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Abstract Significant progress has been made in the field of two-dimensional WS2, yet the precise control of the doping process to achieve desired properties and the interpretation of complex physical phenomena in these novel materials necessitate thorough research. In this study, Nb-doped WS2 is synthesized using chemical vapor deposition technology, leading to triangular flakes with a side length of 12–20 μm. The X-ray photoelectron spectroscopy analysis indicates that the NbW substitution defect functions as an electron acceptor. The interlayer and transverse forces of the Nb-doped WS2 flake approach 1 nN and 150 pN, respectively. As the doping concentration increases, the valence band maximum energy of Nb-doped WS2 ranges from 4.06 eV to 4.3 eV. Furthermore, the performance of the photodetector is discussed.

Abstract Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin–proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.

Vitamin D deficiency has emerged as a significant concern in public health due to its potential association with various metabolic disorders. This study aimed to investigate the relationship between serum vitamin D levels and the susceptibility to hyperlipidemia among adults. Using a multi-stage sampling approach, we recruited a cohort of 2072 eligible individuals aged over 18 years. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured alongside glucolipid metabolic markers, and comprehensive demographic and physical data were collected. The cohort exhibited a hyperlipidemia prevalence of 42.18%, with 19.88% demonstrating vitamin D deficiency. Notably, 23.68% of individuals with vitamin D deficiency also presented hyperlipidemia. Statistical analysis revealed a significantly higher prevalence of hyperlipidemia among those with vitamin D deficiency compared to those with sufficient levels (23.68% vs. 17.11%, P < 0.05). After adjusting for various factors including age, geographical region, exercise status, BMI, fasting glucose level, and blood pressure, lower serum 25(OH)D concentrations were found to significantly increase the risk of hyperlipidemia (Odds Ratio [OR] = 1.41; 95% CI: 1.057, 1.885; P < 0.05). Further stratification of the hyperlipidemic cohort revealed that vitamin D deficiency was associated with 1.459- and 1.578-times higher risks for total cholesterol and triglyceride abnormalities, respectively, compared to those with sufficient vitamin D levels. Moreover, each 10 ng/mL decrease in serum vitamin D level corresponded to an increased risk of total cholesterol (OR = 0.82; 95% CI: 0.728, 0.974; P < 0.05) and triglyceride abnormalities (OR = 0.79; 95% CI: 0.678, 0.927; P < 0.05). However, there were no significant differences observed between vitamin D-sufficient and−deficient groups regarding Low-Density Lipoprotein (LDL) and High-Density Lipoprotein (HDL) abnormalities. These findings underscore the potential role of serum vitamin D deficiency as an independent risk factor contributing to the elevated prevalence of hyperlipidemia in the adult population.

Summary: Alzheimer’s disease (AD) is a complex pathophysiological disease. Allowing for heterogeneity, not only in disease manifestations but also in different progression patterns, is critical for developing effective disease models that can be used in clinical and research settings. We introduce a machine learning model for identifying underlying patterns in Alzheimer’s disease (AD) trajectory using longitudinal multi-modal data from the ADNI cohort and the AIBL cohort. Ten biologically and clinically meaningful disease-related states were identified from data, which constitute three non-overlapping stages (i.e., neocortical atrophy [NCA], medial temporal atrophy [MTA], and whole brain atrophy [WBA]) and two distinct disease progression patterns (i.e., NCA → WBA and MTA → WBA). The index of disease-related states provided a remarkable performance in predicting the time to conversion to AD dementia (C-Index: 0.923 ± 0.007). Our model shows potential for promoting the understanding of heterogeneous disease progression and early predicting the conversion time to AD dementia.

Abstract Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

On carrierless phase retrieval (PR) receivers based on direct detection, bandwidth limitation of electrical-to-optical (E/O) conversion at the transmitter side (Tx) distorts the modulated optical signal. In this paper, we propose the Gercheberg-Saxton (GS)-aided and the data-aided estimation method in order to know the complex-valued of E/O channel response in the absence of phase information. Furthermore, we compare four channel estimation schemes based on the mean square error (MSE) between the estimated and preset channel response in numerical simulation, which are generated by combining least mean square (LMS) or least square (LS) with the proposed GS-aided or data-aided methods. In order to compensate the distortion from E/O frequency response, two compensation schemes including pre-equalization processing at the Tx and post-equalization processing at the Rx are implemented and compared by simulations and experiments. In the experiment, we transmit a single-polarization 30GBaud QPSK signal including a training sequence of 2048 symbols to estimate the E/O conversion frequency response over 55-km single-mode fiber (SMF). The received signal is detected by a PR receiver employing different estimation (LMS/LS) and equalization (pre-/post-) schemes to compare their performance. The experimental results demonstrate that all estimation schemes successfully estimate the frequency response in the absence of phase information, and PR employing pre-equalization with GS-aided-LMS estimation exhibits good robustness, resulting in a received optical power improvement of 0.69 dB to achieve 20% forward-error correction (FEC) threshold.

