A Minkowski Functional Analysis of the Cosmic Microwave Background Weak Lensing Convergence

Minkowski functionals are summary statistics that capture the geometric and morphological properties of fields. They are sensitive to all higher order correlations of the fields and can be used to complement more conventional statistics, such as the power spectrum of the field. We develop a Minkowski functional-based approach for a full likelihood analysis of mildly non-Gaussian sky maps with partial sky coverage. Applying this to the inference of cosmological parameters from the Planck mission's map of the Cosmic Microwave Background's lensing convergence, we find an excellent agreement with results from the power spectrum-based lensing likelihood. While the non-Gaussianity of current CMB lensing maps is dominated by reconstruction noise, a Minkowski functional-based analysis may be able to extract cosmological information from the non-Gaussianity of future lensing maps and thus go beyond what is accessible with a power spectrum-based analysis. We make the numerical code for the calculation of a map's Minkowski functionals, skewness and kurtosis parameters available for download from GitHub.Comment: 22 pages, 13 figure

Impact of TP53 mutation on tumor microenvironment in HPV- HNSCC

TP53 mutations are one of the most frequent genomic alterations in head and neck squamous cell carcinoma (HNSCC). Particularly, TP53 mutations are observed in HPV negative (HPV-) HNSCC patients and have a strong association with poor prognosis. However, the effects of TP53 mutations in tumor microenvironment (TME) have not been characterized in HNSCC. I assessed the extent of immune cell infiltrates among HPV- patients from the TCGA-HNSC Pan-Cancer Atlas dataset. Patients were stratified based on their TP53 mutation status and were eval- uated for their TME and survival status. Gene differential expression and co-mutation comparative analysis were used to identify other co-factors to further elucidate phenotypic variability among HNSCC patients with different TP53 mutation status. Gene set enrichment analysis were applied to identify relevant altered pathways. HPV- HNSCC was found to be associated with poorer survival status and unfavorable TME, and more frequent TP53 alterations. Among HPV- HNSCC patients, the unfavorable clinical outcome co-occurred with higher level of M0 macrophage infiltration and lower level of T follicular helper cell infiltra- tion. Patients with homozygous TP53 mutation were shown to exhibit poorer survival status, which is shown to be exaggerated with the co-occurrence of PIK3CA mutations. I was able to identify immune-related pathways that were down-regulated and highlight gene interactions that might bring about the emergence of this immunosuppressive TME. In conclusion, the poor prognosis associated with TP53 mutation in HN- SCC patients, was, at least partially, caused by the tumor driven suppression of immune response by the enrichment of macrophages and the deficiency of T cells. I identified a subset of HPV- HNSCC patients that associated with a higher risk of poorer clinical outcomes by a particular TP53 mutation status

Exploration of potential novel drug targets and biomarkers for small cell lung cancer by plasma proteome screening

Background: Small cell lung cancer (SCLC) is characterized by extreme invasiveness and lethality. There have been very few developments in its diagnosis and treatment over the past decades. It is urgently needed to explore potential novel biomarkers and drug targets for SCLC.Methods: Two-sample Mendelian Randomization (MR) was performed to investigate causal associations between SCLC and plasma proteins using genome-wide association studies (GWAS) summary statistics of SCLC from Transdisciplinary Research Into Cancer of the Lung Consortium (nCase = 2,791 vs. nControl = 20,580), and was validated in another cohort (nCase = 2,664 vs. nControl = 21,444). 734 plasma proteins and their genetic instruments of cis-acting protein quantitative trait loci (pQTL) were used, whereas external plasma proteome data was retrieved from deCODE database. Bidirectional MR, Steiger filtering and phenotype scanning were applied to further verify the associations.Results: Seven significant (p < 6.81 × 10−5) plasma protein-SCLC pairs were identified by MR analysis, including ACP5 (OR = 0.76, 95% CI: 0.67–0.86), CPB2 (OR = 0.90, 95% CI: 0.86–0.95), GSTM3 (OR = 0.45, 95% CI: 0.33–0.63), SHMT1 (OR = 0.74, 95% CI: 0.64–0.86), CTSB (OR = 0.79, 95% CI: 0.71–0.88), NTNG1 (OR = 0.81, 95% CI: 0.74–0.90) and FAM171B (OR = 1.40, 95% CI: 1.21–1.62). The external validation confirmed that CPB2, GSTM3 and NTNG1 had protective effects against SCLC, while FAM171B increased SCLC risk. However, the reverse causality analysis revealed that SCLC caused significant changes in plasma levels of most of these proteins, including decreases of ACP5, CPB2, GSTM3 and NTNG1, and the increase of FAM171B.Conclusion: This integrative analysis firstly suggested the causal associations between SCLC and plasma proteins, and the identified several proteins may be promising novel drug targets or biomarkers for SCLC

