Effects of chronic exposure to a high fat diet, nutritive or non-nutritive sweeteners on hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes of male Sprague-Dawley rats.

PURPOSE: Diet-related factors are of great significance in the regulation of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonad (HPG) axes. In this study, we aimed to investigate the effects of chronic exposure to a high fat diet (HFD), fructose or sucralose on the endocrine functions. METHODS: Male, Sprague-Dawley rats received a normal chow diet, HFD, 10% fructose or 0.02% sucralose for 10 weeks. Behavioral changes were assessed by open field (OFT) and elevated plus-maze (EPM) tests at week 8. H&E staining was used to observe pathological changes in adrenal cortex, testis and perirenal adipose tissue. Serum hormone concentrations were quantified via enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of genes along the HPA and HPG axes were determined using real-time PCR. RESULTS: All types of dietary interventions increased body weight and disturbed metabolic homeostasis, with anxiogenic phenotype in behavioral tests and damage to cell morphology of adrenal cortex and testis being observed. Along the HPA axis, significantly increased corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) concentrations were observed in the HFD or 0.02% sucralose group. For HPG axis, gonadotropin-releasing hormone (GnRH) and estradiol (E2) concentrations were significantly increased in all dietary intervention groups, while decreased concentrations of follicle-stimulating hormone (FSH) and testosterone (T) were also detected. Moreover, transcriptional profiles of genes involved in the synthesis of hormones and corresponding hormone receptors were significantly altered. CONCLUSION: Long-term consumption of HFD, fructose or sucralose manifested deleterious effects on endocrine system and resulted in the dysregulation of HPA and HPG axes.

Asymmetric Convolution: An Efficient and Generalized Method to Fuse Feature Maps in Multiple Vision Tasks.

Fusing features from different sources is a critical aspect of many computer vision tasks. Existing approaches can be roughly categorized as parameter-free or learnable operations. However, parameter-free modules are limited in their ability to benefit from offline learning, leading to poor performance in some challenging situations. Learnable fusing methods are often space-consuming and timeconsuming, particularly when fusing features with different shapes. To address these shortcomings, we conducted an in-depth analysis of the limitations associated with both fusion methods. Based on our findings, we propose a generalized module named Asymmetric Convolution Module (ACM). This module can learn to encode effective priors during offline training and efficiently fuse feature maps with different shapes in specific tasks. Specifically, we propose a mathematically equivalent method for replacing costly convolutions on concatenated features. This method can be widely applied to fuse feature maps across different shapes. Furthermore, distinguished from parameter-free operations that can only fuse two features of the same type, our ACM is general, flexible, and can fuse multiple features of different types. To demonstrate the generality and efficiency of ACM, we integrate it into several state-of-the-art models on three representative vision tasks: visual object tracking, referring video object segmentation, and monocular 3D object detection. Extensive experimental results on three tasks and several datasets demonstrate that our new module can bring significant improvements and noteworthy efficiency.

Evaluation of specific RBE in different cells of hippocampus under high-dose proton irradiation in rats.

The study aimed to determine the specific relative biological effectiveness (RBE) of various cells in the hippocampus following proton irradiation. Sixty Sprague-Dawley rats were randomly allocated to 5 groups receiving 20 or 30 Gy of proton or photon irradiation. Pathomorphological neuronal damage in the hippocampus was assessed using Hematoxylin-eosin (HE) staining. The expression level of NeuN, Nestin, Caspase-3, Olig2, CD68 and CD45 were determined by immunohistochemistry (IHC). The RBE range established by comparing the effects of proton and photon irradiation at equivalent biological outcomes. Proton20Gy induced more severe damage to neurons than photon20Gy, but showed no difference compared to photon30Gy. The RBE of neuron was determined to be 1.65. Similarly, both proton20Gy and proton30Gy resulted in more inhibition of oligodendrocytes and activation of microglia in the hippocampal regions than photon20Gy and photon30Gy. However, the expression of Olig2 was higher and CD68 was lower in the proton20Gy group than in the photon30Gy group. The RBE of oligodendrocyte and microglia was estimated to be between 1.1 to 1.65. For neural stem cells (NSCs) and immune cells, there were no significant difference in the expression of Nestin and CD45 between proton and photon irradiation (both 20 and 30 Gy). Therefore, the RBE for NSCs and immune cell was determined to be 1.1. These findings highlight the varying RBE values of different cells in the hippocampus in vivo. Moreover, the actual RBE of the hippocampus may be higher than 1.1, suggesting that using as RBE value of 1.1 in clinical practice may underestimate the toxicities induced by proton radiation.

