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Abstract Background The expansion of GGC repeats (typically exceeding 60 repeats) in the 5’ untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson’s disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored. Methods Here, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs. Results Our findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG, were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex. Conclusions Our in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs.

Abstract In the current study, we present a stochastic SAIS (unaware susceptible-aware susceptible-infectious-unaware susceptible) epidemic dynamic model on complex networks with multi-weights. The disease dynamic is influenced by random perturbations to the force of the infection rates, as well as awareness rates. To analyze the problem of extinction, we discuss both the stochastic asymptotic stability in the large and almost surely exponential stability of the trivial solution. Then, we get some sufficient conditions, which guarantee the stochastic persistence of infectious disease. Based on the Erdös-Réyni random graph, the numerical simulations are given. These not only validate our conclusions but also obtain else significative results. Both theoretical results and numerical simulations further reflect that improvement of risk awareness and reduction of decay in awareness are highly effective in preventing disease spread. And then, environmental noises play a significant role in disease transmission.

Abstract Objective This work aimed to investigate the potential correlation between chromosomal polymorphisms and various reproductive abnormalities. Methods We examined 21,916 patients affected by infertility who sought care at the Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University between January 2018 and December 2022. A total of 2227 individuals identified as chromosomal polymorphism carriers constituted the polymorphism group, and 2245 individuals with normal chromosome karyotypes were randomly selected to form a control group. Clinical manifestations, histories of spontaneous miscarriage, abnormal reproductive developments, fetal abnormalities, and male sperm quality anomalies were statistically compared between these two groups. Results Of the 21,916 patients analyzed, 2227 displayed chromosomal polymorphism, representing a 10.16% detection rate. Amongst the male patients, 1622 out of 10,827 exhibited polymorphisms (14.98%), whereas 605 out of 11,089 females showed polymorphisms (5.46%). Female carriers in the polymorphism group, showed statistically significant increased rates of spontaneous abortion (29.75% vs. 18.54%), fetal anomalies (1.32% vs. 0.81%), and uterine abnormalities compared with the control group (1.32% vs. 0.81%). Male carriers in the polymorphism group had higher rates of spontaneous abortion in partners (22.87% vs. 10.37%), fetal anomalies (1.97% vs. 0.25%), compromised sperm quality (41.74% vs. 7.18%), testicular underdevelopment (2.28% vs. 0.92%), and hypogonadotropic hypogonadism (0.62% vs. 0.37%) compared with the control group. Conclusion Chromosomal polymorphisms may have a certain negative effect on reproductive irregularities, including spontaneous abortions, fetal anomalies, and reduced sperm quality in males. Their clinical effects deserve further investigation.

ABSTRACT: Over 1 year, two KPC-producing and two non–KPC-producing Klebsiella pneumoniae strains were isolated from a patient. Genome and DNA hybridization analyses revealed the first three strains as a clonal lineage, with carbapenem resistance changes due to a Tn2-like transposon on an IncR/IncFII plasmid. The fourth strain, carrying three plasmids, caused a lethal infection and represented a different lineage. All strains belonged to the ST11-SL47-OL101 type. This study highlights the Tn2-like transposon's role in carbapenemase gene spread and the importance of distinguishing between bacterial colonization and infection.

In order to study the influence characteristics of cored heat pipes on the temperature field of coal pile and the feasibility of preventing the spontaneous combustion of coal pile, the heat transfer law of two kinds of heat pipes with core and without core under different heat source temperature conditions was tested by experiments, and the heat transfer effect of different arrangement modes of cored heat pipes on large area coal pile was analyzed by numerical simulation. The results show that under different heat source temperature conditions, the maximum cooling range of cored heat pipe is 130.6 K, and the maximum cooling range of non-cored heat pipe is 118.6 K. The influence of heat pipes on the internal temperature field of coal pile can be divided into three regions according to the distance: high efficiency cooling zone, transition zone and slow cooling zone; the high temperature area inside the coal pile is smaller with triangular tube group arrangement; the best heat transfer effect is obtained when the spacing between tubes is 25 cm; compared with the tube group arrangement, the distance between tubes has more influence on the heat transfer effect of the core heat pipe.

Bile acids are liver-derived signaling molecules that can be found in the brain, but their role there remains largely unknown. We found increased brain chenodeoxycholic acid (CDCA) in mice with absent 12α-hydroxylase (Cyp8b1), a bile acid synthesis enzyme. In these Cyp8b1−/−, and in Wt mice administered CDCA, stroke infarct area was reduced. Elevated glutamate-induced excitotoxicity mediated by aberrant N-methyl-D-aspartate receptor (NMDAR) overactivation contributes to neuronal death in ischemic stroke. We found reduced glutamate-induced excitotoxicity in neurons from Cyp8b1−/− and CDCA-treated Wt mice. CDCA decreased NMDAR-mediated excitatory post-synaptic currents by reducing over-activation of NMDAR subunit GluN2B in Wt brains. Synaptic NMDAR activity was also decreased in Cyp8b1−/− brains. Expression and synaptic distribution of GluN2B were unaltered in Cyp8b1−/− mice, suggesting CDCA may directly antagonize GluN2B-containing NMDARs. Supporting our findings, in a case-control cohort of acute ischemic stroke patients, we found lower circulatory CDCA. Together, our data suggest that CDCA, acting in the liver-brain axis, decreases GluN2B-containing NMDAR overactivation, contributing to neuroprotection in stroke.

Introduction: EGFR tyrosine kinase inhibitor (TKI) is the standard adjuvant treatment for patients with stages IB to IIIA EGFR-mutated NSCLC. Nevertheless, adapting this approach to include a molecular residual disease (MRD)-guided de-escalation strategy warrants further investigation. Methods: From January 2019 to December 2022, 71 patients with stages I to III NSCLC and EGFR (exon 19 deletion or L858R) mutations were enrolled in this observational study. A total of 375 blood samples were analyzed using the MRD_Navigator assay. Among them, 27 patients suspended EGFR TKI treatment based on undetectable MRD and were thus included in the adaptive, de-escalation group. Results: Overall, the sensitivity of longitudinal MRD was 86.2%. Only four patients (11.8%) recurred with longitudinal undetectable MRD, indicating a negative predictive value of 88.2%. Of the patients who had detectable MRD after surgery, nine subsequently received EGFR TKI treatment, with only one (11.1%) achieving persistent circulating tumor DNA clearance post–EGFR TKI. Furthermore, 22 patients with stages IB to III disease who had previously suspended their TKI treatment based on undetectable MRD were included in the adaptive group, with an average duration of TKI 3.9 (range: 0–35.0) months. The 2-year disease-free survival rate of these 22 patients was 80.2%, and the median was not reached. Five patients (n = 5 of 22, 22.7%) had disease recurrence during the period of drug cessation but were stable under EGFR TKI treatment until the latest follow-up. Two patients remained in complete remission. Conclusions: Our initial findings underscore the potential of an adaptive, de-escalation approach to adjuvant EGFR TKIs based on circulating tumor DNA-MRD monitoring.