Vehicle logo detection plays a crucial role in various computer vision applications, such as vehicle classification and detection. In this research, we propose an improved vehicle logo detection method leveraging the self-attention mechanism. Our feature-sampling structure integrates multiple attention mechanisms and bidirectional feature aggregation to enhance the discriminative power of the detection model. Specifically, we introduce the multi-head attention for multi-scale feature fusion module to capture multi-scale contextual information effectively. Moreover, we incorporate the bidirectional aggregation mechanism to facilitate information exchange between different layers of the detection network. Experimental results on a benchmark dataset (VLD-45 dataset) demonstrate that our proposed method outperforms baseline models in terms of both detection accuracy and efficiency. Our experimental evaluation using the VLD-45 dataset achieves a state-of-the-art result of 90.3% mAP. Our method has also improved AP by 10% for difficult samples, such as HAVAL and LAND ROVER. Our method provides a new detection framework for small-size objects, with potential applications in various fields.

Background: Chronic cough (CC) affects about 10% of adults, but opioid use in CC is not well understood. Objectives: To determine the use of opioid-containing cough suppressant (OCCS) prescriptions in patients with CC using electronic health records. Design: Retrospective cohort study. Methods: Through retrospective analysis of Midwestern U.S. electronic health records, diagnoses, prescriptions, and natural language processing identified CC – at least three medical encounters with cough, with 56–120 days between first and last encounter – and a ‘non-chronic cohort’. Student’s t -test, Pearson’s chi-square, and zero-inflated Poisson models were used. Results: About 20% of 23,210 patients with CC were prescribed OCCS; odds of an OCCS prescription were twice as great in CC. In CC, OCCS drugs were ordered in 38% with Medicaid insurance and 15% with commercial insurance. Conclusion: Findings identify an important role for opioids in CC, and opportunity to learn more about the drugs’ effectiveness.

Abstract As both L- and D-BAIBA are increased with exercise, we sought to determine if circulating levels would be associated with physical performance. Serum levels of L- and D-BAIBA were quantified in 120 individuals (50% female) aged 20–85 years and categorized as either a “low” (LP), “average” (AP) or “high” performing (HP). Association analysis was performed using Spearman (S) and Pearson (P) correlation. Using Spearman correlation, L-BAIBA positively associated with (1) body mass index BMI (0.23) and total fat mass (0.19) in the 120 participants, (2) total fat mass in the 60 males (0.26), and (3) bone mineral density, BMD, (0.28) in addition to BMI (0.26) in the 60 females. In HP females, L-BAIBA positively associated with BMD (0.50) and lean mass (0.47). D-BAIBA was positively associated with (1) age (P 0.20) in the 120 participants, (2) age (P 0.49) in the LP females and (3) with gait speed (S 0.20) in the 120 participants. However, in HP males, this enantiomer had a negative association with appendicular lean/height (S − 0.52) and in the AP males a negative correlation with BMD (S − 0.47). No associations were observed in HP or AP females, whereas, in LP females, a positive association was observed with grip strength (S 0.45), but a negative with BMD (P − 0.52, S − 0.63) and chair stands (P − 0.47, S − 0.51). L-BAIBA may play a role in BMI and BMD in females, not males, whereas D-BAIBA may be a marker for aging and physical performance. The association of L-BAIBA with BMI and fat mass may reveal novel, not previously described functions for this enantiomer.