Causal relationship between inflammatory cytokines and autoimmune thyroid disease: a bidirectional two-sample Mendelian randomization analysis.

Background: Autoimmune thyroid disease (AITD) ranks among the most prevalent thyroid diseases, with inflammatory cytokines playing a decisive role in its pathophysiological process. However, the causal relationship between the inflammatory cytokines and AITD remains elusive. Methods: A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal connection between AITD and 41 inflammatory cytokines. Genetic variations associated with inflammatory cytokines were sourced from the FinnGen biobank, whereas a comprehensive meta-analysis of genome-wide association studies (GWASs) yielded data on Graves' disease (GD) and Hashimoto thyroiditis. Regarding the MR analysis, the inverse variance-weighted, MR-Egger, and weighted median methods were utilized. Additionally, sensitivity analysis was conducted using MR-Egger regression, MR-pleiotropy residual sum, and outliers. Results: Seven causal associations were identified between inflammatory cytokines and AITD. High levels of tumor necrosis factor-ß and low levels of stem cell growth factor-ß were indicative of a higher risk of GD. In contrast, high levels of interleukin-12p70 (IL-12p70), IL-13, and interferon-γ and low levels of monocyte chemotactic protein-1 (MCP-1) and TNF-α suggested a higher risk of HD. Moreover, 14 causal associations were detected between AITD and inflammatory cytokines. GD increases the levels of macrophage inflammatory protein-1ß, MCP-1, monokine induced by interferon-γ (MIG), interferon γ-induced protein 10 (IP-10), stromal cell-derived factor-1α, platelet-derived growth factor BB, ß-nerve growth factor, IL-2ra, IL-4, and IL-17 in blood, whereas HD increases the levels of MIG, IL-2ra, IP-10, and IL-16 levels. Conclusion: Our bidirectional MR analysis revealed a causal relationship between inflammatory cytokines and AITD. These findings offer valuable insights into the pathophysiological mechanisms underlying AITD.

Selection signatures and landscape genomics analysis to reveal climate adaptation of goat breeds.

Goats have achieved global prominence as essential livestock since their initial domestication, primarily owing to their remarkable adaptability to diverse environmental and production systems. Differential selection pressures influenced by climate have led to variations in their physical attributes, leaving genetic imprints within the genomes of goat breeds raised in diverse agroecological settings. In light of this, our study pursued a comprehensive analysis, merging environmental data with single nucleotide polymorphism (SNP) variations, to unearth indications of selection shaped by climate-mediated forces in goats. Through the examination of 43,300 SNPs from 51 indigenous goat breeds adapting to different climatic conditions using four analytical methods: latent factor mixed models (LFMM), F-statistics (Fst), Extended haplotype homozygosity across populations (XPEHH), and spatial analysis method (SAM), A total of 74 genes were revealed to display clear signs of selection, which are believed to be influenced by climatic conditions. Among these genes, 32 were consistently identified by at least two of the applied methods, and three genes (DENND1A, PLCB1, and ITPR2) were confirmed by all four approaches. Moreover, our investigation yielded 148 Gene Ontology (GO) terms based on these 74 genes, underlining pivotal biological pathways crucial for environmental adaptation. These pathways encompass functions like vascular smooth muscle contraction, cellular response to heat, GTPase regulator activity, rhythmic processes, and responses to temperature stimuli. Of significance, GO terms about endocrine regulation and energy metabolic responses, key for local adaptation were also uncovered, including biological processes, such as cell differentiation, regulation of peptide hormone secretion, and lipid metabolism. These findings contribute to our knowledge of the genetic structure of climate-triggered adaptation across the goat genome and have practical implications for marker-assisted breeding in goats.

