Search

Bohao Dai,1,&ast; Xiaorong Peng,1,&ast; Jia Sun,1 Xueling Zhu,1 Xiang Liu,1 Ye Xiong,1 Zhikai Wan,1 Dairong Xiang,1 Jiangjin Hui,1 Chenxi Ying,2 Huiting Liu,1 Biao Zhu1,&ast; 1The Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Cardivascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Biao Zhu, The Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qing Chun Road, Hangzhou, 310006, People’s Republic of China, Email zhubiao1207@zju.edu.cnBackground: HIV-1 CRF01_AE is becoming the predominant HIV-1 subtype among patients in China. The distribution and characteristics of transmission clusters of HIV-1 CRF01_AE in Zhejiang, Eastern China remains unclear. This study analyzed the epidemiologic characteristics and transmission clusters of HIV-1 CRF01_AE in Zhejiang.Methods: Plasma samples obtained from 152 patients of HIV-1 CRF01_AE not undergoing ART were used to amplify HIV-1 pol and env gene. CRF01_AE drug resistance mutations (DRM) prevalence was analysed using Stanford University’s HIV Drug Resistance Database. A phylogenetic tree was constructed using FastTree (version 2.1.11) based on the GTR nucleotide substitution model and visualized using Figtree (version 1.4.4) and The Interactive Tree of Life; the Chinese HIV Gene Sequence Data Platform was used to construct genetic transmission networks.Results: Majority samples could be grouped into CRF01_AE transmission Clusters 1 (11.2%), 4 (64.5%), and 5 (7.2%). The CD4+ T-cell counts in Cluster 1, 4a, 4b are lower than 5 were 15, 38, 30, and 248 cells/mm3, respectively (P < 0.05). The high X4 tropism rates were 13.2%, 11.8%, 20.0%, and 0.0% in Clusters 1, 4a, 4b, and 5, respectively. DRM rates in Clusters 4a and 4b were 17.6%, and 25.45% respectively (P < 0.05), whereas they were 17.6% and 18.2% in Clusters 1 and 5, respectively. In total, 24 transmission genetic networks, comprising 72 sequences and 61 links, were discovered; of them, 61.2%, 11.7%, and 18.2% were from Clusters 4, 1, and 5, respectively (P < 0.05).Conclusion: In Zhejiang, different CRF01_AE clusters displayed unique clinic features. Cluster 4, particularly Cluster 4b, was considered a high-risk transmission cluster. The surveillance of epidemiology of HIV-1 should be enhanced to minimize its transmission.Keywords: HIV-1 CRF01_AE, drug resistance mutation, transmission cluster

Summary: A wide variety of electrophilic derivatives of itaconate, the Kreb’s cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β in response to these innate activators. In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.

A dual-band sleeve monopole antenna with the substrate-integrated coaxial line (SICL) technology is proposed in this paper. Both the radiation structure and the feeding network are modified from the SICL structure. The antenna provides dual-band operation for LoRa (Long Range Radio) applications covering 433 MHz and 868 MHz bands. This antenna operates as a quarter-wavelength monopole with practical omnidirectional radiation performance for each band. The antenna exhibits a gain of 2.0 dBi at 433 MHz with more than 90% radiation efficiency, and a gain of 1.7 dBi at 868 MHz with more than 90% radiation efficiency. The measured −10 dB impedance bandwidths are from $393 \sim 450$ MHz and $826 \sim 931$ MHz, respectively. A good agreement is observed between the measured and the simulated results, which demonstrates that the proposed scheme can be a possible candidate for LoRa applications.

Although most follicular-derived thyroid cancers are well differentiated and have an overall excellent prognosis following treatment with surgery and radioiodine, management of advanced thyroid cancers, including iodine refractory disease and poorly differentiated/undifferentiated subtypes, is more challenging. Over the past decade, better understanding of the genetic drivers and immune milieu of advanced thyroid cancers has led to significant progress in the management of these patients. Numerous targeted kinase inhibitors are now approved by the U.S Food and Drug administration (FDA) for the treatment of advanced, radioiodine refractory differentiated thyroid cancers (DTC) as well as anaplastic thyroid cancer (ATC). Immunotherapy has also been thoroughly studied and has shown promise in selected cases. In this review, we summarize the progress in the understanding of the genetic landscape and the cellular and molecular basis of radioiodine refractory-DTC and ATC, as well as discuss the current treatment options and future therapeutic avenues.

