Structural variant landscapes reveal convergent signatures of evolution in sheep and goats.

BACKGROUND: Sheep and goats have undergone domestication and improvement to produce similar phenotypes, which have been greatly impacted by structural variants (SVs). Here, we report a high-quality chromosome-level reference genome of Asiatic mouflon, and implement a comprehensive analysis of SVs in 897 genomes of worldwide wild and domestic populations of sheep and goats to reveal genetic signatures underlying convergent evolution. RESULTS: We characterize the SV landscapes in terms of genetic diversity, chromosomal distribution and their links with genes, QTLs and transposable elements, and examine their impacts on regulatory elements. We identify several novel SVs and annotate corresponding genes (e.g., BMPR1B, BMPR2, RALYL, COL21A1, and LRP1B) associated with important production traits such as fertility, meat and milk production, and wool/hair fineness. We detect signatures of selection involving the parallel evolution of orthologous SV-associated genes during domestication, local environmental adaptation, and improvement. In particular, we find that fecundity traits experienced convergent selection targeting the gene BMPR1B, with the DEL00067921 deletion explaining ~10.4% of the phenotypic variation observed in goats. CONCLUSIONS: Our results provide new insights into the convergent evolution of SVs and serve as a rich resource for the future improvement of sheep, goats, and related livestock.

Sfrp5 overexpression reverses oxLDL-induced lipid accumulation in HVSMCs.

Atherosclerosis (AS) is the major cause of multiple cardiovascular diseases. In addition, the lipid accumulation of human vascular smooth muscle cells (HVSMCs) can cause the occurrence of AS. Sfrp5 was known to be downregulated in atherosclerosis; however, the detailed function of Sfrp5 in HVSMCs remains unclear. Specifically, we found that Sfrp5 expression in oxLDL-treated HVSMCs was downregulated. Sfrp5 overexpression inhibited the viability of HVSMCs induced by oxLDL. In addition, oxLDL-induced proliferation and migration in HVSMCs were abolished by Sfrp5 overexpression. Sfrp5 overexpression reduced oxLDL-caused oxidative stress, lipid accumulation, and inflammation in HVSMCs. Meanwhile, oxLDL treatment increased the expressions of Wnt5a, c-Myc, and ß-catenin in HVSMCs, while this phenomenon was rescued by Sfrp5 overexpression. Furthermore, the inhibitory effect of Sfrp5 upregulation on the viability and migration of HVSMCs was reversed by R-spondin. These results indicate that Sfrp5 overexpression could reverse oxLDL-induced lipid accumulation in HVSMCs through inactivating Wnt5a/ß-catenin signaling pathway.

Biocompatibility FeOOH QD@ATP-BODIPY nanocomposite for glutathione detection and intracellular imaging.

Monitoring of glutathione has attracted considerable attention owing to its biological and clinical significance. An eco-friendly, economic, simple, biocompatible probe with excellent sensitivity and selectivity is very important. Herein, FeOOH QD@ATP-BODIPY nanocomposite was fabricated from one-step synthesized FeOOH quantum dots (FeOOH QD) and commercial boron-dipyrromethene-conjugated adenosine 5'-triphosphate (ATP-BODIPY) for glutathione (GSH) sensing in solutions and living cells. Three fascinate merits of FeOOH QD were confirmed: (a) as fluorescence quencher for ATP-BODIPY, (b) as selective recognizer of GSH and (c) with carrier effects and membrane permeability. The construction and response mechanism of the nanocomposite was based on the competitive coordination chemistry and redox reaction of FeOOH QD between GSH and phosphate group of ATP-BODIPY. Under the optimal conditions, the detection limit for GSH was as low as 68.8 nM. Excellent linear range of 0.2-400 µM was obtained. Furthermore, the chemical response of the nanocomposite exhibits high selectivity toward GSH over other electrolytes and biomolecules. It was successfully applied for GSH determination in human serum samples. The MTT assay exhibited FeOOH QD@ATP-BODIPY nanocomposite own good biocompatibility. FeOOH QD@ATP-BODIPY respond to GSH in living cells in situ was also proved via fluorescence imaging. These suggested that the FeOOH QD@ATP-BODIPY nanocomposite had potential application in biological and clinical applications.

Genetic insights into across pancreatitis types: the causal influence of immunoglobulin G N-glycosylation variants on disease risk.