Background: Potentially inappropriate medications (PIMs) are associated with adverse outcomes and higher healthcare costs in older adults. Explicit screening criteria like the Beers Criteria, STOPP criteria, and the Malaysian Potentially Inappropriate Prescribing (MALPIP) criteria served to identify PIMs, but comparative data are scarce.Aim: To evaluate the prevalence of PIMs identified by Beers 2019, STOPP version 2 and MALPIP criteria in Malaysian older adults and examine their predictive ability for adverse outcomes and cost-saving potential.Methods: A historical cohort study was conducted among older adults aged ≥ 60 years on five or more medications in four Malaysian tertiary hospitals. PIMs were identified using Beers, STOPP, and MALPIP criteria. Sensitivity, specificity and predictive abilities of these criteria were analysed against clinical outcomes. Monthly cost savings were calculated based on hypothetical deprescribing scenarios.Results: Among 1069 patients, the prevalence of PIMs was 89.1% using MALPIP, 51.3% with Beers, and 37.0% with STOPP criteria. A moderate concordance was seen between Beers and STOPP criteria (κ = 0.437), and the lowest agreement was observed between the STOPP and MALPIP (κ = 0.131). STOPP criteria significantly predicted hospital readmissions (p = 0.003), while Beers and MALPIP did not show significant predictive abilities across all outcomes. The most common PIMs identified were proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Deprescribing scenarios based on these criteria indicated potential monthly cost savings of MYR 4.83 to MYR 44.84 per patient, with the greatest savings associated with MALPIP criteria.Conclusion: MALPIP demonstrated the highest potential for cost savings, the highest sensitivity but the lowest specificity in PIM detection. Context-specific assessments and clinical judgment are crucial in optimising medication safety and efficacy in geriatric pharmacotherapy. Further research is needed to refine PIM criteria to better predict clinical outcomes and balance the benefits and risks of deprescribing in diverse healthcare settings.

Microsatellite instability (MSI) is an important genomic biomarker for cancer diagnosis and treatment, and sequencing-based approaches are often applied to identify MSI because of its fastness and efficiency. These approaches, however, may fail to identify MSI on one or more sub-clones for certain cancers with a high degree of heterogeneity, leading to erroneous diagnoses and unsuitable treatments. Besides, the computational cost of identifying sub-clonal MSI can be exponentially increased when multiple sub-clones with different length distributions share MSI status. Herein, this paper proposes "scMSI", an accurate and efficient estimation of sub-clonal MSI to identify the microsatellite status. scMSI is an integrative Bayesian method to deconvolute the mixed-length distribution of sub-clones by a novel alternating iterative optimization procedure based on a subtle generative model. During the process of deconvolution, the optimized division of each sub-clone is attained by a heuristic algorithm, aligning with clone proportions that adhere optimally to the sample's clonal structure. To evaluate the performance, 16 patients diagnosed with endometrial cancer, exhibiting positive responses to the treatment despite having negative MSI status based on sequencing-based approaches, were considered. Excitingly, scMSI reported MSI on sub-clones successfully, and the findings matched the conclusions on immunohistochemistry. In addition, testing results on a series of experiments with simulation datasets concerning a variety of impact factors demonstrated the effectiveness and superiority of scMSI in detecting MSI on sub-clones over existing approaches. scMSI provides a new way of detecting MSI for cancers with a high degree of heterogeneity.

Cell migration towards stiff substrates has been coined as durotaxis and implicated in development, wound healing, and cancer, where complex interplays between immune and non-immune cells are present. Compared to the emerging mechanisms underlying the strongly adhesive mesenchymal durotaxis, little is known about whether immune cells - migrating in amoeboid mode - could follow mechanical cues. Here, we develop an imaging-based confined migration device with a stiffness gradient. By tracking live cell trajectory and analyzing the directionality of T cells and neutrophils, we observe that amoeboid cells can durotax. We further delineate the underlying mechanism to involve non-muscle myosin IIA (NMIIA) polarization towards the soft-matrix-side but may not require differential actin flow up- or down-stiffness gradient. Using the protista Dictyostelium, we demonstrate the evolutionary conservation of amoeboid durotaxis. Finally, these experimental phenomena are theoretically captured by an active gel model capable of mechanosensing. Collectively, these results may shed new lights on immune surveillance and recently identified confined migration of cancer cells, within the mechanically inhomogeneous tumor microenvironment or the inflamed fibrotic tissues.

This study focuses on the efficiency of liquid CO2 (LCO2) displacing CH4 in the coal under optimal Ti and Pi. The objective is to study the influence on the efficiency of LCO2 injection to displace CH4 under the different temperature (Ti) and pressure (Pi). Thereafter, an in-situ test is conducted on LCO2 injecting to enhance coalbed methane (LCO2-ECBM) in a high-gas coalbed. Results showed that low temperature inhibited the movement activity of CO2/CH4 in coal, a significant delayed effect is exhibited during CO2 displacing CH4, and the maximum displacement efficiency (ηmax) is only 56.02 %. The competitive-adsorption effect of CO2/CH4 intensified, and ηmax increased to 84.13 % as Ti gradually increased. The CH4 desorption rate and migration dynamics in the coal intensified as Pi increased, resulting in a significant increase in efficiency, and ηmax reached 92.87 %. At 30 °C, where CH4 is present in the coal, an appropriate increase in Pi caused the maximum replacement ratio to decrease from 1.60:1 to 0.40:1, indicating a higher efficiency. An In-situ test of LCO2-ECBM showed that the concentration and flow rate of methane increased by nearly three times, and the CBM extraction time and borehole layout number have been shortened by one-third and half, respectively.

Objectives COVID-19 had significant influences on everyone’s lives. This study aimed to explore impacts of COVID-19 on mental and sexual health and access to health services among gay, bisexual and other men who have sex with men (GBMSM) in Singapore. Methods This qualitative study recruited 16 self-identified GBMSM via purposive sampling and semi-structured individual interviews were conducted. Three themes and seven sub-themes were derived from analysis done using the framework method. Results Participants shared how COVID-19 led to negative emotions and experiences at an intrapersonal level and interpersonal level (with families or partners), which were also worsened by prevailing stigma that GBMSM already face in Singapore and within their social networks. Sexual behaviours associated with HIV and other sexually transmitted infections risk and substance use were seen to be maladaptive coping methods of social isolation due to COVID-19. These dynamics were all exacerbated by the closure of “non-essential” services, which included many important services for mental and sexual health that were relevant to the GBMSM community. Conclusions Changes in policies and community efforts should be explored to improve these areas, enhancing the psychosocial and sexual well-being of GBMSM.

