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Bulk quantum Hall effect (QHE), the natural extension of the two-dimensional (2D) QHE, is one of the representative phenomena of coherent electron transport. However, bulk QHE has rarely been reported in real materials with macroscopic sizes. Here, we report a novel bulk QHE in macroscopic millimeter-sized and nanostructured TaP crystals consisting of nanometer-scale lamellae. Specifically, the simultaneous quantum plateaus were observed in both transverse resistivity ρ xy and vertical resistivity ρ zz . The bulk QHE is attributable to synergetic action between Landau cyclotron movement under magnetic field B and periodically modulated potential due to the nanometer-scaled lamellae. This mechanism would form the fixed number of edge states along B -perpendicular and B -parallel directions respectively, equivalent to stacked 2D-QHE layers, leading to quantized ρ xy and ρ zz . Our work verifies that microstructure engineering could result in the coherent transport of electrons and generate new quantum phenomena in bulk materials.

Background: FGFR2 fusion has become a promising therapeutic target in iCCAs; however, the procedure for screening FGFR2 fusion has not been conventionally developed., Methods: FGFR2 fusion was identified using DNA + RNA-based NGS and FISH, and the concordance between DNA + RNA-based NGS, FISH, and IHC was compared., Results: FGFR2 fusions were detected in 9 out of 76 iCCAs (11.8%). The consistency of FISH and DNA + RNA-based NGS for FGFR2 fusions was high (κ value = 0.867, P = 0.001), while the consistency of IHC and DNA + RNA-based NGS was lower (κ value = 0.464, P = 0.072). All nine FGFR2 fusion-positive iCCAs were MSS with a median TMB of 2.1 mut/Mb, and only one had a CPS (PD-L1) above 5. Two FGFR2 fusion-positive iCCA patients were treated with and benefited from FGFR inhibitor therapy., Conclusions: FGFR2 fusion should be assessed for advanced iCCA patients. We recommend DNA + RNA-based NGS as the preferred option to supply all possible therapeutic targets. FISH should be preferred if the tumor sample is insufficient for NGS or if the patient is inclined to receive FGFR inhibitors promptly. Although IHC is not the preferred method to identify FGFR2 fusion, it might be used as preliminary screening for FGFR2 alterations if the hospital cannot offer NGS or FISH, and the results need to be validated before FGFR2 inhibitors treatment., Competing Interests: Declarations Conflict of interest The authors declare that they have no conflict of interest. Ethical approval This study was approved by the Institutional Review Board of TMUCIH (bc20240020) in compliance with the Helsinki Declaration. Written informed consent was obtained from individual or guardian participants., (© 2024. Japanese Society of Gastroenterology.)

Background: Manipulation under anesthesia (MUA) has been recommended for refractory arthrofibrosis after anterior cruciate ligament (ACL) reconstruction. However, the effectiveness of MUA to restore normal kinematics of the arthrofibrotic knee is still unclear. The objective of this study was to evaluate tibiofemoral and patellofemoral kinematics in six degrees-of-freedom (6DOF) in patients with arthrofibrosis before and after MUA., Methods: Computed tomography and dual fluoroscopic imaging system were used to assess in vivo knee kinematics. Ten patients (6 women and 4 men; 32.6 ± 6.5y, 168.4 ± 7.8 cm, 61.8 ± 13.2 kg) were included in this study. The tibiofemoral and patellofemoral kinematics in 6DOF were collected before and one year after MUA. A simple analysis of variance was used to evaluate kinematic data of preoperative arthrofibrotic knee, postoperative arthrofibrotic knee, and the contralateral knee., Results: The patella in the postoperative arthrofibrotic knee shifted significantly more inferiorly compared to the preoperative knee at 45° (P = 0.010), 60° (P = 0.008), and 75° (P = 0.049) of flexion. The patellar flexion in the postoperative arthrofibrotic knee significantly increased at 45° (P = 0.048), 60° (P = 0.037), and 75° (P = 0.006) of flexion compared to the preoperative arthrofibrotic knee. The patellar tilt was significantly decreased at 60° (P = 0.006) and at 75° (P = 0.037) of knee flexion in the postoperative arthrofibrotic knee compared to the contralateral knee. MUA significantly increased tibial internal rotation angle in the arthrofibrotic knee at 45° (P = 0.047), at 60° (P = 0.033), and at 75° (P = 0.021) of knee flexion., Conclusions: MUA could restore normal patellar inferior shift, flexion, and tibial rotation compared to the contralateral side. However, the MUA could not restore normal patellar tilt of the arthrofibrotic knee. This indicated that improvement of patellar tilt should be emphasized in postoperative rehabilitation., (© 2024. The Author(s).)

