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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]

Introduction: The purpose of this study was to assess the application of the early warning score system (EWS-S) and gauge physician awareness, perceptions of necessity and attitudes regarding these tools based on previously experienced unnoticed clinical deterioration (CDET).Methods: A cross-sectional survey was carried out via an online questionnaire at a large 3,500-bed Class 3A general hospital in China. A total of 299 physicians of adult general wards were asked to answer a translated questionnaire that was localised from the original version. Demographic profiles of patients were included as well as three other sections assessing awareness of CDET/EWS-S and gauging attitudes towards and perceptions of the necessity of EWS-S at our hospital.Results: A high level of physician awareness of the CDET problem was observed. Most physicians knew about the existence of a systematic assessment tool for clinical application. Physicians with previous experience in reanimation, unplanned transfer to intensive care unit (UTICU) and/or death tended to consider EWS-S necessary in attentive and well-trained staff (p < 0.05). Physicians who had previous experience with UTICU were more likely to recommend implementing EWS-S in their wards compared with those without such experience (p < 0.05).Conclusion: Most physicians have positive attitudes towards EWS-S. However, their awareness should be further heightened. Physicians who had previous experience with CDET/UTICU were more likely to employ EWS-S in their clinical practices. To better facilitate the implementation of EWS-S in Chinese hospitals, existing facilities, policy supports, standardised managements and the development of information systems should be strengthened. [ABSTRACT FROM AUTHOR]

In persons living with HIV-1 (PLWH) who start antiretroviral therapy (ART), plasma virus decays in a biphasic fashion to below the detection limit. The first phase reflects the short half-life (<1 d) of cells that produce most of the plasma virus. The second phase represents the slower turnover (t1/2 = 14 d) of another infected cell population, whose identity is unclear. Using the intact proviral DNA assay (IPDA) to distinguish intact and defective proviruses, we analyzed viral decay in 17 PLWH initiating ART. Circulating CD4+ T cells with intact proviruses include few of the rapidly decaying first-phase cells. Instead, this population initially decays more slowly (t1/2 = 12.9 d) in a process that largely represents death or exit from the circulation rather than transition to latency. This more protracted decay potentially allows for immune selection. After ~3 mo, the decay slope changes, and CD4+ T cells with intact proviruses decay with a half-life of 19 mo, which is still shorter than that of the latently infected cells that persist on long-term ART. Two-long-terminal repeat (2LTR) circles decay with fast and slow phases paralleling intact proviruses, a finding that precludes their use as a simple marker of ongoing viral replication. Proviruses with defects at the 5' or 3' end of the genome show equivalent monophasic decay at rates that vary among individuals. Understanding these complex early decay processes is important for correct use of reservoir assays and may provide insights into properties of surviving cells that can constitute the stable latent reservoir. [ABSTRACT FROM AUTHOR]

HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We show here that, for diverse LRAs, latency reversal observed in model systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals. [ABSTRACT FROM AUTHOR]

The role of dyslipidemia in the development of retinal dysfunction remains poorly understood. Using an animal model of diet-induced obesity/pre-type 2 diabetes, we investigated molecular defects in the retina arising from consumption of a diet high in saturated fats and sugars (i.e., a Western diet). We found that feeding mice a Western diet increased the abundance of retinal sphingolipids, attenuated protein kinase B (Akt) phosphorylation, enhanced JNK activation, and increased retinal cell death. When we used palmitate or C6-ceramide (Cer) to assess sphingolipid-mediated signaling in cultured murine and human cells, we observed similar effects on Akt, JNK, and cell death. Furthermore, both Western diet and C6-Cer exposure enhanced expression of the stress-response protein regulated in development and DNA damage response 1 (REDD1) and loss of REDD1 increased C6-Cer-induced JNK activation and cell death. Exogenous REDD1 expression repressed JNK-mediated phosphorylation in cultured cells. We found that thioredoxin-interacting protein (TXNIP) expression was elevated in REDD1-deficient cell lines and C6-Cer promoted TXNIP expression in both wild-type and REDD1-deficient cells. Likewise, TXNIP knockdown attenuated JNK activation and caspase 3 cleavage after either C6-Cer exposure or REDD1 deletion. The results support a model wherein Cer-induced REDD1 expression attenuates TXNIP-dependent JNK activation and retinal cell death. [ABSTRACT FROM AUTHOR]