Background and purposeTriggering receptor expressed on myeloid cells-1 (TREM-1) was reported to be critical for mediating the neurological function after stroke, while the impact of soluble TREM-1 (sTREM-1) on cognitive impairment after ischemic stroke is unclear. We aimed to explore the association between sTREM-1 and post-stroke cognitive impairment (PSCI).MethodsWe prospectively recruited consecutive ischemic stroke patients who admitted hospital within 7 days of onset. Serum sTREM-1 concentrations were measured after admission. Cognitive function was assessed at 90 days follow-up using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). PSCI was defined as a MMSE score of

Abstract During oxidative phosphorylation, mitochondria continuously produce reactive oxygen species (ROS), and untimely ROS clearance can subject mitochondria to oxidative stress, ultimately resulting in mitochondrial damage. Mitophagy is essential for maintaining cellular mitochondrial quality control and homeostasis, with activation involving both ubiquitin-dependent and ubiquitin-independent pathways. Over the past decade, numerous studies have indicated that different forms of regulated cell death (RCD) are connected with mitophagy. These diverse forms of RCD have been shown to be regulated by mitophagy and are implicated in the pathogenesis of a variety of diseases, such as tumors, degenerative diseases, and ischemia‒reperfusion injury (IRI). Importantly, targeting mitophagy to regulate RCD has shown excellent therapeutic potential in preclinical trials, and is expected to be an effective strategy for the treatment of related diseases. Here, we present a summary of the role of mitophagy in different forms of RCD, with a focus on potential molecular mechanisms by which mitophagy regulates RCD. We also discuss the implications of mitophagy-related RCD in the context of various diseases.

Abstract Schizophrenic patients’ brain tumor magnetic resonance imaging (MRI) images are important references for doctors to diagnose and treat schizophrenia. However, automatic segmentation of these images is a professional and tedious task. Existing methods suffer from problems such as large model parameters, long computation time, and inadequate image processing. To achieve more accurate segmentation of brain tumors, we propose brain tumor MRI images for automatic segmentation using self-supervised contrastive learning in schizophrenia patients (BTCSSSP). First, a denoising algorithm based on progressive principal component analysis approximation and adaptive clustering is designed to process the noisy MRI images. Second, a brightness-aware image enhancement algorithm is developed to address the problems of non-uniformity, unclear boundaries, and poor spatial resolution of the MRI images. Finally, a cross-scale U-Net network with selective feature fusion attention module is designed based on self-supervised contrastive learning to achieve automatic segmentation of brain tumor MRI images. The results show that the BTCSSSP method yields higher Recall and Precision than existing methods. The maximum recall is 95%, and the image segmentation precision is 95%, thus indicating good practical applicability.

Abstract Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Abstract Rosa roxburghii Tratt, a valuable plant in China with long history, is famous for its fruit. It possesses various secondary metabolites, such as L-ascorbic acid (vitamin C), alkaloids and poly saccharides, which make it a high nutritional and medicinal value. Here we characterized the chromosome-level genome sequence of R. roxburghii, comprising seven pseudo-chromosomes with a total size of 531 Mb and a heterozygosity of 0.25%. We also annotated 45,226 coding gene loci after masking repeat elements. Orthologs for 90.1% of the Complete Single-Copy BUSCOs were found in the R. roxburghii annotation. By aligning with protein sequences from public platform, we annotated 85.89% genes from R. roxburghii. Comparative genomic analysis revealed that R. roxburghii diverged from Rosa chinensis approximately 5.58 to 13.17 million years ago, and no whole-genome duplication event occurred after the divergence from eudicots. To fully utilize this genomic resource, we constructed a genomic database RroFGD with various analysis tools. Otherwise, 69 enzyme genes involved in L-ascorbate biosynthesis were identified and a key enzyme in the biosynthesis of vitamin C, GDH (L-Gal-1-dehydrogenase), is used as an example to introduce the functions of the database. This genome and database will facilitate the future investigations into gene function and molecular breeding in R. roxburghii.

Abstract Traditional village toponyms contain rich vernacular geographical information, profound cultural connotations, and social group memories. Studying the meanings and spatial distribution characteristics of traditional village toponyms and their formation mechanism is significant for the sustainable development and protection of the intangible culture of traditional villages. However, previous studies mainly focused on qualitative description combined with geospatial analysis techniques to explore their spatial distribution and influencing factors, but there has yet to be an in-depth study on why such a pattern is formed. Thus, this study employs statistics, a GIS kernel density estimation method, a geodetector, and historical data to examine the spatial distribution, influence factors, and formation mechanisms of various toponyms in traditional villages in western Hunan, China. The results show that (1) the toponyms in traditional villages in western Hunan can be categorized into natural and cultural landscape toponyms. Natural landscape toponyms predominate in the northwest, whereas cultural landscape toponyms are more concentrated in the southeast, with Huayuan, Longshan, and Dong Autonomous Counties as the primary focal points; (2)Natural toponyms are shaped by terrain, river proximity, and vegetation, whereas cultural toponyms cluster due to natural features and historic trail influence, mirroring the historical migration and settlement patterns in the development of western Hunan; (3)Multiple influencing factors, regulatory powers, and curing processes reveal the formation mechanism of the spatial patterns of toponyms. This study offers a novel lens for recognizing and understanding the characteristics of human settlement environments and culture in traditional villages. Moreover, the results of this study can provide scientific guidance for the cultural protection of traditional villages on a cross-regional scale.

Cyclophosphamide (CTX) is an anticancer medication that suppresses host immunity as well as adversely affects mucosal inflammation and gut microflora dysbiosis. The gut microflora is recognized as a substantial factor in host metabolism and immunological homeostasis. To improve immunity and inhibit cytotoxic and homeostatic imbalances triggered by CTX, it is essential to monitor immunoregulators. In this research, we assessed the impact of Octopus peptide hydrolysate (OPH) on immune modulation, intestinal integrity, and gut microbial composition in CTX-induced immune-deficient mice. The results revealed that OPH increased body weight, and immunological organ indices, and improved the histological changes in the colon, thymus, and spleen. The OPH stimulated the secretion of cytokines (IL-1β, IL-6, and TNF-α) and antibodies (IgM and IgA) while reducing the ratio of lipopolysaccharide (LPS) and diamine oxidase (DAO) in the serum. OPH further enhanced goblet cell and mucus production, upregulated the expression of gut tight-junction proteins (Occludin, Zonula Occludin-1, Mucin-2, and Claudin-1), and activated the TLR4/NF-κB cascade (p-IκBα, P65/p-p65). In addition, OPH treatment declined the Bacteroidetes/Firmicutes ratio, enhanced the relative ratio of Alistipes/Lachnospiraceae, and reversed the ecological equilibrium of the gut microflora. The findings revealed that OPH serves as a prebiotic to prevent CTX-mediated disruption in the intestinal barrier and boosts gut mucosal immunity by attenuating gut microflora imbalance, implying that OPH could be used as an immunological ingredient in nutritious foods to regulate the immune system and protect the gut from inflammatory diseases.