Summary: Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Introduction Ovarian hyperstimulation syndrome (OHSS) is the most significant short-term complication of pharmacological ovarian stimulation. Symptoms range from mild abdominal discomfort to rare complications such as renal failure, thromboembolism and respiratory distress syndrome.Currently, clinical practice typically involves monitoring the patient until the condition becomes severe, at which point they are admitted to hospital, where drainage of ascitic fluid (paracentesis) may take place. Preliminary studies have indicated that earlier outpatient paracentesis may reduce the progression of OHSS and prevent hospitalisation in women.Methods and analysis This UK, multicentre, pragmatic, two-arm, parallel-group, adaptive (group sequential with one interim analysis), open-label, superiority, confirmatory, group sequential, individually randomised controlled trial, with internal pilot will assess the clinical and cost-effectiveness and safety of outpatient paracentesis versus conservative management (usual care) for moderate or severe OHSS. 224 women from 20 National Health Service and private fertility units will be randomised (1:1) and followed up for up to 13.5 months. The primary outcome is the rate of OHSS related hospital admission of at least 24 hours within 28 days postrandomisation. The primary analysis will be an intention to treat with difference in hospitalisation rates as measure of treatment effect. Secondary outcomes include time to resolution of symptoms, patient satisfaction, adverse events and cost-effectiveness. A qualitative substudy will facilitate the feasibility of recruitment. Participant recruitment commenced in June 2022.Ethics and dissemination London—Southeast Research Ethics Committee approved the protocol (reference: 22/LO/0015). Findings will be submitted to peer-reviewed journals and abstracts to relevant national and international conferences, as well as being disseminated to trial participants and patient groups.Trial registration number ISRCTN71978064.

Background: This study aims to provide evidence of factors that impact participant reported serious depression and serious anxiety among individuals receiving injectable opioid agonist treatment (iOAT). Methods: Data from an 18-month longitudinal retrospective cohort of individuals receiving iOAT was utilized. The outcomes of serious depression and serious anxiety were ascertained via self-report in the European Addiction Severity Index. Two Generalized Linear Mixed Models were formulated using Penalized Quasi-Likelihood method. Results: Analyses included 131 participants. Average age was 49.04 years, 31 % self-identified as female, and 30 % self-identified as Indigenous. Adjusted analysis identified the importance of poorer physical health (AOR:1.06; 95 % CI: 1.03, 1.08), illicit opioid use (AOR: 1.03; 95 %CI: 1.01, 1.06), emotional abuse (AOR: 2.01; 95 % CI: 1.17, 3.44), and social isolation (AOR: 1.95; 95 % CI: 1.06, 3.58) with serious depression. Adjusted analysis of serious anxiety identified associations with age (AOR: 0.95; 95 % CI: 0.92, 0.98), illicit benzodiazepine use (AOR:1.31 95 % CI: 1.06, 1.61), poorer physical health (AOR: 1.05; 95 % CI: 1.03, 1.07), and social problems (AOR: 2.09; 95 % CI: 1.18, 3.71). Limitations: Generalizability of study findings may be limited given the criteria used to enroll participants and to define depression and anxiety. Conclusion: Depression and anxiety are highly prevalent among clients receiving iOAT. While both disorders share several factors, there are distinct characteristics associated with each outcome. These include poorer physical health, experiences of abuse, illicit substance use, and social problems. Understanding factors that influence depression and anxiety in iOAT can assist providers in supporting iOAT clients' mental health and developing individualized care plans.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

In brief: The causes of subfertility and recurrent pregnancy loss are often unclear. This study shows that endometrial gland cilia from women with subfertility have ultrastructural defects. Endometrial glands secrete products into the endometrium and are necessary for embryo implantation and successful pregnancy. However, structural and functional abnormalities in endometrial gland cilia from women with reproductive failure remain poorly understood. This was a cross-sectional study where endometrial biopsies were collected at days 19-23 of the menstrual cycle from women with unexplained recurrent pregnancy loss (n = 15), unexplained subfertility (n = 11) or from egg donor control participants (n = 10). Endometrial gland cilia ultrastructure was imaged by transmission electron microscopy and cilia defects assessed by an electron-microscopist from a national primary ciliary dyskinesia diagnostic centre. Endometrial glands were isolated, and the cilia beat frequency recorded by high speed video. Subfertile women have proportionately lower ultrastructurally normal cilia (P < 0.05); higher frequency of absent dynamin arms (P < 0.01) or inner arm defects (P < 0.01) and lower cilia beat frequency (P < 0.05). The mechanisms underlying these obversions have yet to be determined. Recent studies have identified cilia related gene expression changes associated with reproductive failure and this study adds to the growing body of literature revealing structural and functional changes. The observation that cilia defects occurred at a higher frequency in endometrial glands of subfertile women raises the question of its mechanistic role in implantation. [ABSTRACT FROM AUTHOR]

