Search

Heart rate variability (HRV) is an important metric in cardiovascular health monitoring. Spectral analysis of HRV provides essential insights into the functioning of the cardiac autonomic nervous system. However, data artefacts could degrade signal quality, potentially leading to unreliable assessments of cardiac activities. In this study, we introduced a novel approach for estimating uncertainties in HRV spectrum based on matrix completion. The proposed method utilises the low-rank characteristic of HRV spectrum matrix to efficiently estimate data uncertainties. In addition, we developed a refined matrix completion technique to enhance the estimation accuracy and computational cost. Benchmarking on five public datasets, our model shows effectiveness and reliability in estimating uncertainties in HRV spectrum, and has superior performance against five deep learning models. The results underscore the potential of our developed matrix completion-based statistical machine learning model in providing reliable HRV spectrum uncertainty estimation.

Abstract By September 2022, more than 600 million cases of SARS-CoV-2 infection have been reported globally, resulting in over 6.5 million deaths. COVID-19 mortality risk estimators are often, however, developed with small unrepresentative samples and with methodological limitations. It is highly important to develop predictive tools for pulmonary embolism (PE) in COVID-19 patients as one of the most severe preventable complications of COVID-19. Early recognition can help provide life-saving targeted anti-coagulation therapy right at admission. Using a dataset of more than 800,000 COVID-19 patients from an international cohort, we propose a cost-sensitive gradient-boosted machine learning model that predicts occurrence of PE and death at admission. Logistic regression, Cox proportional hazards models, and Shapley values were used to identify key predictors for PE and death. Our prediction model had a test AUROC of 75.9% and 74.2%, and sensitivities of 67.5% and 72.7% for PE and all-cause mortality respectively on a highly diverse and held-out test set. The PE prediction model was also evaluated on patients in UK and Spain separately with test results of 74.5% AUROC, 63.5% sensitivity and 78.9% AUROC, 95.7% sensitivity. Age, sex, region of admission, comorbidities (chronic cardiac and pulmonary disease, dementia, diabetes, hypertension, cancer, obesity, smoking), and symptoms (any, confusion, chest pain, fatigue, headache, fever, muscle or joint pain, shortness of breath) were the most important clinical predictors at admission. Age, overall presence of symptoms, shortness of breath, and hypertension were found to be key predictors for PE using our extreme gradient boosted model. This analysis based on the, until now, largest global dataset for this set of problems can inform hospital prioritisation policy and guide long term clinical research and decision-making for COVID-19 patients globally. Our machine learning model developed from an international cohort can serve to better regulate hospital risk prioritisation of at-risk patients.

Abstract Collaborative efforts in artificial intelligence (AI) are increasingly common between high-income countries (HICs) and low- to middle-income countries (LMICs). Given the resource limitations often encountered by LMICs, collaboration becomes crucial for pooling resources, expertise, and knowledge. Despite the apparent advantages, ensuring the fairness and equity of these collaborative models is essential, especially considering the distinct differences between LMIC and HIC hospitals. In this study, we show that collaborative AI approaches can lead to divergent performance outcomes across HIC and LMIC settings, particularly in the presence of data imbalances. Through a real-world COVID-19 screening case study, we demonstrate that implementing algorithmic-level bias mitigation methods significantly improves outcome fairness between HIC and LMIC sites while maintaining high diagnostic sensitivity. We compare our results against previous benchmarks, utilizing datasets from four independent United Kingdom Hospitals and one Vietnamese hospital, representing HIC and LMIC settings, respectively.

Abstract Deep neural networks have been integrated into the whole clinical decision procedure which can improve the efficiency of diagnosis and alleviate the heavy workload of physicians. Since most neural networks are supervised, their performance heavily depends on the volume and quality of available labels. However, few such labels exist for rare diseases (e.g., new pandemics). Here we report a medical multimodal large language model (Med-MLLM) for radiograph representation learning, which can learn broad medical knowledge (e.g., image understanding, text semantics, and clinical phenotypes) from unlabelled data. As a result, when encountering a rare disease, our Med-MLLM can be rapidly deployed and easily adapted to them with limited labels. Furthermore, our model supports medical data across visual modality (e.g., chest X-ray and CT) and textual modality (e.g., medical report and free-text clinical note); therefore, it can be used for clinical tasks that involve both visual and textual data. We demonstrate the effectiveness of our Med-MLLM by showing how it would perform using the COVID-19 pandemic “in replay”. In the retrospective setting, we test the model on the early COVID-19 datasets; and in the prospective setting, we test the model on the new variant COVID-19-Omicron. The experiments are conducted on 1) three kinds of input data; 2) three kinds of downstream tasks, including disease reporting, diagnosis, and prognosis; 3) five COVID-19 datasets; and 4) three different languages, including English, Chinese, and Spanish. All experiments show that our model can make accurate and robust COVID-19 decision-support with little labelled data.

Abstract Background Associations between kidney function and dementia risk are inconclusive. Chronic kidney disease (CKD) severity is determined by levels of both estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR). However, whether there is a graded increase in dementia risk for worse eGFR in each ACR category is unclear. Also, whether genetic risk for dementia impacts the associations is unknown. The current study aims to investigate the associations between eGFR and albuminuria with dementia risk both individually and jointly, whether the associations vary by different follow-up periods, and whether genetic factors modified the associations. Methods In 202,702 participants aged ≥ 60 years from the UK Biobank, Cox proportional-hazards models were used to examine the associations between eGFR and urine albumin creatinine ratio (ACR) with risk of incident dementia. GFR was estimated based on serum creatinine, cystatin C, or both. The models were restricted to different follow-up periods (

Abstract We aimed to identify potential novel predictors for breast cancer among post-menopausal women, with pre-specified interest in the role of polygenic risk scores (PRS) for risk prediction. We utilised an analysis pipeline where machine learning was used for feature selection, prior to risk prediction by classical statistical models. An “extreme gradient boosting” (XGBoost) machine with Shapley feature-importance measures were used for feature selection among $$\approx$$ ≈ 1.7 k features in 104,313 post-menopausal women from the UK Biobank. We constructed and compared the “augmented” Cox model (incorporating the two PRS, known and novel predictors) with a “baseline” Cox model (incorporating the two PRS and known predictors) for risk prediction. Both of the two PRS were significant in the augmented Cox model ( $$p

Abstract Polygenic risk scores (PRS) are proposed for use in clinical and research settings for risk stratification. However, there are limited investigations on how different PRS diverge from each other in risk prediction of individuals. We compared two recently published PRS for each of three conditions, breast cancer, hypertension and dementia, to assess the stability of using these algorithms for risk prediction in a single large population. We used imputed genotyping data from the UK Biobank prospective cohort, limited to the White British subset. We found that: (1) 20% or more of SNPs in the first PRS were not represented in the more recent PRS for all three diseases, by the same SNP or a surrogate with R2 > 0.8 by linkage disequilibrium (LD). (2) Although the difference in the area under the receiver operating characteristic curve (AUC) obtained using the two PRS is hardly appreciable for all three diseases, there were large differences in individual risk prediction between the two PRS. For instance, for each disease, of those classified in the top 5% of risk by the first PRS, over 60% were not so classified by the second PRS. We found substantial discordance between different PRS for the same disease, indicating that individuals could receive different medical advice depending on which PRS is used to assess their genetic susceptibility. It is desirable to resolve this uncertainty before using PRS for risk stratification in clinical settings.