IntroductionWith the goal of patient engagement, an initiative was formulated to equip each patient in the general wards with a tablet whereby they can access their health information and patient education materials and communicate with their healthcare team. This paper presented the methodology of the implementation efforts as well as an evaluation of the preliminary outcomes.MethodsThe process of hospital-wide implementation was shared using the implementation research logic model. The bedside tablets were rolled out hospital-wide in a step-wedge manner over 12 months. Barriers and facilitators to this implementation were discussed together with strategies to optimize the situation. Preliminary outcomes of the implementation were evaluated using the RE-AIM framework.ResultsThe initial adoption rate for the bedside tablet was low. Additional strategies, such as survey audits and provision of feedback, development of education materials for patients, facilitation, and purposefully re-examining the implementation strategies, were used to improve adoption. The trend of adoption increased over the course of 2 years from the start of implementation.DiscussionThe initial lower adoption rates may reflect Singapore's paternalistic healthcare culture. While this implementation was driven by the need to move away from paternalism and toward patient engagement, more time is required for significant cultural change.

BackgroundNovel β-lactam antibiotics as well as other kinds of antibiotics have been used to treat complicated urinary tract infections (cUTIs); however, their efficacy and safety remain controversial.ObjectiveWe conducted a systematic review with meta-analysis to explore the efficacy and safety of novel β-lactam antibiotics versus other antibiotics against cUTIs.MethodsPubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched systematically from inception through 15 March 2024 for clinical trials comparing novel β-lactam antibiotics with other antibiotics for treatment of cUTIs. Random-effects models were used to evaluate the impact of treatment on the risk ratio (RR) of clinical response, microbiologic response, adverse effects (AEs), serious adverse effects (SAEs). The quality of evidence was evaluated with the Cochrane Risk of Bias assessment tool. The review was registered in INPLASY (INPLASY202440054).ResultsTen randomized controlled trials involving 5, 925 patients met our inclusion criteria. Our meta-analysis revealed that there was no significant difference in overall clinical response (RR = 1.02), AEs (RR = 1.07), SAEs (RR = 1.20) between novel β-lactam antibiotics groups and other antibiotics groups. However, a significant difference was found in a subgroup of clinical cure rates at the end of treatment between novel β-lactam antibiotics groups and carbapenems groups, with low heterogeneity (RR = 1.02). A significant difference was observed in microbiologic response (RR = 1.11). Subgroup analysis revealed a significant difference in microbiologic response between novel BBL/BLS groups and carbapenems groups (RR = 1.13, I2 = 21%, P = 0.005). Differences was observed between novel BBL/BLS groups and piperacillin/tazobactam sodium groups (RR = 1.21, I2 = 70%, P = 0.02). Similar results were obtained from subgroup analysis of the difference in microbiologic response between novel β-lactam antibiotics groups and ertapenem groups (RR = 0.92, I2 = 0, P = 0.01).ConclusionNovel β-lactam antibiotics had similar overall clinical cure, AEs, SAE, to other antibiotics in the treatment of cUTIs. However, novel β-lactam antibiotics demonstrated superior clinical cure rates compared to carbapenems in a subgroup analysis, and exhibited better microbiologic response than other antibiotics.

Patients with the target gene mutation frequently derive significant clinical benefits from target therapy. However, differences in the abundance level of mutations among patients resulted in varying survival benefits, even among patients with the same target gene mutations. Currently, there is a lack of rational and interpretable models to assess the risk of treatment failure. In this study, we investigated the underlying coupled factors contributing to variations in medication sensitivity and established a statistically interpretable framework, named SAFE-MIL, for risk estimation. We first constructed an effectiveness label for each patient from the perspective of exploring the optimal grouping of patients’ positive judgment values and sampled patients into 600 and 1,000 groups, respectively, based on multi-instance learning (MIL). A novel and interpretable loss function was further designed based on the Hosmer-Lemeshow test for this framework. By integrating multi-instance learning with the Hosmer-Lemeshow test, SAFE-MIL is capable of accurately estimating the risk of drug treatment failure across diverse patient cohorts and providing the optimal threshold for assessing the risk stratification simultaneously. We conducted a comprehensive case study involving 457 non-small cell lung cancer patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors. Results demonstrate that SAFE-MIL outperforms traditional regression methods with higher accuracy and can accurately assess patients’ risk stratification. This underscores its ability to accurately capture inter-patient variability in risk while providing statistical interpretability. SAFE-MIL is able to effectively guide clinical decision-making regarding the use of drugs in targeted therapy and provides an interpretable computational framework for other patient stratification problems. The SAFE-MIL framework has proven its effectiveness in capturing inter-patient variability in risk and providing statistical interpretability. It outperforms traditional regression methods and can effectively guide clinical decision-making in the use of drugs for targeted therapy. SAFE-MIL offers a valuable interpretable computational framework that can be applied to other patient stratification problems, enhancing the precision of risk assessment in personalized medicine. The source code for SAFE-MIL is available for further exploration and application at https://github.com/Nevermore233/SAFE-MIL.

Hyperthyroidism and thyroid cancer significantly impact health, and often require Radioactive Iodine (RAI) therapy. Anxiety is common in patients undergoing RAI, particularly related to dietary compliance. This study aimed to assess the effectiveness of the mobile health application, DietLens in reducing anxiety and increasing satisfaction in patients preparing for RAI therapy, focusing on low-iodine diet (LID). A quasi-experimental study was conducted in a Singapore tertiary hospital outpatient department from March 13, 2019 to March 27, 2020, involving patients scheduled for their first RAI treatment. Participants were divided into a control group receiving standard care and an intervention group using DietLens alongside standard care. Anxiety levels were assessed using the Zung Self-Rating Anxiety Scale, and satisfaction levels were measured through self-reported questionnaires. In the study, 56 participants were initially divided into control (n = 28) and intervention (n = 28) groups. After accounting for dropouts, 50 participants finished the study, with each group comprising 25 individuals. Anxiety levels were similar between groups pre-intervention. Post-intervention, the intervention group displayed a significant decrease in anxiety levels compared to the control group (independent t-test: t (48) = 2.50, p = 0.02). The multivariate linear regression analysis indicated that being in the intervention group was significantly associated with a decrease in post-intervention anxiety score (β = −4.03, 95 % CI: −7.33 to −0.72, p = 0.02). Fisher's Exact Test revealed a borderline significant difference in satisfaction with educational materials and the overall treatment process, with 100 % of the intervention group expressing satisfaction compared to 80 % in the control group, resulting in a p-value of 0.052 in both instances. DietLens was effective in reducing anxiety and enhancing satisfaction related to RAI therapy preparation, particularly in managing a LID, highlighting a beneficial role for digital interventions in healthcare settings.

Investigating the composition of household dust can provide crucial insights into potential environmental and health implications. This study aimed to determine the concentration of selected metals in 30 household floor dust samples collected from two cities in Peninsular Malaysia, namely Melaka and Butterworth. The samples were collected using nylon socks attached to a vacuum cleaner nozzle during January-February 2021. All samples were sieved through a 200-µm sieve, acid-digested with aqua regia, and analyzed using inductively coupled plasma mass spectrometry (ICP-MS). Mean metal concentrations decreased in the order of Fe>Al>Mg>Zn>Mn>Ba>Cu>Cr>Pb. Cd was not detected in any samples. The median concentrations of Al, Ba, and Mg from Melaka were significantly higher than those from Butterworth. Hazard indexes for all metals were less than one, indicating a low noncarcinogenic risk of exposure to occupants via inhalation, dust ingestion, and skin absorption. Statistical analyses revealed that the levels of metals in household dust were influenced by factors such as the location and age of the house, the presence of air conditioning, and the time since the last paint. This study highlights the presence of metals in indoor settings of different cities in Malaysia, providing fundamental data for future research in the field.

Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary heart disease. Here, we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum- and PDGF-BB-induced vascular smooth muscle cells (VSMCs), and in tissues of carotid artery injury-induced neointimal hyperplasia. Smyd2 overexpression in VSMCs (Smyd2-vTg) facilitates, but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown significantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice. Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor (SRF) target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation. HDAC3 directly interacts with and deacetylates SRF, which enhances SRF transcriptional activity in VSMCs. Moreover, SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter. RGFP966, a specific inhibitor of HDAC3, not only counteracts the pro-proliferation effect of SMYD2 overexpression on VSMCs, but also inhibits carotid artery injury-induced neointima formation in mice. HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner. Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.

Abstract Despite the central role of human leukocyte antigen class I (HLA-I) in tumor neoantigen presentation, quantitative determination of presentation capacity remains elusive. Based on a pooled pan-cancer genomic dataset of 885 patients treated with immune checkpoint inhibitors (ICIs), we developed a score integrating the binding affinity of neoantigens to HLA-I, as well as HLA-I allele divergence, termed the HLA tumor-Antigen Presentation Score (HAPS). Patients with a high HAPS were more likely to experience survival benefit following ICI treatment. Analysis of the tumor microenvironment indicated that the antigen presentation pathway was enriched in patients with a high HAPS. Finally, we built a neural network incorporating factors associated with neoantigen production, presentation, and recognition, which exhibited potential for differentiating cancer patients likely to benefit from ICIs. Our findings highlight the clinical utility of evaluating HLA-I tumor antigen presentation capacity and describe how ICI response may depend on HLA-mediated immunity.

Huoxiang Zhengqi San (HXZQS), a traditional Chinese herbal formula, enjoys widespread use in Chinese medicine to treat diarrhea with cold-dampness trapped spleen syndrome (CDSS), which is induced by exposure to cold and high humidity stress. This study aimed to explore its therapeutic mechanisms in mice, particularly focusing on the intestinal microbiota. Forty male SPF-grade KM mice were allocated into two groups: the normal control group (H-Cc, n = 10) and the CDSS group (H-Mc, n = 30). After modeling, H-Mc was subdivided into H-Mc (n = 15) and HXZQS treatment (H–Tc, n = 15) groups. Intestinal samples were analyzed for enzyme activity and microbiota composition. Our findings demonstrated a notable reduction in intestinal lactase activity post-HXZQS treatment (P

Objectives Build the theoretical and evidence-base for a digital platform (map-OR) which delivers intraoperative language tests during awake craniotomy and facilitates collaborative sharing of brain mapping data.Design Mixed methodology study including two scoping reviews, international survey, synthesis of development guiding principles and a risk assessment using failure modes and effects analysis.Setting The two scoping reviews examined the literature published in the English language. International survey was completed by members of awake craniotomy teams from 14 countries.Main outcome measures Scoping review 1: number of technologies described for language mapping during awake craniotomy. Scoping review 2: barriers and facilitators to adopting novel technology in surgery. International survey: degree of language mapping technology penetration into clinical practice.Results A total of 12 research articles describing 6 technologies were included. The technologies required a range of hardware components including portable devices, virtual reality headsets and large integrated multiscreen stacks. The facilitators and barriers of technology adoption in surgery were extracted from 11 studies and mapped onto the 4 Unified Theory of Acceptance and Use of Technology constructs. A total of 37 awake craniotomy teams from 14 countries completed the survey. Of the responses, 20 (54.1%) delivered their language tests digitally, 10 (27.0%) delivered tests using cards and 7 (18.9%) used a combination of both. The most commonly used devices were tablet computers (67.7%; n=21) and the most common software used was Microsoft PowerPoint (60.6%; n=20). Four key risks for the proposed digital platform were identified, the highest risk being a software and internet connectivity failure during surgery.Conclusions This work represents a rigorous and structured approach to the development of a digital platform for standardized intraoperative language testing during awake craniotomy and for collaborative sharing of brain mapping data.Trial registration number Scoping review protocol registrations in OSF registries (scoping review 1: osf.io/su9xm; scoping review 2: osf.io/x4wsc).

Historically, the central nervous system (CNS) was regarded as ‘immune-privileged’, possessing its own distinct immune cell population. This immune privilege was thought to be established by a tight blood-brain barrier (BBB) and blood-cerebrospinal-fluid barrier (BCSFB), which prevented the crossing of peripheral immune cells and their secreted factors into the CNS parenchyma. However, recent studies have revealed the presence of peripheral immune cells in proximity to various brain-border niches such as the choroid plexus, cranial bone marrow (CBM), meninges, and perivascular spaces. Furthermore, emerging evidence suggests that peripheral immune cells may be able to infiltrate the brain through these sites and play significant roles in driving neuronal cell death and pathology progression in neurodegenerative disease. Thus, in this review, we explore how the brain-border immune niches may contribute to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). We then discuss several emerging options for harnessing the neuroimmune potential of these niches to improve the prognosis and treatment of these debilitative disorders using novel insights from recent studies.

Abstract Previous studies on the molecular classification of cholangiocarcinoma (CCA) focused on certain anatomical sites, and disregarded tissue contamination biases in transcriptomic profiles. We aim to provide universal molecular classification scheme and prognostic biomarker of CCAs across anatomical locations. Comprehensive bioinformatics analysis is performed on transcriptomic data from 438 CCA cases across various anatomical locations. After excluding CCA tumors showing normal tissue expression patterns, we identify two universal molecular subtypes across anatomical subtypes, explore the molecular, clinical, and microenvironmental features of each class. Subsequently, a 30-gene classifier and a biomarker (called “CORE-37”) are developed to predict the molecular subtype of CCA and prognosis, respectively. Two subtypes display distinct molecular characteristics and survival outcomes. Key findings are validated in external cohorts regardless of the stage and anatomical location. Our study provides a CCA classification scheme that complements the conventional anatomy-based classification and presents a promising prognostic biomarker for clinical application.

Parkinson’s disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson’s disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson’s disease, followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a “dying back” mechanism. Recently, several new animal and cellular models with Parkinson’s disease-linked mutations affecting the endocytic pathway have been created and extensively characterized. These models faithfully recapitulate certain Parkinson’s disease-like features at the animal, circuit, and cellular levels, and exhibit defects in synaptic membrane trafficking, further supporting the findings from human genetics and clinical studies. In this review, we will first summarize the cellular and molecular findings from the models of two Parkinson’s disease-linked clathrin uncoating proteins: auxilin (DNAJC6/PARK19) and synaptojanin 1 (SYNJ1/PARK20). The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect. Subsequently, we will delve into the involvement of several clathrin-mediated endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), identified as Parkinson’s disease risk factors through genome-wide association studies, in Parkinson’s disease pathogenesis. We will also explore the direct or indirect roles of some common Parkinson’s disease-linked proteins (alpha-synuclein (PARK1/4), Parkin (PARK2), and LRRK2 (PARK8)) in synaptic endocytic trafficking. Additionally, we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways, particularly autophagy. Given that synaptic dysfunction is considered as an early event in Parkinson’s disease, a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel targets for early diagnosis and the development of interventional therapies for Parkinson’s disease. Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson’s disease.