SBFI26 induces triple-negative breast cancer cells ferroptosis via lipid peroxidation.

SBFI26, an inhibitor of FABP5, has been shown to suppress the proliferation and metastasis of tumour cells. However, the underlying mechanism by which SBFI26 induces ferroptosis in breast cancer cells remains largely unknown. Three breast cancer cell lines were treated with SBFI26 and CCK-8 assessed cytotoxicity. Transcriptome was performed on the Illumina platform and verified by qPCR. Western blot evaluated protein levels. Malondialdehyde (MDA), total superoxide dismutase (T-SOD), Fe, glutathione (GSH) and oxidized glutathione (GSSG) were measured. SBFI26 induced cell death time- and dose-dependent, with a more significant inhibitory effect on MDA-MB-231 cells. Fer-1, GSH and Vitamin C attenuated the effects but not erastin. RNA-Seq analysis revealed that SBFI26 treatment significantly enriched differentially expressed genes related to ferroptosis. Furthermore, SBFI26 increased intracellular MDA, iron ion, and GSSG levels while decreasing T-SOD, total glutathione (T-GSH), and GSH levels.SBFI26 dose-dependently up-regulates the expression of HMOX1 and ALOX12 at both gene and protein levels, promoting ferroptosis. Similarly, it significantly increases the expression of SAT1, ALOX5, ALOX15, ALOXE3 and CHAC1 that, promoting ferroptosis while downregulating the NFE2L2 gene and protein that inhibit ferroptosis. SBFI26 leads to cellular accumulation of fatty acids, which triggers excess ferrous ions and subsequent lipid peroxidation for inducing ferroptosis.

Operative treatment of pulmonary primitive neuroectodermal tumor: a case report and literature review.

BACKGROUND: Pulmonary primitive neuroectodermal tumor (PNET), a member of the Ewing sarcoma family of tumors, is a rare malignancy that is associated with a grim prognosis. To date, fewer than 30 cases of pulmonary PNET have been reported. In this case report, we present the clinical details of a 12-year-old girl with pulmonary PNET who underwent surgical treatment. We also conducted an analysis and summary of other relevant studies and the surgical outcomes. CASE PRESENTATION: In May 2018, a 12-year-old girl was admitted with symptoms of cough and blood-tinged phlegm. A computed tomography scan revealed a large mass, measuring 12.9 cm × 8.1 cm, in the right middle and lower lungs. A percutaneous lung biopsy confirmed poorly differentiated tumor cells with a nested growth pattern. Immunohistochemical staining demonstrated positive expression of CD99, CD56, Vimentin, and Synaptophysin. The patient was diagnosed with pulmonary PNET. Following three cycles of neoadjuvant chemotherapy, a substantial reduction in tumor volume was observed. Subsequently, the patient underwent a surgical procedure involving pneumonectomy and partial resection of the left atrium with the assistance of cardiopulmonary bypass. The patient was discharged 37 days after surgery. During a three-year follow-up period, she exhibited no signs of tumor recurrence and has successfully returned to school. CONCLUSIONS: This case highlights the successful management of an advanced PNET with neoadjuvant chemotherapy, pneumonectomy, and partial resection of the left atrium employing cardiopulmonary bypass. The patient remained disease-free after three years. Our analysis of surgically treated cases indicates that neoadjuvant chemotherapy can contribute to improved prognoses for PNET patients. It is crucial to emphasize that complete surgical excision remains the cornerstone of treatment, underscoring the importance of surgeons considering radical surgical approaches whenever feasible for patients with pulmonary PNETs.

Diosmetin Ameliorates HFD-induced Cognitive Impairments via Inhibiting Metabolic Disorders, Mitochondrial Dysfunction and Neuroinflammation in Male SD Rats.