A polygenic risk score estimates the genetic risk of an individual for some disease or trait, calculated by aggregating the effect of many common variants associated with the condition. With the increasing availability of genetic data in large cohort studies such as the UK Biobank, inclusion of this genetic risk as a covariate in statistical analyses is becoming more widespread. Previously this required specialist knowledge, but as tooling and data availability have improved it has become more feasible for statisticians and epidemiologists to calculate existing scores themselves for use in analyses. While tutorial resources exist for conducting genome-wide association studies and generating of new polygenic risk scores, fewer guides exist for the simple calculation and application of existing genetic scores. This guide outlines the key steps of this process: selection of suitable polygenic risk scores from the literature, extraction of relevant genetic variants and verification of their quality, calculation of the risk score and key considerations of its inclusion in statistical models, using the UK Biobank imputed data as a model data set. Many of the techniques in this guide will generalize to other datasets, however we also focus on some of the specific techniques required for using data in the formats UK Biobank have selected. This includes some of the challenges faced when working with large numbers of variants, where the computation time required by some tools is impractical. While we have focused on only a couple of tools, which may not be the best ones for every given aspect of the process, one barrier to working with genetic data is the sheer volume of tools available, and the difficulty for a novice to assess their viability. By discussing in depth a couple of tools that are adequate for the calculation even at large scale, we hope to make polygenic risk scores more accessible to a wider range of researchers.

Abstract Background When using a continuous outcome measure in a randomised controlled trial (RCT), the baseline score should be measured in addition to the post-intervention score, and it should be analysed using the appropriate statistical analysis. Methods We derive the correlation between the change score and baseline score and show that there is always a correlation (usually negative) between the change score and baseline score. We discuss the following correlations and provide the mathematical derivations in the Appendix:Correlation between change score and baseline scoreCorrelation between change score and post scoreCorrelation between change score and average score. The setting here is a parallel, two-arm RCT, but the method discussed in this paper is applicable for any studies or trials that have a continuous outcome measure; it is not restricted to RCTs. Results We show that using the change score as the outcome measure does not address the problem of regression to the mean, nor does it take account of the baseline imbalance. Whether the outcome is change score or post score, one should always adjust for baseline using analysis of covariance (ANCOVA); otherwise, the estimated treat effect may be biased. We show that these correlations also apply when comparing two measurement methods using Bland-Altman plots. Conclusions The correlation between baseline and post-intervention scores can be derived using the variance sum law. We can then use the derived correlation to calculate the required sample size in the design stage. Baseline imbalance may occur in RCTs, and ANCOVA should be used to adjust for baseline in the analysis stage.

Objective To identify factors associated with hypertension control among treated middle-aged UK adults.Methods A cross-sectional population-based study including 99 468 previously diagnosed, treated hypertensives enrolled in the UK Biobank. Hypertension control was defined as systolic blood pressure 30 units per week compared with none), black ethnicity (OR 0.73, 95% CI 0.65 to 0.82 compared with white), obesity (OR 0.73, 95% CI 0.71 to 0.76 compared with normal body mass index). The strongest positive association with control was having ≥3 comorbidities (OR 2.09, 95% CI 1.95 to 2.23). Comorbidities associated with control included cardiovascular disease (OR 2.11, 95% CI 2.04 to 2.19), migraines (OR 1.68, 95% CI 1.56 to 1.81), diabetes (OR 1.32, 95% CI 1.27 to 1.36) and depression (OR 1.27, 95% CI 1.20 to 1.34).Conclusions In one of the largest population-based analyses of middle-aged adults with measured blood pressure, the majority of treated hypertensives were uncontrolled. Risk factors for hypertension were associated with a lower probability of control. Having a comorbidity was associated with higher probability of control, possibly due to more frequent interaction with the healthcare system and/or appropriate management of those at greater cardiovascular risk.

Introduction. Hypertension is a leading risk factor for cardiovascular mortality and an emerging public health concern in sub-Saharan Africa. Few studies have examined performance on the management of hypertension in this region, where the context may be distinct from other developing regions. Objectives. We aimed to determine the prevalence and correlates of hypertension, awareness, treatment, and control among adults in Botswana, a middle-income African country undergoing rapid demographic transition and with high HIV burden. Methods. In this 2014 cross-sectional survey of adults aged 15–69 years, information on sociodemographic characteristics, lifestyle behavior, and medical history was collected through in-person interviews and physical measurements (body mass index and triplicate blood pressure (BP)). Hypertension was defined as self-report of use of antihypertensives in the previous two weeks and/or having elevated BP (≥140/90 mmHg). Multivariable logistic regression was employed to explore factors associated with hypertension, awareness (report of previous diagnosis), treatment (antihypertensives), and control (BP

We illustrate the approach of randomising treatments and compare it with the traditional approach of randomising patients, using a case study drawn from the authors’ experience in clinical trials. The setting is a double-blind parallel two-arm randomised controlled trial (RCT), but the method in this paper can be extended to single-blind, cross-over, or multi-arm RCTs.We propose the concept of two different levels of blinding: full blinding and partial blinding. We subsequently show how to maintain the maximal level of blinding. Using an example, we show that a pharmacist can be fully blinded if the investigational medical products (IMPs) that they prescribe (instead of patients) are randomised, and they can be partially blinded if they need to dispense replacement (i.e., surplus) IMPs. A small number of surplus IMPs is commonly required in a clinical trial to replace lost or damaged IMPs. We note that the concept of full blinding and partial blinding is different from double-blind trial, and the level of blinding is relevant in both single-blind and double-blind trials.A trial statistician needs to work closely with all parties in the design of the randomisation, including the pharmacist, the trial manager, and the manufacturer. We detail what should and should not be shown in the various documents that the trial statistician need to provide to the pharmacist and to the manufacturer. We provide template tables for these documents. Keywords: Randomisation, Blinding, Single-blind, Double-blind, Placebo, Randomised controlled trial (RCT), Investigational medical product (IMP), Pharmacist

Conventional methods for estimating cardiopulmonary variables usually require complex gas analyzers and the active co-operation of the patient. Therefore, they are not compatible with the crowded environment of the intensive care unit (ICU) or operating theatre, where patient co-operation is typically impossible. However, it is these patients that would benefit the most from accurate estimation of cardiopulmonary variables, because of their critical condition. This paper describes the results of a collaborative development between an anesthesiologists and biomedical engineers to create a compact and non-invasive system for the measurement of cardiopulmonary variables such as lung volume, airway dead space volume, and pulmonary blood flow. In contrast with conventional methods, the compact apparatus and non-invasive nature of the proposed method allow it to be used in the ICU, as well as in general clinical settings. We propose the use of a non-invasive method, in which tracer gases are injected into the patient's inspired breath, and the concentration of the tracer gases is subsequently measured. A novel breath-by-breath tidal ventilation model is then used to estimate the value of a patient's cardiopulmonary variables. Experimental results from an artificial lung demonstrate minimal error in the estimation of known parameters using the proposed method. Results from analysis of a cohort of 20 healthy volunteers (within the Oxford University Hospitals NHS Trust) show that the values of estimated cardiopulmonary variables from these subjects lies within the expected ranges. Advantages of this method are that it is non-invasive, compact, portable, and can perform analysis in real time with less than 1 min of acquired respiratory data.