Abstract Histone methyltransferase SETDB1 (SET domain bifurcated histone lysine methyltransferase 1, also known as ESET or KMT1E) is known to be involved in the deposition of the di- and tri-methyl marks on H3K9 (H3K9me2 and H3K9me3), which are associated with transcription repression. SETDB1 exerts an essential role in the silencing of endogenous retroviruses (ERVs) in embryonic stem cells (mESCs) by tri-methylating H3K9 (H3K9me3) and interacting with DNA methyltransferases (DNMTs). Additionally, SETDB1 is engaged in regulating multiple biological processes and diseases, such as ageing, tumors, and inflammatory bowel disease (IBD), by methylating both histones and non-histone proteins. In this review, we provide an overview of the complex biology of SETDB1, review the upstream regulatory mechanisms of SETDB1 and its partners, discuss the functions and molecular mechanisms of SETDB1 in cell fate determination and stem cell, as well as in tumors and other diseases. Finally, we discuss the current challenges and prospects of targeting SETDB1 for the treatment of different diseases, and we also suggest some future research directions in the field of SETDB1 research.

Abstract Background The biomarkers of immune checkpoint inhibitors in the treatment of non‐small cell lung cancer (NSCLC) patients have limited predictive performance. In this study we aimed to investigate the feasibility of molecular tumor burden index (mTBI) in circulating tumor DNA (ctDNA) as a predictor for immunotherapy in patients with NSCLC. Methods From February 2017 to November 2020, pretreatment and on‐treatment (3~6 weeks after first cycle of immunotherapy) dynamic plasma ctDNA samples from NSCLC patients receiving immune monotherapy or combination therapy were analyzed by targeted capture sequencing of 1021 genes. PyClone was used to infer the mTBI. The impact of pretreatment mTBI on survival outcomes was verified in the POPLAR/OAK trials. Results We found that patients without detectable baseline ctDNA had better survival outcomes (median overall survival [OS]: not reached vs. 12.8 months; hazard ratio [HR], 0.15; p = 0.035]). RB1 and SMARCA4 mutations were remarkably associated with worse survival outcomes. Furthermore, lower pretreatment mTBI was associated with superior OS (median: not reached vs. 8.1 months; HR, 0.22; p = 0.024) and PFS (median: 32.9 vs. 5.4 months; HR, 0.35; p = 0.045), but not objective response, which was validated in the POPLAR/OAK cohort, suggesting that baseline mTBI was a prognostic factor for NSCLC immunotherapy. Early dynamic changes of mTBI (ΔmTBI) significantly distinguished responsive patients, and patients with mTBI decrease to more than 68% at the final tumor evaluation had longer OS (median: 38.2 vs. 4.0 months; HR, 0.18; p = 0.017) and PFS (median: not reached vs. 2.3 months; HR, 0.24; p = 0.030). Conclusion ΔmTBI had a good sensitivity to identify potential beneficial patients based on the best effect CT scans, demonstrating that mTBI dynamics were predictive of benefit from immune checkpoint blockade.

Abstract Background During the early stages of Trichinella spiralis infection, macrophages predominantly undergo polarization to the M1-like phenotype, causing the host’s inflammatory response and resistance against T. spiralis infection. As the disease progresses, the number of M2-type macrophages gradually increases, contributing to tissue repair processes within the host. While cysteine protease overexpression is typically associated with inflammation, the specific role of T. spiralis cathepsin L (TsCatL) in mediating macrophage polarization remains unknown. The aim of this study was to assess the killing effect of macrophage polarization mediated by recombinant T. spiralis cathepsin L domains (rTsCatL2) on newborn larvae (NBL). Methods rTsCatL2 was expressed in Escherichia coli strain BL21. Polarization of the rTsCatL2-induced RAW264.7 cells was analyzed by enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), western blot, immunofluorescence and flow cytometry. The effect of JSH-23, an inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), on rTsCatL2-induced M1 polarization investigated. Cytotoxic effects of polarized macrophages on NBL were observed using in vitro killing assays. Results Following the co-incubation of rTsCatL2 with RAW264.7 murine macrophage cells, qPCR and ELISA revealed increased transcription and secretion levels of inducible nitric oxide synthase (iNOS), interleukin (IL)-6, IL-1β and tumor necrosis factor alpha (TNF-α) in macrophages. Western blot analysis showed a significant increase in iNOS protein expression, while the expression level of arginase-1 protein remained unchanged. Flow cytometry revealed a substantial increase in the number of CD86-labeled macrophages. The western blot results also indicated that rTsCatL2 increased the expression levels of phospho-NF-κB and phospho-nuclear factor-κB inhibitor alpha (IκB-α) proteins in a dose-dependent manner, while immunofluorescence revealed that rTsCatL2 induced nuclear translocation of the p65 subunit of NF-κB (NF-κB p65) protein in macrophages. The inhibitory effect of JSH-23 suppressed and abrogated the effect of rTsCatL2 in promoting M1 macrophage polarization. rTsCatL2 mediated polarization of macrophages to the M1-like phenotype and enhanced macrophage adhesion and antibody-dependent cell-mediated cytotoxicity (ADCC) killing of NBL. Conclusions The results indicated that rTsCatL2 induces macrophage M1 polarization via the NF-κB pathway and enhances the ADCC killing of NBL. This study provides a further understanding of the interaction mechanism between T. spiralis and the host. Graphical Abstract

Coal-to-liquid technology is a key technology to ensuring national energy security, with the Fischer–Tropsch synthesis process at its core. However, in actual production, Fischer–Tropsch wax residue exhibits the characteristics of spontaneous combustion due to heat accumulation, posing a fire hazard when exposed to air for extended periods. This significantly threatens the safe production operations of coal-to-liquid chemical enterprises. This study primarily focuses on the experimental investigation of the oxidative spontaneous combustion process of three typical types of wax residues produced during Fischer–Tropsch synthesis. Differential Scanning Calorimetry (DSC) was used to test the thermal flow curves of the three wax residue samples. Kinetic analysis was performed using the Kissinger–Akahira–Sunose (KAS) and Flynn–Wall–Ozawa (FWO) methods to calculate their apparent activation energy. This study analyzed the thermal behavior characteristics, exothermic properties, and kinetic parameters of three typical wax residue samples, exploring the ease of reaction between wax residues and oxygen and their tendency for spontaneous combustion. The results indicate that Wax Residue 1 is rich in low-carbon chain alkanes and olefins, Wax Residue 2 contains relatively fewer low-carbon chain alkanes and olefins, while Wax Residue 3 primarily consists of high-carbon chain alkanes and olefins. This leads to different thermal behavior characteristics among the three typical wax residue samples, with Wax Residue 1 having the lowest heat release and average apparent activation energy and Wax Residue 3 having the highest heat release and average apparent activation energy. These findings suggest that Wax Residue 1 has a higher tendency for spontaneous combustion. This research provides a scientific basis for the safety management of the coal chemical industry, and further exploration into the storage and handling methods of wax residues could reduce fire risks in the future.

