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Abstract The question of whether artificial intelligence (AI) can surpass human capabilities is crucial in the application of AI in clinical medicine. To explore this, an interpretable deep learning (DL) model was developed to assess myopia status using retinal refraction maps obtained with a novel peripheral refractor. The DL model demonstrated promising performance, achieving an AUC of 0.9074 (95% CI 0.83–0.97), an accuracy of 0.8140 (95% CI 0.70–0.93), a sensitivity of 0.7500 (95% CI 0.51–0.90), and a specificity of 0.8519 (95% CI 0.68–0.94). Grad-CAM analysis provided interpretable visualization of the attention of DL model and revealed that the DL model utilized information from the central retina, similar to human readers. Additionally, the model considered information from vertical regions across the central retina, which human readers had overlooked. This finding suggests that AI can indeed surpass human capabilities, bolstering our confidence in the use of AI in clinical practice, especially in new scenarios where prior human knowledge is limited.

Abstract Timely and effective diagnosis of fungal keratitis (FK) is necessary for suitable treatment and avoiding irreversible vision loss for patients. In vivo confocal microscopy (IVCM) has been widely adopted to guide the FK diagnosis. We present a deep learning framework for diagnosing fungal keratitis using IVCM images to assist ophthalmologists. Inspired by the real diagnostic process, our method employs a two-stage deep architecture for diagnostic predictions based on both image-level and sequence-level information. To the best of our knowledge, we collected the largest dataset with 96,632 IVCM images in total with expert labeling to train and evaluate our method. The specificity and sensitivity of our method in diagnosing FK on the unseen test set achieved 96.65% and 97.57%, comparable or better than experienced ophthalmologists. The network can provide image-level, sequence-level and patient-level diagnostic suggestions to physicians. The results show great promise for assisting ophthalmologists in FK diagnosis.

Purpose: To investigate the risk factors for patients with focal choroidal excavation (FCE) and their correlation with chorioretinal diseases. Design: Retrospective cross-sectional study. Subjects: Patients with FCE were enrolled, while healthy subjects were recruited for the control group. Methods: The study collected demographic information, clinical features, and multimodal images. Parameters of FCE identified using spectral-domain OCT (SD-OCT) were manually measured using built-in software and subsequently analyzed statistically. Main Outcome Measures: Subfoveal choroidal thickness (SFCT), subexcavation choroidal thickness (SECT), and the greatest depth and width of each excavation were manually measured using built-in calipers in OCT software. Results: Twenty-one patients (13/8, male/female) with FCE were included in this study. The average age was 45.2 years, and their best-corrected visual acuity (BCVA) was 0.4 logarithm of the minimum angle of resolution (Snellen equivalent, 20/50). Focal choroidal excavation was present in 28 eyes of 21 patients, including isolated FCE (12 eyes) and complicated FCE (16 eyes) with choroidal neovascularization (sCNV), central serous chorioretinopathy, and other conditions. Patients with complicated FCE were significantly older than those isolated FCE (P = 0.015). The SFCT of the healthy subjects was significantly less than that of the fellow eyes of the patients with FCE (P

Abstract Background Proton-pump inhibitors (PPIs) prevent aspirin-associated gastric and duodenal mucosal damage. However, long-term use of PPIs can lead to various adverse reactions, such as gastric polyps and enterochromaffin-like cell hyperplasia. Current research indicates that the abovementioned adverse reactions are mainly related to hypergastrinemia. We investigated whether low-frequency administration of omeprazole could effectively repair aspirin-induced mucosal damage and reduce the increase in gastrin levels associated with long-term use of PPIs. Methods Sprague‒Dawley rats were divided into four treatment groups: daily aspirin, daily aspirin and omeprazole once every day (qd), daily aspirin and omeprazole once every other day (qod), and daily aspirin and omeprazole once every three days (1/d3). After 15 days of feeding, blood samples were collected, and the stomachs of sacrificed rats were subjected to macroscopic, histological, and immunohistochemical studies. Moreover, in clinical practice, patients with peptic ulcers caused by aspirin took a standard dose of omeprazole (20 mg) every other day. Two months later, gastroscopy was performed to examine the healing of the ulcers. Results Both the omeprazole qd and omeprazole qod administrations effectively prevented aspirin-induced gastric peptic ulcers, with no significant difference between the two groups in the inhibition of parietal cell secretion of gastric acid and cell apoptosis. However, omeprazole 1/d3 failed to completely prevent aspirin-induced gastric mucosal injury. Notably, the gastrin levels, cell proliferation ability and cholecystokinin B receptor expression of the omeprazole qd group were significantly higher than those of the omeprazole qod group. In clinical work, patients with peptic ulcers caused by aspirin were given a standard dose of omeprazole every other day, and their ulcers healed after 2 months, as observed by gastroscopy. Conclusions Omeprazole administration once every other day can effectively prevent aspirin-induced peptic ulcers and reduce hypergastrinemia, which may reduce the long-term adverse effects of PPI treatment.