Objective: Depression, a prevalent and severe mental disorder, continues to be a significant area of research concerning its pathogenesis and therapeutic approaches. Conventional antidepressants are often limited by delayed therapeutic effects and notable adverse reactions, necessitating the development of innovative and efficacious treatment modalities. Multiple lines of evidence suggest that peripheral and central inflammation play a role in depression, and that anti-inflammatory drugs can ameliorate depressive symptoms in patients with inflammation-related depression. Pinocembrin (PB), a natural bioactive compound, is renowned for its anti-inflammatory and antioxidant properties, while the effect and mechanism of PB are still unclear. Consequently, this study employs PB as an intervention to investigate its effects on depression in mice model, with the objective of establishing a novel therapeutic strategy and foundational data for the treatment of depression., Methods: (1) The acute inflammation model used lipopolysaccharide (LPS) to induce depression-like behavior in mice by injecting LPS intraperitoneally at a dose of 0.83 mg/kg. The effects of PB (20 mg/kg, i.p.) and the NLRP3 inflammasome inhibitor MCC950 (10 mg/kg, i.p.) on improving depression behavior in mice were evaluated. (2) To explore the specific mechanism of PB in improving depression-like behavior in LPS mice by regulating NLRP3 and Netrin-1/DCC pathway., Results: The results showed that after intraperitoneal injection of LPS, the mice exhibited a significant decrease in body weight, sucrose preference score, and a significant increase in tail suspension immobility time. Treatment with PB and MCC950 increased the sucrose preference score and decreased the tail suspension immobility time. Besides, PB and MCC950 could inhibit the expression of NLRP3 related neuroinflammation, down-regulated the Netrin-1/DCC signaling pathway, and improved hippocampal neuroplasticity in mice., Conclusion: In conclusion, PB significantly improved LPS-induced depression-like behavior in mice by reducing the expression of hippocampal NLRP3 inflammasome and down-regulating the Netrin-1/DCC signaling pathway. Additionally, PB was found to regulate α-amino-3-hydroxy-5-methyl-4 isoxazole receptor (AMPAR) and postsynaptic density 95 (PSD95), protecting excitatory synaptic transmission and enhancing synaptic plasticity. This study demonstrates the effectiveness of PB in improving depressive symptoms induced by LPS and provides a new strategy for the clinical treatment of depression., Competing Interests: Declaration of competing interest I declare that there are no conflicts of interest in relation to the manuscript titled “Pinocembrin alleviates LPS-induced depressive-like behavior in mice via the NLRP3/DCC signaling pathway” submitted to Biochemical and Biophysical Research Communications. I confirm that the results and interpretations reported in the manuscript are original and have not been plagiarized. I certify that I have read and understand the journal conflict of interest policy, and I understand that failure to disclose a conflict of interest may result in the manuscript being rejected or retracted. I understand that this information will be subject to peer review, and I am willing to provide further information or clarification if required. I confirm that I have no known conflicts of interest that would influence the results or interpretation of the data presented in this manuscript, and I understand that failure to disclose a conflict of interest is unethical and may result in sanctions being imposed on me., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fibrinogen-fibrin degradation products (DR-70) are derived from tumor cells or metastases. Our previous study reported the diagnostic values in dogs with tumors, but no research has yet to be conducted to establish DR-70 as a prognostic marker. Herein, we investigated changes in DR-70 concentrations and disease courses in dogs with tumors. Overall survival time (OST) analysis was performed in 195 dogs with tumors, stratified with a recommended cut-off (1.514 µg/mL). Continual DR-70 measurements were performed during the medical interventions of 27 dogs with neoplasms. Clinical conditions and medical records were retrospectively reviewed. According to a cut-off value, dogs with plasma DR-70 concentrations above 1.514 µg/mL had shorter survival rates than those with concentrations below this threshold. In cases with complete or partial remission in response to treatment, the DR-70 concentration was decreased compared with that at the first visit, whereas it was increased in patients with disease progression. Our study suggested that changes in DR-70 concentration can be used as a prognostic biomarker for canine neoplasms. Furthermore, increased plasma DR-70 levels might be associated with shorter survival, and DR-70 concentrations may reflect responses to medical intervention.

Rationale: Macrophages are immune cells found throughout the body and exhibit morphological and functional diversity. Macrophages have been implicated in a wide range of diseases, including autoimmune diseases, acute liver injury, cardiovascular diseases, lung diseases and tumours. Ion channels are transmembrane glycoproteins with important functions in maintaining homeostasis in the intra- and extracellular environment and mediating signal transduction. Many studies have shown that different types of ion channels influence the role of macrophages in the development of various diseases. In recent years, studies on the role of ion channels in macrophages in immune regulation and inflammatory responses have attracted much attention., Objective and Findings: In order to gain a deeper understanding of the role of macrophage ion channels, this paper reviews the recent research progress on the role of macrophage ion channels in recent years. The aim is to explore the role of different ion channels in the regulation of macrophage function and their impact on a variety of disease processes. The most studied channels are calcium, sodium and potassium channels, most of which are located in the cell membrane. Among these, TRP channels have a more complex role in M1 and M2 macrophage types., Conclusion: Ion channels are critical for the functional regulation of macrophages. Targeting ion channels provides new avenues for disease prevention and treatment. This review provides researchers with new ideas and introduces readers to the current state of research on ion channels in macrophages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To compare the performance of radiologists when assisted by an S-detect system with that of radiologists or an S-detect system alone in diagnosing breast masses on US images in a dual-center setting., Methods: US images were retrospectively identified 296 breast masses (150 benign, 146 malignant) by investigators at two medical centers. Six radiologists from the two centers independently analyzed the US images and classified each mass into categories 2 to 5. The radiologists then re-reviewed the images with the assistance of the S-detect system. The diagnostic value of radiologists alone, S-detect system alone, and S-detect alone, and radiologists + S-detect were analyzed and compared., Results: Radiologists had significantly decreased the average false negative rate (FNR) for diagnosing breast masses using S-detect system (- 10.7%) (P < 0.001) and increased the area under the receiver operating characteristic curve (AUC) from 0.743 to 0.788 (P < 0.001). Seventy-seven out of 888 US images from six radiologists in this study were changed positively (from false negative to true positive or from false positive to true negative) with the S-detect, while 39 out of 888 US images were altered negatively., Conclusion: Radiologists had better performance for the diagnosis of malignant breast masses on US images with an S-detect system than without., Advances in Knowledge: The study used a dual-center design and compared the performance of the radiologists alone, the S-detect alone, and the radiologists combined with the S-detect. The study reported an improvement in sensitivity and AUC particularly for low to intermediate-level radiologists, involved cases and radiologists from two different centers, and compared the diagnostic value of using S-detect system for masses of different sizes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