Background: While a few case-control studies indicated a possible correlation of IgG N-glycosylation patterns with pancreatitis, their restricted sample sizes and methodologies prevented conclusive insights into causality or distinguishing traits across pancreatitis types. Method: We conducted a two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 77 IgG N-glycosylation traits and various types of pancreatitis, including acute pancreatitis (AP), chronic pancreatitis (CP), alcohol acute pancreatitis (AAP), and alcohol chronic pancreatitis (ACP). This analysis utilized summary-level data from genome-wide association studies (GWAS), employing methods such as IVW, MR-Egger, and weighted median. To ensure the robustness of our findings, several sensitivity analyses, including Cochran's Q statistic, leave-one-out, MR-Egger intercept, and MR-PRESSO global test were conducted. Result: Our study uncovered the causal relationship between specific IgG N-glycosylation traits and various types of pancreatitis. Notably, an increase in genetically predicted IGP7 levels was associated with a decreased risk of developing AP. For CP, our data suggested a protective effect associated with higher levels of both IGP7 and IGP31, contrasting with increased levels of IGP27 and IGP65, which were linked to a heightened risk. Moreover, in the case of AAP, elevated IGP31 levels were causatively associated with a lower incidence, while higher IGP26 levels correlated with an increased risk for ACP. Conclusion: This study establishes causal relationship between specific IgG N-glycosylation patterns and varying risks of different pancreatitis forms, underscoring their potential as predictive biomarkers. These findings necessitate further exploration into the underlying mechanisms, promising to inform more personalized diagnostic and therapeutic strategies in pancreatitis management.

Strategies to Diversification of the Mechanical Properties of Organic Crystals.

Structurally ordered soft materials that respond to complementary stimuli are susceptible to control over their spatial and temporal morphostructural configurations by intersectional or combined effects such as gating, feedback, shape-memory, or programming. In the absence of general and robust design and prediction strategies for their mechanical properties, at present, combined chemical and crystal engineering approaches could provide useful guidelines to identify effectors that determine both the magnitude and time of their response. Here, we capitalize on the purported ability of soft intermolecular interactions to instigate mechanical compliance by using halogenation to elicit both mechanical and photochemical activity of organic crystals. Starting from (E)-1,4-diphenylbut-2-ene-1,4-dione, whose crystals are brittle and photoinert, we use double and quadruple halogenation to introduce halogen-bonded planes that become interfaces for molecular gliding, rendering the material mechanically and photochemically plastic. Fluorination diversifies the mechanical effects further, and crystals of the tetrafluoro derivative are not only elastic but also motile, displaying the rare photosalient effect.

Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis.

Wnt/ß-catenin signalling is aberrantly activated in most colorectal cancer (CRC) and is one key driver involved in the initiation and progression of CRC. However, mutations of APC gene in CRC patients retain certain activity of APC protein with decreased ß-catenin signalling and DKK4 expression significantly upregulates and represses Wnt/ß-catenin signalling in human CRC tissues, suggesting that a precisely modulated activation of the Wnt/ß-catenin pathway is essential for CRC formation and progression. The underlying reasons why a specifically reduced degree, not a fully activating degree, of ß-catenin signalling in CRC are unclear. Here, we showed that a soluble extracellular inhibitor of Wnt/ß-catenin signalling, DKK4, is an independent factor for poor outcomes in CRC patients. DKK4 secreted from CRC cells inactivates ß-catenin in fibroblasts to induce the formation of stress fibre-containing fibroblasts and myofibroblasts in culture conditions and in mouse CRC xenograft tissues, resulting in restricted expansion in tumour masses at primary sites and enhanced CRC metastasis in mouse models. Reduced ß-catenin activity by a chemical inhibitor MSAB promoted the CRC metastasis. Our findings demonstrate why reduced ß-catenin activity is needed for CRC progression and provide a mechanism by which interactions between CRC cells and stromal cells affect disease promotion.

In vitro and in vivo study of antibacterial and anti-encrustation coating on ureteric stents.