Abstract Background Studies examining the potential association between cooking oil and frailty risk in older adults have produced conflicting outcomes. Therefore, our objective was to explore the relationship between cooking oil (vegetable and animal fat oils), changes in oil usage, and the risk of frailty in older adults. Methods We included 4,838 participants aged ≥ 65 years without frailty (frailty index

Objective To evaluate the effects of silver and iodine dressings on healing time, healing rate, exudate amount, pain and anti-infective efficacy.Design Systematic review and meta-analysis.Data sources Databases including PubMed, Cochrane Library, Embase, Web of Science and CINAHL were surveyed up to May 2024.Eligibility criteria Randomised controlled trials comparing silver and iodine dressings on wound healing in humans.Data extraction and synthesis Evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Data extraction was done independently by two reviewers, with the risk of bias assessed using the Cochrane tool. Narrative synthesis was performed to evaluate the effects of silver and iodine dressings on healing time, healing rate, pain, exudate amount and anti-infective efficacy. Meta-analysis using Review Manager V.5.4 calculated standardised mean differences for healing time and relative risks for rate to quantify the impacts of the treatments.Results 17 studies (18 articles) were included. The meta-analysis indicated that silver dressings significantly reduced healing time compared with iodine dressings (SMD=-0.95, 95% CI −1.62 to −0.28, I2=92%, p=0.005, moderate-quality evidence), with no significant difference in enhancing healing rate (RR=1.29, 95% CI 0.90 to 1.85, I2=91%, p=0.16, low-quality evidence). Based on low-quality evidence, for exudate amount (3/17), 66.7% (2/3) of the studies favoured silver dressings over iodine in reducing exudate volume. For pain (7/17), 57.1% (4/7) of the studies reported no significant difference between silver and iodine dressings, while 42.9% (3/7) studies indicated superior pain relief with silver dressings. For anti-infective efficacy (11/13), 54.5% (6/11) of the studies showed equivalence between silver and iodine dressings, while 36.4% (4/11) suggested greater antibacterial efficacy for silver.Conclusion Silver dressings, demonstrating a comparable healing rate to iodine dressings, significantly reduce healing time, suggesting their potential as a superior adjunct in wound care.PROSPERO registration number CRD42020199602.

Abstract Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy.

[This corrects the article DOI: 10.1371/journal.pone.0232238.].

Abstract Background Lifestyle changes are important for the prevention and management of metabolic syndrome (MetS), but studies that focus on gender differences in the lifestyle risk factors of MetS are limited in China. This research aimed to generate a healthy lifestyle index (HLI) to assess the behavioral risk factors of MetS and its components, and to explore the gender differences in HLI score and other influencing factors of MetS. Methods A convenience sample of 532 outpatients were recruited from a general hospital in Changsha, China. The general information and HLI scores [including physical activity (PA), diet, smoking, alcohol use, and body mass index (BMI)] of the subjects were collected through questionnaires, and each patient’s height, weight, waist circumference, and other physical signs were measured. Logistic regression analysis was used to analyze the risk factors of MetS and its components. Results The prevalence of MetS was 33.3% for the whole sample (46.3% in males and 23.3% in females). The risk of MetS increased with age, smoking, unhealthy diet, and BMI in males and with age and BMI in females. Our logistic regression analysis showed that lower HLI (male: OR = 0.838,95%CI = 0.757–0.929; female: OR = 0.752, 95%CI = 0.645–0.876) and older age (male: OR = 2.899, 95%CI = 1.446–5.812; female: OR = 4.430, 95%CI = 1.640–11.969) were independent risk factors of MetS, for both sexes. Conclusion Low levels of HLI and older ages were independent risk factors of MetS in both males and females. The association between aging and MetS risk was stronger in females, while the association between unhealthy lifestyles and MetS risk was stronger in males. Our findings reinforced the expected gender differences in MetS prevalence and its risk factors, which has implications for the future development of gender-specific MetS prevention and intervention programs.