Currently, accumulating evidence has indicated that overnutrition-associated obesity may result in not only metabolic dysregulations, but also cognitive impairments. This study aimed to investigate the protective effects of Diosmetin, a bioflavonoid compound with multiple biological functions, on cognitive deficits induced by a high fat diet (HFD) and the potential mechanisms. In the present study, oral administration of Diosmetin (25, 50 and 100 mg/kg) for 12 weeks significantly reduced the body weight, restored glucose tolerance and normalized lipid profiles in the serum and liver in HFD-induced obese rats. Diosmetin also significantly ameliorated depression-like behaviors and impaired spatial memory in multiple behavioral tests, including the open field test, elevated plus-maze and Morris water maze, which was in accordance with the decreased pathological changes and neuronal damage in different regions of hippocampus as suggested by H&E and Nissl staining. Notably, our results also indicated that Diosmetin could significantly improve mitochondrial dysfunction induced by HFD through upregulating genes involved in mitochondrial biogenesis and dynamics, increasing mitochondrial ATP levels and inhibiting oxidative stress. Moreover, the levels of key enzymes involved in the TCA cycle were also significantly increased upon Diosmetin treatment. Meanwhile, Diosmetin inhibited HFD-induced microglial overactivation and down-regulated inflammatory cytokines both in the serum and hippocampus. In conclusion, these results indicated that Diosmetin might be a novel nutritional intervention to prevent the occurrence and development of obesity-associated cognitive dysfunction via metabolic regulation and anti-inflammation.

Selecting Monoclonal Cell Lineages from Somatic Reprogramming Using Robotic-Based Spatial-Restricting Structured Flow.

Somatic cell reprogramming generates induced pluripotent stem cells (iPSCs), which serve as a crucial source of seed cells for personalized disease modeling and treatment in regenerative medicine. However, the process of reprogramming often causes substantial lineage manipulations, thereby increasing cellular heterogeneity. As a consequence, the process of harvesting monoclonal iPSCs is labor-intensive and leads to decreased reproducibility. Here, we report the first in-house developed robotic platform that uses a pin-tip-based micro-structure to manipulate radial shear flow for automated monoclonal iPSC colony selection (~1 s) in a non-invasive and label-free manner, which includes tasks for somatic cell reprogramming culturing, medium changes; time-lapse-based high-content imaging; and iPSCs monoclonal colony detection, selection, and expansion. Throughput-wise, this automated robotic system can perform approximately 24 somatic cell reprogramming tasks within 50 days in parallel via a scheduling program. Moreover, thanks to a dual flow-based iPSC selection process, the purity of iPSCs was enhanced, while simultaneously eliminating the need for single-cell subcloning. These iPSCs generated via the dual processing robotic approach demonstrated a purity 3.7 times greater than that of the conventional manual methods. In addition, the automatically produced human iPSCs exhibited typical pluripotent transcriptional profiles, differentiation potential, and karyotypes. In conclusion, this robotic method could offer a promising solution for the automated isolation or purification of lineage-specific cells derived from iPSCs, thereby accelerating the development of personalized medicines.

Feasibility of tracheal reconstruction using silicone-stented aortic allografts.

OBJECTIVES: Tracheal reconstruction post-extensive resection remains an unresolved challenge in thoracic surgery. This study evaluates the use of aortic allografts (AAs) for tracheal replacement and reconstruction in a rat model, aiming to elucidate the underlying mechanisms of tracheal regeneration. METHODS: AAs from female rats were employed for tracheal reconstruction in 36 male rats, with the replacement exceeding half of the tracheal length. To avert collapse, silicone stents were inserted into the AA lumens. No immunosuppressive therapy was administered. The rats were euthanized biweekly, and the AAs were examined for neovascularization, cartilage formation, respiratory epithelial ingrowth, submucosal gland regeneration and the presence of the Sex-determining region of Y-chromosome (SRY) gene. RESULTS: All procedures were successfully completed without severe complications. The AA segments were effectively integrated into the tracheal framework, with seamless distinction at suture lines. Histological analysis indicated an initial inflammatory response, followed by the development of squamous and mucociliary epithelia, new cartilage ring formation and gland regeneration. In situ hybridization identified the presence of the SRY gene in newly formed cartilage rings, confirming that regeneration was driven by recipient cells. CONCLUSIONS: This study demonstrates the feasibility of AAs transforming into functional tracheal conduits, replicating the main structural and functional characteristics of the native trachea. The findings indicate that this approach offers a novel pathway for tissue regeneration and holds potential for treating extensive tracheal injuries.