Background: The King-Devick (K-D) test of rapid number naming is a reliable visual performance measure that is a sensitive sideline indicator of concussion when time scores worsen (lengthen) from preseason baseline. Within cohorts of youth athletes, 18 years old, baseline K-D times become faster with increasing age. We determined the relation of rapid numbernaming time scores on the K-D test to electronic measurements of saccade performance during preseason baseline assessments in a collegiate ice hockey team cohort. Within this group of young adult athletes, we also sought to examine the potential role for player age in determining baseline scores. Methods: Athletes from a collegiate ice hockey team received preseason baseline testing as part of an ongoing study of rapid rink-side performance measures for concussion. These included the K-D test (spiral-bound cards and tablet computer versions). Participants also performed a laboratory-based version of the K-D test with simultaneous infrared-based video-oculographic recordings using an Eye-Link 1000+. This allowed measurement of the temporal and spatial characteristics of eye movements, including saccadic velocity, duration, and intersaccadic interval (ISI). Results: Among 13 male athletes, aged 18-23 years (mean 20.5 ± 1.6 years), prolongation of the ISI (a combined measure of saccade latency and fixation duration) was the measure most associated with slower baseline time scores for the EyeLink-paired K-D (mean 38.2 ± 6.2 seconds, r = 0.88 [95% CI 0.63-0.96], P = 0.0001), the K-D spiral-bound cards (36.6 ± 5.9 seconds, r = 0.60 [95% CI 0.08-0.87], P = 0.03), and K-D computerized tablet version (39.1 ± 5.4 seconds, r = 0.79 [95% CI 0.42-0.93], P = 0.001). In this cohort, older age was a predictor of longer (worse) K-D baseline time performance (age vs EyeLink-paired K-D: r = 0.70 [95% CI 0.24-0.90], P = 0.008; age vs K-D spiralbound cards: r = 0.57 [95% CI 0.03-0.85], P = 0.04; age vs K-D tablet version: r = 0.59 [95% CI 0.06-0.86], P = 0.03) as well as prolonged ISI (r = 0.62 [95% CI 0.11-0.87], P = 0.02). Slower baseline K-D times were not associated with greater numbers of reported prior concussions. Conclusions: Rapid number-naming performance using the K-D at preseason baseline in this small cohort of collegiate ice hockey players is best correlated with ISI among eye movement-recording measures. Baseline K-D scores notably worsened with increasing age, but not with numbers of prior concussions in this small cohort. While these findings require further investigation by larger studies of contact and noncontact sports athletes, they suggest that duration of contact sports exposure may influence preseason test performance. [ABSTRACT FROM AUTHOR]

Diabetes-induced visual dysfunction is associated with significant neuroretinal cell death. The current study was designed to investigate the role of the Protein Regulated in Development and DNA Damage Response 1 (REDD1) in diabetes-induced retinal cell death and visual dysfunction. We recently demonstrated that REDD1 protein expression was elevated in response to hyperglycemia in the retina of diabetic rodents. REDD1 is an important regulator of Akt and mammalian target of rapamycin and as such plays a key role in neuronal function and survival. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 protein expression concomitant with caspase activation and cell death. By contrast, in REDD1-deficient R28 cells, neither hyperglycemic conditions nor the absence of insulin in culture medium were sufficient to promote cell death. In the retinas of streptozotocin-induced diabetic mice, retinal apoptosis was dramatically elevated compared with nondiabetic controls, whereas no difference was observed in diabetic and nondiabetic REDD1-deficient mice. Electroretinogram abnormalities observed in b-wave and oscillatory potentials of diabetic wild-type mice were also absent in REDD1-deficient mice. Moreover, diabetic wild-type mice exhibited functional deficiencies in visual acuity and contrast sensitivity, whereas diabetic REDD1-deficient mice had no visual dysfunction. The results support a role for REDD1 in diabetes-induced retinal neurodegeneration. [ABSTRACT FROM AUTHOR]

A recent analysis of the newly sequenced rainbow trout ( Oncorhynchus mykiss) genome suggested that duplicated gluconeogenic g6pc paralogues, fixed in this genome after the salmonid-specific 4th whole genome duplication, may have a role in the setting up of the glucose-intolerant phenotype in this carnivorous species. This should be due to the sub- or neo-functionalization of their regulation. In the present short communication we thus addressed the question of the regulation of these genes by insulin, hormone involved in the glucose homeostasis, and its interaction with glucose and amino acids in vitro. The stimulation of trout hepatocytes with insulin revealed an atypical up-regulation of g6pcb2 ohnologues and confirmed the sub- or neo-functionalization of the five g6pc genes at least at the regulatory level. Intriguingly, when hepatocytes were cultured with high levels of glucose and/or AAs in presence of insulin, most of the g6pc paralogues were up-regulated. It strongly suggested a cross-talk between insulin and nutrients for the regulation of these genes. Moreover these results strengthened the idea that g6pc duplicated genes may significantly contribute to the setting up of the glucose-intolerant phenotype in trout via their atypical regulation by insulin alone or in interaction with nutrients. These findings open new perspectives to better understand in vivo glucose-intolerant phenotype in trout fed a high carbohydrate diet. [ABSTRACT FROM AUTHOR]