Abstract Background The incidence of androgenetic alopecia in males is on the rise annually, with hair transplantation using follicular unit extraction (FUE) gaining increasing acceptance as an appropriate treatment for these individuals. Methods A retrospective study was undertaken, involving 158 male patients diagnosed with androgenetic alopecia, who underwent treatment between January 2016 and December 2020 at the Medical Cosmetology Department of the First Affiliated Hospital of Xi’an Medical University. Demographic data and treatment characteristics were documented and analyzed. Clinical efficacy, operation-related complications, patient satisfaction rates, and quality of life scores were assessed and analyzed. Results Following FUE hair transplantation, over 90% of the hair follicles survived in 158 patients, with more than 85% of patients achieving a hair follicle survival rate exceeding 95% at 12 months post-operation. Patient satisfaction rates exceeded 98%, while the complication rate was below 6%. Conclusion Our findings demonstrate that FUE is a minimally invasive hair transplant technique associated with a high hair follicle survival rate and optimal hair density. This approach proves effective in treating male androgenetic alopecia and merits further clinical application.

Abstract Objectives Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Four types of RNA modification writers (m6A, m1A, A-I editing, and APA) are widely involved in tumorigenesis and the TME. We aimed to comprehensively explore the role of the four RNA modification writers in the progression and immune microenvironment of HNSCC. Materials and methods We first obtained transcription profile data and transcriptional variation of the four types of RNA modification writers from The Cancer Genome Atlas (TCGA) database. HNSCC patients in TCGA dataset were divided into different clusters based on the four types of RNA modification writers. Univariate Cox and Least absolute shrinkage and selection operator (LASSO) analyses were performed to conduct a Writer-score scoring system, which was successfully verified in the GSE65858 dataset and our clinical sample dataset. Finally, we evaluated the relationship between different RNA modification clusters (Writer-score) and immunological characteristics of HNSCC. Results Two different RNA modification clusters (A and B) were obtained. These RNA modification clusters (Writer-score) were strongly associated with immunological characteristics (immunomodulators, cancer immunity cycles, infiltrating immune cells (TIICs), inhibitory immune checkpoints, and T cell inflamed score (TIS)) of HNSCC. Conclusions This study identified two different RNA modification clusters and explored the potential relationship between RNA modification clusters (Writer-score) and immunological characteristics, offering a new theoretical basis for precision immunotherapy in patients with HNSCC.

Abstract Background The aim of this study was to assess the prognostic significance of serum direct bilirubin (DBIL) for patients newly diagnosed with myelodysplastic syndromes (MDS). Methods The clinical, laboratory, and follow-up data of MDS patients were collected, and the associations of DBIL levels with overall survival (OS) and leukemia-free survival (LFS) were analyzed. Result In total, 262 MDS patients were assigned to the high DBIL level group or the normal DBIL level group in the retrospective study. High DBIL was associated with older age, reduced hemoglobin, higher levels of β2-microglobin, lactate dehydrogenase, and serum ferritin, along with the number of co-mutations (> 1) and a higher frequency of ASXL1, KIT, and KRAS mutations. Multivariate analyses found that high DBIL level was an independent adverse predictor for OS (p = 0.002, hazard ratio = 2.723, 95%CI = 1.442–5.143) but not for LFS (p = 0.057, hazard ratio = 1.678, 95%CI = 0.986–2.857). A novel nomogram based on DBIL, sex, age, β2-microglobulin, lactate dehydrogenase, the Revised International Prognostic Scoring System (IPSS-R) was constructed, which demonstrated superior accuracy compared with the IPSS-R (C-index, 0.790 vs. 0.731, respectively). Conclusion An elevated DBIL level was identified as an independent adverse prognostic factor for MDS patients. An individualized prediction model was established and validated to improve prediction of OS and LFS.

Abstract This paper introduces the novel Adaptive Peak Price with Lazy Updates (APPLU) approach for short-term portfolio optimization (SPO), a method that innovatively combines the Radial Basis Function (RBF) and a new lazy update approach to address the unique challenges of SPO. Our approach is tailored to balance the dual objectives of maximizing returns and minimizing transaction costs, which are critical concerns in dynamically allocating wealth among various assets over time. Unlike conventional methods that primarily rely directly on peak price information, APPLU introduces an adaptive peak price using RBFs to capture continuous depreciation information of assets, thereby alleviating the aggressive nature of traditional peak price strategies and avoiding frequent trades. Furthermore, we propose a new lazy update approach that employs unsquared $$l^{2}$$ l 2 -norm regularization to represent portfolio changes. This approach contrasts with squared $$l^{2}$$ l 2 -norm regularization, which disproportionately penalizes larger portfolio changes while being more lenient towards smaller changes. Thereby, our methodology offers a more balanced and effective approach to portfolio adjustment. Extensive experiments conducted on seven real datasets demonstrate that APPLU outperforms existing strategies in terms of cumulative return and risk-adjusted return, while effectively controlling transaction costs and maintaining a moderate wealth accumulation strategy.

