Pan-cancer analysis reveals CCL5/CSF2 as potential predictive biomarkers for immune checkpoint inhibitors.

BACKGROUND: Currently, there are no optimal biomarkers available for distinguishing patients who will respond to immune checkpoint inhibitors (ICIs) therapies. Consequently, the exploration of novel biomarkers that can predict responsiveness to ICIs is crucial in the field of immunotherapy. METHODS: We estimated the proportions of 22 immune cell components in 10 cancer types (6,128 tumors) using the CIBERSORT algorithm, and further classified patients based on their tumor immune cell proportions in a pan-cancer setting using k-means clustering. Differentially expressed immune genes between the patient subgroups were identified, and potential predictive biomarkers for ICIs were explored. Finally, the predictive value of the identified biomarkers was verified in patients with urothelial carcinoma (UC) and esophageal squamous cell carcinoma (ESCC) who received ICIs. RESULTS: Our study identified two subgroups of patients with distinct immune infiltrating phenotypes and differing clinical outcomes. The patient subgroup with improved outcomes displayed tumors enriched with genes related to immune response regulation and pathway activation. Furthermore, CCL5 and CSF2 were identified as immune-related hub-genes and were found to be prognostic in a pan-cancer setting. Importantly, UC and ESCC patients with high expression of CCL5 and low expression of CSF2 responded better to ICIs. CONCLUSION: We demonstrated CCL5 and CSF2 as potential novel biomarkers for predicting the response to ICIs in patients with UC and ESCC. The predictive value of these biomarkers in other cancer types warrants further evaluation in future studies.

Enhancing Vaxign-DL for Vaccine Candidate Prediction with added ESM-Generated Features.

Many vaccine design programs have been developed, including our own machine learning approaches Vaxign-ML and Vaxign-DL. Using deep learning techniques, Vaxign-DL predicts bacterial protective antigens by calculating 509 biological and biomedical features from protein sequences. In this study, we first used the protein folding ESM program to calculate a set of 1,280 features from individual protein sequences, and then utilized the new set of features separately or in combination with the traditional set of 509 features to predict protective antigens. Our result showed that the usage of ESM-derived features alone was able to accurately predict vaccine antigens with a performance similar to the orginal Vaxign-DL prediction method, and the usage of the combined ESM-derived and orginal Vaxign-DL features significantly improved the prediction performance according to a set of seven scores including specificity, sensitivity, and AUROC. To further evaluate the updated methods, we conducted a Leave-One-Pathogen-Out Validation (LOPOV) study, and found that the usage of ESM-derived features significantly improved the the prediction of vaccine antigens from 10 bacterial pathogens. This research is the first reported study demonstrating the added value of protein folding features for vaccine antigen prediction.

Role of TOMM34 on NF-κB activation-related hyperinflammation in severely ill patients with COVID-19 and influenza.

BACKGROUND: Highly pathogenic respiratory RNA viruses such as SARS-CoV-2 and its associated syndrome COVID-19 pose a tremendous threat to the global public health. Innate immune responses to SARS-CoV-2 depend mainly upon the NF-κB-mediated inflammation. Identifying unknown host factors driving the NF-κB activation and inflammation is crucial for the development of immune intervention strategies. METHODS: Published single-cell RNA sequencing (scRNA-seq) data was used to analyze the differential transcriptome profiles of bronchoalveolar lavage (BAL) cells between healthy individuals (n = 27) and patients with severe COVID-19 (n = 21), as well as the differential transcriptome profiles of peripheral blood mononuclear cells (PBMCs) between healthy individuals (n = 22) and severely ill patients with COVID-19 (n = 45) or influenza (n = 16). Loss-of-function and gain-of-function assays were performed in diverse viruses-infected cells and male mice models to identify the role of TOMM34 in antiviral innate immunity. FINDINGS: TOMM34, together with a list of genes encoding pro-inflammatory cytokines and antiviral immune proteins, was transcriptionally upregulated in circulating monocytes, lung epithelium and innate immune cells from individuals with severe COVID-19 or influenza. Deficiency of TOMM34/Tomm34 significantly impaired the type I interferon responses and NF-κB-mediated inflammation in various human/murine cell lines, murine bone marrow-derived macrophages (BMDMs) and in vivo. Mechanistically, TOMM34 recruits TRAF6 to facilitate the K63-linked polyubiquitination of NEMO upon viral infection, thus promoting the downstream NF-κB activation. INTERPRETATION: In this study, viral induction of TOMM34 is positively correlated with the hyperinflammation in severely ill patients with COVID-19 and influenza. Our findings also highlight the physiological role of TOMM34 in the innate antiviral signallings. FUNDING: A full list of funding sources can be found in the acknowledgements section.