Abstract Declining physical performance with age and disease is an important indicator of declining health. Biomarkers that identify declining physical performance would be useful in predicting treatment outcomes and identifying potential therapeutics. γ-aminobutyric acid (GABA), a muscle autocrine factor, is a potent inhibitor of muscle function and works as a muscle relaxant. L-α-aminobutyric acid (L-AABA) is a biomarker for malnutrition, liver damage, and depression. We sought to determine if GABA and L-AABA may be useful for predicting physical performance. Serum levels of GABA and L-AABA were quantified in 120 individuals divided by age, sex, and physical capacity into low, average, and high performer groups. Analyses explored correlations between serum levels and physical performance. Both GABA and the ratio of GABA/AABA (G/A), but not AABA, were highly positively associated with age (Pearson correlations r = 0.35, p = 0.0001 for GABA, r = 0.31, p = 0.0007 for G/A, n = 120). GABA showed negative associations in the whole cohort with physical performance [fast gait speed, 6 min walk test (6MWT), PROMIS score, and SF36PFS raw score] and with subtotal and femoral neck bone mineral density. L-AABA was positively associated with usual gait speed, 6MWT, total SPPB score, and SF36PFS raw score in the total cohort of 120 human subjects, also with 6MWT and SF36PFS raw score in the 60 male subjects, but no associations were observed in the 60 females. As both GABA and L-AABA appear to be indicative of physical performance, but in opposite directions, we examined the G/A ratio. Unlike GABA, the G/A ratio showed a more distinct association with mobility tests such as total SPPB score, usual and fast gait speed, 6MWT, and SF36PFS raw score in the males, regardless of age and metabolic status. Serum G/A ratio could be potentially linked to physical performance in the male population. Our findings strongly suggest that GABA, L-AABA, and the G/A ratio in human serum may be useful markers for both age and physical function. These new biomarkers may significantly enhance the goal of identifying universal biomarkers to accurately predict physical performance and the beneficial effects of exercise training for older adults.

Graph de-anonymization is a technique used to reveal connections between entities in anonymized graphs, which is crucial in detecting malicious activities, network analysis, social network analysis, and more. Despite its paramount importance, conventional methods often grapple with inefficiencies and challenges tied to obtaining accurate query graph data. This paper introduces a neural-based inexact graph de-anonymization, which comprises an embedding phase, a comparison phase, and a matching procedure. The embedding phase uses a graph convolutional network to generate embedding vectors for both the query and anonymized graphs. The comparison phase uses a neural tensor network to ascertain node resemblances. The matching procedure employs a refined greedy algorithm to discern optimal node pairings. Additionally, we comprehensively evaluate its performance via well-conducted experiments on various real datasets. The results demonstrate the effectiveness of our proposed approach in enhancing the efficiency and performance of graph de-anonymization through the use of graph embedding vectors.

Cross-sectional size of a long bone shaft influences its mechanical properties. We recently used high-resolution peripheral quantitative computed tomography (HRpQCT) to create reference data for size measures of the radial and tibial diaphyses. However, data did not take into account the impact of bone length. Human bone exhibits relatively isometric allometry whereby cross-sectional area increases proportionally with bone length. The consequence is that taller than average individuals will generally have larger z-scores for bone size outcomes when length is not considered. The goal of the current work was to develop a means of determining whether an individual's cross-sectional bone size is suitable for their bone length. HRpQCT scans performed at 30 % of bone length proximal from the distal end of the radius and tibia were acquired from 1034 White females (age = 18.0 to 85.3 y) and 392 White males (age = 18.4 to 83.6 y). Positive relationships were confirmed between bone length and cross-sectional areas and estimated mechanical properties. Scaling factors were calculated and used to scale HRpQCT outcomes to bone length. Centile curves were generated for both raw and bone length scaled HRpQCT data using the LMS approach. Excel-based calculators are provided to facilitate calculation of z-scores for both raw and bone length scaled HRpQCT outcomes. The raw z-scores indicate the magnitude that an individual's HRpQCT outcomes differ relative to expected sex- and age-specific values, with the scaled z-scores also considering bone length. The latter enables it to be determined whether an individual or population of interest has normal sized bones for their length, which may have implications for injury risk. In addition to providing a means of expressing HRpQCT bone size outcomes relative to bone length, the current study also provides centile curves for outcomes previously without reference data, including tissue mineral density and moments of inertia.

While a hippocampal–cortical dialogue is generally thought to mediate memory consolidation, which is crucial for engram function, how it works remains largely unknown. Here, we examined the interplay of neural signals from the retrosplenial cortex (RSC), a neocortical region, and from the hippocampus in memory consolidation by simultaneously recording sharp-wave ripples (SWRs) of dorsal hippocampal CA1 and neural signals of RSC in free-moving mice during the delayed spatial alternation task (DSAT) and subsequent sleep. Hippocampal–RSC coordination during SWRs was identified in nonrapid eye movement (NREM) sleep, reflecting neural reactivation of decision-making in the task, as shown by a peak reactivation strength within SWRs. Using modified generalized linear models (GLMs), we traced information flow through the RSC–CA1–RSC circuit around SWRs during sleep following DSAT. Our findings show that after spatial training, RSC excitatory neurons typically increase CA1 activity prior to hippocampal SWRs, potentially initiating hippocampal memory replay, while inhibitory neurons are activated by hippocampal outputs in post-SWRs. We further identified certain excitatory neurons in the RSC that encoded spatial information related to the DSAT. These neurons, classified as splitters and location-related cells, showed varied responses to hippocampal SWRs. Overall, our study highlights the complex dynamics between the RSC and hippocampal CA1 region during SWRs in NREM sleep, underscoring their critical interplay in spatial memory consolidation.