Functional Organization of a Neural Network for Aversive Olfactory Learning in Caenorhabditis elegans

Many animals use their olfactory systems to learn to avoid dangers, but how neural circuits encode naive and learned olfactory preferences, and switch between those preferences, is poorly understood. Here, we map an olfactory network, from sensory input to motor output, which regulates the learned olfactory aversion of Caenorhabditis elegans for the smell of pathogenic bacteria. Naive animals prefer smells of pathogens but animals trained with pathogens lose this attraction. We find that two different neural circuits subserve these preferences, with one required for the naive preference and the other specifically for the learned preference. Calcium imaging and behavioral analysis reveal that the naive preference reflects the direct transduction of the activity of olfactory sensory neurons into motor response, whereas the learned preference involves modulations to signal transduction to downstream neurons to alter motor response. Thus, two different neural circuits regulate a behavioral switch between naive and learned olfactory preferences.Organismic and Evolutionary BiologyPhysic

Compound heterozygous mutation of the SNX14 gene causes autosomal recessive spinocerebellar ataxia 20

Objective: The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays.Methods: Clinical information of the proband was collected. Peripheral blood was collected from core family members to identify the initial reason for growth and developmental delays by whole exome sequencing (WES) and Sanger sequencing. To ascertain the consequences of the newly discovered variants, details of the variants detected were analyzed by bioinformatic tools. Furthermore, we performed in vitro experimentation targeting SNX14 gene expression to confirm whether the variants could alter the expression of SNX14.Results: The proband had prenatal ultrasound findings that included flattened frontal bones, increased interocular distance, widened bilateral cerebral sulci, and shortened long bones, which resulted in subsequent postnatal developmental delays. The older sister also displayed growth developmental delays and poor muscle tone. WES identified compound heterozygous variants of c.712A>T (p.Arg238Ter) and .2744A>T (p.Gln915Leu) in the SNX14 gene in these two children. Both are novel missense variant that originates from the father and mother, respectively. Sanger sequencing confirmed this result. Following the guideline of the American College of Medical Genetics and Genomics (ACMG), the SNX14 c.712A>T (p.Arg238Ter) variant was predicted to be pathogenic (P), while the SNX14 c.2744A>T (p.Gln915Leu) variant was predicted to be a variant of uncertain significance (VUS). The structural analysis revealed that the c.2744A>T (p.Gln915Leu) variant may impact the stability of the SNX14 protein. In vitro experiments demonstrated that both variants reduced SNX14 expression.Conclusion: The SNX14 gene c.712A>T (p.Arg238Ter) and c.2744A>T (p.Gln915Leu) were identified as the genetic causes of growth and developmental delay in two affected children. This conclusion was based on the clinical presentations of the children, structural analysis of the mutant protein, and in vitro experimental validation. This discovery expands the range of SNX14 gene variants and provides a foundation for genetic counseling and guidance for future pregnancies in the affected children’s families

Impact of stress hyperglycemia ratio on mortality in patients with critical acute myocardial infarction: insight from American MIMIC-IV and the Chinese CIN-II study

Background: Among patients with acute coronary syndrome and percutaneous coronary intervention, stress hyperglycemia ratio (SHR) is primarily associated with short-term unfavorable outcomes. However, the relationship between SHR and long-term worsen prognosis in acute myocardial infarction (AMI) patients admitted in intensive care unit (ICU) are not fully investigated, especially in those with different ethnicity. This study aimed to clarify the association of SHR with all-cause mortality in critical AMI patients from American and Chinese cohorts. Methods: Overall 4,337 AMI patients with their first ICU admission from the American Medical Information Mart for Intensive Care (MIMIC)-IV database (n = 2,166) and Chinese multicenter registry cohort Cardiorenal ImprovemeNt II (CIN-II, n = 2,171) were included in this study. The patients were divided into 4 groups based on quantiles of SHR in both two cohorts. Results: The total mortality was 23.8% (maximum follow-up time: 12.1 years) in American MIMIC-IV and 29.1% (maximum follow-up time: 14.1 years) in Chinese CIN-II. In MIMIC-IV cohort, patients with SHR of quartile 4 had higher risk of 1-year (adjusted hazard radio [aHR] = 1.87; 95% CI: 1.40–2.50) and long-term (aHR = 1.63; 95% CI: 1.27–2.09) all-cause mortality than quartile 2 (as reference). Similar results were observed in CIN-II cohort (1-year mortality: aHR = 1.44; 95%CI: 1.03–2.02; long-term mortality: aHR = 1.32; 95%CI: 1.05–1.66). In both two group, restricted cubic splines indicated a J-shaped correlation between SHR and all-cause mortality. In subgroup analysis, SHR was significantly associated with higher 1-year and long-term all-cause mortality among patients without diabetes in both MIMIC-IV and CIN-II cohort. Conclusion: Among critical AMI patients, elevated SHR is significantly associated with and 1-year and long-term all-cause mortality, especially in those without diabetes, and the results are consistently in both American and Chinese cohorts