Abstract Background Diabetic foot is a serious complication of diabetes with a high disability and mortality rate, which can be prevented by early screening. General practitioners play an essential role in diabetic foot risk screening, yet the screening behaviors of general practitioners have rarely been studied in primary care settings. This study aimed to investigate foot risk screening behaviors and analyze their influencing factors among general practitioners. Methods A cross-sectional study was conducted among 844 general practitioners from 78 community health centers in Changsha, China. A self-designed and validated questionnaire was used to assess the general practitioner’s cognition, attitude, and behaviors on performing diabetic foot risk screening. Multivariate linear regression was conducted to investigate the influencing factors of risk screening behaviors. Results The average score of diabetic foot risk screening behaviors among the general practitioners was 61.53 ± 14.69, and 271 (32.1%) always or frequently performed foot risk screening for diabetic patients. Higher training frequency (β = 3.197, p

PurposeThe aim of this study is to apply deep learning techniques for the development and validation of a system that categorizes various phases of dry age-related macular degeneration (AMD), including nascent geographic atrophy (nGA), through the analysis of optical coherence tomography (OCT) images.MethodsA total of 3,401 OCT macular images obtained from 338 patients admitted to Shenyang Aier Eye Hospital in 2019–2021 were collected for the development of the classification model. We adopted a convolutional neural network (CNN) model and introduced hierarchical structure along with image enhancement techniques to train a two-step CNN model to detect and classify normal and three phases of dry AMD: atrophy-associated drusen regression, nGA, and geographic atrophy (GA). Five-fold cross-validation was used to evaluate the performance of the multi-label classification model.ResultsExperimental results obtained from five-fold cross-validation with different dry AMD classification models show that the proposed two-step hierarchical model with image enhancement achieves the best classification performance, with a f1-score of 91.32% and a kappa coefficients of 96.09% compared to the state-of-the-art models. The results obtained from the ablation study demonstrate that the proposed method not only improves accuracy across all categories in comparison to a traditional flat CNN model, but also substantially enhances the classification performance of nGA, with an improvement from 66.79 to 81.65%.ConclusionThis study introduces a novel two-step hierarchical deep learning approach in categorizing dry AMD progression phases, and demonstrates its efficacy. The high classification performance suggests its potential for guiding individualized treatment plans for patients with macular degeneration.

Abstract Aim This study was conducted to increase knowledge on the actuality of resilience, social support and quality of life among inflammatory bowel disease patients in China to provide evidence for psychological support. Design Using convenience sampling, 249 outpatients and inpatients with inflammatory bowel disease from a hospital who completed the questionnaires were enrolled in the analytic questionnaire‐based study. Methods Demographic information forms, Resilience Scale for Inflammatory Bowel Disease, Social Support Rating Scale and Short Health Scale were administered. Results It was found that the resilience of patients with inflammatory bowel disease should be enhanced. When considering factors that influence resilience, the place of residence (living in rural areas) and utilization of social support should be considered. Resilience demonstrated a positive correlation with utilization of social support, and different place of residence was related to resilience. Targeted interventions should be implemented to increase patients’ resilience and quality of life.