1T-TiSe 2 , a promising candidate of the sought-after excitonic insulator, possesses an enigmatic charge density wave (CDW) order of which the microscopic origin is formidable to settle owing to the chicken-and-egg entanglement between the electron and lattice degrees of freedom. Its CDW experiences an intriguing but elusive quantum melting and eventually enters the superconducting phase under metal intercalation, suggesting the possible role of melted-order fluctuation in gluing the electron paring. Employing the spectroscopic imaging scanning tunneling microscope (STM), we access the pure electronic behavior by visualizing the CDW melting process of monolayer 1T-TiSe 2 in both the space and energy-band dimensions. In real space, the native lattice imperfections disturb the local order parameter and stimulate the melting of CDW. In energy-band space, different states exhibit varying stiffness against the melting stimuli, yielding distinctive melted textures. The evolution of CDW topological defects and the structure factor in the quantum melting process provide a straightforward avenue to evaluate the CDW coherency, which shows that the CDW stiffness scales with the strength of the p-d Coulomb correlation. Our study reveals the quantum melting of CDW with an altering band-orbital-correlation character and puts compelling emphasis on the indispensable role of excitonic interaction in stabilizing the charge order of monolayer TiSe 2 .

Host hemolymph is an important place of growth and development for most endoparasitoids. Immunofluorescence assay showed that parasitism induced Chilo suppressalis larvae to produce large numbers of granulocytes, but high temperatures led to granulocytes apoptosis and loss of phagocytosis. In addition, high temperatures activated the endoplasmic reticulum apoptotic pathway, leading to apoptosis of prohemocytes. In the present study, the initiator Cscaspase-8 was obtained from the rice pest C. suppressalis. The results of real-time PCR showed that Cscaspase-8 expression was highest in hemocytes; furthermore, transcription was most highly in female adults. Cscaspase-8 was significantly induced when larvae were exposed to 39 °C for a 2-h period. Cscaspase-8 expression was significantly elevated after 2 d of parasitism. Results of the interference test showed that the survival rate of C. suppressalis larvae is not affected by Cscaspase-8 gene silencing under high temperature and parasitism stress. However, developmental delays were observed in Cotesia chilonis larvae when the host Cscaspase-8 gene was knocked down. These results contribute to the current knowledge on the regulatory mechanisms of apoptosis in insects subjected to high temperature and parasitism stress., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The hippocampus is a brain region that is essential for the initial encoding of episodic memories. However, the consolidation of these memories is thought to occur in the neocortex, under guidance of the hippocampus, over the course of days and weeks. Communication between the hippocampus and the neocortex during hippocampal sharp wave-ripple oscillations is believed to be critical for this memory consolidation process. Yet, the synaptic and circuit basis of this communication between brain areas is largely unclear. To address this problem, we perform in vivo whole-cell patch-clamp recordings in the frontal neocortex and local field potential recordings in CA1 of head-fixed mice exposed to a virtual-reality environment. In mice trained in a goal-directed spatial task, we observe a depolarization in frontal principal neurons during hippocampal ripple oscillations. Both this ripple-associated depolarization and goal-directed task performance can be disrupted by chemogenetic inactivation of somatostatin-positive (SOM + ) interneurons. In untrained mice, a ripple-associated depolarization is not observed, but it emerges when frontal parvalbumin-positive (PV + ) interneurons are inactivated. These results support a model where SOM + interneurons inhibit PV + interneurons during hippocampal activity, thereby acting as a disinhibitory gate for hippocampal inputs to neocortical principal neurons during learning., Competing Interests: Competing interests statement:The authors declare no competing interest.

Exposure load (EL) is an indicator of multiple chemical exposures based on human biomonitoring data. We used EL methodology and human biomonitoring health-based guidance values (HB2GVs) as exposure thresholds to create a new metric called Cumulative Health Risk from Exposure Load (CHREL). HB2GVs are derived by calculating the concentration of a biomarker consistent with a health protective exposure guidance value. CHREL analysis was conducted using Canadian Health Measures Survey (CHMS) cycle 3 and 4 biomonitoring data. Based on 18 chemicals, more than half of the Canadian population had an estimated CHREL TOTAL of 1 or more, indicative of chemical exposures potentially above selected exposure guidance values. Females had a significantly lower CHREL TOTAL compared to males, 12-19 year olds had a lower CHREL TOTAL compared to older age groups (significant compared to 40-59 year olds), and nonsmokers had a significantly lower CHREL TOTAL than smokers. Small segments of the population had a CHREL LIVER or a CHREL NERV of 1 or more, indicating exposures potentially above guideline levels for chemicals affecting the liver or nervous system. CHREL CANC was calculated based on 6 chemicals with HB2GVs derived for cancer endpoints. At the 10 -5 risk level, most people had an estimated CHREL CANC of 3, indicative of multiple chemicals that may exceed negligible cancer risk. The most important contributors to exposures above HB2GVs were inorganic arsenic, mercury, acrylamide, xylenes, benzene and triclosan. Keeping certain assumptions, uncertainties and limitations in mind, the CHREL indicator can be used to obtain a picture of potential cumulative health risks from combined chemical exposures in a population, and as a comparative measure between subpopulations, including vulnerable subgroups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to assess the efficacy and safety of monoclonal antibody therapies (MATs) for interstitial cystitis/bladder pain syndrome (IC/BPS)., Methods: A systematic search was conducted across databases including PubMed, Embase, clinicalTrial.gov, and the Cochrane Library Central Register of Controlled Trials. Randomized controlled trials (RCTs) comparing MATs versus placebo were included. Primary outcomes comprised the Global Response Assessment (GRA) scale and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI). Additional analyses encompassed mean daily frequency of voids, the O'Leary-Sant Interstitial Cystitis Problem Index, pain scores, and complications. Statistical analyses were performed using Review Manager 5.3., Results: Five high-quality RCTs, comprising 263 patients with IC/BPS, were ultimately selected. MATs were generally effective in treating IC/BPS. Patients receiving MATs exhibited a higher satisfaction rate (odds ratio [OR]: 2.7, confidence interval [CI]: 1.31-5.58, p = 0.007) and lower ICSI scores (mean difference [MD]: -1.44, CI: -2.36 to -0.52, p = 0.002). Moreover, MAT recipients experienced reduced pain (MD: -0.53, CI: -0.79 to -0.26, p < 0.0001) and decreased frequency of urination (MD: -1.91, CI: -2.55 to -1.27, p < 0.00001). Importantly, there were no disparities regarding complication incidence in the MAT and control groups., Conclusions: The current findings indicate that MATs are effective and safe for treating IC/BPS. Nonetheless, future RCTs with larger sample sizes and long-term follow-up are warranted., (© 2024 Wiley Periodicals LLC.)