Abstract In this study, peripheral whole blood samples from 22 hospitalized patients and 10 healthy individuals were analyzed using a combination of Data Independent Acquisition (DIA) and Enzyme-Linked Immunosorbent Assay (ELISA) techniques to identify differentially expressed proteins (DEPs) in sepsis patients’ plasma. The aim was to provide accurate and detailed biomarkers, such as SPP1, for determining the pathological stages of sepsis. SPP1, known as osteopontin1 is a pleiotropic protein with a wide distribution and multifunctional effects. Its protein expression is associated with inflammatory changes, including variations in expression levels in infectious diseases, allergic diseases, and situations involving tissue damage. The registration number was ChiCTR1900021261.The full date of first registration year is 2018. In the affiliated hospital of southwest medical university, 22 sepsis patients were hospitalized from January 2019 to September 2020 and 10 normal healthy individuals were selected for DIA-based quantitative proteomics analysis. In addition to gene ontology analysis and Kyoto Encyclopedia of genes and genomes analysis, enrichment analysis of data was performed and target protein network was screened through joint protein–protein interaction and visualization techniques. The selected protein targets were then validated by Elisa kit. The software was used to analyze the differences comparing the control group to the sepsis group and the sepsis group, as well as between sepsis survivals and non-survivals, and a ROC curve was drawn to evaluate the diagnostic value and prognostic effect of the method of the corresponding target proteins. A total of 174 DEPs were screened by bioinformatics analysis. An analysis of go pathway enrichment revealed the following: These proteins were mainly involved in biological processes among them are the inflammation response, the metabolism of extracellular matrix, the secretion of cell secretions, the activation of cells, and the immune response. According to the Kegg pathway analysis, they were mainly involved in complement cascade polymerization, extracellular protease and glycosylase activation, protein synthesis process, biotin metabolism, leukocyte transmembrane migration, bacterial infection and phagosome formation. SPP1 was identified as a possible plasma biomarker and was therefore further validated using Elisa. As a result of experiments, it has been demonstrated that level in sepsis patients is significantly compared to the normal control group and the level is also higher in non-survivals of sepsis. The ROC curve can be used to see that it can diagnose sepsis more accurately and improve prognostic ability prediction. Cell experiments confirm that SPP1 is highly expressed in sepsis. There is a significant difference in the levels of SPP1 protein between the normal group and the sepsis group; it not only has good diagnostic significance for sepsis, but also provides corresponding reference value for patient prognosis; Therefore, it is more likely to become a biological marker of sepsis over time.

Abstract The electron transfer process (ETP) is able to avoid the redox cycling of catalysts by capturing electrons from contaminants directly. However, the ETP usually leads to the formation of oligomers and the reduction of oxidants to anions. Herein, the charge-confined Fe single-atom catalyst (Fe/SCN) with Fe-N3S1 configuration was designed to achieve ETP-mediated contaminant activation of the oxidant by limiting the number of electrons gained by the oxidant to generate 1O2. The Fe/SCN-activate periodate (PI) system shows excellent contaminant degradation performance due to the combination of ETP and 1O2. Experiments and DFT calculations show that the Fe/SCN-PI* complex with strong oxidizing ability triggers the ETP, while the charge-confined effect allows the single-electronic activation of PI to generate 1O2. In the Fe/SCN + PI system, the 100% selectivity dechlorination of ETP and the ring-opening of 1O2 avoid the generation of oligomers and realize the transformation of large-molecule contaminants into small-molecule biodegradable products. Furthermore, the Fe/SCN + PI system shows excellent anti-interference ability and application potential. This work pioneers the generation of active species using ETP’s electron to activate oxidants, which provides a perspective on the design of single-atom catalysts via the charge-confined effect.

Abstract Systems with broken continuous symmetry in ideal lattices cannot be rectified through rearrangement or deformation. Topological metamaterials featuring nontrivial, artificially induced phase transitions have emerged as pivotal constituents for engineering these topological defects, which, until now, have mostly been experimentally realized in linear or planar configurations. Buckminster Fuller lent his name to the C60 ball-shaped carbon allotrope, which is not only the roundest molecule in existence but also embodies 3D topological defects. Here, we construct a C540 metamaterial composed of interspersed pentagons in a hexagonal network of hollow tubes and cavities. By 3D printing this giant closed-cage topology, the nontrivial state-confinements can be fully controlled and visualized, which, in contrast, in synthesized or naturally found fullerenes, is highly challenging. Thanks to our macroscopic metamaterials approach, we are able to map in real-space topological pentagon states probed by sound waves. Our results show how a seemingly unrelated approach can unveil deep physical understanding in carbon allotropes and potentially in a plethora of other complex systems in the near future.