The shearer positioning method is of great significance to the automation of longwall mining. The research teams in the Longwall Automation Steering Committee (LASC) of Australia and China University of Mining and Technology (CUMT) have focused on shearer positioning and identified the shearer inertial navigation system, the measurement of longwall retreat and creep displacement, and the backward calibration of the shearer trajectory as three key technologies to obtain accurate shearer positioning information. In underground environments without GPS, due to the characteristics of inertial navigation system (INS) autonomous full-parameter navigation, shearer positioning based on INS is adopted by the LASC and CUMT, and error reduction algorithms are proposed to inhibit the rapid error accumulation of INS. In order to obtain the periodic calibration information when the shearer reaches the end of the longwall face, it is necessary to measure the retreat and creep displacements in order to back-correct the shearer trajectory. Finding a suitable measurement method for this task is challenging, especially in the presence of dust and moisture. The LASC used a scanning laser and FMR 250 microwave radar to measure these two displacements, while CUMT adopted an ultra-wideband (UWB) radar. In terms of the backward calibration method, minimum-variance fixed-interval smoothing (MFS) proposed by LASC and the global optimization model (GOM) for the shearer trajectory from CUMT are described in detail. The experiment demonstrates that the GOM outperforms MFS in terms of accuracy but requires more computational resources. Therefore, our next research objective is to develop an efficient and accurate algorithm for performing backward calibration on the shearer trajectory.

Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS’s ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of β-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While β-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.

Spatial equality of parks is a significant issue in environmental justice studies. In cities with high-density development and limited land resources, this study uses a supply-demand adjusted two-step floating catchment area model (2SFCA), paying attention to residents' subjective preferences and psychological accessibility. It assesses equality of access to urban parks from two dimensions: spatial equality and quantitative equality at a fine scale of 100 × 100 m grid resolution. The spatial equality of urban parks in Chengdu is measured under different transportation modes (walking, cycling, and driving) based on multi-source geospatial big data and machine learning approaches. The results show: (1) There were significant differences in the spatial distribution of park accessibility under different modes of transportation. The spatial distribution under walking was significantly influenced by the park itself, while the distribution of rivers significantly influenced the spatial distribution under cycling and driving; (2) Accessibility to urban parks was almost universally equal in terms of driving, relatively equal in terms of cycling, and seriously unequal in terms of walking; (3) Spatial local autocorrelation analysis shows that park accessibility tended to be significantly clustered, with little spatial variation; and (4) The supply and demand of urban parks were relatively equal. The results can help urban planners to formulate effective strategies to alleviate spatial inequality more reasonably and precisely. The applied research methods can further improve the system of scientific evaluation from a new perspective.

Antiretroviral therapy (ART) effectively inhibits HIV-1 replication but is not curative due to the persistence of a latent viral reservoir in resting CD4+ T cells. This reservoir is a major barrier to cure. Sequencing studies have revealed that the population of proviruses persisting in ART-treated individuals is dominated by defective proviruses that cannot give rise to viral rebound due to fatal defects including large deletions and APOBEC3-mediated hypermutation. Near full genome sequencing (nFGS) of individual proviruses is used in reservoir assays to provide an estimate of the fraction of proviruses that are intact. nFGS methods rely on a long-distance outer PCR capturing most (~9 kb) of the genome, followed by nested inner PCRs. The outer PCR is carried out at limit dilution, and interpretation of the results is based on the assumption that all proviruses are quantitatively captured. Here, we evaluate nFGS methods using the intact proviral DNA assay (IPDA), a multiplex digital droplet PCR assay that quantitates intact and defective proviruses with single molecule sensitivity using only short, highly efficient amplicons. We analyzed proviral templates of known sequence to avoid the additional complication of sequence polymorphism. With the IPDA, we quantitated molecular yields at each step of nFGS methods. We demonstrate that nFGS methods are inefficient and miss ~70% of full-length proviruses due to amplification failure at the initial outer PCR step. In contrast, proviruses with large internal deletions encompassing 70% of the genome can be quantitatively amplified under the same conditions. Accurate measurement of the latent reservoir of HIV-1 is essential for evaluating the efficacy of cure strategies, and the bias against full length proviruses in nFGS methods must be considered.