Ginseng, a highly esteemed herbal medicine, has been utilized over 5000 years, predominantly in Far Eastern countries. Ginseng is categorized into garden ginseng (GG) and ginseng under forest (FG). However, in contrast to FG, excessive intake of GG may lead to potential adverse effects due to disruption of epithelial cell integrity, and the specific population groups that may be at higher risk. In this work, untargeted metabolomics were used to determine the heterogeneity between GG and FG, the data indicates that the content of Ethyl caffeate, Homoorientin, Citric acid and Quinic acid in GG were higher than in FG. Mass spectrometry imaging showed that ethyl caffeate and Homoorientin were concentrated on the brownish yellow exocarp of the primary root. Our experiments demonstrated that excessive exposure to ethyl caffeate and Homoorientin exacerbated the inflammatory response of HUVECs and reduced the expression of cell junctions. This suggest that the compounds causing adverse effects from excessive intake of GG are mainly concentrated in the yellow exocarp of the primary root of GG. These results suggest that untargeted metabolomics coupled with MALDI-MSI can visualize the spatial distribution of endogenous differential molecules of the same herb in different growth environments or developmental stages., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2024. Published by Elsevier B.V.)

Background: Arundinelleae is a small tribe within the Poaceae (grass family) possessing a widespread distribution that includes Asia, the Americas, and Africa. Several species of Arundinelleae are used as natural forage, feed, and raw materials for paper. The tribe is taxonomically cumbersome due to a paucity of clear diagnostic morphological characters. There has been scant genetic and genomic research conducted for this group, and as a result the phylogenetic relationships and species boundaries within Arundinelleae are poorly understood., Results: We compared and analyzed 11 plastomes of Arundinelleae, of which seven plastomes were newly sequenced. The plastomes range from 139,629 base pairs (bp) (Garnotia tenella) to 140,943 bp (Arundinella barbinodis), with a standard four-part structure. The average GC content was 38.39%, but varied in different regions of the plastome. In all, 110 genes were annotated, comprising 76 protein-coding genes, 30 tRNA genes, and four rRNA genes. Furthermore, 539 simple sequence repeats, 519 long repeats, and 10 hyper-variable regions were identified from the 11 plastomes of Arundinelleae. A phylogenetic reconstruction of Panicoideae based on 98 plastomes demonstrated the monophyly of Arundinella and Garnotia, but the circumscription of Arundinelleae remains unresolved., Conclusion: Complete chloroplast genome sequences can improve phylogenetic resolution relative to single marker approaches, particularly within taxonomically challenging groups. All phylogenetic analyses strongly support the monophyly of Arundinella and Garnotia, respectively, but the monophylly of Arundinelleae was not well supported. The intergeneric phylogenetic relationships within Arundinelleae require clarification, indicating that more data is necessary to resolve generic boundaries and evaluate the monophyly of Arundinelleae. A comprehensive taxonomic revision for the tribe is necessary. In addition, the identified hyper-variable regions could function as molecular markers for clarifying phylogenetic relationships and potentially as barcoding markers for species identification in the future., (© 2024. The Author(s).)

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB 1 )-selective, cannabinoid receptor type 2 (CB 2 )-selective, and CB 1 /CB 2 mixed agonists in the cisplatin CIPN model, using both male and female mice. CB 1 selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB 2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB 1 selective agonism decreasing plasma estradiol while CB 2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB 1 /CB 2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB 2 acting compound while selective CB 1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. SIGNIFICANCE STATEMENT: CIPN is a common side effect of chemotherapy. We have found that both CB 1 and CB 2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB 1 -mediated antinociception developed faster in females and did not develop for CB 2 -mediated antinociception. Additionally, we found contrasting roles for CB 1 /CB 2 receptors in the regulation of plasma estradiol in females, with CB 1 agonism attenuating estradiol and CB 2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

To analyze the causes of ozone pollution in the Pearl River Delta （PRD） Region during the summer and autumn transition seasons, a case study was carried out in Guangzhou, which is located in the center of the PRD Region, to analyze the ozone photochemical production and destruction pathways as well as emission reduction scenarios using a box model based on comprehensive observation. The results showed that the stagnant meteorological conditions and high temperature during the observation period were suitable for the photochemical production of ozone, which led to widespread and prolonged ozone pollution. Aromatic hydrocarbons （AHs） contributed the most to the ozone formation potential （OFP）, and m / p -xylene, toluene, and o -xylene were the major three VOC species contributing to the OFP. Box model analysis revealed that the averaged net O 3 production rate during the polluted period was 23.2×10 -9 h -1 and the peak reached 39.2×10 -9 h -1 . The HO 2 ·+NO and NO 2 +·OH reaction pathways contributed the most to the local photochemical ozone production （51.2%） and destruction （47.0%）, respectively. Observed ozone concentration was primarily controlled by both the local photochemical O 3 production and the export-dominated transport. The RIR and EKMA analyses showed that O 3 formation in Guangzhou during the summer-autumn transition seasons was mainly a VOC-limited regime and AHs showed the greatest sensitivity to O 3 production. Toluene, m / p -xylene, o -xylene, n -butane, and propylene were the five key components affecting O 3 generation. The analysis of reduction scenarios showed that reducing anthropogenic VOC emissions was the most favorable way to reduce O 3 concentrations； however, if NO x emission was controlled after reducing VOCs, the O 3 concentration would rebound in a short time. Our results suggested that the synergistic reduction of VOCs and NO x while mainly focusing on VOCs alleviation should be implemented to continuously reduce ozone concentrations in the future.