Abstract Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomic resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomic resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, anti-predator strategies, and resilience and adaptive responses. They also serve as essential models for studying broad genomic traits, such as evolutionary genome expansions and contractions, as they exhibit the widest range of genome sizes among all animal taxa and possess multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The emergence of long-read sequencing technologies, combined with advanced molecular and computational techniques that improve scaffolding and reduce computational workloads, is now making it possible to address some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC, https://mvs.unimelb.edu.au/amphibian-genomics-consortium ) in early 2023. This burgeoning community already has more than 282 members from 41 countries. The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and call on the research and conservation communities to unite as part of the AGC to enable amphibian genomics research to “leap” to the next level.

Abstract Previous studies have pointed to a potential link between Obstructive Sleep Apnea (OSA) and gastrointestinal diseases, suggesting that this relationship might be influenced by the presence of Metabolic Syndrome. However, the exact role of these factors in determining gastrointestinal diseases has not been thoroughly explored. In our study, we utilized data from the Genome-wide Association Studies (GWAS) database, focusing on OSA, metabolic syndrome characteristics such as Body Mass Index (BMI), waist circumference, triglycerides, cholesterol, hypertension, type 2 diabetes, and common gastrointestinal diseases including chronic gastritis, gastric ulcers, irritable bowel syndrome, colorectal cancer, inflammatory bowel disease, cholecystitis, nonalcoholic fatty liver, and dyspepsia. By applying Single-variable and Multi-variable Mendelian randomization methods, we aimed to assess the correlation between OSA and gastrointestinal diseases and investigate whether this correlation is influenced by metabolic syndrome. Our findings revealed a strong association between OSA and an increased risk of chronic gastritis, gastric ulcers, inflammatory bowel disease, and nonalcoholic fatty liver disease. No significant connections were found with irritable bowel syndrome, colorectal cancer, cholecystitis, or dyspepsia. Additionally, OSA was linked to metabolic syndrome traits like BMI, waist circumference, triglycerides, hypertension, and type 2 diabetes. Further analysis showed that BMI, triglycerides, and hypertension were causally related to inflammatory bowel disease; BMI, waist circumference, hypertension, and type 2 diabetes to nonalcoholic fatty liver disease; and triglycerides, hypertension, and type 2 diabetes to chronic gastritis. The multivariable analysis indicated that hypertension mediates the relationship between OSA and chronic gastritis; BMI, triglycerides, and hypertension mediate the link between OSA and inflammatory bowel disease; and waist circumference mediates the connection between OSA and nonalcoholic fatty liver disease. To wrap up, this finding helps us understand how these issues might be related and stresses the role of metabolic syndrome in preventing them, which could lessen their effect on health.

Abstract Background Immunocompromised patients face higher risks of Severe Acute Respiratory Syndrome Coronavirus 2 infection and co-infections, leading to a possibility of high disease severity and poor outcomes. Conversely, immunosuppression can mitigate the excessive inflammatory response induced by the virus, potentially reducing disease severity. This study aims to investigate the prognostic differences and early inflammatory response characteristics in various types of immunocompromised patients with severe coronavirus disease 2019 (COVID-19) admitted to intensive care unit (ICU), summarize their clinical features, and explore potential mechanisms. Methods A retrospective analysis was conducted on critically ill COVID-19 patients admitted to the ICU of 59 medical centers in mainland China during the Omicron outbreak from November 2022 to February 2023. Patients were categorized into two groups based on their immunosuppression status: immunocompromised and immunocompetent. Immunocompromised patients were further subdivided by etiology into cancer patients, solid organ transplant (SOT) patients, and other immunocompromised groups, with immunocompetent patients serving as controls. The mortality rates, respiratory support, complications, and early inflammatory cytokine dynamics upon ICU admission among different populations were analyzed. Results A total of 2030 critically ill COVID-19 patients admitted to ICU were included, with 242 in the immunocompromised group and 1788 in the immunocompetent group. Cancer patients had a higher median age of 69 years (IQR 59, 77), while SOT patients were generally younger and had less severe illness upon ICU admission, with a median APACHE II score of 12.0 (IQR 8.0, 20.0). Cancer patients had a twofold increased risk of death (OR = 2.02, 95% CI 1.18–3.46, P = 0.010) compared to immunocompetent patients. SOT and cancer patients exhibited higher C-reactive protein and serum ferritin levels than the immunocompetent group in their early days of ICU admission. The CD8+ T cells dynamics were inversely correlated in cancer and SOT patients, with Interleukin-6 levels consistently lower in the SOT group compared to both immunocompetent and cancer patients. Conclusion Critically ill COVID-19 patients admitted to the ICU exhibit distinct clinical outcomes based on their immunosuppression status, with cancer patients facing the highest mortality rate due to variations in inflammatory responses linked to their immunosuppression mechanisms. Monitoring dynamic changes in inflammatory markers and immune cells, particularly CD8+ T lymphocytes and IL-6, may offer valuable prognostic insights for these patients.