Luteolin ameliorates pentetrazole-induced seizures through the inhibition of the TLR4/NF-κB signaling pathway.

Epilepsy represents a prevalent neurological disorder in the population, and the existing antiepileptic drugs (AEDs) often fail to adequately control seizures. Inflammation is recognized as a pivotal factor in the pathophysiology of epilepsy. Luteolin, a natural flavonoid extract, possesses anti-inflammatory properties and exhibits promising neuroprotective activity. Nevertheless, the precise molecular mechanisms underlying the antiepileptic effects of luteolin remain elusive. In this study, we established a rat model of epilepsy using pentylenetetrazole (PTZ) to induce seizures. A series of behavioral experiments were conducted to assess behavioral abilities and cognitive function. Histological techniques, including HE staining, Nissl staining, and TUNEL staining, were employed to assess hippocampal neuronal damage. Additionally, Western blotting, RT-qPCR, and ELISA were utilized to analyze the expression levels of proteins involved in the TLR4/IκBα/NF-κB signaling pathway, transcription levels of apoptotic factors, and levels of inflammatory cytokines, respectively. Luteolin exhibited a dose-dependent reduction in seizure severity, prolonged the latency period of seizures, and shortened seizure duration. Furthermore, luteolin prevented hippocampal neuronal damage in PTZ-induced epileptic rats and partially restored behavioral function and learning and memory abilities. Lastly, PTZ kindling activated the TLR4/IκBα/NF-κB pathway, leading to elevated levels of the cytokines TNF-α, IL-6 and IL-1ß, which were attenuated by luteolin. Luteolin exerted anticonvulsant and neuroprotective activities in the PTZ-induced epileptic model. Its mechanism was associated with the inhibition of the TLR4/IκBα/NF-κB pathway, alleviating the immune-inflammatory response in the post-epileptic hippocampus.

Protocol for induction of human kidney cell fibrosis.

Here, we present a protocol for inducing fibrosis in human kidney-2 (HK2) cells followed by quantitative real-time PCR analysis of fibrosis-related genes. We describe steps for growing and expanding cells, inducing HK2 fibrosis, and collecting cells for downstream applications. Given the limited cell quantity in culture flasks and the challenges of cell collection, we utilized 10-cm Petri dishes for cell harvesting, with each experimental group comprising five replicate samples. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Bioinspired Selenium-Nitrogen Exchange (SeNEx) Click Chemistry Suitable for Nanomole-Scale Medicinal Chemistry and Bioconjugation.

Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage is of great importance for expanding the click chemistry toolbox. We report the first selenium-nitrogen exchange (SeNEx) click reaction between benzoselenazolones and terminal alkynes (Se-N to Se-C), which is inspired by the biochemical SeNEx between Ebselen and cysteine (Cys) residue (Se-N to Se-S). The formed selenoalkyne connection is readily elaborated, thus endowing this chemistry with multidimensional molecular diversity. Besides, this reaction is modular, predictable, and high-yielding, features fast kinetics (k2≥14.43 M-1 s-1), excellent functional group compatibility, and works well at miniaturization (nanomole-scale), opening up many interesting opportunities for organo-Se synthesis and bioconjugation, as exemplified by sequential click chemistry (coupled with ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) and sulfur-fluoride exchange (SuFEx)), selenomacrocycle synthesis, nanomole-scale synthesis of Se-containing natural product library and DNA-encoded library (DEL), late-stage peptide modification and ligation, and multiple functionalization of proteins. These results indicated that SeNEx is a useful strategy for new click chemistry developments, and the established SeNEx chemistry will serve as a transformative platform in multidisciplinary fields such as synthetic chemistry, material science, chemical biology, medical chemistry, and drug discovery.