Boosting External Quantum Efficiency to 12.0 % of an Ultraviolet OLED by Engineering the Horizontal Dipole Orientation of a Hot Exciton Emitter.

Currently, much research effort has been devoted to improving the exciton utilization efficiency and narrowing the emission spectra of ultraviolet (UV) fluorophores for organic light-emitting diode (OLED) applications, while almost no attention has been paid to optimizing their light out-coupling efficiency. Here, we developed a linear donor-acceptor-donor (D-A-D) triad, namely CDFDB, which possesses high-lying reverse intersystem crossing (hRISC) property. Thanks to its integrated narrowband UV photoluminescence (PL) (λPL: 397 nm; FWHM: 48 nm), moderate PL quantum yield (ϕPL: 72 %, Tol), good triplet hot exciton (HE) conversion capability, and large horizontal dipole ratio (Θ//: 92 %), the OLEDs based on CDFDB not only can emit UV electroluminescence with relatively good color purity (λEL: 398 nm; CIEx,y: 0.161, 0.040), but also show a record maximum external quantum efficiency (EQEmax) of 12.0 %. This study highlights the important role of horizontal dipole orientation engineering in the molecular design of HE UV-OLED fluorophores.

Ontology-based modeling, integration, and analysis of heterogeneous clinical, pathological, and molecular kidney data for precision medicine.

Many data resources generate, process, store, or provide kidney related molecular, pathological, and clinical data. Reference ontologies offer an opportunity to support knowledge and data integration. The Kidney Precision Medicine Project (KPMP) team contributed to the representation and addition of 329 kidney phenotype terms to the Human Phenotype Ontology (HPO), and identified many subcategories of acute kidney injury (AKI) or chronic kidney disease (CKD). The Kidney Tissue Atlas Ontology (KTAO) imports and integrates kidney-related terms from existing ontologies (e.g., HPO, CL, and Uberon) and represents 259 kidney-related biomarkers. We have also developed a precision medicine metadata ontology (PMMO) to integrate 50 variables from KPMP and CZ CellxGene data resources and applied PMMO for integrative kidney data analysis. The gene expression profiles of kidney gene biomarkers were specifically analyzed under healthy control or AKI/CKD disease states. This work demonstrates how ontology-based approaches support multi-domain data and knowledge integration in precision medicine.

Association between movement behavior patterns and cardiovascular risk among Chinese adults aged 40-75: a sex-specific latent class analysis.