Abstract Plants and microorganisms have been co-evolving and interacting for billions of years. Prior researchers have explored the plant’s immune system responses and interaction with diverse microbes, but several ambiguities need further explanation. This review provides insight into mechanisms underlying plant–microbe interaction and knowledge dearth domains, along with possibilities to use beneficial microbes to improve plant growth, disease resistance, nutritional value, and productivity. Microorganisms in the phyllosphere and the rhizosphere could be beneficial or pathogenic. Host plants use their innate immune system and the antagonistic competence of plant-growth-promoting microbes against pathogens. The innate immune system of plants has two paramount protection forms involving different types of immune receptors, which assist in recognizing non-self-components. The first group of receptors is membrane-resident pattern recognition receptors (PRRs), which are responsible for sensing microbe-associated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs). The second group consists of intracellular immune sensors, specifically resistance (R) proteins, astute in recognizing the structure or function of strain-specific pathogen effectors injected into host plant cells. Plants activate their pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) defense mechanisms to counter the infection. Plants benefit from certain microbes by promoting their growth, disease resistance, and resilience under various stress conditions in exchange for shelter and nutrients. Graphical Abstract

Abstract The relationship between albumin-corrected anion gap (ACAG) and severe disorder of consciousness (SDOC), in-hospital mortality, and long-term mortality in patients with ischemic stroke (IS) remains unclear. This study investigates the association of ACAG with SDOC and other outcomes in IS using data from the MIMIC-IV database. A total of 2,379 IS patients were included, with a demographic breakdown showing 51% were male and an SDOC incidence of 16.4%. Analysis through Cox proportional hazards models indicated that ACAG is significantly associated with the risks of both SDOC and mortality. Additionally, restricted cubic spline(RCS) analysis suggested a nearly linear relationship between increasing ACAG levels and the incidence of SDOC. Kaplan-Meier curves demonstrated significant differences in the incidence rates of SDOC, in-hospital mortality, and long-term mortality across varying ACAG levels. The findings suggest that ACAG serves as an independent predictor for SDOC, in-hospital mortality, and long-term mortality in IS patients. Nonetheless, further prospective studies are needed to confirm these causal relationships.

Abstract Intestinal stem cells (ISCs) are responsible for intestinal homeostasis and are important for the regeneration of damaged intestine. We established an ionizing radiation (IR)-induced intestinal injury model and observed that Gelsolin KO mice had increased radiosensitivity. The deletion of Gelsolin aggravated intestinal damage and reduced the number of ISCs after lethal IR. The intestinal organoid experiments showed that Gelsolin deletion inhibited ISCs function after IR. Notably, RNA sequencing and RT-PCR results showed IL-17 signaling pathway was down-regulated and Th17 cells differentiation was inhibited in Gelsolin KO mice. Moreover, recombinant IL-17 A ameliorated IR-induced intestinal injury and promoted ISCs regeneration. To figure out the role of Gelsolin in Th17 cells differentiation, flow cytometry was used and we found that Gelsolin targets Th17 cells functionality via the p-STAT3/RORγt axis. By establishing the co-culture system, we proved that Th17 cells promoted self-renewal and budding abilities in Gelsolin-deficient organoids. Finally, we found that Gelsolin was protective against DSS-induced colitis and that this protective effect was not specific or limited to the IR induced intestinal injury model. Based on these results, we proved Gelsolin maintained the regeneration of ISCs by sustaining Th17 cells functions via the p-STAT3/RORγt axis. Graphical abstract

Abstract During space flight, prolonged weightlessness stress exerts a range of detrimental impacts on the physiology and psychology of astronauts. These manifestations encompass depressive symptoms, anxiety, and impairments in both short-term memory and motor functions, albeit the precise underlying mechanisms remain elusive. Recent studies have revealed that hindlimb unloading (HU) animal models, which simulate space weightlessness, exhibited a disorder in memory and motor function associated with endogenous formaldehyde (FA) accumulation in the hippocampus and cerebellum, disruption of brain extracellular space (ECS), and blockage of interstitial fluid (ISF) drainage. Notably, the impairment of the blood-brain barrier (BBB) caused by space weightlessness elicits the infiltration of albumin and hemoglobin from the blood vessels into the brain ECS. However, excessive FA has the potential to form cross-links between these two proteins and amyloid-beta (Aβ), thereby obstructing ECS and inducing neuron death. Moreover, FA can inhibit N-methyl-D-aspartate (NMDA) currents by crosslinking NR1 and NR2B subunits, thus impairing memory. Additionally, FA has the ability to modulate the levels of certain microRNAs (miRNAs) such as miRNA-29b, which can affect the expression of aquaporin-4 (AQP4) so as to regulate ECS structure and ISF drainage. Especially, the accumulation of FA may inactivate the ataxia telangiectasia-mutated (ATM) protein kinase by forming cross-linking, a process that is associated with ataxia. Hence, this review presents that weightlessness stress-derived FA may potentially serve as a crucial catalyst in the deterioration of memory and motor abilities in the context of microgravity.