Abstract Background The carcinogenic effect of NUP37 has been reported recently in a variety of tumors, but its research in the field of glioma has not been paid attention. The main purpose of this study is to reveal the relationship between NUP37 and prognosis or clinical characteristics of glioma patients. Methods First, as a retrospective study, this study included thousands of tissue samples based on a variety of public databases and clinicopathological tissues. Second, a series of bioinformatics analysis methods were used to analyze the NUP37 and glioma samples from multiple databases such as the CGGA, TCGA, GEO, HPA, and GEPIA. Third, to analyze the relationship between the expression level of NUP37 in tumor tissues and cells and a variety of clinical prognostic molecular characteristics, whether it can be an independent risk factor leading to poor prognosis in glioma and whether it has clinical diagnostic value; GSEA was used to analyze the cancer‐related signaling pathways that may be activated by high expression of NUP37. Fifth, CMap was used to analyze small molecule drugs that may inhibit NUP37 expression. Finally, the meta‐analysis of thousands of tissue samples from seven datasets and cell proliferation and migration experiments confirmed that NUP37 has a malignant effect on glioma. Results NUP37 is highly expressed in glioma patient tissues and glioma cells, significantly correlates with reduced overall survival, and may serve as an independent prognostic factor with some diagnostic value. Silencing NUP37 suppresses malignant biological behaviors of glioma cells. 4 small molecule drugs that had potential targeting inhibitory effects on NUP37 overexpression. Conclusions This study demonstrates for the first time a malignant role of NUP37 in glioma and provides a vision to unravel the complex pathological mechanisms of glioma and a potentially valuable biomarker for implementing individualized diagnosis and treatment of glioma.

Background and Aims: TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays a pivotal role in many cancers including liver cancer, we sought to determine the role of TRIM21 in hepatocarcinogenesis. Methods: We examined the correlation between TRIM21 expression and the disease using publicly available data sets and 49 cases of HCC clinical samples. We used TRIM21 genetic knockout mice to determine how TRIM21 ablation impact HCC induced by the carcinogen DEN plus phenobarbital (PB). We explored the mechanism that loss of TRIM21 protects cells from DEN-induced oxidative damage and cell death. Results: There is a positive correlation between TRIM21 expression and HCC. Consistently, TRIM21-knockout mice are resistant to DEN-induced hepatocarcinogenesis. This is accompanied by decreased cell death and tissue damage upon DEN treatment, hence reduced hepatic tissue repair response and compensatory proliferation. Cells deficient in TRIM21 display enhanced p62 sequestration of Keap1 and are protected from DEN-induced ROS induction and cell death. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient mutant TRIM21 impedes the protection from DEN-induced oxidative damage and cell death in TRIM21-deficient cells. Conclusions: Increased TRIM21 expression is associated with human HCC. Genetic ablation of TRIM21 leads to protection against oxidative hepatic damage and decreased hepatocarcinogenesis, suggesting TRIM21 as a preventive and therapeutic target.

The purpose of this systematic review and meta-analysis of the literature was to analyze and evaluate the impact of prematurity and accelerated weight gain on the risk of childhood and adolescent obesity. CINAHL, Embase, PubMed, and Web of Science databases were searched until December 2019 which yielded 19 studies with a total of 169,439 children enrolled were systematically reviewed. The results revealed that preterm infants had a greater likelihood of childhood obesity (defined as BMI ≥95th percentile for age-sex), than term infants (OR = 1.19, 95% CI [1.13, 1.26]). However, no difference of childhood obesity was found between "small for gestational age"(SGA) and "appropriate for gestational age"(AGA) among preterms. Accelerated weight gain (defined as weight gain velocity during first two years after birth) significantly increased the likelihood of subsequent childhood obesity among preterms (aOR = 1.87, 95% CI [1.57, 2.231]). In conclusion, accelerated weight gain at infancy among preterm children may be a critical contributor to obesity in later life. Establishing optimal growth trajectories and timely referral to health care providers may be of clinical importance.