BACKGROUND: Cardiovascular disease (CVD) is a major global health threat, particularly in China, contributing to over 40% of deaths. While sleep behaviors, sedentary behaviors, and physical activities are recognized as independent lifestyle risk factors for CVD, there remains limited understanding of specific movement behavior patterns and their CVD risks, especially considering sex-specific differences. This study examines movement behavior patterns among Chinese adults (40-75) and their associations with cardiovascular risk, with a focus on sleep, physical activity (PA), and sedentary behavior (SB). METHODS: Data pertaining to 13,465 male participants and 15,613 female participants, collected from the Chronic Disease and Risk Factor Surveillance Survey in Nanjing from February 2020 to December 2022. The latent class analysis method was employed to identify underlying movement patterns across sexes. Multinomial logistic regression models assessed CVD risk, and the China-PAR model calculated 10-year risk. RESULTS: Three male and four female movement patterns emerged. Active Movers (17.10% males, 5.93% females) adhered to PA recommendations but had poorer sleep quality. Moderate Achievers (61.42% males, 45.32% females) demonstrated moderate behavior. Sedentary Sleepers (21.48% males, 10.20% females) exhibited minimal PA but good sleep. Female Moderate Physical Activity (MPA) Dominant Movers demonstrated a prevalent adherence to recommended MPA levels. Active movers had the lowest CVD risk. After adjusting for potential confounders, moderate achievers (OR = 1.462, 95% CI 1.212, 1.764) and sedentary sleepers (OR = 1.504, 95% CI 1.211, 1.868) were both identified as being associated with a high-risk of cardiovascular diseases (CVDs) compared to active movers in males, demonstrating a similar trend for intermediate risk. Such associations were not statistically significant among females. CONCLUSIONS: Our study revealed sex-specific movement patterns associated with CVD risks among middle-aged Chinese adults. We suggest that adopting an active movement behavior pattern, characterized by meeting or exceeding recommended levels of vigorous physical activity (VPA) and reducing sedentary behavior, is beneficial for all middle-aged adults, particularly males. An active lifestyle could help counteract the adverse effects of relatively poor sleep quality on the risk of developing CVD in this population. Integrating sleep, PA, and SB information provides a holistic framework for understanding and mitigating CVD risks.

Untangling pathways of risk factors associated with hypertension among dysglycemia adults in eastern China: a structural equation model approach.

BACKGROUND AND AIMS: Using structural equation model (SEM) to test a conceptual model of pathways of developing hypertension among dysglycemia (IFG and T2DM) adults in Eastern China, emphasizing the unique mediation effect of insulin resistance and obesity on the relationship between modified/unmodified factors and hypertension. METHODS AND RESULTS: Participants with dysglycemia (n = 10,401) were extracted from the survey of Chronic Disease and Risk Factor Surveillance in Nanjing, the capital of Jiangsu Province in China. Dietary patterns were identified by using principal component analysis (PCA). SEM was employed to evaluate multiple pathways of hypertension among participants with IFG and T2DM. Three dietary patterns were derived using PCA. The tuber animal food pattern (OR = 0.825, 95% CI 0.723-0.940) and the balanced food pattern (OR = 0.812, 95% CI 0.715-0.922) were negatively associated with hypertension, while the Chinese rural food pattern (OR = 1.163, 95% CI 1.019-1.328) was positively associated with hypertension. The best SEM model showed that BMI (0.140), smoking (0.048) and Chinese rural food pattern (0.022) positively associated with hypertension; while tuber animal food pattern (- 0.025) had a negative direct effect on hypertension. Notably, insulin resistance could mediate the link between lifestyles (smoking and dietary patterns) and hypertension. CONCLUSION: Accordingly, we emphasized the importance of lifestyle intervention, mainly including obesity management, choosing healthy diets and decreasing smoking control, which may profoundly benefit this high-risk group among Chinese population.

Acupoint massage at Shenque (CV 8) for chronic fatigue syndrome: a randomized controlled trial. / ç¥žé˜™ç©´ä½æŒ‰æ‘©æ²»ç–—æ ¢æ€§ç–²åŠ³ç»¼åˆå¾ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the clinical efficacy of acupoint massage at Shenque (CV 8) for chronic fatigue syndrome (CFS). METHODS: A total of 71 patients with CFS were randomized into an observation group (36 cases, 2 cases were eliminated, 3 cases dropped out) and a control group (35 cases). Using a specially made massage instrument, acupoint massage was adopted at the the five points of Shenque (CV 8), i.e. the center and the upper, lower, left, and right parts of the inner wall. The manipulation was given 10 min a time, once every 2 days, 3 times a week for 4 weeks continuously. No intervention was delivered in the control group. Before and after treatment, the scores of fatigue scale-14 (FS-14) and Pittsburgh sleep quality index (PSQI) were observed, and the clinical efficacy was evaluated in the both groups. RESULTS: After treatment, the physical fatigue and mental fatigue scores, as well as the total score of FS-14 were decreased compared with those before treatment in the observation group (P<0.001); the above scores in the observation group were lower than those in the control group (P<0.001). After treatment, excepted for the sleep time and hypnotic scores, the remaining item scores and the total score of PSQI were decreased compared with those before treatment in the observation group (P<0.05); the each item score and the total score of PSQI were lower than those in the control group (P<0.05). The total effective rate in the observation group was superior to that in the control group (P<0.01). CONCLUSIONS: Acupoint massage at Shenque (CV 8) can effectively improve the fatigue state and sleep quality in patients with chronic fatigue syndrome.