Mesenchymal stem cells (MSCs) have shown great potential in the treatment of several inflammatory diseases due to their immunomodulatory ability, which is mediated by exosomes secreted by MSCs (MSC-Exs). The incidence of inflammatory bowel disease (IBD) is increasing globally, but there is currently no long-term effective treatment. As an emerging therapy, MSC-Exs have proven to be effective in alleviating IBD experimentally, and the specific mechanism continues to be explored. The gut microbiota plays an important role in the occurrence and development of IBD, and MSCs and MSC-Exs can effectively regulate gut microbiota in animal models of IBD, but the mechanism involved and whether the outcome can relieve the characteristic dysbiosis necessary to alleviate IBD still needs to be studied. This review provides current evidence on the effective modulation of the gut microbiota by MSC-Exs, offering a basis for further research on the pathogenic mechanism of IBD and MSC-Ex treatments through the improvement of gut microbiota.

Summary: Background: Alzheimer's disease (AD) is a heterogeneously progressive neurodegeneration disorder with varied rates of deterioration, either between subjects or within different stages of a certain subject. Estimating the course of AD at early stages has treatment implications. We aimed to analyze disease progression to identify distinct patterns in AD trajectory. Methods: We proposed a deep learning model to identify underlying patterns in the trajectory from cognitively normal (CN) to a state of mild cognitive impairment (MCI) to AD dementia, by jointly predicting time-to-conversion and clustering out distinct subgroups characterized by comprehensive features as well as varied progression rates. We designed and validated our model on the ADNI dataset (1370 participants). Prediction of time-to-conversion in AD trajectory was used to validate the expression of the identified patterns. Causality between patterns and time-to-conversion was further inferred using Mendelian randomization (MR) analysis. External validation was performed on the AIBL dataset (233 participants). Findings: The proposed model clustered out patterns characterized by significantly different biomarkers and varied progression rates. The discovered patterns also showed a strong prediction ability, as indicated by hazard ratio (CN→MCI, HR = 3.51, p

Purpose: Aluminum is an environmental toxicant whose long-term exposure is closely associated with nervous system impairment. This study mainly investigated neurological impairment induced by subchronic aluminum exposure via activating NLRP3-medicated pyroptosis pathway. Methods: In vivo, Kunming mice were exposed to AlCl3 (30.3 mg/kg, 101 mg/kg and 303 mg/kg) via drinking water for 3 months, and administered with Rsv (100 mg/kg) by gavage for 1 month. Cognitive impairment was assessed by Morris water maze test, and pathological injury was detected via H&E staining. BBB integrity, pyroptosis and neuroinflammation were evaluated through western blotting and immunofluorescence methods. In vitro, BV2 microglia was treated with AlCl3 (0.5 mM, 1 mM and 2 mM) to sensitize pyroptosis pathway. The protein interaction was verified by co-immunoprecipitation, and neuronal damage was estimated via a conditioned medium co-culture system with BV2 and TH22 cells. Results: Our results showed that AlCl3 induced mice memory disorder, BBB destruction, and pathological injury. Besides, aluminum caused glial activation, sensitized DDX3X-NLRP3 pyroptosis pathway, released cytokines IL-1β and IL-18, initiating neuroinflammation. BV2 microglia treated with AlCl3 emerged hyperactivation and pyroptotic death, and Ddx3x knockdown inhibited pyroptosis signaling pathway. DDX3X acted as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome and G3BP1 stress granules. Furthermore, aluminum-activated microglia had an adverse effect on co-cultured neurons and destroyed nervous system homeostasis. Conclusion: Aluminum exposure could induce pyroptosis and neurotoxicity. DDX3X determined live or die via selectively regulating pro-survival stress granules or pro-death NLRP3 inflammasome. Excessive activation of microglia might damage neurons and aggravate nerve injury.