Objectives. Metabolic syndrome (MetS) is now becoming a serious public health threat. Some behaviors risk factors were considered to be associated with MetS and interacted to adversely affect MetS. However, the clustering effects of behavior risk factors of MetS among Chinese population remain unclear. The aim of this study is to observe the behavior risk factors and their clustering effects of MetS in China. Methods. A cross-sectional study design was used. Subjects were recruited in the departments of Cardiology Clinic, Endocrine Clinic, and Health Management from March to December 2019. A demographic sheet was designed to collect the demographic and clinical characteristics of the subjects. International Physical Activity Questionnaire-Short was applied to evaluate the level of PA in this study. Other behavior risk factors were observed by the questionnaire. The stepwise logistic regression analysis was performed to identify the determinants of MetS. The multiple logistic regression analysis was used to analyze the clustering effects of behavior risk factors in MetS. Results. There are a total of 532 eligible subjects (56.6% females; mean age was 48.4±15.3 years), and approximately 33.3% were diagnosed as MetS. The subjects with a smoking habit (heavy and long-time history) had a 1.833-fold higher risk for MetS than their counterparts (none and light smoking), and the subjects that preferred salty taste had a 1.626-fold higher risk for MetS than the comparison cohort. Smoking and alcohol drinking had the highest clustering effect on MetS among the behavior risk factors. Conclusions. The main finding of this study was that smoking and salty taste preference were the independent determinants of MetS. Smoking and alcohol consumption had the highest clustering effect on southern Chinese MetS.

We recently identified the multipass transmembrane protein SERINC5 as an antiviral protein that can potently inhibit HIV-1 infectivity and is counteracted by HIV-1 Nef. We now report that the anti-HIV-1 activity, but not the sensitivity to Nef, is conserved among vertebrate SERINC5 proteins. However, a Nef-resistant SERINC5 became Nef sensitive when its intracellular loop 4 (ICL4) was replaced by that of Nef-sensitive human SERINC5. Conversely, human SERINC5 became resistant to Nef when its ICL4 was replaced by that of a Nef-resistant SERINC5. In general, ICL4 regions from SERINCs that exhibited resistance to a given Nef conferred resistance to the same Nef when transferred to a sensitive SERINC, and vice versa. Our results establish that human SERINC5 can be modified to restrict HIV-1 infectivity even in the presence of Nef.

(1) Background: The King-Devick (KD) rapid number naming test is sensitive for concussion diagnosis, with increased test time from baseline as the outcome measure. Eye tracking during KD performance in concussed individuals shows an association between inter-saccadic interval (ISI) (the time between saccades) prolongation and prolonged testing time. This pilot study retrospectively assesses the relation between ISI prolongation during KD testing and cognitive performance in persistently-symptomatic individuals post-concussion. (2) Results: Fourteen participants (median age 34 years; 6 women) with prior neuropsychological assessment and KD testing with eye tracking were included. KD test times (72.6 ± 20.7 s) and median ISI (379.1 ± 199.1 msec) were prolonged compared to published normative values. Greater ISI prolongation was associated with lower scores for processing speed (WAIS-IV Coding, r = 0.72, p = 0.0017), attention/working memory (Trails Making A, r = −0.65, p = 0.006) (Digit Span Forward, r = 0.57, p = −0.017) (Digit Span Backward, r= −0.55, p = 0.021) (Digit Span Total, r = −0.74, p = 0.001), and executive function (Stroop Color Word Interference, r = −0.8, p = 0.0003). (3) Conclusions: This pilot study provides preliminary evidence suggesting that cognitive dysfunction may be associated with prolonged ISI and KD test times in concussion.

Summary: Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of KrasG12D-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC. : Bott et al. demonstrate that GLUL-mediated glutamine synthesis plays a critical role in converging the TCA cycle and nitrogen metabolism to promote nitrogen-dependent anabolic processes in pancreatic cancer. Ablation of GLUL suppresses PDAC development and may have important clinical implications. Keywords: glutamine, pancreatic cancer, α-ketoglutarate, nitrogen metabolism, hexosamine, nucleotide, glutamine synthetase, glutamate ammonia ligase, K-Ras

To tackle the problem of graduate employability (GE), higher education researchers and practitioners are suggesting the inclusion of employability modules in university curricula. However, the orthodoxy of the major-based undergraduate curriculum (MBUC) has rarely been challenged in the GE literature. Drawing on Clarke's (2018) [Clarke, M. (2018). Rethinking graduate employability: The role of capital, individual attributes and context. "Studies in Higher Education," 43(11), 1923-1937. https://doi.org/10.1080/03075079.2017.1294152] integrated employability model, this paper explores how MBUC affects undergraduate students' GE development. The data were 27 interviews with undergraduates majoring in Portuguese at six Chinese universities. Findings show that the MBUC weakens students' perceived employability by cultivating a single rather than compound skill set, limiting their social circles and, therefore, horizons for action and delaying their career self-management. More directly, it affects GE in some cases by overproducing a homogeneously skilled workforce. We argue that in many fields of the current world of work, the MBUC may have contradicted its original, and once achieved, goal of enhancing GE for a particular profession; rather, in practice, it has become an obstacle to GE development.