Production of single cell protein rich in potassium by Nectaromyces rattus using biogas slurry and molasses.

Single-cell protein (SCP) is a vital supplement for animal protein feed. This study utilized biogas slurry and sugarcane molasses to ferment Nectaromyces rattus for the production of SCP. The optimal batch fermentation conditions were obtained in a 5L jar with a tank pressure of 0.1 MPa, an initial speed of 300 rpm, and an inoculum volume of 30%. The highest cell dry weight concentrations of the fed-batch fermentation without reflux and the fed-batch fermentation with reflux were 46.33 g/L and 29.71 g/L, respectively. The nitrogen conversion rates (47.05% and 44.12%) and the cell yields of total organic carbon (1 g/g and 1.17 g/g) of both fermentation modes were compared. The SCP contained 42.32% amino acids. Its high concentrations of potassium (19859.96 mg/kg) and phosphorus (7310.44 mg/kg) present a novel approach for the extraction of these essential nutrients from biogas slurry. The enrichment of K was related to the H+ efflux and sugar transport.

A Natural-Position X-Ray for Evaluating Cervical Vertebra Physiology Curvature Before and After Conservative Treatment.

BACKGROUND Abnormal physiological curvature is one of the symptoms of early cervical spondylosis. An X-ray taken with the patient standing in a natural position can best reflect the real cervical vertebra physiological curvature. The purpose of this research was to study the value of natural-position X-ray in evaluating cervical vertebra physiology curvature before and after conservative treatment. MATERIAL AND METHODS This study included 135 participants of different ages diagnosed with cervical disease and who received conservative treatment for more than 12 months. The natural- and regular-position X-rays were performed before and after treatment. The positive change of D value in Borden's measurement and C2~7 Cobb angle should be recognized as an improvement of cervical vertebra physiology curvature. RESULTS Before treatment, the C2~7 Cobb angle of the regular-position group was larger than that of natural-position group. After treatment, the C2~7 Cobb angle of the natural-position group was larger than that of the regular-position group, and the D value increased after treatment in both groups. The effective rate of cervical physiological curvature of the natural-position group was higher than that of the regular-position group. CONCLUSIONS Natural-position X-ray has greater accuracy in evaluating cervical vertebra physiology curvature before and after conservative treatment compared with regular-position X-ray.

Metabolomics Differences of the Donor Livers Between In Situ and Ex Situ Conditions During Ischemia-free Liver Transplantation.

BACKGROUND: Ischemia-free liver transplantation (IFLT) has been innovated to avoid graft ischemia during organ procurement, preservation, and implantation. However, the metabolism activity of the donor livers between in the in situ and ex situ normothermic machine perfusion (NMP) conditions, and between standard criteria donor and extend criteria donor remains unknown. METHODS: During IFLT, plasma samples were collected both at the portal vein and hepatic vein of the donor livers in situ during procurement and ex situ during NMP. An ultra-high performance liquid chromatography-mass spectrometry was conducted to investigate the common and distinct intraliver metabolite exchange. RESULTS: Profound cysteine and methionine metabolism, and aminoacyl-tRNA biosynthesis were found in both in situ and ex situ conditions. However, obvious D-arginine and D-ornithine metabolism, arginine and proline metabolism were only found in the in situ condition. The suppressed activities of the urea cycle pathway during ex situ condition were confirmed in an RNA expression level. In addition, compared with extend criteria donor group, standard criteria donor group had more active intraliver metabolite exchange in metabonomics level. Furthermore, we found that the relative concentration of p-cresol, allocystathionine, L-prolyl-L-proline in the ex situ group was strongly correlated with peak alanine aminotransferase and aspartate aminotransferase at postoperative days 1-7. CONCLUSIONS: In the current study, we show the common and distinct metabolism activities during IFLT. These findings might provide insights on how to modify the design of NMP device, improve the perfusate components, and redefine the criteria of graft viability.