Associations between Paternal Obesity and Cardiometabolic Alterations in Offspring via Assisted Reproductive Technology.

CONTEXT: Both assisted reproductive technology (ART) and obesity are associated with adverse cardiometabolic alterations in offspring. However, the combined effects of paternal obesity and ART on offspring cardiometabolic health are still unclear. OBJECTIVE: To clarify cardiometabolic changes in offspring of obese fathers conceived using ART. DESIGN: Retrospective cohort study conducted between June 2014 and October 2019. SETTING: Center for reproductive medicine. PATIENTS: A total of 2890 singleton visits aged 4-10 years were followed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Age-and sex-specific z-score of body mass index(BMI), blood pressure, insulin resistance and lipid profile were examined. RESULTS: We observed a strong association between paternal BMI categories and offspring BMI, blood pressure, and insulin resistance. Compared to offspring of fathers with normal weight, multivariable-adjusted mean difference for BMI z-score were 0.53 (95%CI: 0.37-0.68) for obese fathers, 0.17 (95%CI: 0.05-0.30) for overweight fathers, and -0.55 (95%CI: -0.95--0.15) for underweight fathers; corresponding values for systolic blood pressure z-score were 0.21(95%CI: 0.07-0.35), 0.10 (95%CI: -0.01-0.21), and -0.24 (95%CI: -0.59-0.11), and corresponding values for HOMA-IR z-score were 0.31(95%CI: 0.16-0.46), 0.09(95%CI: -0.02-0.21), and -0.11 (95%CI: -0.48-0.28), respectively. The mediation analyses suggested that 57.48% to 94.75% of the associations among paternal obesity and offspring cardiometabolic alterations might be mediated by offspring BMI. CONCLUSIONS: Paternal obesity was associated with an unfavourable cardiometabolic profile in ART-conceived offspring. Mediation analyses indicated that offspring BMI was a possible mediator of the association between paternal obesity and the offspring impaired metabolic changes.

Association between maternal polycystic ovarian syndrome undergoing assisted reproductive technology and pregnancy complications and neonatal outcomes: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is recognized as the most prevalent endocrine disorder among women of reproductive age. While the utilization of assisted reproductive technology (ART) has resulted in favorable outcomes for infertility treatment in PCOS patients, the inherent pathophysiological features of the condition give rise to complications and consequences during pregnancy and delivery for both the mother and offspring. This study was to assess the correlation between maternal PCOS and various pregnancy complications and neonatal outcomes undergone ART. METHODS: A systematic search was conducted on PubMed, EmBase, and the Cochrane Library to identify observational studies that investigated the association between PCOS and the risk of various pregnancy complications and neonatal outcomes, including gestational diabetes mellitus (GDM), hypertension in pregnancy (PIH), preeclampsia (PE), preterm birth, abortion, congenital malformations (CA), small for gestational age (SGA), large for gestational age (LGA), low birth weight (LBW), macrosomia, neonatal intensive care unit (NICU) admission and birth weight. Eligible studies were selected based on predetermined inclusion and exclusion criteria. The meta-analysis was conducted using Review Manager and Stata software, with odds ratios (ORs) or mean difference (MD), confidence intervals (CIs), and heterogeneity (I2) being calculated. The search was conducted up to March 2023. RESULTS: A total of 33 studies with a combined sample size of 92,810 participants were identified. The findings indicate that PCOS is significantly associated with an increased risk of GDM (OR 1.51, 95% CI:1.17-1.94), PIH (OR 1.72, 95% CI:1.25-2.39), PE (OR 2.12, 95% CI:1.49-3.02), preterm birth (OR 1.29, 95% CI:1.21-1.39), and LBW (OR 1.29, 95% CI:1.14-1.47). In subgroup analyses, the risks of GDM (OR 1.80, 95% CI:1.23-2.62) and abortion (OR 1.41, 95% CI:1.08-1.84) were elevated in fresh embryo transferred (ET) subgroup, whereas elevated risk of PE (OR 1.82, 95% CI:1.17-2.83) and preterm birth (OR 1.31, 95% CI:1.21-1.42) was identified in frozen ET subgroup. Whatever with or without hyperandrogenism, patients with PCOS had a higher risk in preterm birth (OR 1.69, 95% CI: 1.31-2.18; OR 1.24, 95% CI:1.02-1.50) and abortion (OR 1.38, 95% CI:1.12-1.71; OR 1.23, 95% CI:1.06-1.43). CONCLUSION: Our findings suggest that individuals with PCOS undergone ART are at a notably elevated risk for experiencing pregnancy complications and unfavorable neonatal outcomes. Nevertheless, to establish a definitive association between PCOS and pregnancy-related outcomes, it is necessary to conduct extensive prospective, blinded cohort studies and effectively control for confounding variables.