Gannan navel orange is a famous brand in China but the isolation of its endophytic fungi was rarely reported. In this study, a total of 54 strains of endophytic fungi were successfully isolated from the pulp, peel, twig, and leaf of Gannan navel orange; they were successfully identified to belong to 17 species of 12 genera. All these strains were fermented using potato-dextrose agar (PDA) medium, and their secondary metabolites were then extracted with ethyl acetate (EtOAc). The antibacterial assays of Escherichia coli (E. coli), methicillin-resistant Staphylococcus aureus (MRSA), and Xanthomonas citri subsp. citri (Xcc) were also performed for the EtOAc extracts of these strains. As a result, the extracts of both Geotrichum sp. (gc-1-127-30) and Diaporthe biconispora (gc-1-128-79) demonstrated significant antibacterial activities against Xcc, and the MIC value for the extract of Colletotrichum gloeosporioides against MRSA was low to 62.5 μg/mL. Moreover, the chemical components of the extracts of Colletotrichum sp., Diaporthe biconispora, and Annulohypoxylon atroroseum were primarily investigated, and they successfully led to the isolation of 24 compounds involving a new botryane sesquiterpene. Among the isolated products, compound 2 showed significant inhibitory activities toward SA, MRSA, E. coli, and Xcc with MIC values of 12.5, 3.1, 125, and 12.5 μg/mL, respectively. This study revealed that the endophytic fungi of Gannan navel orange showed high potency to produce secondary metabolites with significant antibacterial effects.

West Pearl River Delta (WPRD) is sinking as a result of the jointed effect of natural and anthropogenic factors. Land subsidence has increasingly become a concern because of tremendous population growth and rapid urbanization over this region in the last few decades. In this study, sixty-seven Sentinel-1 images, acquired between 2016 and 2021, were analyzed with the persistent scatterer interferometry technique (PSI), to monitor and reveal the ground subsidence characteristics in the WPRD. It is found that the overall vertical deformation velocities observed in the WPRD ranged between −70 mm/year and 10 mm/year. Three subsidence bowls were found in the study area (Gaolan island of Zhuhai, the junction area of Zhuhai and Zhongshan, and the junction area of Zhongshan and Jiangmen). The spatial–temporal subsidence characteristics have been analyzed. It is discovered that the ground subsidence is mostly dispersed in Quaternary deposits and is highly relevant to the thickness of sediments, indicating that soft soil consolidation is one of the primary causes contributing to land subsidence. Furthermore, land use maps for 2016 and 2021 were generated using Landsat-8 images for the investigation on the relationship between land subsidence and land use. The results obtained from analysis demonstrated that the rapid subsiding areas mainly occurred in the land-use classes as follows: aquaculture, urban land, and agricultural land. The land use conversion pattern with more significant anthropogenic influence usually causes a higher subsidence rate. In addition, based on soft soil thickness, groundwater exploitation, land use, elevation, and strata lithology, a Random Forest Regression (RFR) model was used to predict subsidence rates (R2 = 0.631, RMSE = 2.7 mm/year). The importance of these influencing factors of land subsidence was calculated based on the RFR algorithm. The results indicated that soft soil thickness, elevation, groundwater exploitation, strata lithology, and landcover type are the most significant factors affecting subsidence. The applicability of geological data and land-use history for land subsidence prediction has been demonstrated with the use of the RFR algorithm.

Premature ovarian failure (POF), or premature ovarian insufficiency (POI), is a multifactorial and heterogeneous disease characterized by amenorrhea, decreased estrogen levels and increased female gonadotropin levels. The incidence of POF is increasing annually, and POF has become one of the main causes of infertility in women of childbearing age. The etiology and pathogenesis of POF are complex and have not yet been clearly elucidated. In addition to genetic factors, an increasing number of studies have revealed that epigenetic changes play an important role in the occurrence and development of POF. However, we found that very few papers have summarized epigenetic variations in POF, and a systematic analysis of this topic is therefore necessary. In this article, by reviewing and analyzing the most relevant literature in this research field, we expound on the relationship between DNA methylation, histone modification and non-coding RNA expression and the development of POF. We also analyzed how environmental factors affect POF through epigenetic modulation. Additionally, we discuss potential epigenetic biomarkers and epigenetic treatment targets for POF. We anticipate that our paper may provide new therapeutic clues for improving ovarian function and maintaining fertility in POF patients.

Introduction: Aluminum is everywhere in nature and is a recognized neurotoxicant closely associated with various neurodegenerative diseases. Neuroinflammation occurs in the early stage of neurodegenerative diseases, but the underlying mechanism by which aluminum induces neuroinflammation remains unclear. Material and methods: A 3-month subchronic aluminum exposure mouse model was established by drinking water containing aluminum chloride (AlCl3). Microglia BV2 cells and hippocampal neuron HT22 cells were treated with AlCl3 in vitro. BBG and YC-1 were used as intervention agents. Results: Aluminum could activate microglia and increase the level of extracellular ATP, stimulate P2X7 receptor, HIF-1α, activate NLRP3 inflammasome and CASP-1, release more cytokine IL-1β, and induce an inflammatory response in nerve cells. There was a mutual regulatory relationship between P2X7 and HIF-1α at mRNA and protein levels. The co-culture system of BV2-HT22 cells observed that conditioned medium from microglia treated with aluminum could aggravate neuronal morphological damage, inflammatory response and death. While BBG and YC-1 intervention could rescue these injuries to some extent. Conclusion: The P2X7‐NLRP3 pathway was involved in aluminum-induced neuroinflammation and injury. P2X7 and HIF-1α might mutually regulate and promote the progression of neuroinflammation, both BBG and YC-1 could relieve it.