This study aims to investigate the influence of a new semi-rigid knee joint braces on kinematics using the Opti-knee knee joint kinematic analysis system at various exercise speeds. Twenty-four healthy young male adults were recruited for this study. Participants were randomly assessed while wearing and not wearing knee brace at four different speeds on a treadmill: normal walking (3.6 km/h), brisk walking (5.4 km/h), jogging (9 km/h), and moderate intensity running (10.8 km/h). Six degrees of freedom kinematic data from the knee joint were collected. Paired t-tests were conducted to calculate the kinematic differences. At speeds of 3.6 km/h and 5.4 km/h, wearing the knee brace led to reduced knee joint mobility in anterior-posterior translation, superior-inferior translation, internal-external rotation, and flexion-extension angles during the stance phase ( P < 0.05). At 9 km/h, wearing the brace reduced knee joint internal-external rotation and flexion-extension mobility during the stance phase ( P < 0.05). At 10.8 km/h, wearing the brace reduced knee joint flexion-extension mobility during the stance phase ( P < 0.05). Wearing brace has significant influence on knee kinematics at four speeds, and the effect of brace varies with the speed of movement.

CRISPR/Cas9 is a popular genome editing technology, yet its clinical application is hindered by off-target effects. Many deep learning-based methods are available for off-target prediction. However, few can predict off-target activities with insertions or deletions (indels) between single guide RNA and DNA sequence pairs. Additionally, the analysis of off-target data is challenged due to a data imbalance issue. Moreover, the prediction accuracy and interpretability remain to be improved. Here, we introduce a deep learning-based framework, named Crispr-SGRU, to predict off-target activities with mismatches and indels. This model is based on Inception and stacked BiGRU. It adopts a dice loss function to solve the inherent imbalance issue. Experimental results show our model outperforms existing methods for off-target prediction in terms of accuracy and robustness. Finally, we study the interpretability of this model through Deep SHAP and teacher-student-based knowledge distillation, and find it can provide meaningful explanations for sequence patterns regarding off-target activity.

This study examined the associations between household social, economic, and physical environments and the trajectory of functional limitations over time among middle-aged and older adults in China, and how this relationship differs by gender, age, and residence. Linear growth curve models were applied to a sample of 13,564 respondents aged 45 years and older from four waves of the China Health and Retirement Longitudinal Study (CHARLS 2011-2018). Living alone, particularly for rural, female, and older respondents, was associated with a faster functional decline when compared to living with a spouse and without children. Improved housing quality was associated with a slower functional decline. Living with young descendants and without adult children for urban residents and a lower expenditure per capita for younger respondents were associated with a faster functional decline. These findings suggest that policies aimed at enhancing living conditions have the potential to improve physical functioning of older adults., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Strong evidence indicates that environmental stressors are the risk factors for male testosterone deficiency (TD). However, the mechanisms of environmental stress-induced TD remain unclear. Based on our all-cause male reproductive cohort, we found that serum ferrous iron (Fe 2 ⁺) levels were elevated in TD donors. Then, we explored the role and mechanism of ferroptosis in environmental stress-reduced testosterone levels through in vivo and in vitro models. Data demonstrated that ferroptosis and lipid droplet deposition were observed in environmental stress-exposed testicular Leydig cells. Pretreatment with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, markedly mitigated environmental stress-reduced testosterone levels. Through screening of core genes involved in lipid droplets formation, it was found that environmental stress significantly increased the levels of perilipins 4 (PLIN4) protein and mRNA in testicular Leydig cells. Further experiments showed that Plin4 siRNA reversed environmental stress-induced lipid droplet deposition and ferroptosis in Leydig cells. Additionally, environmental stress increased the levels of METTL3, METTL14, and total RNA m6A in testicular Leydig cells. Mechanistically, S-adenosylhomocysteine, an inhibitor of METTL3 and METTL14 heterodimer activity, restored the abnormal levels of Plin4, Fe 2 ⁺ and testosterone in environmental stress-treated Leydig cells. Collectively, these results suggest that Plin4 exacerbates environmental stress-decreased testosterone level via inducing ferroptosis in testicular Leydig cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aristolochic acids are a class of naturally occurring compounds in Aristolochiaceae that have similar structural skeletons and chemical properties. Exposure to aristolochic acids is a risk factor for severe kidney disease and urinary system cancer. However, the carcinogenicity of aristolochic acids to the liver, which is the main site of aristolochic acid metabolism, is unclear. Although the characteristic fingerprint of aristolochic acid-induced mutations has been detected in the liver and aristolochic acids are known to be hepatotoxic, whether aristolochic acids can directly cause liver cancer is yet to be verified. This review summarizes the findings of long-term carcinogenicity studies of aristolochic acids in experimental animals. We propose that spatiotemporal heterogeneity in the carcinogenicity of these phytochemicals could explain why direct evidence of aristolochic acids causing liver cancer has never been found in adult individuals. We also summarized the reported approaches to mitigate aristolochic acid-induced hepatotoxicity to better address the associated global safety issue and provide directions and recommendations for future investigation., (© 2024. The Author(s).)