Central Mechanism of Acupuncture Treatment in Patients with Migraine: Study Protocol for Randomized Controlled Neuroimaging Trial.

Purpose: Acupuncture has been recognized as an effective and safe alternative therapy for migraine, but its central mechanism has not yet been adequately explained. Meanwhile, research into the clinical efficacy and central mechanism of true acupuncture (TA) and sham acupuncture (SA) is lacking. It is necessary to investigate whether TA has better efficacy than SA, and how they achieve different effects. This study aims to evaluate the efficacy of TA and SA, observe the brain response caused by TA and SA, and further investigate the central nervous mechanism of TA and SA treatment for patients with migraine. Patients and Methods: This is a randomized controlled neuroimaging trial combining acupuncture treatment with functional magnetic resonance imaging, with patients and outcome assessors blinded. A total of 60 patients with migraine will be randomly allocated to receive 12 sessions of either TA or SA treatments (three sessions per week for 4 weeks), and 30 healthy participants will be recruited as the healthy control (HC) group. Outcome assessment and neuroimaging will be conducted before and after the entire intervention. A headache diary and questionnaires of life quality and psychological properties will be used to evaluate clinical efficacy. Multimodal magnetic resonance imagining data analysis will be used to investigate the central mechanism of TA or SA in treating migraine. Pearson's correlation analysis will be used to reveal the relationship between the brain response and clinical improvements. Conclusion: The results of this study will reveal the brain response to TA and SA in patients with migraine and contribute to further expanding the knowledge of their central mechanism. Study Registration: This trial has been approved by the ethics committee of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (DZMEC-KY-2020-38) and registered in the Chinese Clinical Trial Registry (registration number ChiCTR2000033995).

Flammulina velutipes-derived carbon dots for fluorescence detection and imaging of hydroxyl radical.

Monitoring hydroxyl radical (•OH) fluctuation is of great importance to study some relative pathological processes and to predict early diagnosis of diseases. Efficient •OH-responsive fluorescent sensors based on carbon dots (CDs) have been reported, but most researches have focused on the new strategies for the synthesis and doping of the CDs. Herein, a kind of biomass CDs (F-CDs) with Flammulina velutipes (F. velutipes) as the carbon source was prepared by a one-step hydrothermal method without any additional modification. The prepared F-CDs have remarkable sensitivity and selectivity and there is a good linear relationship from 0 to 12 µM with a low detection limit of 95 nM for quantitative •OH assay. With excitation-independent emission, favourable biocompatibility and low toxicity, the F-CDs can penetrate cell membranes as •OH-responsive fluorescent sensors to detect intracellular •OH in A549 cells stimulated by phorbol 12-myristate 13-acetate (PMA) and successfully monitor the •OH concentration levels by the corresponding fluorescence change. Given the combined benefits of the green and eco-friendly approach, the F-CDs show promise as novel theranostics tools for early detection and treatment of related diseases.

Low C/N promotes stable partial nitrification by enhancing the cooperation of functional microorganisms in treating high-strength ammonium landfill leachate.

Partial nitrification is an effective process for treating high-strength ammonium landfill leachate with low C/N ratio, for the cooperation with denitrification can save almost 40% carbon addition in biological nitrogen removal. However, high ammonia loading often causes the instability of partial nitrification process. Less carbon addition can promote the stability of partial nitrification and increase the nitrite accumulation ratio (NAR). Nevertheless, the microbial mechanisms within remain further elusive. In this study, two laboratory-scale sequencing batch reactors were constructed and operated for 125 days, which were fed with ammonia synthetic wastewater with C/N of 0.6 (CN system) and C/N of 0.0 as the control (N system). CN system performed more stably and had the highest NAR of 100%. Extracellular polymeric substances (EPS) generated from carbon source provided spatial and nutrient niches to tighten the cooperation of functional microorganisms, thus, enhanced the stability and efficiency of partial nitrification. Thauera was the dominant denitrifier in CN system. Nitrosomonas was one of the most important autotrophic ammonia oxidizing bacteria, while Paracoccus and Flavobacterium were the main heterotrophic nitrification-aerobic denitrification (HN-AD) bacteria in CN system. The enrichment of HN-AD bacteria outcompeted nitrite oxidizing bacteria (NOB), therefore leaded to higher nitrite accumulation in CN system. The findings of this study may be conducive to increasing the understanding of the microbial collaboration mechanisms of partial nitrification, thereby provides theoretical support for the improvement of biological nitrogen removal technology.