Exome sequencing has enabled the identification of causative genes of monogenic forms of autism, amongst them, in 2016, CSNK2A1, the gene encoding the catalytic subunit of the kinase CK2, linking this kinase to Okur-Chung Neurodevelopmental Syndrome (OCNDS), a newly described neurodevelopmental condition with many symptoms resembling those of autism spectrum disorder. Thus far, no preclinical model of this condition exists. Here we describe a knock-in mouse model that harbors the K198R mutation in the activation segment of the α subunit of CK2. This region is a mutational hotspot, representing one-third of patients. These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in mice die mid-gestation while heterozygous knock-in mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous knock-in mice showed alterations in cognition and memory-assessing paradigms, enhanced stereotypies, altered circadian activity patterns, and nesting behavior. Phosphoproteome analysis from brain tissue revealed alterations in the phosphorylation status of major pre- and postsynaptic proteins of heterozygous knock-in mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of knock-in mice. Taken together, heterozygous knock-in mice (CK2α K198R/+ ) exhibit significant face validity, presenting ASD-relevant phenotypes, synaptic deficits, and alterations in synaptic plasticity, all of which strongly validate this line as a mouse model of OCNDS., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Empirical findings suggest reduced cortico-striatal structural connectivity in patients with major depressive disorder (MDD). However, the relationship between the abnormal structural covariance and one-year outcome of first-episode drug-naive patients has not been evaluated. This longitudinal study aimed to identify specific changes of ventral striatum-related brain structural covariance and grey matter volume in forty-two first-episode patients with major depression disorder compared with thirty-seven healthy controls at the baseline and the one-year follow-up conditions. At the baseline, patients showed decreased structural covariance between the left ventral striatum and the bilateral superior frontal gyrus (SFG), bilateral middle frontal gyrus (MFG), right supplementary motor area (SMA) and left precentral gyrus and increased grey matter volume at the left fusiform and left parahippocampus. At the one-year follow-up, patients showed decreased structural covariance between the left ventral striatum and the right SFG, right MFG, left precentral gyrus and left postcentral gyrus, and increased structural covariance between the right ventral striatum and the right amygdala, right hippocampus, right parahippocampus, right superior temporal pole, right insula and right olfactory bulb and decreased volume at the left SMA compared with controls. These findings suggest that specific ventral striatum connectivity changes contribute to the early brain development of the MDD., Competing Interests: Declaration of competing interest All authors have nothing to disclose relevant conflict of interest to the present work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Non-specific lipid-transfer proteins (nsLTPs) are a group of small, cysteine-rich proteins that are involved in the transport of cuticular wax and other lipid compounds. Accumulating evidence suggests that dynamic changes in cuticular waxes are strongly associated with fruit russeting, an undesirable visual quality that negatively affects consumer appeal in pears. Currently, the regulatory role of nsLTPs in cuticular wax deposition and pear fruit skin russeting remains unclear. Here, we characterized the variations of cuticular waxes in non-treated (russeted) and preharvest bagging treated (non-russeted) pear fruits throughout fruit development and confirmed that the contents of cuticular waxes were significantly negatively correlated with the occurrence of pear fruit russeting. Based on RNA-Sequencing (RNA-Seq) and quantitative real-time PCR (qRT-PCR) analyses, two nsLTP genes (PpyLTP36 and PpyLTP39) were identified, which exhibited high expression levels in non-russeted pear fruit skins and were significantly repressed during fruit skin russeting. Subcellular localization analysis demonstrated that PpyLTP36 and PpyLTP39 were localized to the plasma membrane (PM). Further, transient Virus-Induced Gene Silencing (VIGS) analyses of PpyLTP36 and PpyLTP39 in pear fruits significantly reduced cuticular wax deposition. In conclusion, PpyLTP36 and PpyLTP39 are involved in the transmembrane transport of cuticular wax and are associated with pear fruit skin russeting., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Swine wastewater (SW) contains high levels of traditional pollutants, antibiotics, and antibiotic resistance genes (ARGs), necessitating effective elimination. Two parallel aerobic granular sludge (AGS) reactors, R 1 and R 2 , were constructed and optimized for treating SW from two pig farms, identified as SW 1 and SW 2 . R 2 showed higher antibiotic removal efficiency, particularly in the removal of sulfonamides, while fluoroquinolones tended to adsorb onto the sludge. Process optimization by introducing an additional anoxic phase enhanced denitrification and reduced effluent ARG levels, also aiding in the improved removal of fluoroquinolones. The nitrite-oxidizing bacteria (NOB) Nitrospira accumulated after the treatment process, reaching 12.8 % in R 1 and 14.1 % in R 2 , respectively. Mantel's test revealed that pH, NH 4 + -N, and Mg significantly affected ARGs and microbial community. Sulfadiazine and sulfamethazine were found to significantly impact ARGs and the microbial communities. This study provides innovative insights into the application of AGS for the treatment of real SW., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The emergence of the SARS-CoV-2 Omicron variant has posed a significant global public health challenge. Elucidating the laboratory profiles of individuals infected with this variant is crucial for assessing organ damage. This study aimed to investigate the variations in liver function tests and their correlation with demographic characteristics and inflammatory markers in patients with early Omicron variant infections., Patients and Methods: A retrospective cohort study was conducted on 1133 mild or asymptomatic COVID-19 cases at Tianjin First Central Hospital. Data on age, gender, body mass index (BMI), and serum markers were collected and analyzed. Statistical analyses were performed using SPSS software, version 24.0., Results: Abnormal liver function parameters, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TBIL), were observed in 314 (27.71%) patients. "Hepatocellular type" was identified in 56 (4.94%) patients, "cholestatic type" in 185 (16.33%) patients, and "mixed type" in 73 (6.44%) patients. In the mixed group, we observed a pronounced elevation in the levels of ALT, AST, and GGT. Moreover, the hepatocellular group exhibited a statistically significant increase in AST and ALT concentrations relative to both the normal and cholestatic groups. Notably, the cholestatic group demonstrated a substantial increment in ALP levels. Males had a significantly higher prevalence of "abnormal liver enzyme markers" compared to females. Patients with "abnormal liver enzyme markers" exhibited significantly decreased immunoglobulin G (IgG) levels and elevated levels of inflammatory markers, including procalcitonin (PCT), interleukin-6 (IL6), as well as C-reactive protein (CRP) compared to normal group. Logistic regression analysis revealed that male gender and PCT levels were significantly associated with the risk of abnormal liver enzyme markers. Patients in hepatocellular group were likely accompanied with high CRP levels, whereas those in the cholestatic type were associated with high IL6 levels., Conclusion: Early Omicron infection might cause liver stress response. Elevated liver enzyme marker levels were correlated with age, gender, inflammatory factors, and IgG., Competing Interests: The author(s) report no conflicts of interest in this work., (© 2024 Cao et al.)

Depression is a significant mental health issue with extensive economic implications, and recent studies suggest it may be transmitted between individuals. However, the mechanisms of this contagion remain unclear, and the social buffering effect has been understudied. This research employs three rodent models, including stress crossover, cohabitation-induced, and non-contact induced depression contagion models, to explore these mechanisms. Here, we report that that naive mice cohabiting with depressed mice showed increased corticosterone levels and depressive behaviors, unlike those with stressed mice, who did not exhibit these changes and even mitigated desperation in stressed mice. Non-contact cohabitation did not produce significant behavioral differences, but exposure to bedding from depressed mice reduced sucrose preference in naive mice. This study introduces reliable models of depression contagion, suggesting it operates independently of stress transmission. The interplay between depression contagion and social buffering may vary in different contexts. These findings provide new insights into the mechanisms of depression contagion and potential strategies for preventing depressive disorders., (© 2024. The Author(s).)

Lignin is a key metabolite for terrestrial plants. Two types of aromatic amino acids, phenylalanine (Phe) and tyrosine (Tyr), serve as the precursors for lignin biosynthesis. In most plant species, Phe is deaminated by Phe ammonia-lyase (PAL) to initiate lignin biosynthesis, but in grass species, Phe and Tyr are deaminated by Phe/Tyr ammonia-lyase (PTAL). To understand the efficiency of PAL and PTAL, we used transgenic and non-transgenic Arabidopsis with PAL and crop-weedy rice hybrids (CWRH) with PTAL to analyze lignin-biosynthesis-associated metabolites. The transgenic plants overexpressed the exogenous 5-enolpyruvylshikimate-3-phosphate synthase ( EPSPS ) gene, whereas the non-transgenic plants normally expressed the endogenous EPSPS gene. Our results show significantly increased Phe/Tyr contents in transgenic Arabidopsis and CWRH plants, leading to substantially increased lignin and biomass. In addition, the PTAL pathway promotes a much greater proportion of increased lignin and biomass in transgenic CWRH than in transgenic Arabidopsis lineages. Evidently, more efficient lignin biosynthesis characterized the grass species possessing the PTAL pathway. These findings are important for a better understanding of the PAL and PTAL's functions in the phenylpropanoid metabolic pathways in the evolution of plant species. These findings also have great value for implications such as effective carbon fixation by enhancing lignin biosynthesis through genetic engineering of their key genes in appropriately selected plant species.