Objective: To evaluate the application and effectiveness of prenatal ultrasound in diagnosing and managing conjoined twins., Methods: A retrospective analysis was conducted on 20 cases of conjoined twins diagnosed at our hospital between January 2016 and December 2022. The types of conjoined twins, ultrasonographic characteristics, and associated anomalies were assessed., Results: The gestational age at diagnosis ranged from 10 to 35 weeks, with an average of 14.21 ± 5.69 weeks. Thirteen cases were detected in the first trimester, five in the early second trimester, one at 23 + 2 weeks, and one at 35 weeks. Thoracopagus was the most common type (11 cases, 55%), followed by omphalopagus (4 cases, 20%), cephalopagus (4 cases, 20%), and parapagus dicephalus (1 case, 5%). In the first trimester, the most common abnormalities observed included increased nuchal translucency (NT), cystic hygroma, hydrops fetalis, and generalized edema. Major birth defects identified in conjoined twins were omphalocele (3 cases), congenital heart malformations (3 cases), neural tube defects (2 cases), urachal cyst (1 case), and umbilical cyst (1 case). Pregnancy was terminated in 18 cases, one case resulted in spontaneous abortion during the second trimester, and one case was delivered by cesarean section at 37 weeks, with successful separation and recovery., Conclusion: Prenatal ultrasound is the primary diagnostic tool for conjoined twins. It effectively assesses the extent of twin fusion, provides critical information for clinical decision-making, and aids in the management of obstetric care., (© 2024 Wiley Periodicals LLC.)

Contemporary domain generalization methods have demonstrated effectiveness in aiding the generalized diagnosis of medical images with multi-source data by joint optimization. However, the centralized training paradigm employed by these approaches becomes infeasible when data are non-shared across domains due to the high privacy of medical data. Despite attempts by existing federated domain generalization methods to address this issue, the simultaneous attainment of strict privacy protection and a satisfactory level of generalization ability on out-of-distribution data remains a persistent challenge. In this paper, to tackle this challenging problem, we propose a novel approach called the Bilateral Proxy Framework (BPF). The BPF leverages the client-side proxies to facilitate the strict privacy-preserving communications with the server and ensure smoother and more stable convergences of local models through mutual distillation. Meanwhile, the server-side proxy adopts a distance-based strategy and a parameter moving average scheme, which enhances the stability and robustness of the global model, particularly by averting abrupt parameter changes that could result in fluctuations or overfitting. Through these advancements, our framework strives to enhance the generalization capability of the global model, enabling more accurate and reliable medical image diagnosis in federated settings. The effectiveness of our method is demonstrated with superior performance over state-of-the-arts on both simulated and real-world distribution medical image diagnosis tasks.