OBJECTIVES: To investigate the ability of propolis-coated ureteric stents to solve complications, especially urinary tract infections (UTIs) and crusting, in patients with long-term indwelling ureteric stents through antimicrobial and anti-calculus activities. MATERIALS AND METHODS: Polyurethane (PU) ureteric stents were immersed in the ethanol extract of propolis (EEP), a well-known antimicrobial honeybee product, and subjected to chemical, hydrophilic, and seismic tests. The antimicrobial activity of the EEP coating was then examined by in vitro investigation. Proteus mirabilis infection was induced in rats within uncoated and EEP-coated groups, and the infection, stone formation, and inflammation were monitored at various time points. RESULTS: The characterisation results showed that the hydrophilicity and stability of the EEP surface improved. In vitro tests revealed that the EEP coating was biocompatible, could eliminate >90% of bacteria biofilms attached to the stent and could maintain bacteriostatic properties for up to 3 months. The in vivo experiment revealed that the EEP-coating significantly reduced the amount of bacteria, stones, and salt deposits on the surface of the ureteric stents and decreased inflammation in the host tissue. CONCLUSIONS: Compared with clinically used PU stents, EEP-coated ureteric stents could better mitigate infections and prevent encrustation. Thus, this study demonstrated that propolis is a promising natural dressing material for ureteric stents.

Tlr5 deficiency exacerbates lupus-like disease in the MRL/lpr mouse model.

Introduction: Leaky gut has been linked to autoimmune disorders including lupus. We previously reported upregulation of anti-flagellin antibodies in the blood of lupus patients and lupus-prone mice, which led to our hypothesis that a leaky gut drives lupus through bacterial flagellin-mediated activation of toll-like receptor 5 (TLR5). Methods: We created MRL/lpr mice with global Tlr5 deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice. Result: Contrary to our hypothesis that the deletion of Tlr5 would attenuate lupus, our results showed exacerbation of lupus with Tlr5 deficiency in female MRL/lpr mice. Remarkably higher levels of proteinuria were observed in Tlr5 -/- MRL/lpr mice suggesting aggravated glomerulonephritis. Histopathological analysis confirmed this result, and Tlr5 deletion significantly increased the deposition of IgG and complement C3 in the glomeruli. In addition, Tlr5 deficiency significantly increased renal infiltration of Th17 and activated cDC1 cells. Splenomegaly and lymphadenopathy were also aggravated in Tlr5-/- MRL/lpr mice suggesting impact on lymphoproliferation. In the spleen, significant decreased frequencies of regulatory lymphocytes and increased germinal centers were observed with Tlr5 deletion. Notably, Tlr5 deficiency did not change host metabolism or the existing leaky gut; however, it significantly reshaped the fecal microbiota. Conclusion: Global deletion of Tlr5 exacerbates lupus-like disease in MRL/lpr mice. Future studies will elucidate the underlying mechanisms by which Tlr5 deficiency modulates host-microbiota interactions to exacerbate lupus.

TCDD and CH223191 Alter T Cell Balance but Fail to Induce Anti-Inflammatory Response in Adult Lupus Mice.

Aryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.

Lactic acid fermentation of goji berries (Lycium barbarum) prevents acute alcohol liver injury and modulates gut microbiota and metabolites in mice.

Juice fermented with lactic acid bacteria (LAB) has received attention due to its health benefits, such as antioxidant and anti-inflammatory. Previous research on LAB-fermented goji juice mainly focused on exploring the changes in the metabolite profile and antioxidant activity in vitro, whereas the liver protection properties of LAB-fermented goji juice in vivo are still unknown. This study aimed to investigate the effects of Lacticaseibacillus paracasei E10-fermented goji juice (E10F), Lactiplantibacillus plantarum M-fermented goji juice (MF), Lacticaseibacillus rhamnosus LGG-fermented goji juice (LGGF) on preventing acute alcoholic liver injury with physiology, gut microbial, and metabolic profiles in mice. Compared with goji juice, E10F, MF, and LGGF enhanced the protective effect against liver injury by reducing serum alanine transaminase (ALT) levels, improving the hepatic glutathione (GSH) antioxidant system, and attenuating inflammation by decreasing the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß. Furthermore, E10F, MF, and LGGF increased intestinal integrity, restructured the gut microbiota including Bacteroides and Lactobacillus, and altered gut microbial metabolites including kyotorphin, indolelactic acid, and N-methylserotonin. Pretreatment of different LAB-fermented goji juice in mice showed significant differences in gut microbiota and metabolism. The correlation analysis demonstrated that the increase of Lactobacillus, indolelactic acid, and N-methylserotonin by E10F, MF, and LGGF was positively correlated with reduced inflammation and improved liver and gut function. Taken together, E10F, MF, and LGGF all have the potential to be converted into dietary interventions to combat acute alcoholic liver injury. It provided a reference for the study of the hepatoprotective effect of LAB-fermented goji juice.