Abstract Background Rapid on-site evaluation (ROSE) plays an important role during transbronchial sampling, providing an intraoperative cytopathologic evaluation. However, the shortage of cytopathologists limits its wide application. This study aims to develop a deep learning model to automatically analyze ROSE cytological images. Methods The hierarchical multi-label lung cancer subtyping (HMLCS) model that combines whole slide images of ROSE slides and serum biological markers was proposed to discriminate between benign and malignant lesions and recognize different subtypes of lung cancer. A dataset of 811 ROSE slides and paired serum biological markers was retrospectively collected between July 2019 and November 2020, and randomly divided to train, validate, and test the HMLCS model. The area under the curve (AUC) and accuracy were calculated to assess the performance of the model, and Cohen’s kappa (κ) was calculated to measure the agreement between the model and the annotation. The HMLCS model was also compared with professional staff. Results The HMLCS model achieved AUC values of 0.9540 (95% confidence interval [CI]: 0.9257–0.9823) in malignant/benign classification, 0.9126 (95% CI: 0.8756–0.9365) in malignancy subtyping (non-small cell lung cancer [NSCLC], small cell lung cancer [SCLC], or other malignancies), and 0.9297 (95% CI: 0.9026–0.9603) in NSCLC subtyping (lung adenocarcinoma [LUAD], lung squamous cell carcinoma [LUSC], or NSCLC not otherwise specified [NSCLC-NOS]), respectively. In total, the model achieved an AUC of 0.8721 (95% CI: 0.7714–0.9258) and an accuracy of 0.7184 in the six-class classification task (benign, LUAD, LUSC, NSCLC-NOS, SCLC, or other malignancies). In addition, the model demonstrated a κ value of 0.6183 with the annotation, which was comparable to cytopathologists and superior to trained bronchoscopists and technicians. Conclusion The HMLCS model showed promising performance in the multiclassification of lung lesions or intrathoracic lymphadenopathy, with potential application to provide real-time feedback regarding preliminary diagnoses of specimens during transbronchial sampling procedures. Clinical trial number Not applicable.

Abstract Background Abnormalities in lipid metabolism are common among adult asthmatics. However, the precise directionality linking asthma to blood lipid levels remains controversial. Our study aimed to evaluate the association between the Non-HDL to HDL Ratio (NHHR), a lipid composite index, and asthma prevalence among the adult population in the United States. Methods Utilizing adult participants’ data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2009 to 2018, the study employed a multivariable logistic regression model, adjusting for covariables, to establish the relationship between NHHR levels and the prevalence of asthma. Furthermore, smoothing curve fitting and subgroup analyses were conducted to investigate the robustness of this association. Results This study included 26,023 adult individuals (mean age = 49.63 ± 17.66). In the fully adjusted model, a significant inverse association was observed between log-transformed NHHR values and asthma prevalence (OR = 0.85, 95% CI: 0.79–0.93). Subgroup analysis revealed that gender served as a modulator, altering the association between NHHR levels and asthma prevalence. A more pronounced negative association between lnNHHR and asthma prevalence was noted among male participants [(Male: OR = 0.78, 95% CI: 0.69–0.88) vs. (Female: OR = 0.92, 95% CI: 0.83–1.03), P for interaction = 0.0313]. Conclusions Our study revealed an inverse association between NHHR levels and the prevalence of asthma in the US adult population, which is influenced by gender. NHHR measurement may be a potential tool for early identification and prediction of adult asthmatics in specific populations.