Midbrain organoids provide an innovative cellular source for transplantation therapies of neurodegenerative diseases. Here, we present a protocol for midbrain organoid-derived cell transplantation into a Parkinson's disease mouse model. We describe steps for midbrain organoid generation, single-cell suspension preparation, and cell transplantation. This approach is valuable for studying the efficacy of midbrain organoids as a potential cellular source for restoring motor function. For complete details on the use and execution of this protocol, please refer to Fu et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Three new species of Isodon (Lamiaceae) from China are described and illustrated, based on both morphological evidence and our recent phylogenomic studies of the genus. Isodonattenuatus , a herbaceous new species known only from the Fanjing Mountain, is shown to be sister to I.villosus , but they can be easily distinguished by leaf and inflorescence indumentum, calyx teeth shape and corolla tube morphology. Isodongongshanensis , a herbaceous new species collected from the Hengduan Mountains in southwest China, represents a distinct lineage within the genus. Isodonsukungii , a shrubby new species also endemic to the Hengduan Mountains, was previously misidentified as I.tenuifolius , but they are phylogenetically distantly related and differ in lamina size and margin, inflorescence type and corolla length and shape., Competing Interests: The authors have declared that no competing interests exist., (Ya-Ping Chen, Hua Peng, Alan J. Paton, Chun-Lei Xiang.)

Serine protease 50 (PRSS50/TSP50) is highly expressed in spermatocytes. Our study investigated its role in testicular development and spermatogenesis. Initially, PRSS50 knockdown was observed to impair DNA synthesis in spermatocytes. To further explore this, we generated PRSS50 knockout ( Prss50 -/- ) mice ( Mus musculus ), which exhibited abnormal spermatid nuclear compression and reduced male fertility. Furthermore, dysplastic seminiferous tubules and decreased sex hormones were observed in 4-week-old Prss50 -/- mice, accompanied by meiotic progression defects and increased apoptosis of spermatogenic cells. Mechanistic analysis indicated that PRSS50 deletion resulted in increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and elevated levels of MAP kinase phosphatase 3 (MKP3), a specific ERK antagonist, potentially accounting for testicular dysplasia in adolescent Prss50 -/- mice. Taken together, these findings suggest that PRSS50 plays an important role in testicular development and spermatogenesis, with the MKP3/ERK signaling pathway playing a significant role in this process.

This study proposes a new method to evaluate the effectiveness of orebody grade estimations, drawing upon the analysis of existing evaluation methods for grade estimation. This new approach addresses factors such as uneven sampling and asymmetric estimation range, which are challenging to overcome with existing evaluation techniques. The core principle of this method involves documenting how frequently individual samples are used during grade estimation and calculating the total distance weights for each sample. Subsequently, the usage frequency and total weight of the samples are standardized, and these standardized values are weighted based on the sample grades. A comparison is made between the weighted sample grades and the estimated grades, with the closeness between the two serving as a metric for assessing the effectiveness of the estimation. This study compares the new evaluation method to the direct comparison and cross-validation methods, examining the effectiveness of grade estimation using the inverse distance weighting (IDW) method. The findings revealed that: (1) The new evaluation method theoretically accounts for the systematic deviation between the statistical measures of estimated and sample grades resulting from uneven sample distribution, offering a fresh approach for enhancing the effectiveness of orebody grade estimation. (2) In the grade estimation of experimental Fe samples, the frequency of usage and the sum of distance weights were unequal. This inequality significantly contributes to the systematic deviation between the estimated and sample grades. (3) Comparing the new evaluation method to others confirms the stability and reliability of the new approach for evaluating the effectiveness of orebody grade estimation. This novel method demonstrates theoretical advantages and practical utility. (4) The deviation between the estimated grades and the statistical results of sample grades is influenced by the distribution pattern of sample grades, the spatial relationship between samples and estimation blocks, and the inherent systematic error associated with the IDW method. This systematic error cannot be overlooked., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Effective lineage-specific differentiation is essential to fulfilling the great potentials of human pluripotent stem cells (hPSCs). In this report, we investigate how modulation of medium pH and associated metabolic changes influence mesendoderm differentiation from hPSCs. We show that daily medium pH fluctuations are critical for the heterogeneity of cell fates in the absence of exogenous inducers. Acidic environment alone leads to cardiomyocyte generation without other signaling modulators. In contrast, medium alkalinization is inhibitory to cardiac fate even in the presence of classic cardiac inducers. We then demonstrate that acidic environment suppresses glycolysis to facilitate cardiac differentiation, while alkaline condition promotes glycolysis and diverts the differentiation toward other cell types. We further show that glycolysis inhibition or AMPK activation can rescue cardiac differentiation under alkalinization, and glycolysis inhibition alone can drive cardiac cell fate. This study highlights that pH changes remodel metabolic patterns and modulate signaling pathways to control cell fate., Competing Interests: Declaration of interests W.L. and G.C. filed a patent application based on cardiomyocyte differentiation that is induced by acidic pH., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

To study the level of heavy metal pollution and ecological risks in the soil around typical mining areas in Tongling, a total of 150 soil samples were collected from the study area. The content characteristics of 10 elements, namely, As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Fe, and Zn, in the soils were analyzed. Methods including enrichment factor, the geo-accumulation index, single-factor pollution index, Nemero comprehensive pollution index, and potential ecological risk index were used to evaluate the pollution status of heavy metals in the soil of the study area. The pollution sources of heavy metals in the soil were also analyzed using correlation analysis, cluster analysis, and principal component analysis. The results showed that except for Cr and Fe, the average contents of the other eight heavy metal elements were higher than the soil background values in the study area. Pb, Zn, As, Cu, and Cd had a high degree of variation and were significantly affected by external interference. The spatial distribution showed that both Cr and Ni showed a decreasing trend from the edge to the central region, whereas the other eight heavy metals showed a decreasing trend from the central region to the surrounding areas. The pollution level of Cd and Cu in the soil of the research area was relatively severe. The overall ecological risk was at a medium to low level. Cd and Hg were the main contributing factors. As, Cd, Cu, Fe, Mn, Pb, and Zn mainly came from agricultural, industrial, and transportation sources, whereas Cr and Ni were mainly from natural sources. However, the sources of Hg were relatively complex. The research results can provide a scientific basis for the prevention and control of soil heavy metal pollution in metal mining areas, as well as the remediation of mine pollution.

In fish species, there is limited analysis of signature transcriptome profiles at the single-cell level in gonadal cells. Here, the molecular signatures of distinct ovarian cell categories in adult Nile tilapia (Oreochromis niloticus) were analysed using single-nucleus RNA sequencing (snRNA-seq). We identified four cell types (oogonia, oocytes, granulosa cell, and thecal cell) based on their specifically expressed genes and biological functions. Similarly, we found some key pathways involved in ovarian development that may affect germline-somatic interactions. A cell-to-cell communication network between the distinct cell types was constructed. We found that the bidirectional communication is mandatory for the development of germ cells and somatic cells in fish ovaries, and the granulosa cells and thecal cells play a central regulating role in the cell network in fish ovary. Additionally, we identified some novel candidate marker genes for various types of ovarian cells and also validated them using in situ hybridization. Our work reveals an ovarian atlas at the cellular and molecular levels and contributes to providing insights into oogenesis and gonad development in fish., (© 2024 Fisheries Society of the British Isles.)