A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes.

Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized. Here, we constructed the first single-nucleus transcriptomic landscape of primate liver aging, in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells. Upon in-depth dissection of this rich dataset, we identified impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark of the aged liver, and consequently, forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes, manifesting as impaired detoxification and accelerated cellular senescence. This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

Common gastrointestinal diseases and chronic obstructive pulmonary disease risk: a bidirectional Mendelian randomization analysis.

Background: Observational studies suggest an association between gastrointestinal diseases and chronic obstructive pulmonary disease (COPD), but the causal relationship remains unclear. Methods: We conducted bidirectional Mendelian randomization (MR) analysis using summary data from genome-wide association study (GWAS) to explore the causal relationship between common gastrointestinal diseases and COPD. Gastrointestinal diseases included gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), irritable bowel syndrome (IBS), Crohn's disease (CD), ulcerative colitis (UC), functional dyspepsia (FD), non-infectious gastroenteritis (NGE), and constipation (CP). Significant MR analysis results were replicated in the COPD validation cohort. Results: Bidirectional MR analysis supported a bidirectional causal relationship between GERD and COPD, and COPD was also found to increase the risk of IBS and CP. Our study also provided evidence for a bidirectional causal relationship between PUD and COPD, although the strength of evidence may be insufficient. Furthermore, we provided evidence that there is no causal association between CD, UC, FD, NGE, and COPD. Conclusion: This study offers some evidence to clarify the causal relationship between common gastrointestinal diseases and COPD. Further research is needed to understand the underlying mechanisms of these associations.

Identification of prosthetic joint infection by Candida using metagenomic shotgun sequencing.

Background: Periprosthetic joint infection (PJI) is a serious complication after total knee arthroplasty. Fungal infections are prone to biofilm formation, which makes it hard to diagnose and clarify the pathogenic species. Case Presentation: This case study provides evidence of a novel PJI pathogen that is otherwise difficult to detect using conventional methods. A patient was reviewed with persistent postoperative pain, swelling and eventually drainage around the left knee after undergoing a bilateral total knee arthroplasty 2 years previously for progressive osteoarthritis. By using metagenomic shotgun sequencing to analyse both bacterial and fungal agent sequences, we were able to identify fungal strains of Candida tropicalis, a rarely reported and difficult-to-culture PJI pathogen. Conclusion: Metagenomic shotgun sequencing enables the detection of difficult-to-detect pathogens and the formulation of treatment recommendations for fungal infections with low positive rates based on gene content analysis.

The development of upright face perception depends on evolved orientation-specific mechanisms and experience.

Here we examine whether our impressive ability to perceive upright faces arises from evolved orientation-specific mechanisms, our extensive experience with upright faces, or both factors. To do so, we tested Claudio, a man with a congenital joint disorder causing his head to be rotated back so that it is positioned between his shoulder blades. As a result, Claudio has seen more faces reversed in orientation to his own face than matched to it. Controls exhibited large inversion effects on all tasks, but Claudio performed similarly with upright and inverted faces in both detection and identity-matching tasks, indicating these abilities are the product of evolved mechanisms and experience. In contrast, he showed clear upright superiority when detecting "Thatcherized" faces (faces with vertically flipped features), suggesting experience plays a greater role in this judgment. Together, these findings indicate that both evolved orientation-specific mechanisms and experience contribute to our proficiency with upright faces.