Subtype and Site Specific-Induced Metabolic Vulnerabilities in Prostate Cancer

Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer [androgen receptor-expressing prostate cancer (ARPC) and aggressive variant prostate cancer (AVPC)]. Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared with AVPC. Unbiased screening of metabolic signaling pathways in patient-derived xenograft models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared with AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacologic interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759\u27s inhibitory effects in subcutaneous and bone-localized C4-2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone

Clinical features and independent predictors of postoperative refractory trauma to anal fistula combined with T2DM: A propensity score-matched analysis-retrospective cohort study

BackgroundRefractory wound is a common postoperative complication in anal fistula surgery, when combined with type 2 diabetes mellitus (T2DM) it presents a slower recovery time and more complex wound physiology. The study aims to investigate factors associated with wound healing in patients with T2DM.Materials and methods365 T2DM patients who underwent anal fistula surgery at our institution were recruited from June 2017 to May 2022. Through propensity score-matched (PSM) analysis, multivariate logistic regression analysis was applied to determine independent risk factors affecting wound healing.Results122 pairs of patients with no significant differences were successfully established in matched variables. Multivariate logistic regression analysis revealed that uric acid (OR: 1.008, 95% CI: 1.002–1.015, p = 0.012), maximal fasting blood glucose (FBG) (OR: 1.489, 95% CI: 1.028–2.157, p = 0.035) and random intravenous blood glucose (OR: 1.130, 95% CI: 1.008–1.267, p = 0.037) elevation and the incision at 5 o’clock under the lithotomy position (OR: 3.510, 95% CI: 1.214–10.146, p = 0.020) were independent risk factors for impeding wound healing. However, neutrophil percentage fluctuating within the normal range can be considered as an independent protective factor (OR: 0.906, 95% CI: 0.856–0.958, p = 0.001). After executing the receiver operating characteristic (ROC) curve analysis, it was found that the maximum FBG expressed the largest under curve area (AUC), glycosylated hemoglobin (HbA1c) showed the strongest sensitivity at the critical value and maximum postprandial blood glucose (PBG) had the highest specificity at the critical value. To promote high-quality healing of anal wounds in diabetic patients, clinicians should not only pay attention to surgical procedures but also take above-mentioned indicators into consideration

Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions

Syntaxin of plants71 plays essential roles in plant development and stress response via regulating pH homeostasis

SYP71, a plant-specific Qc-SNARE with multiple subcellular localization, is essential for symbiotic nitrogen fixation in nodules in Lotus, and is implicated in plant resistance to pathogenesis in rice, wheat and soybean. Arabidopsis SYP71 is proposed to participate in multiple membrane fusion steps during secretion. To date, the molecular mechanism underlying SYP71 regulation on plant development remains elusive. In this study, we clarified that AtSYP71 is essential for plant development and stress response, using techniques of cell biology, molecular biology, biochemistry, genetics, and transcriptomics. AtSYP71-knockout mutant atsyp71-1 was lethal at early development stage due to the failure of root elongation and albinism of the leaves. AtSYP71-knockdown mutants, atsyp71-2 and atsyp71-3, had short roots, delayed early development, and altered stress response. The cell wall structure and components changed significantly in atsyp71-2 due to disrupted cell wall biosynthesis and dynamics. Reactive oxygen species homeostasis and pH homeostasis were also collapsed in atsyp71-2. All these defects were likely resulted from blocked secretion pathway in the mutants. Strikingly, change of pH value significantly affected ROS homeostasis in atsyp71-2, suggesting interconnection between ROS and pH homeostasis. Furthermore, we identified AtSYP71 partners and propose that AtSYP71 forms distinct SNARE complexes to mediate multiple membrane fusion steps in secretory pathway. Our findings suggest that AtSYP71 plays an essential role in plant development and stress response via regulating pH homeostasis through secretory pathway