Bony union is a primary predictor of outcome after surgical fixation of long bone fractures. Murine models offer many advantages in assessing bony healing due to their low costs and small size. However, current fracture recovery investigations in mice frequently rely on animal sacrifice and costly analyses. The modified Radiographic Union Score for Tibia fractures (mRUST) scoring system is a validated metric for evaluating bony healing in humans utilizing plain radiographs, which are relatively inexpensive and do not require animal sacrifice. However, its use has not been well established in murine models. The aim of this study was to characterize the longitudinal course of mRUST and compare mRUST to other conventional murine fracture analyses. 158 mice underwent surgically created midshaft femur fractures. Mice were evaluated after fracture creation and at 7, 10, 14, 17, 21, 24, 28, 35, and 42 days post-injury. mRUST scoring of plain radiographs was performed by three orthopaedic surgeons in a randomized, blinded fashion. Interrater correlations were calculated. Micro-computed tomography (μCT) was analyzed for tissue mineral density (TMD), total callus volume (TV), bone volume (BV), trabecular thickness, trabecular number, and trabecular separation. Histomorphometry measures of total callus area, cartilage area, fibrous tissue area, and bone area were performed in a blinded fashion. Ultimate torque, stiffness, toughness, and twist to failure were calculated from torque-twist curves. A sigmoidal log-logistic curve fit was generated for mRUST scores over time which shows mRUST scores of 4 to 6 at 7 days post-injury that improve to plateaus of 14 to 16 by 24 days post-injury. mRUST interrater correlations at each timepoint ranged from 0.51 to 0.86, indicating substantial agreement. mRUST scores correlated well with biomechanical, histomorphometry, and μCT parameters, such as ultimate torque (r=0.46, p

Both oil spill and microplastics (MPs) are major issues in marine environments. After a spill, the oil film may disperse into the water column as droplets under the function of sea waves. The oil dispersion may be affected due to the attachment of oil to MPs. In this paper, the impacts of salinity and temperature on the dispersion of spilled oil in the presence of MPs were individually studied by batch conical flask oscillation experiments. The results indicated that the rise in salinity or temperature displayed a more significant effect on promoting, rather than inhibiting, oil dispersion with MPs. When the salinity rose from 15% to 35%, the oil dispersion efficiency (ODE) with the 13 μm polyethylene (PE) and polystyrene (PS) MPs was increased by 10.4% and 12.9%, respectively; when the temperature rose from 10 °C to 25 °C, the corresponding ODE was increased by 15.6% and 12.7%, respectively. In addition, the volumetric mean diameter (VMD) of the dispersed oil droplets decreased with an increase in salinity or temperature. Furthermore, the 13 μm MPs showed a higher impact on the oil dispersion than 106 μm of MPs, and the ODE with PE MPs was greater than that with PS MPs. The findings of this study expanded the understanding of the migration of spilled oil in seawater in the presence of MPs and may further improve the capability of predicting the impact of oil spills by marine environment managers.

Abstract Background Sarcopenia, cachexia and frailty have overlapping features and clinical consequences, but often go unrecognized. The objective was to detect patients described by clinicians as having sarcopenia, cachexia or frailty within electronic health records (EHR) and compare clinical variables between cases and matched controls. Methods We conducted a case-control study using retrospective data from the Indiana Network for Patient Care multi-health system database from 2016 to 2017. The computable phenotype combined ICD codes for sarcopenia, cachexia and frailty, with clinical note text terms for sarcopenia, cachexia and frailty detected using natural language processing. Cases with these codes or text terms were matched to controls without these codes or text terms matched on birth year, sex and race. Two physicians reviewed EHR for all cases and a subset of controls. Comorbidity codes, laboratory values, and other coded clinical variables were compared between groups using Wilcoxon matched-pair sign-rank test for continuous variables and conditional logistic regression for binary variables. Results Cohorts of 9594 cases and 9594 matched controls were generated. Cases were 59% female, 69% white, and a median (1st, 3rd quartiles) age 74.9 (62.2, 84.8) years. Most cases were detected by text terms without ICD codes n = 8285 (86.4%). All cases detected by ICD codes (total n = 1309) also had supportive text terms. Overall 1496 (15.6%) had concurrent terms or codes for two or more of the three conditions (sarcopenia, cachexia or frailty). Of text term occurrence, 97% were used positively for sarcopenia, 90% for cachexia, and 95% for frailty. The remaining occurrences were negative uses of the terms or applied to someone other than the patient. Cases had lower body mass index, albumin and prealbumin, and significantly higher odds ratios for diabetes, hypertension, cardiovascular and peripheral vascular diseases, chronic kidney disease, liver disease, malignancy, osteoporosis and fractures (all p