Cell-type-specific inhibitory circuitry from a connectomic census of mouse visual cortex.

Mammalian cortex features a vast diversity of neuronal cell types, each with characteristic anatomical, molecular and functional properties. Synaptic connectivity powerfully shapes how each cell type participates in the cortical circuit, but mapping connectivity rules at the resolution of distinct cell types remains difficult. Here, we used millimeter-scale volumetric electron microscopy1 to investigate the connectivity of all inhibitory neurons across a densely-segmented neuronal population of 1352 cells spanning all layers of mouse visual cortex, producing a wiring diagram of inhibitory connections with more than 70,000 synapses. Taking a data-driven approach inspired by classical neuroanatomy, we classified inhibitory neurons based on the relative targeting of dendritic compartments and other inhibitory cells and developed a novel classification of excitatory neurons based on the morphological and synaptic input properties. The synaptic connectivity between inhibitory cells revealed a novel class of disinhibitory specialist targeting basket cells, in addition to familiar subclasses. Analysis of the inhibitory connectivity onto excitatory neurons found widespread specificity, with many interneurons exhibiting differential targeting of certain subpopulations spatially intermingled with other potential targets. Inhibitory targeting was organized into "motif groups," diverse sets of cells that collectively target both perisomatic and dendritic compartments of the same excitatory targets. Collectively, our analysis identified new organizing principles for cortical inhibition and will serve as a foundation for linking modern multimodal neuronal atlases with the cortical wiring diagram.

Is it harmful to me or to us? A dyadic analysis of Chinese young adults' dysfunctional individuation and romantic relationship satisfaction.

This study aimed at examining how romantically involved Chinese young adults' dysfunctional individuation was associated with their and their partners' perceptions of romantic relationship satisfaction. We recruited 296 Chinese couples who were currently in heterosexual romantic relationships at the university. The couples completed self-report measures of their dysfunctional individuation and relationship satisfaction. Results from the cross-sectional actor-partner interdependence model (APIM) indicated that (a) for both genders, actor effects existed: Chinese young adults' dysfunctional individuation was negatively associated with their romantic relationship satisfaction; (b) in terms of partners' effects, women's dysfunctional individuation was negatively associated with men's perceptions of relationship satisfaction; but (c) men's dysfunctional individuation was not significantly associated with women's perceptions of relationship satisfaction. The findings were the first to reveal the actor and partner effects of dysfunctional individuation on romantic relationship satisfaction. The study results provided practical implications regarding how young adults can have satisfying romantic relationships.

Revealing varying relationships between wastewater mercury emissions and economic growth in Chinese cities.

Mercury emission from industrial wastewater has a great impact on the aquatic environment but is not well studied. Inventory analysis, decoupling and decomposition methods have been conducted based on the China Pollution Source Census dataset, which combines industry removal efficiencies to calculate mercury emissions from industrial wastewater in 340 cities in China during 2000-2010. The results show that over these 11 years, total mercury emissions and per capita mercury emissions increased by approximately 5 times, while the emission intensity increased by only about 3%. From 2000 to 2010, only 0.59% of cities showed strong decoupling between economic growth and mercury emissions, and 37.65% of cities showed weak decoupling, whereas 38.82% of cities showed negative decoupling. We attribute the decoupling of economic development and emissions in individual cities to several socioeconomic factors and find that a decline in emission intensity is the main driver. The Gini coefficient indicates a significant imbalance between cities' emissions, but this situation improved during 2000-2010. The objective of this article is to provide a historical perspective on the situation of mercury emissions from wastewater in China, thereby contributing' to the broader understanding of industrial pollution.

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis.

Background: Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis. Methods: Systems analyses integrating single-cell RNA-sequencing and complementary immunological approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming was assessed by integrated biochemical and genetic approaches. The inter-cellular propagation of homeostasis resolution was evaluated by co-culture assays with donor monocytes trained by 4-PBA and recipient naïve monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high fat diet-fed ApoE -/- mouse model with i.p. 4-PBA administration. Furthermore, the selective efficacy of 4-PBA trained monocytes were examined by i.v. transfusion of ex vivo trained monocytes by 4-PBA into recipient high fat diet-fed ApoE -/- mice. Results: In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 via reducing peroxisome stress and attenuating SYK-mTOR signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPARγ neddylation mediated by TOLLIP. 4-PBA trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo . Conclusion: Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision-therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.