The link between dietary carbohydrate/protein and de novo lipogenesis (DNL) remains debatable in carnivorous fish. We aimed to evaluate and compare the response of hepatic lipogenic gene expression to dietary carbohydrate intake/glucose and dietary protein intake/amino acids (AAs) during acute stimulations using both in vivo and in vitro approaches. For the in vivo trial, three different diets and a controlled-feeding method were employed to supply fixed amount of dietary protein or carbohydrate in a single meal; for the in vitro trial, primary hepatocytes were stimulated with a low or high level of glucose (3 mM or 20 mM) and a low or high level of AAs (one-fold or four-fold concentrated AAs). In vitro data showed that a high level of AAs upregulated the expression of enzymes involved in DNL [fatty acid synthase (FAS) and ATP citrate lyase (ACLY)], lipid bioconversion [elongation of very long chain fatty acids like-5 (Elovl5), Elovl2, Δ6 fatty acyl desaturase (D6D) and stearoyl-CoA desaturase-1 (SCD1)], NADPH production [glucose-6-phosphate dehydrogenase (G6PDH) and malic enzyme (ME)], and transcriptional factor sterol regulatory element binding protein 1-like, while a high level of glucose only elevated the expression of ME. Data in trout liver also showed that high dietary protein intake induced higher lipogenic gene expression (FAS, ACLY, and Elovl2) regardless of dietary carbohydrate intake, while high carbohydrate intake markedly suppressed the expression of acetyl-CoA carboxylase (ACC) and Elovl5. Overall, we conclude that, unlike rodents or humans, hepatic fatty acid biosynthetic gene expression in rainbow trout is more responsive to dietary protein intake/AAs than dietary carbohydrate intake/glucose during acute stimulations. This discrepancy probably represents one important physiological and metabolic difference between carnivores and omnivores. [ABSTRACT FROM AUTHOR]

Our aim was to investigate the potential role of TOR (target of rapamycin) signaling pathway in the regulation of hepatic glucose metabolism in rainbow trout. Fasted fish were first treated with a single intraperitoneal injection of rapamycin or vehicle and then submitted to a second intraperitoneal administration of glucose 4 h later. Our results revealed that intraperitoneal administration of glucose induced hyperglycemia for both vehicle and rapamycin treatments, which peaked at 2 h. Plasma glucose level in vehicle-treated fish was significantly higher than in rapamycin-treated fish at 8 and 17 h, whereas it remained at the basal level in rapamycin-treated fish. Glucose administration significantly enhanced the phosphorylation of Akt and ribosomal protein S6 kinase (S6K1) in vehicle-treated fish, while rapamycin completely abolished the activation of S6K1 in rapamycin-treated fish, without inhibiting the phosphorylation of Akt on Thr-308 or Ser-473. Despite the lack of significant variation in phosphoenolpyruvate carboxykinase mRNA abundance, mRNA abundance for glucokinase (GK), glucose 6-phosphatase (G6Pase) I and II, and fructose 1,6-bisphosphatase (FBPase) was reduced by rapamycin 17 h after glucose administration. The inhibition effect of rapamycin on GK and FBPase was further substantiated at the activity level. The suppression of GK gene expression and activity by rapamycin provided the first in vivo evidence in fish that glucose regulates hepatic GK gene expression and activity through a TORC1-dependent manner. Unlike in mammals, we observed that acute rapamycin treatment improved glucose tolerance through the inhibition of hepatic gluconeogenesis in rainbow trout. [ABSTRACT FROM AUTHOR]

In response to cellular insult, several pathways can be activated, including necrosis, apoptosis, and autophagy. Because glucocorticoids (GCs) have been shown to induce both osteocyte apoptosis and autophagy, we sought to determine whether osteocyte cell fate in the presence of GCs was dose dependent by performing in vivo and in vitro studies. Male Swiss-Webster mice were treated with slow-release prednisolone pellets at 1.4, 2.8, and 5.6 mg/kg/d for 28 d. An osteocyte cell line, MLO-Y4 cells, was treated with various doses of dexamethasone. We found that GC treatments dose dependently decreased activation of antioxidant-, autophagy-, and antiapoptosis-focused RT-PCR gene pathways in mouse cortical bone. The activation of antioxidant genes was correlated with autophagy gene expression after the GC treatments. The presence of osteocyte autophagy, as detected by immunostaining for LC3, increased ~50% at the distal femur cortical bone region but not at trabecular bone region at the 1.4 and 2.8 mg/kg/d GC dose levels. The number of apoptotic osteocytes was increased at the cortical bone region by ~40% initially observed at the 2.8 mg/kg/d dose level. In addition, the presence of the osteocyte autophagy was associated with an increased protein level of cathepsin K in vitro after the GC treatments. In summary, we found that GC treatment dose-dependently decreased antioxidant gene expression, with lower GC doses activating autophagy, whereas a higher dose increased apoptosis. These data suggest that autophagy may provide a mechanism for osteocytes to survive the stress after GC exposure and provide further insight into how GCs alter bone cell fate. [ABSTRACT FROM AUTHOR]