In view of the operational risk issues such as safety and economy caused by the connection of new energy and multiple types of electric vehicles (EVs) to the AC–DC distribution network, an AC–DC distribution network operational risk assessment method that takes into account multiple risk factors is proposed. First, a probability distribution model of scenery output and EV timing is constructed, and the starting charge state of multiple types of EVs is replaced by the number of daily driving miles subjectively set; then, based on the complex network theory, timing safety indicators, such as voltage overrun risk and branch power overload operation risk, are proposed, and the economic risk is established according to the economic operation of the distribution grid; Furthermore, a risk assessment matrix for grid-connected EVs with different capacities is constructed, and the principal component analysis (PCA) method is used to reduce the dimension of the risk assessment matrix and calculate the objective weight coefficient; finally, taking the improved IEEE 33 node AC/DC power distribution system as an example, the comprehensive risk evaluation based on PCA is compared with the traditional one, and the results show that when the safety and economic risk factors are considered at the same time, the operation risk in a certain range has a downward trend when the proposed method is adopted, which has a positive guiding significance for the planning of EV capacity in a certain area.

Background Previous narrative reviews have concluded that dietary nitrate (NO3 −) improves maximal neuromuscular power in humans. This conclusion, however, was based on a limited number of studies, and no attempt has been made to quantify the exact magnitude of this beneficial effect. Such information would help ensure adequate statistical power in future studies and could help place the effects of dietary NO3 − on various aspects of exercise performance (i.e., endurance vs. strength vs. power) in better context. We therefore undertook a systematic review and individual participant data meta-analysis to quantify the effects of NO3 − supplementation on human muscle power. Methods The literature was searched using a strategy developed by a health sciences librarian. Data sources included Medline Ovid, Embase, SPORTDiscus, Scopus, Clinicaltrials.gov, and Google Scholar. Studies were included if they used a randomized, double-blind, placebo-controlled, crossover experimental design to measure the effects of dietary NO3 − on maximal power during exercise in the non-fatigued state and the within-subject correlation could be determined from data in the published manuscript or obtained from the authors. Results Nineteen studies of a total of 268 participants (218 men, 50 women) met the criteria for inclusion. The overall effect size (ES; Hedge’s g) calculated using a fixed effects model was 0.42 (95% confidence interval (CI) 0.29, 0.56; p = 6.310 × 10− 11). There was limited heterogeneity between studies (i.e., I2 = 22.79%, H2 = 1.30, p = 0.3460). The ES estimated using a random effects model was therefore similar (i.e., 0.45, 95% CI 0.30, 0.61; p = 1.064 × 10− 9). Sub-group analyses revealed no significant differences due to subject age, sex, or test modality (i.e., small vs. large muscle mass exercise). However, the ES in studies using an acute dose (i.e., 0.54, 95% CI 0.37, 0.71; p = 6.774 × 10− 12) was greater (p = 0.0211) than in studies using a multiple dose regimen (i.e., 0.22, 95% CI 0.01, 0.43; p = 0.003630). Conclusions Acute or chronic dietary NO3 − intake significantly increases maximal muscle power in humans. The magnitude of this effect–on average, ~ 5%–is likely to be of considerable practical and clinical importance.

Flood susceptibility modeling helps understand the relationship between influencing factors and occurrence of urban flooding and further provides spatial distribution of flood risk, which is critical for flood-risk reduction. Machine learning methods have been widely applied in flood susceptibility modeling, but traditional supervised learning requires both positive (flood) and negative (non-flood) samples in model training. Historical flood inventory data usually contain positive-only data, whereas negative data selected from areas without flood records are prone to be contaminated by positive data, which is referred to as case-control sampling with contaminated controls. In order to address this problem, we propose to apply a novel positive-unlabeled learning algorithm, namely positive and background learning with constraints (PBLC), in flood susceptibility modeling. PBLC trains a binary classifier from case-control positive and unlabeled samples without requiring truly labeled negative data. With historical records of flood locations and environmental covariates, including elevation, slope, aspect, plan curvature, profile curvature, slope length factor, stream power index, topographic position index, topographic wetness index, distance to rivers, distance to roads, land use, normalized difference vegetation index, and precipitation, we compared the performances of the traditional artificial neural network (ANN) and the novel PBLC in flood susceptibility modeling in the city of Guangzhou, China. Experimental results show that PBLC can produce more calibrated probabilistic prediction, more accurate binary prediction, and more reliable susceptibility mapping of urban flooding than traditional ANN, indicating that PBLC is effective in addressing the problem of case-control sampling with contaminated controls and it can be successfully applied in urban flood susceptibility mapping.