Salviapenghuana , a new species from Guizhou Province of southwestern China, is described and illustrated. Morphologically, Salviapenghuana is similar to S.filicifolia , but can be easily distinguished from the latter by ovate-lanceolate bracts, purple corolla, and foot-shaped fused lower arms of connective. In addition, S.penhuana is morphologically similar to S.cavaleriei , but differs by having 3-4-pinnate leave, ovate-lanceolate bracts, puberulent calyx, and longer upper arms of connective. Based on the fibril root, small calyx and corolla, and completely reduced posterior thecae, S.penghuana should be placed in section Sobiso of subg. Glutinaria., Competing Interests: The authors have declared that no competing interests exist., (Feng-Jin Qiu, Deng-Li Yu, Hong-Bo Lan, Ming-Tai An, Yan-Fei Geng, Chun-Lei Xiang, Guo-Xiong Hu.)

Background: Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials., Objective: We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis., Methods: Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300 mg every 2 weeks up to 52 weeks. Efficacy outcomes included the proportions of patients with ≥ 50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale., Results: In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week 52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥ 2-point reduction was achieved in 39.3% of patients at week 16, increasing to 58.9% at week 52. The proportions of patients with ≥ 3-point and ≥ 4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week 52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events., Conclusions: Long-term treatment with stapokibart for 52 weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021)., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Phlomoidesbomiensis , a new species in Bomi County, Xizang, China, was described and illustrated. In addition, Phlomoideslongidentata , previously only known from Nepal and Bhutan, is newly recorded from Dingri County, Xizang, China. The phylogenetic placement of both species within the genus was analysed using nine plastid DNA markers ( atpB-rbcL , psbA-trnH , rpl16 , rpl32-trnL , rps16 , trnK , trnL-trnF , trnS-trnG , trnT-trnL ). Both species have brown-black trichomes inside the upper corolla lip and nested within the same subclade of Clade II. A diagnostic key to the Phlomoides species belonging to this subclade is provided., Competing Interests: The authors have declared that no competing interests exist., (Yue Zhao, Ya-Ping Chen, Rui-Zhu Bai, Colin A. Pendry, Alexander P. Sukhorukov, Chun-Lei Xiang.)

Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men, the incidence of which gradually increases with age and leads to lower urinary tract symptoms (LUTS), which seriously affects the quality of life of patients. Chinese herbal medicines (CHMs) are widely used for the treatment of BPH in China and some other countries. To explore the molecular mechanisms of CHMs for BPH, we conducted a review based on peer-reviewed English-language publications in PubMed and Web of Science databases from inception to December 31, 2023. This article primarily reviewed 32 papers on the use of CHMs and its active compounds in the treatment of BPH, covering animal and cell experiments, and identified relevant mechanisms of action. The results suggest that the mechanisms of action of CHMs in treating BPH may involve the regulation of sex hormones, downregulation of cell growth factors, anti-inflammatory and antioxidative effects, inhibition of cell proliferation, and promotion of apoptosis. CHMs also exhibit α-blocker-like effects, with the potential to relax urethral smooth muscle and alleviate LUTS. Additionally, we also reviewed 4 clinical trials and meta-analyses of CHMs for the treatment of BPH patients, which provided initial evidence of the safety and effectiveness of CHMs treatment. CHMs treatment for BPH shows advantages as a multi-component, multi-target, and multi-pathway therapy, which can mitigate the severity of the disease, improve LUTS, and may become a reliable treatment option in the future., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Increasing evidence supports the association between impaired oral health and elevated mortality. However, there is currently a lack of research on the impact of tooth loss and periodontal disease on survival outcomes in cancer survivors. This study aims to clarify the effect of tooth loss and periodontitis on all-cause mortality on cancer survivors., Methods: The clinical data of cancer survivors were collected from National Health and Nutrition Examination Survey (NHANES) 1999-2018. Mortality data were obtained by linking to records in the National Death Index until December 31, 2019. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal threshold for discriminating mortality based on the number of teeth lost. Kaplan-Meier survival curves and Cox regression analysis were performed to calculate hazard ratios (HRs) and 95 % confidence intervals (95 % CI) for tooth loss and periodontitis., Results: A total of 3271 cancer survivors were assessed for tooth loss status, while 1267 patients were evaluated for periodontitis status. The prevalence of any tooth loss and CDC-AAP periodontitis was 83.5 % and 47.2 %, respectively. The ROC curve showed the cut-off point of tooth loss for predicting mortality is > 5. Cancer survivors with tooth loss>5 had significantly lower bone density (1.06 vs. 1.13 g/cm 2 , P  < 0.001), elevated C-reactive protein level (0.3 vs. 0.18 mg/dL, P  < 0.001), and a trend of lower lean body mass (46.9 vs. 47.6 kg, P  = 0.093). Besides, cancer survivors with severe periodontitis also exhibited elevated C-reactive protein level (0.34 vs. 0.21 mg/dL, P  = 0.033). All-cause mortality significantly increased in cancer survivors with either tooth loss>5 (HR = 1.290, P  = 0.001) or severe CDC-AAP periodontitis (HR = 1.682, P  = 0.016) in the multivariate Cox regression analysis., Conclusion: Tooth loss and periodontitis are strong risk factors for reduced overall survival in cancer survivors. Cancer survivors should emphasize diligent oral hygiene and consistent dental check-ups to optimize long-term oral health. The causal relationship between oral health and survival rates in cancer survivors requires further validation through randomized controlled trials., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Herba Patriniae and Coix seed (HC) constitute a widely utilized drug combination in the clinical management of colorectal cancer (CRC) that is known for its diuretic, anti-inflammatory, and swelling-reducing properties. Although its efficacy has been demonstrated in a clinical setting, the active compounds and their mechanisms of action in CRC treatment remain to be fully elucidated., Aim: To identify the active, CRC-targeting components of HC and to elucidate the mechanisms of action involved., Methods: Active HC components were identified and screened using databases. Targets for each component were predicted. CRC-related targets were obtained from human gene databases. Interaction targets between HC and CRC were identified. A "drug-ingredient-target" network was created to identify the core components and targets involved. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to elucidate the key pathways involved. Molecular docking between core targets and key components was executed. In vitro experiments validated core monomers., Results: Nineteen active components of HC were identified, with acacetin as the primary active compound. The predictive analysis identified 454 targets of the active compounds in HC. Intersection mapping with 2685 CRC-related targets yielded 171 intervention targets, including 30 core targets. GO and KEGG analyses indicated that HC may influence the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Molecular docking showed that acacetin exhibited an optimal interaction with AKT1 , identifying PI3K , AKT , and P53 as key genes likely targeted by HC during CRC treatment. Acacetin inhibited HT-29 cell proliferation and migration, as well as promoted apoptosis, in vitro . Western blotting analysis revealed increased p53 and cleaved caspase-3 expression and decreased levels of p-PI3K , p-Akt , and survivin, which likely contributed to CRC apoptosis., Conclusion: Acacetin, the principal active compound in the HC pair, inhibited the proliferation and migration of HT-29 cells and promoted apoptosis through the PI3K/Akt/p53 signaling pathway., Competing Interests: Conflict-of-interest statement: Authors have no conflicts of interest to declare., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)