Background/Aims: Carnivores exhibit poor utilization of dietary carbohydrates and glucose intolerant phenotypes, yet it remains unclear what are the causal factors and underlying mechanisms. We aimed to evaluate excessive amino acids (AAs)-induced effects on insulin signaling, fatty acid biosynthesis and glucose metabolism in rainbow trout and determine the potential involvement of mTORC1 and p38 MAPK pathway. Methods: We stimulated trout primary hepatocytes with different AA levels and employed acute administration of rapamycin to inhibit mTORC1 activation. Results: Increased AA levels enhanced the phosphorylation of ribosomal protein S6 kinase (S6K1), S6, and insulin receptor substrate 1 (IRS-1) on Ser302 but suppressed Akt and p38 phosphorylation; up-regulated the expression of genes related to gluconeogenesis and fatty acid biosynthesis. mTORC1 inhibition not only inhibited the phosphorylation of mTORC1 downstream targets, but also blunted IRS-1 Ser302 phosphorylation and restored excessive AAs-suppressed Akt phosphorylation. Rapamycin also inhibited fatty acid biosynthetic and gluconeogenic gene expression. Conclusion: High levels of AAs up-regulate hepatic fatty acid biosynthetic gene expression through an mTORC1-dependent manner, while attenuate insulin-mediated repression of gluconeogenesis through elevating IRS-1 Ser302 phosphorylation, which in turn impairs Akt activation and thereby weakening insulin action. We propose that p38 MAPK probably also involves in these AAs-induced metabolic changes.

Nitrogen (N) deposition has increased significantly globally since the industrial revolution. Previous studies on the response of gaseous emissions to N deposition have shown controversial results, pointing to the system-specific effect of N addition. Here we conducted an N addition experiment in a temperate natural forest in northeastern China to test how potential changes in N deposition alter soil N2O emission and its sources from nitrification and denitrification. Soil N2O emission was measured using closed chamber method and a separate incubation experiment using acetylene inhibition method was carried out to determine denitrification fluxes and the contribution of nitrification and denitrification to N2O emissions between Jul. and Oct. 2012. An NH4NO3 addition of 50 kg N/ha/yr significantly increased N2O and N2 emissions, but their "pulse emission" induced by N addition only lasted for two weeks. Mean nitrification-derived N2O to denitrification-derived N2O ratio was 0.56 in control plots, indicating higher contribution of denitrification to N2O emissions in the study area, and this ratio was not influenced by N addition. The N2O to (N2+N2O) ratio was 0.41-0.55 in control plots and was reduced by N addition at one sampling time point. Based on this short term experiment, we propose that N2O and denitrification rate might increase with increasing N deposition at least by the same fold in the future, which would deteriorate global warming problems.

Augmentation of the peak bone mass (PBM) may be one of the most effective interventions to reduce the risk of developing osteoporosis later in life; however treatments to augment PBM are currently limited. Our study evaluated whether a greater PBM could be achieved either in the progesterone nuclear receptor knockout mice (PRKO) or by using a nuclear progesterone receptor (nPR) antagonist, RU486 in mice. Compared to their wild type (WT) littermates the female PRKO mice developed significantly higher cancellous and cortical mass in the distal femurs, and this was associated with increased bone formation. The high bone mass phenotype was partially reproduced by administering RU486 in female WT mice from 1-3 months of age. Our results suggest that the inhibition of the nPR during the rapid bone growth period (1-3 months) increases osteogenesis, which results in acquisition of higher bone mass. Our findings suggest a crucial role for progesterone signaling in bone acquisition and inhibition of the nPR as a novel approach to augment bone mass, which may have the potential to reduce the burden of osteoporosis.

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates β-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of β-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy. [ABSTRACT FROM AUTHOR]