Abstract Assembly of a high-quality genome is important for downstream comparative and functional genomic studies. However, most tools for genome assembly assessment only give qualitative reports, which do not pinpoint assembly errors at specific regions. Here, we develop a new reference-free tool, Clipping information for Revealing Assembly Quality (CRAQ), which maps raw reads back to assembled sequences to identify regional and structural assembly errors based on effective clipped alignment information. Error counts are transformed into corresponding assembly evaluation indexes to reflect the assembly quality at single-nucleotide resolution. Notably, CRAQ distinguishes assembly errors from heterozygous sites or structural differences between haplotypes. This tool can clearly indicate low-quality regions and potential structural error breakpoints; thus, it can identify misjoined regions that should be split for further scaffold building and improvement of the assembly. We have benchmarked CRAQ on multiple genomes assembled using different strategies, and demonstrated the misjoin correction for improving the constructed pseudomolecules.

Defects in genes involved in the DNA damage response cause homologous recombination repair deficiency (HRD). HRD is found in a subgroup of cancer patients for several tumor types, and it has a clinical relevance to cancer prevention and therapies. Accumulating evidence has identified HRD as a biomarker for assessing the therapeutic response of tumor cells to poly(ADP-ribose) polymerase inhibitors and platinum-based chemotherapies. Nevertheless, the biology of HRD is complex, and its applications and the benefits of different HRD biomarker assays are controversial. This is primarily due to inconsistencies in HRD assessments and definitions (gene-level tests, genomic scars, mutational signatures, or a combination of these methods) and difficulties in assessing the contribution of each genomic event. Therefore, we aim to review the biological rationale and clinical evidence of HRD as a biomarker. This review provides a blueprint for the standardization and harmonization of HRD assessments.

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole‐exome sequencing (WES) and T‐cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non‐silent mutations from multi‐samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi‐cancers. IHC using antibodies against CD4, CD8, and PD‐L1 demonstrated scant T‐cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T‐cell clones shared across tumor regions in any of the patients, while over 94% of T‐cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi‐regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T‐cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma.

Abstract Background Aberrant proliferation of vascular smooth muscle cells (VSMCs) is the cause of neointima formation followed by vascular injury. Autophagy is involved in this pathological process, but its function is controversial. Recently, we found that methyltransferase like 3 (METTL3) inhibited VSMC proliferation by activating autophagosome formation. Moreover, we also demonstrated that METTL3 reduced the levels of phosphorylated mammalian target of rapamycin (p-mTOR) and cyclin dependent kinase 1 (p-CDK1/CDC2), which were critical for autophagy and proliferation regulation. However, whether mTOR and CDK1 mediated the function of METTL3 on autophagy and proliferation in VSMCs remains unknown. Results We showed that the activator of mTOR, MHY1485 largely reversed the effects of METTL3 overexpression on VSMC autophagy and proliferation. Rapamycin, the inhibitor of mTOR, obviously nullified the pro-proliferation effects of METTL3 knockdown by activating autophagy in VSMCs. Unexpectedly, mTOR did not contribute to the impacts of METTL3 on migration and phenotypic switching of VSMCs. On the other hand, by knockdown of CDK1 in VSMC with METTL3 deficiency, we demonstrated that CDK1 was involved in METTL3-regulated proliferation of VSMCs, but this effect was not mediated by autophagy. Conclusions We concluded that mTOR but not CDK1 mediated the role of METTL3 on VSMC proliferation and autophagy.

Summary: Background: The high heterogeneity of tumour and the complexity of tumour microenvironment (TME) greatly impacted the tumour development and the prognosis of cancer in the era of immunotherapy. In this study, we aimed to portray the single cell-characterised landscape of lung adenocarcinoma (LUAD), and develop an integrated signature incorporating both tumour heterogeneity and TME for prognosis stratification. Methods: Single-cell tagged reverse transcription sequencing (STRT-seq) was performed on tumour tissues and matched normal tissues from 14 patients with LUAD for immune landscape depiction and candidate key genes selection for signature construction. Kaplan–Meier survival analyses and in-vitro cell experiments were conducted to confirm the gene functions. The transcriptomic profile of 1949 patients from 11 independent cohorts including nine public datasets and two in-house cohorts were obtained for validation. Findings: We selected 11 key genes closely related to cell-to-cell interaction, tumour development, T cell phenotype transformation, and Ma/Mo cell distribution, including HLA-DPB1, FAM83A, ITGB4, OAS1, FHL2, S100P, FSCN1, SFTPD, SPP1, DBH-AS1, CST3, and established an integrated 11-gene signature, stratifying patients to High-Score or Low-Score group for better or worse prognosis. Moreover, the prognostically-predictive potency of the signature was validated by 11 independent cohorts, and the immunotherapeutic predictive potency was also validated by our in-house cohort treated by immunotherapy. Additionally, the in-vitro cell experiments and drug sensitivity prediction further confirmed the gene function and generalizability of this signature across the entire RNA profile spectrum. Interpretation: This single cell-characterised 11-gene signature might offer insights for prognosis stratification and potential guidance for treatment selection. Funding: Support for the study was provided by National key research and development project (2022YFC2505004, 2022YFC2505000 to Z.W. and J.W.), Beijing Natural Science Foundation (7242114 to J.X.), National Natural Science Foundation of China of China (82102886 to J.X., 81871889 and 82072586 to Z.W.), Beijing Nova Program (20220484119 to J.X.), NSFC general program (82272796 to J.W.), NSFC special program (82241229 to J.W.), CAMS Innovation Fund for Medical Sciences (2021-1-I2M-012, 2022-I2M-1-009 to Z.W. and J.W.), Beijing Natural Science Foundation (7212084 to Z.W.), CAMS Key lab of translational research on lung cancer (2018PT31035 to J.W.), Aiyou Foundation (KY201701 to J.W.). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022003 to J.X.)

