant steroid intervention improved bile drainage and survival with native liver in type 3 BA patients, without increasing early-stage SAEs.

Enhanced resolution of marine viruses with violet side scatter.

Marine viruses make up an essential compartment of the marine ecosystem. They are the most abundant organisms and represent one of the biggest sources of unknown biodiversity. Viruses also have an important impact on bacterial and algal mortality in the ocean, and as such have a major influence on microbial diversity and biogeochemical cycling. However, little is known about the abundance and distribution patterns of viruses across the oceans and seas. Over the last 20 years, flow cytometry has been the technique of choice to detect and count the viral particles in natural samples. Nevertheless, due to their small size, the detection of marine viruses is still extremely challenging. In this article we describe how a new generation of flow cytometer which uses the side scatter (SSC) of violet photons from a 405 nm laser beam helps to improve the resolution for detecting marine viruses. To the best of our knowledge, this is the first report where virioplankton has been detected in aquatic samples using flow cytometry with a 405 nm violet SSC instead of a 488 nm blue SSC.

The bidirectional relationship between NAFLD and type 2 diabetes: A prospective population-based cohort study.

BACKGROUND AND AIMS: To explore the bidirectional relationship between NAFLD and type 2 diabetes and the possible directions of the main effect. METHODS AND RESULTS: 30 633 participants from the Jinchang cohort were enrolled. Firstly, cox proportional hazards regression model was used to assess the unidirectional causality between NAFLD and prediabetes and type 2 diabetes. Secondly, cross-lag path analysis model was conducted to estimate the bidirectional relationship between NAFLD and prediabetes and type 2 diabetes, and to determine the direction of the main effects. Finally, potential effect modifications were also considered by age, sex, hyperlipidemia, and overweight/obesity. We found that NAFLD increased the risk of prediabetes and type 2 diabetes with adjusted HR (95%CI) of 1.355(95%CI: 1.255-1.462) and 1.898(95%CI: 1.415-2.545), respectively. Prediabetes and type 2 diabetes also increased the risk of NAFLD, with adjusted HR (95%CI) of 1.245(95%CI: 1.115-1.392) and 1.592(95%CI: 1.373-1.846), respectively. Cross-lag path analysis showed that NAFLD significantly affected the incidence of prediabetes (ß = 0.285, P < 0.001), while the effect on type 2 diabetes was not statistically significant. The effect of prediabetes and type 2 diabetes on the risk of NAFLD was weak, and the path coefficients were 0.076 and 0.037, respectively. Stratified analyses showed similar results. CONCLUSION: This study provides evidence that there was a bidirectional causal association between NAFLD and type 2 diabetes, and the progression from NAFLD through prediabetes to type 2 diabetes may be the main pathway.

A study of temperature variability on admissions and deaths for cardiovascular diseases in Northwestern China.

OBJECTIVE: To explore the effect of temperature variability (TV) on admissions and deaths for cardiovascular diseases (CVDs). METHOD: The admissions data of CVDs were collected in 4 general hospitals in Jinchang City, Gansu Province from 2013 to 2016. The monitoring data of death for CVDs from 2013 to 2017 were collected through the Jinchang City Center for Disease Control and Prevention. Distributed lag nonlinear model (DLNM) was combined to analyze the effects of TV (daily temperature variability (DTV) and hourly temperature variability (HTV)) on the admissions and deaths for CVDs after adjusting confounding effects. Stratified analysis was conducted by age and gender. Then the attribution risk of TV was evaluated. RESULTS: There was a broadly linear correlation between TV and the admissions and deaths for CVDs, but only the association between TV and outpatient and emergency room (O&ER) visits for CVDs have statistically significant. DTV and HTV have similar lag effect. Every 1 ℃ increase in DTV and HTV was associated with a 3.61% (95% CI: 1.19% ~ 6.08%), 3.03% (95% CI: 0.27% ~ 5.86%) increase in O&ER visits for CVDs, respectively. There were 22.75% and 14.15% O&ER visits for CVDs can attribute to DTV and HTV exposure during 2013-2016. Males and the elderly may be more sensitive to the changes of TV. Greater effect of TV was observed in non-heating season than in heating season. CONCLUSION: TV was an independent risk factor for the increase of O&ER visits for CVDs, suggesting effective guidance such as strengthening the timely prevention for vulnerable groups before or after exposure, which has important implications for risk management of CVDs.