The Chinese government's reclassification of Classical Swine Fever (CSF) from a class Ⅰ to a class Ⅱ animal infectious disease, now also including CSF under the disease eradication program, reflects the significant progress made through extensive immunization with CSF vaccines. In light of this advancement, there is an imperative need for an expedient and accurate method to assess the levels of immunoprotection against classical swine fever virus (CSFV) in vaccinated pigs, a critical component in the campaign to eradicate the disease. This study develops an indirect enzyme-linked immunosorbent assay (iELISA) based on a highly glycosylated E2 protein stable expressed in CHO-K1 mammalian cells. Statistical analysis revealed strong positive correlations between the iELISA and VNT results (r = 0.9063, p < 0.0001) that were much greater than those between the IDEXX ELISA and VNT results (r = 0.8126, p < 0.0001). Taking the VNT data as the standard, the consistency of the iELISA (κ =0.880) was greater than that of the IDEXX ELISA (κ =0.699). In summary, the iELISA provides a more efficient and precise method for assessing CSFV immunity in pigs. Its reliable detection of immunoprotection levels against CSFV makes it an essential tool for optimizing CSF vaccination strategies. Consequently, its application can significantly support the ongoing efforts to eradicate CSF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Increased blood-brain barrier (BBB) permeability is implicated in the pathophysiology of major depressive disorder (MDD). While aerobic exercise has shown promise in mitigating MDD symptoms by potentially preserving BBB integrity, the detailed mechanisms remain unclear. This study explores these mechanisms to assess aerobic exercise's therapeutic potential for MDD., Methods: Male C57BL/6 J mice were used in this study to investigate the effects of aerobic exercise on CUS-induced BBB permeability and depressive-like behaviors. Chronic unpredictable stress (CUS)-induced MDD mouse models were divided into three groups: Control, CUS, and CUS+Exercise. We monitored body weight, blood S100β levels, and cytokines via ELISA. Claudin-5 and Caveolin-1 (CAV-1) expressions in the medial prefrontal cortex were evaluated using Western blotting and immunofluorescence. BBB permeability was assessed using biocytin-TMR and Alb-Alexa 594 tracers. Transmission electron microscopy was used to observe ultrastructural changes in the BBB directly. Depression-related behaviors were tested through several behavioral assays., Results: CUS significantly increased CAV-1 expression and Alb-Alexa 594 leakage, suggesting enhanced transcellular BBB permeability. Despite unchanged Claudin-5 levels, its tight junction ultrastructure was altered, leading to increased biocytin-TMR leakage. Aerobic exercise ameliorated these disruptions, reduced inflammatory cytokines, and improved behavioral outcomes in CUS mice., Conclusion: Disruptions in both paracellular and transcellular BBB pathways are pivotal in depression development. Aerobic exercise offers potential therapeutic benefits for MDD linked with BBB dysfunction by mitigating stress-induced structural and functional changes., Competing Interests: Declaration of Competing Interest The authors affirm that there are no commercial or financial involvements that might present a conflict of interest in the conduct of this research., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Anatomic anterior cruciate ligament (ACL) reconstruction is considered the gold standard treatment for ACL injuries because it aims to restore the knee's normal anatomy and stability, while also protecting long-term knee health. Long-term clinical and radiological outcomes after ACL reconstruction using the modified TT technique are unclear., Objective: To assess the clinical and radiological outcomes following ACL reconstruction using modified transtibial (TT) techniques at a minimum 12-month follow-up., Design: A systematic review with meta-analysis., Methods: PubMed, EMBASE, Web of Science, the Cochrane Library, and MEDLINE databases were searched from the inception to December 1, 2022. PICO search strategy was used to identify studies applying modified TT techniques on patients with ACL reconstruction and a minimum follow-up of 12 months. Eligible studies were identified independently by two reviewers. We extracted data on patient demographics, surgical characteristics, patient reported outcomes including subjective evaluations and clinical outcomes. Radiological data including femoral and tibial tunnel position, femoral and tibial tunnel length, and femoral tunnel angle were also extracted. The tunnel position was evaluated using the quadrant method based on three-dimensional computed tomography (3D CT) images. The standardized mean difference (SMD) and 95 % confidence interval (CI) were calculated for clinical and radiological outcomes., Results: Sixteen studies involving 628 patients were finally included. The SMD of Lysholm (90.39; 95 % CI 83.41-97.38), IKDC (86.07; 95 % CI 79.84-92.31), and Tegner (6.15; 95 % CI 3.96-8.33) scores were considered satisfactory. The depth of the femoral tunnel showed a pooled SMD of 30.08 % (95 % CI 28.25-31.91 %), and the height showed a pooled SMD of 37.72 % (95 % CI 35.75-39.70 %). The pooled SMD for the femoral tunnel angle in the coronal plane was 48.27°(95 % CI 43.14-53.40°), and the pooled SMD for the femoral tunnel length was 33.98 mm (95 % CI 29.03-38.93 mm)., Conclusions: This investigation has shown that modified TT technique can create an anatomic femoral tunnel and maintain optimal tunnel length and angulation. Most patients had satisfactory subjective outcomes and physical examinations after ACL reconstruction using modified TT technique. This information may assist in guiding expectations of clinicians and patients following ACL reconstruction with modified TT technique., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: Tangbi capsule (TBC) is a traditional Chinese medicine prescription, which has the potential to improve the vascular insufficiency of lower extremities and limb numbness in diabetes. However, the potential mechanism remains unknown. This study aims to investigate the pharmacological effects and mechanism of TBC on rats with diabetic lower extremities arterial disease (LEAD)., Methods: The mechanism of TBC on diabetic LEAD was investigated through metabolomics and transcriptomics analysis, and the main components of TBC were determined by mass spectrometry. The efficacy and mechanism of TBC on diabetic LEAD rats were investigated through in vitro experiments, histopathology, blood flow monitoring, western blot, and real-time polymerase chain reaction., Results: Mass spectrometry analysis identified 31 active chemical components in TBC including (2R)-2,3-Dihydroxypropanoic acid, catechin, citric acid, miquelianin, carminic acid, salicylic acid, formononetin, etc. In vitro analysis showed that TBC could reduce endothelial cell apoptosis and promote angiogenesis. Histopathological analysis showed that TBC led to an obvious improvement in diabetic LEAD as it improved fibrous tissue proliferation and reduced arterial wall thickening. In addition, TBC could significantly increase the expression levels of HIF-1α, eNOS, and VEGFA proteins and genes while reducing that of calpain-1 and TGF-β, suggesting that TBC can repair vascular injury. Compared with the model group, there were 47 differentially expressed genes in the whole blood of TBC groups, with 25 genes upregulated and 22 downregulated. Eighty-seven altered metabolites were identified from the serum samples. Combining the changes in differentially expressed genes and metabolites, we found that TBC could regulate arginine biosynthesis, phenylalanine metabolism, pyrimidine metabolism, arachidonic acid metabolism, pyrimidine metabolism, arachidonic acid metabolism, nucleotide metabolism, vitamin B6 metabolism and other metabolic pathways related to angiogenesis, immune-inflammatory response, and cell growth to improve diabetic LEAD., Conclusion: TBC improved vascular endothelial injury, apoptosis, lipid accumulation, liver and kidney function, and restored blood flow in the lower extremities of diabetic LEAD rats. The mechanism of TBC in the treatment of diabetic LEAD may be related to the modulation of inflammatory immunity, lipid metabolism, and amino acid metabolism. This study presented preliminary evidence to guide the use of TBC as a therapy option for diabetic LEAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Luo, Wang, Yao, Hu, Zhao, Wen, Zhang, Wu, Fan and Song.)