BackgroundMetabolic reprogramming plays a significant role in the advancement of lung adenocarcinoma (LUAD), yet the precise metabolic changes remain incompletely understood. This study aims to uncover metabolic indicators associated with the progression of LUAD.MethodsA total of 1083 subjects were recruited, including 670 LUAD, 135 benign lung nodules (BLN) and 278 healthy controls (HC). Gas chromatography-mass spectrometry (GC/MS) was used to identify and quantify plasma metabolites. Odds ratios (ORs) were calculated to determine LUAD risk factors, and machine learning algorithms were utilized to differentiate LUAD from BLN.ResultsHigh levels of oxalate, glycolate, glycine, glyceric acid, aminomalonic acid, and creatinine were identified as risk factors for LUAD (adjusted ORs>1.2, P

The human gut microbiome plays a critical role in maintaining our health. Fluctuations in the diversity and structure of the gut microbiota have been implicated in the pathogenesis of several metabolic and inflammatory conditions. Dietary patterns, medication, smoking, alcohol consumption, and physical activity can all influence the abundance of different types of microbiota in the gut, which in turn can affect the health of individuals. Intestinal phages are an essential component of the gut microbiome, but most studies predominantly focus on the structure and dynamics of gut bacteria while neglecting the role of phages in shaping the gut microbiome. As bacteria-killing viruses, the distribution of bacteriophages in the intestine, their role in influencing the intestinal microbiota, and their mechanisms of action remain elusive. Herein, we present an overview of the current knowledge of gut phages, their lifestyles, identification, and potential impact on the gut microbiota.

The intricate mechanical interplay between cell membranes and enclosed filaments or filament networks plays an essential role in governing cellular morphological transformations and various cellular activities. A profound understanding of fundamental mechanical mechanisms underlying these interactions can be gained by exploring mechanical behaviors of a filament–vesicle system. Here we theoretically investigate the axial stretching of a lipid vesicle containing an enclosed filament loop. The vesicle either freely adjusts its volume or maintains a fixed volume. Depending on the relative stiffness and size of the filament loop to the vesicle as well as the vesicle scenario, the vesicle prior to stretching exhibits a spherical, prolate or oblate shape, and during stretching it undergoes morphological transformations with pronounced filament distortion and reorientation. The filament–vesicle system could exhibit a spring-softening or -stiffening response during stretching. Moreover, effects of filament inhomogeneity on the stretching process are studied. Our results could serve as a quantitative benchmark for further investigations into cellular complexity.

Abstract Background E1A-associated 300-kDa protein (P300), an endogenous histone acetyltransferase, contributes to modifications of the chromatin landscape of genes involved in multiple cardiovascular diseases. Ferroptosis of vascular smooth muscle cells (VSMCs) is a novel pathological mechanism of aortic dissection. However, whether P300 regulates VSMC ferroptosis remains unknown. Methods Cystine deprivation (CD) and imidazole ketone erastin (IKE) were used to induce VSMC ferroptosis. Two different knockdown plasmids targeting P300 and A-485 (a specific inhibitor of P300) were used to investigate the function of P300 in the ferroptosis of human aortic smooth muscle cells (HASMCs). Cell counting kit-8, lactate dehydrogenase and flow cytometry with propidium iodide staining were performed to assess the cell viability and death under the treatment of CD and IKE. BODIPY-C11 assay, immunofluorescence staining of 4-hydroxynonenal and malondialdehyde assay were conducted to detect the level of lipid peroxidation. Furthermore, co-immunoprecipitation was utilized to explore the interaction between P300 and HIF-1α, HIF-1α and P53. Results Compared with normal control, the protein level of P300 was significantly decreased in HASMCs treated with CD and IKE, which was largely nullified by the ferroptosis inhibitor ferrostatin-1 but not by the autophagy inhibitor or apoptosis inhibitor. Knockdown of P300 by short-hairpin RNA or inhibition of P300 activity by A-485 promoted CD- and IKE-induced HASMC ferroptosis, as evidenced by a reduction in cell viability and aggravation of lipid peroxidation of HASMCs. Furthermore, we found that hypoxia-inducible factor-1α (HIF-1α)/heme oxygenase 1 (HMOX1) pathway was responsible for the impacts of P300 on ferroptosis of HASMCs. The results of co-immunoprecipitation demonstrated that P300 and P53 competitively bound HIF-1α to regulate the expression of HMOX1. Under normal conditions, P300 interacted with HIF-1α to inhibit HMOX1 expression, while reduced expression of P300 induced by ferroptosis inducers would favor HIF-1α binding to P53 to trigger HMOX1 overexpression. Furthermore, the aggravated effects of P300 knockdown on HASMC ferroptosis were largely nullified by HIF-1α knockdown or the HIF-1α inhibitor BAY87-2243. Conclusion Thus, our results revealed that P300 deficiency or inactivation facilitated CD- and IKE-induced VSMC ferroptosis by activating the HIF-1α/HMOX1 axis, which may contribute to the development of diseases related to VSMC ferroptosis.

Abstract Background SETD2 protects against genomic instability via maintenance of homologous recombination repair (HRR) and mismatch repair (MMR) in neoplastic cells. However, it remains unclear whether SETD2 dysfunction is a complementary or independent factor to microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) for immunocheckpoint inhibitor (ICI) treatment, and little is known regarding whether this type of dysfunction acts differently in various types of cancer. Methods This cohort study used multidimensional genomic data of 6726 sequencing samples from our cooperative and non-public GenePlus institute from April 1 through April 10, 2020. MSIsensor score, HRD score, RNAseq, mutational data, and corresponding clinical data were obtained from the TCGA and MSKCC cohort for seven solid tumor types. Results A total of 1021 genes underwent target panel sequencing reveal that SETD2 mutations were associated with a higher TMB. SETD2 deleterious mutation dysfunction affected ICI treatment prognosis independently of TMB-H (p

Effects of rare-earth (RE) and precipitates on twin evolution in cast Mg-10Gd-3Y-0.5Zr (wt.%) (GW103) alloys of solid solution (T4) and aged (T6) states are investigated performing quasi-static room temperature compression tests and microstructural characterization. It is found that both {10–12} and {11–21} extension twins (ET1 and ET2) can appear in the T4 and T6 states but with different emergence sequences. As the aging heat treatment leads to consumption of RE solutes which could inhibit atomic shuffling required for nucleation of ET1 but not ET2, ET2 occurs prior to ET1 in the T4 state, and ET1 emerges before ET2 in the T6 state. The extension twins here mainly coordinate the plastic deformation through the non-Schmid effect. Our results shed light on the influence of RE elements on twin evolution in magnesium alloys and have implications in developing high-performance Mg-RE alloys.

As a standard clean production technology, the wide use of green control techniques (GCT) helps improve the quality of agricultural products and protect the environment. However, the level of application of GCT by Chinese farmers is not high. The market, as the ultimate place to realize the value of grain and the returns of grain farmers, plays an essential part in promoting GCT. Based on survey data from grain farmers in Sichuan Province, China, this study used a conditional mixed process (CMP) model to examine the effect of farmers’ market participation on their GCT adoption behavior and a mediated effects model to test the impact mechanism. The study further explored the effect of farmers’ market participation capability on their GCT adoption behavior. The results showed that (1) farmers’ market participation could significantly increase the likelihood of adopting GCT. (2) Market participation could influence farmers’ adoption behavior through agricultural income, market information, and green cognition. (3) Further research found that farmers were more likely to adopt GCT if their market participation capability was strong. These findings highlight the fact that developing countries have increased their efforts to encourage farmers to participate in markets and to enhance their market participation capability, thereby facilitating the adoption of GCT by farmers.