Ranitidine as an adjuvant regulates macrophage polarization and activates CTLs through the PI3K-Akt2 signaling pathway.

Adjuvants are an indispensable component of vaccines, but there are few adjuvants for human vaccines. H2 receptor blockers, inhibiting gastric acid secretion, have immune enhancement effects. Ranitidine (RAN) is a water-soluble H2 receptor blocker, and whether it has an immune-enhancing effect is still unknown. In this study, flow cytometry, western blotting, and immunofluorescence methods were used to analyze whether RAN could activate macrophage polarization to the M1 phenotype in vivo and in vitro. Here, we found that the M1 inflammatory cytokine levels and surface markers in RAW264.7 cells were upregulated by NF-κB activation, possibly through the PI3K-Akt2 signaling pathway, after RAN treatment. Endocytic function was also enhanced by feedback regulation of Akt2/GSK3ß/Dynmin1 signaling. Furthermore, to evaluate the adjuvant function of RAN, we used OVA plus RAN as a vaccine to inhibit the growth of B16-OVA tumors in mice. We also found that in the RAN adjuvant group, macrophage polarization to M1, Th1 cell differentiation, and cytotoxic T lymphocyte (CTL) activation were significantly upregulated. The tumor growth of mice was inhibited, and the survival rate of mice was significantly improved. This study provides new evidence for the mechanism by which RAN activates the immune response and is expected to provide a new strategy for the research and development of tumor vaccine adjuvants.

Influence of surface nanotopography and wettability on early phases of peri-implant soft tissue healing: an in-vivo study in dogs.

BACKGROUND: It is well established that nanotopography and wettability of implant surfaces contribute to osseointegration and long-term implant success. However, the effects of a hydrogenated surface with nanotubular and superhydrophilic properties on peri-implant soft tissue remain unclear. This study was designed to study the impact of a modified abutment surface on early soft tissue integration compared with a machined surface. METHODS: Thirty-six implants were placed at the bone level in the bilateral mandible of six beagles, followed by healing abutments belonging to the standard machined Ti-6Al-4V alloy abutments (TC4-M), anodized abutments with nanotubes (TC4-Nano), and hydrogenated abutments (TC4-H/Nano) groups, which were randomly screwed to the implants. After two and four weeks of wound healing, the animals were euthanized for histological evaluation. RESULTS: A superhydrophilic nanotubular surface developed on the hydrogenated abutment. Histological and histometric analyses revealed similar peri-implant soft tissue healing and dimensions for the three types of abutments at two and four weeks. Connective tissue (CT) length was longer around TC4-H/Nano abutments compared with standard abutments; however, the differences were not statistically significant. Moreover, collagen fibers in the TC4-H/Nano group extended and were attached perpendicularly to the superhydrophilic surface. CONCLUSIONS: Our results revealed that the soft tissue interface adjacent to the hydrogenated abutment is comparable to that of the machined abutment. A tendency of increased CT length and perpendicular collagen fibers was observed around the modified abutment. This study suggests that nanotubular/superhydrophilic surfaces could be a promising modification to enhance soft tissue sealing. However, comprehensive studies should be conducted to evaluate the peri-implant soft tissue around the modified abutment immunohistochemically, histopathologically, and clinically.

Investigating the influence of substituent groups in TTM based radicals for the excitation process: a theoretical study.

Tri-(2,4,6-trichlorophenyl)methyl (TTM) based radicals can be promising in providing relatively high fluorescence quantum efficiency. In this study, we have evaluated the photoluminescence properties of a series of TTM-based radicals by means of DFT and TD-DFT methods. The optimized structures of the ground states (D0) and the first excited states (D1) of all the radicals are calculated and the computed emission bands are comparable with previous experimental results. knr is determined from transition dipole moments (µ12) and the energy gaps between D0 and D1 (ΔE), both of which can be regulated by the conjugated structures from the substituent groups. knr was derived from the mode-averaging method and is consistent with the experimental results. Factors influencing kr and knr, including the potential energy differences (ΔG0), the vibrational reorganization energies (λ) and the electron coupling term (Hab), are discussed. By comparing kr and knr in solvents with different polarities (cyclohexane, toluene, and chloroform), TTM based radicals in cyclohexane exhibit the most promising fluorescence efficiencies. Besides, two substituted radicals, namely 2Br-TTM-3PCz and 2F-TTM-3PCz, have been fabricated. The results show that fluorine atoms are able to increase ΔG0 and a considerably small knr has been predicted. We expect that our calculation can benefit the design of light-emitting molecules in further experiments.