Background: Observational studies have found a correlation between the levels of blood lipids and the development and progression of endometriosis (EM). However, the causality and direction of this correlation is unclear. This study aimed to examine the bidirectional connection between lipid profiles and the risk of EM using publicly available genome-wide association study (GWAS) summary statistics., Methods: Eligible exposure variables such as levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were selected using a two-sample Mendelian randomization (MR) analysis method following a series of quality control procedures. Data on EM were obtained from the publicly available Finnish database of European patients. Inverse variance weighted (IVW), MR Egger, weighted median, and weighted mode methods were used to analyze the causal relationship between lipid exposure and EM, exclude confounders, perform sensitivity analyses, and assess the stability of the results. Reverse MR analyses were performed with EM as exposure and lipid results as study outcomes., Results: IVW analysis results identified HDL as a protective factor for EM, while TG was shown to be a risk factor for EM. Subgroup analyses based on the site of the EM lesion identified HDL as a protective factor for EM of the uterus, while TG was identified a risk factor for the EM of the fallopian tube, ovary, and pelvic peritoneum. Reverse analysis did not reveal any effect of EM on the levels of lipids., Conclusion: Blood lipids, such as HDL and TG, may play an important role in the development and progression of EM. However, EM does not lead to dyslipidemia., (© 2024. The Author(s).)