Nitrification resistance and functional redundancy maintain the system stability of partial nitrification in high-strength ammonium wastewater system.

The sudden change of ammonia loading in high-strength ammonium wastewater treatment can directly affect the system stability by altering microbial community dynamics. To maintain the system stability, the effects of ammonia shock loading on microbial community dynamics must be studied. Two sets of sequencing batch reactors were operated with 6 shock cycles (maximum volumetric loading rate of 1928 mg N/(L·d)). CN system contained both organic carbon and ammonia and N system contained only ammonia. Comparing with N system, CN system operated more stably and had higher nitrite accumulation rate. Free ammonia (FA) was the select stress for the turnover of CN microbial communities, while the N communities didn t shift much. The increase of Nitrosomonas and the appearance of heterotrophic nitrification-aerobic denitrification bacteria in CN system presented its resistance and redundancy against FA impact, while the increase of functional genes exhibited functional genes redundancy which maintained the system stability.

Incorporating plasmonic featurization with machine learning to achieve accurate and bidirectional prediction of nanoparticle size and size distribution.

Determination of nanoparticle size and size distribution is important because these key parameters dictate nanomaterials' properties and applications. Yet, it is only accomplishable using low-throughput electron microscopy. Herein, we incorporate plasmonic-domain-driven feature engineering with machine learning (ML) for accurate and bidirectional prediction of both parameters for complete characterization of nanoparticle ensembles. Using gold nanospheres as our model system, our ML approach achieves the lowest prediction errors of 2.3% and ±1.0 nm for ensemble size and size distribution respectively, which is 3-6 times lower than previously reported ML or Mie approaches. Knowledge elicitation from the plasmonic domain and concomitant translation into featurization allow us to mitigate noise and boost data interpretability. This enables us to overcome challenges arising from size anisotropy and small sample size limitations to achieve highly generalizable ML models. We further showcase inverse prediction capabilities, using size and size distribution as inputs to generate spectra with LSPRs that closely match experimental data. This work illustrates a ML-empowered total nanocharacterization strategy that is rapid (<30 s), versatile, and applicable over a wide size range of 200 nm.

A theoretical framework for mechanics of diaphragm.

A theoretical framework is developed for mechanics of the diaphragm. The diaphragm is modeled as an anisotropic elastic material surface with activation functionality. A constitutive function is formulated that relates the stresses in the diaphragm to the surface deformation gradient, the anisotropy vector, and the muscle activation parameter. The equilibrium equations for the diaphragm are derived to determine the deformed shape of the diaphragm in the process of respiration with the associated transdiaphragmatic pressures. A numerical solution is presented, that demonstrates the capability of the model to recover the experimental observations and to predict the shape and stresses of the diaphragm.

After He Jiankui's Case: Chinese Legislative Modifications in Human Embryo Gene Editing.

This article systematically discusses Chinese current legal status and rules for human embryo gene editing in both administrative law and criminal law after several legislative modifications, and further systematically evaluates the values and the defects of these modifications. After He Jiankui's case, Chinese legislators devoted themselves to improve human embryo gene editing legislation. As a result, human embryo gene editing's legal status becomes more determined. Rules for human embryo gene editing in Chinese administrative law have gradually become a complete system centering on "CBL-regulation," and the promulgation of Amendment (XI) to the Criminal Law reconciles the controversy existed in academic circles. Chinese rules for human embryo gene editing are moving from "doubtful development" to "complete legal system."