The impact of immunoglobulin G N-glycosylation level on COVID-19 outcome: evidence from a Mendelian randomization study.

Background: The coronavirus disease 2019 (COVID-19) pandemic has exerted a profound influence on humans. Increasing evidence shows that immune response is crucial in influencing the risk of infection and disease severity. Observational studies suggest an association between COVID-19 and immunoglobulin G (IgG) N-glycosylation traits, but the causal relevance of these traits in COVID-19 susceptibility and severity remains controversial. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to explore the causal association between 77 IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity using summary-level data from genome-wide association studies (GWAS) and applying multiple methods including inverse-variance weighting (IVW), MR Egger, and weighted median. We also used Cochran's Q statistic and leave-one-out analysis to detect heterogeneity across each single nucleotide polymorphism (SNP). Additionally, we used the MR-Egger intercept test, MR-PRESSO global test, and PhenoScanner tool to detect and remove SNPs with horizontal pleiotropy and to ensure the reliability of our results. Results: We found significant causal associations between genetically predicted IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity. Specifically, we observed reduced risk of COVID-19 with the genetically predicted increased IgG N-glycan trait IGP45 (OR = 0.95, 95% CI = 0.92-0.98; FDR = 0.019). IGP22 and IGP30 were associated with a higher risk of COVID-19 hospitalization and severity. Two (IGP2 and IGP77) and five (IGP10, IGP14, IGP34, IGP36, and IGP50) IgG N-glycosylation traits were causally associated with a decreased risk of COVID-19 hospitalization and severity, respectively. Sensitivity analyses did not identify any horizontal pleiotropy. Conclusions: Our study provides evidence that genetically elevated IgG N-glycosylation traits may have a causal effect on diverse COVID-19 outcomes. Our findings have potential implications for developing targeted interventions to improve COVID-19 outcomes by modulating IgG N-glycosylation levels.

Gene expression networks involved in multiple cellular programs coexist in individual hepatocellular cancer cells.

The gene expression networks of a single cell can be used to reveal cell type- and condition-specific patterns that account for cell states, cell identity, and its responses to environmental changes. We applied single cell sequencing datasets to define mRNA patterns and visualized potential cellular capacities among hepatocellular cancer cells. The expressing numbers and levels of genes were highly heterogenous among the cancer cells. The cellular characteristics were dependent strongly on the expressing numbers and levels of genes, especially oncogenes and anti-oncogenes, in an individual cancer cell. The transcriptional activations of oncogenes and anti-oncogenes were strongly linked to inherent multiple cellular programs, some of which oppose and contend against other processes, in a cancer cell. The gene expression networks of multiple cellular programs proliferation, differentiation, apoptosis, autophagy, epithelial-mesenchymal transition, ATP production, and neurogenesis coexisted in an individual cancer cell. The findings give rise a hypothesis that a cancer cell expresses balanced combinations of genes and undergoes a given biological process by rapidly transmuting gene expressing networks.

CAVE: Connectome Annotation Versioning Engine.

Advances in Electron Microscopy, image segmentation and computational infrastructure have given rise to large-scale and richly annotated connectomic datasets which are increasingly shared across communities. To enable collaboration, users need to be able to concurrently create new annotations and correct errors in the automated segmentation by proofreading. In large datasets, every proofreading edit relabels cell identities of millions of voxels and thousands of annotations like synapses. For analysis, users require immediate and reproducible access to this constantly changing and expanding data landscape. Here, we present the Connectome Annotation Versioning Engine (CAVE), a computational infrastructure for immediate and reproducible connectome analysis in up-to petascale datasets (~1mm3) while proofreading and annotating is ongoing. For segmentation, CAVE provides a distributed proofreading infrastructure for continuous versioning of large reconstructions. Annotations in CAVE are defined by locations such that they can be quickly assigned to the underlying segment which enables fast analysis queries of CAVE's data for arbitrary time points. CAVE supports schematized, extensible annotations, so that researchers can readily design novel annotation types. CAVE is already used for many connectomics datasets, including the largest datasets available to date.