Objective: The possible enhancing effect of anlotinib on programmed death receptor ligand (PD-L1) antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium, including lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), were determined to identify patients who would benefit from this treatment. Methods: PD-L1 positivity in LECs, BECs, and tumor cells (TCs) was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450 (PD-L1 antibody) alone or in combination with anlotinib in patients with non-small cell lung cancer. Progression-free survival (PFS) with different levels of PD-L1 expression was compared between the two groups. Results: Among 75 patients, the median PFS (mPFS) was longer in patients who received TQB2450 with anlotinib [10 and 12 mg (161 and 194 days, respectively)] than patients receiving TQB2450 alone (61 days) [hazard ratio (HR) 10 mg = 0.390 (95% confidence interval {CI}, 0.201–0.756), P = 0.005; HR 12 mg = 0.397 (0.208–0.756), P = 0.005]. The results were similar among 58 patients with high PD-L1 expression in LECs and TCs [159 and 209 vs. 82 days, HR 10 mg = 0.445 (0.210–0.939), P = 0.034; HR 12 mg = 0.369 (0.174–0.784), P = 0.009], and 53 patients with high PD-L1 expression in BECs and TCs [161 and 209 vs. 41 days, HR 10 mg = 0.340 (0.156–0.742), P = 0.007; HR 12 mg = 0.340 (0.159–0.727), P = 0.005]. No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases. Conclusions: Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs. Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs, which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Based on autumn precipitation data from 1961 to 2021 in Shanxi Province， NCEP/NCAR reanalysis data， and sea surface temperature data， the spatial-temporal variation characteristics and cause diagnosis of autumn precipitation in Shanxi Province were analyzed and discussed by using EOF analysis， correlation analysis and regression analysis.The results show that the autumn precipitation in Shanxi Province was relatively high before the mid-1970s， but decreased afterwards， and began to increase again in the mid-2000s.Further exploration of the causes of this interdecadal variation from the perspective of atmospheric circulation reveals that， during periods of excessive precipitation， the 200 hPa latitudinal wind field is located in the north of the East Asian westerly jet， which is beneficial for enhancing the upward movement in Shanxi； The 500 hPa geopotential height field exhibits a significant “+-+” anomaly distribution in the Europe and Asia region， which is conducive to the southward eruption of high latitude cold air； The 850 hPa wind field is conducive to the transport of low latitude water vapor to Shanxi， and under such high and low altitude circulation configuration， it is conducive to an increase in precipitation in Shanxi.At the same time， there is a close relationship between autumn precipitation and sea surface temperature anomaly in Shanxi.When the sea surface temperature in the central North Pacific is higher and in the tropical Middle East Pacific is lower from March to May， the autumn precipitation in the southern part of Shanxi is prone to behigher.

Abstract Objective This study aimed to investigate the risk factors affecting the presence of carotid plaque in asymptomatic adults. Methods Asymptomatic adults (age > 40 years, no symptoms of cardiovascular and cerebrovascular diseases) undergoing routine health examinations from physical examination department were included in this study. Carotid plaque was measured by Resona 7OB and Resona 8EXP color Doppler ultrasound and L9-3U and L4-5WU probes. The focal carotid intima–media thickness was greater than 1.1 mm, and the local protrusion of the artery wall into the artery lumen suggested the presence of carotid atherosclerotic plaque. According to their ultrasound results, 1077 asymptomatic adults were divided into a group with carotid plaque (477) and a group without carotid plaque (600). Results A total of 1077 asymptomatic adults were included in this study, of whom 44.3% had carotid plaque. The proportion of men with carotid plaque was 84.5%. Multifactorial logistic analysis suggested that age, fasting blood glucose (FBG), total cholesterol (TC), homocysteine (Hcy) and male gender were risk factors for carotid atherosclerosis. The predictive probability of these risk factor indicators derived from the multifactorial model was calculated using receiver operating characteristic (ROC) curves with SPSS 25.0 software. The calculated area under the receiver operating characteristic curve (AUC) was 0.715 (95% CI, 0.685–0.746). Conclusion Age, FBG, TC, Hcy and male gender are risk factors for carotid atherosclerosis in asymptomatic adults. Gender differences in carotid atherosclerosis deserve further attention.

Abstract Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMBR630H) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMBR630H knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMBR630H knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.

Abstract High signal-to-noise ratio (SNR) seismic waveform data are conductive to various studies in seismology. Seismic denoising aims to enhance SNR by eliminating additive noise through signal processing while preserving important features of the seismic signal. Conventional parametric seismic denoising methods often require selecting appropriate parameters to achieve optimal results, which may be limiting when dealing with various types and scales of seismic data. Here, we develop an adaptive parameter-free denoising method by combining general cross-validation (GCV) thresholding and pixel connectivity in synchrosqueezed (SS) domain. In this denoising framework, the synchrosqueezed continuous wavelet transform (SS-CWT) is first applied to obtain a high-resolution time–frequency representation. Then, the GCV approach, which allows for choosing the (nearly) optimal threshold without relying on any prior knowledge about the noise level, is employed to attenuate most of the low-energy noise. After that, the relatively isolated high-energy residual noise remaining in the SS-CWT spectrum is removed using pixel connectivity thresholding. Finally, the inverse SS-CWT is applied to the thresholded spectrum to obtain the denoised seismic record. As the thresholds for GCV and pixel connectivity are derived from the spectrum characteristics of the data being analyzed, the proposed denoising approach is highly adaptive and parameter-free. We demonstrate the effectiveness and versatility of the proposed denoising framework using synthetic data and real seismic data from diverse monitoring scenarios, including land, ocean, and emerging distributed acoustic sensing (DAS). The results indicate that the method is a stable and efficient tool for seismic data denoising. Graphical Abstract