Robustness, deformability, maneuverability, and ease of fabrication are among the most desirable features of soft robots that can adapt to various working environments and complex terrains. Herein, polymeric thin‐film‐based flexible robots are designed, prototyped, and examined that use mechanical instability and electrostatic force actuation for locomotion. An electrostatic actuator is first developed using a buckled beam that can deform by up to 68% of its height under an applied voltage. A centimeter‐scale robotic bug is then designed that shows superb flexibility, adaptability, and maneuverability by incorporating origami structural elements. For instance, the robotic bug can be completely smashed and still recover its mobility, walk on various terrains, slopes (up to 30°) and narrow spaces, overcome hurdles, make turns, and even move backward with a crawling (linear) and turning (rotation) speed up to 40 mm s−1 and ≈45° s−1, respectively. Such remarkable characteristics are controlled by a set of parameters such as the amplitude and frequency of the input voltage and/or the origami geometries. The facile and tunable design and the actuation principle can potentially enable ample opportunities for the development of the next‐generation soft robotics.

HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts

HIV-infected patients have an increased risk of cardiovascular disease (CVD). Impaired endothelial function is an early risk factor for CVD in the general population. It is presumed that HIV infection is associated with impaired endothelial function, but results have been inconsistent.Our objectives were to determine the relationships between HIV infection, virologic suppression with antiretroviral therapy (ART), in vivo measures of conduit artery and microvascular endothelial function, and circulating biomarkers of pathways associated with CVD.We performed a cross-sectional analysis of three prospectively enrolled groups from a single center: 28 were HIV-infected and virologically-suppressed on a regimen of FTC/TDF/EFV (HIV+ART+), 44 were HIV-infected but not on ART (HIV+ART-), and 39 were HIV-uninfected healthy volunteers (HIV-) matched to the HIV+ART- group for age, sex, smoking status, and height. None had diabetes, uncontrolled hypertension, known CVD, or other pro-inflammatory condition. Flow mediated dilation (FMD), nitroglycerin-mediated dilation (NTGMD), reactive hyperemia velocity time integral (RHVTI), and FMD/RHVTI of the brachial artery were measured, as well as circulating biomarkers of systemic inflammation, metabolism, oxidative stress, and endothelial activation.No significant differences were found amongst the three groups in FMD (P = 0.46), NTGMD (P = 0.42), RHVTI (P = 0.17), and FMD/RHVTI (P = 0.22) in unadjusted comparisons. Adjusted ANOVA models which included brachial artery diameter, demographics, and conventional CVD risk factors did not appreciably change these findings. In pairwise comparisons, the HIV+ART- group had significantly higher soluble tumor necrosis factor receptor II, soluble CD163, β-2 microglobulin, interferon-γ- induced protein-10, tissue inhibitor of metalloproteinase-1, and vascular cell adhesion molecule-1 compared to the other two groups (all p

With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef.GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.

Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [-1.06 (1.45)%] and PTX [-1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [-83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.ClinicalTrials.gov NCT00796822.

Only in recent years have phospholipase A2 enzymes (PLA2s) emerged as cancer targets. In this work, we report the first detection of elevated PLA2 activities in plasma from patients with colorectal, lung, pancreatic, and bladder cancers as compared to healthy controls. Independent sets of clinical plasma samples were obtained from two different sites. The first set was from patients with colorectal cancer (CRC; n = 38) and healthy controls (n = 77). The second set was from patients with lung (n = 95), bladder (n = 31), or pancreatic cancers (n = 38), and healthy controls (n = 79). PLA2 activities were analyzed by a validated quantitative fluorescent assay method and subtype PLA2 activities were defined in the presence of selective inhibitors. The natural PLA2 activity, as well as each subtype of PLA2 activity was elevated in each cancer group as compared to healthy controls. PLA2 activities were increased in late stage vs. early stage cases in CRC. PLA2 activities were not influenced by sex, smoking, alcohol consumption, or body-mass index (BMI). Samples from the two independent sites confirmed the results. Plasma PLA2 activities had approximately 70% specificity and sensitivity to detect cancer. The marker and targeting values of PLA2 activity have been suggested.