Numerous studies have suggested that the primary cause of failure in transtibial anterior cruciate ligament reconstruction (ACLR) is often attributed to non-anatomical placement of the bone tunnels, typically resulting from improper tibial guidance. We aimed to establish the optimal tibial tunnel angle for anatomical ACLR by adapting the transtibial (TT) technique. Additionally, we aimed to assess graft bending angle (GBA) and length changes during in vivo dynamic flexion of the knee. Twenty knee joints underwent a CT scan and dual fluoroscopic imaging system (DFIS) to reproduce relative knee position during dynamic flexion. For the single-legged lunge, subjects began in a natural standing position and flexed the right knee beyond 90° When performing the lunge task, the subject supported the body weight on the right leg, while the left leg was used to keep the balance. The tibial and femoral tunnels were established on each knee using a modified TT technique for single-bundle ACLR. The tibial tunnel angulation to the tibial axis and the sagittal plane were measured. Considering that ACL injuries tend to occur at low knee flexion angles, GBA and graft length were measured between 0° and 90° of flexion in this study. The tibial tunnel angulated the sagittal plane at 42.8° ± 3.4°, and angulated the tibial axis at 45.3° ± 5.1° The GBA was 0° at 90° flexion of the knee and increased substantially to 76.4 ± 5.5° at 0° flexion. The GBA significantly increased with the knee extending from 90° to 0° (p < 0.001). The ACL length was 30.2mm±3.0 mm at 0° flexion and decreased to 27.5mm ± 2.8 mm at 90° flexion (p = 0.072). To achieve anatomic single-bundle ACLR, the optimal tibial tunnel should be angulated at approximately 43° to the sagittal plane and approximately 45° to the tibial axis using the modified TT technique. What's more, anatomical TT ACLR resulted in comparable GBA and a relatively constant ACL length from 0° to 90° of flexion. These findings provide theoretical support for the clinical application and the promotion of the current modified TT technique with the assistance of a robot to achieve anatomical ACLR., Competing Interests: Competing interests The authors declare no potential conflicts of interest. All procedures in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards., (Copyright © 2024 IPEM. Published by Elsevier Ltd. All rights reserved.)

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study examined the relationship between household environments and trajectories of cognitive function among middle-aged and older adults in China and its urban/rural, gender, and age variations. We estimated multi-level linear growth curve models using a representative sample of 16,111 respondents aged 45 years and over from the China Health and Retirement Longitudinal Study (2011-2018). Older people who lived with a spouse, but not with children, and those with higher living expenditures, better housing quality, and indoor clean fuels for cooking had a slower cognitive decline. Living arrangement more strongly predicted men's cognitive decline, while living expenditure, solid fuel use, and housing quality significantly predicted only women's cognitive decline. Only for older adults and rural residents, those living alone had significantly faster cognitive decline than those living with a spouse only. These findings underscore the importance of improving the living conditions of older adults to help alleviate their cognitive decline., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To investigate the value of ultrasonography in the diagnosis of heterotopic pregnancy and the follow-up., Methods: A retrospective analysis of 50 cases of clinically diagnosed heterotopic pregnancy in our hospital was performed, the clinical characteristics and ultrasonographic manifestations of the patients were summarized, the reasons for initial ultrasound missed diagnosis and misdiagnosis were analyzed, and the pregnancy outcomes were followed up., Results: Among the 50 cases, the initial ultrasound diagnoses of intrauterine pregnancy were all gestational sac type, 32 cases of ectopic pregnancy were located in the fallopian tube, and 10 cases were located in the uterine horn, 1 case at cervix, and 1 case at caesarean section scar. Forty-one cases were consistent with surgery and/or pathology, representing initial ultrasound diagnosis coincidence rate of about 82%. Six cases were missed in the initial ultrasound examination (12%), and three cases were misdiagnosed (6%). The maximum diameter of the intrauterine gestational sac was 9-48 mm, the average was about 24.90 ± 9.56 mm, the maximum diameter of the ectopic pregnancy gestational sac or mass was 11-63 mm, and the average was about 31.45 ± 13.82 mm (p < 0.05). Intrauterine pregnancy outcomes were followed up, 45 patients with complete data and 5 patients were lost to follow-up. The follow-up rate was about 90%., Conclusion: Combining the patient's medical history and clinical characteristics can reduce missed diagnosis and misdiagnosis of heterotopic pregnancy. Ultrasonography has important value in the assessment of intrauterine pregnancy growth and development, and the integrity of maternal uterus., (© 2024 Wiley Periodicals LLC.)

Background: Polycystic ovary syndrome (PCOS) is characterized by excess androgens, ovulatory dysfunction, and polycystic ovaries. The mechanisms underlying ovulatory and metabolic disorders in PCOS remain elusive, hampering therapeutic development. Enhanced metabolic health correlates with increased microbiota gene content and microbial diversity. We aimed to explore the impact of gut microbiota and serum steroids on PCOS regulation associated with androgen excess. Methods: The fecal samples of patients with hyperandrogenic PCOS ( n = 14) and control group with PCOS ( n = 14) were analyzed by 16S rRNA gene sequencing. The peripheral venous blood of all subjects was collected to detect serum hormones. The association between gut microbiota and serum hormones was analyzed with the R language. Results: Our findings reveal that the hyperandrogenic PCOS group exhibits lower richness and diversity of gut microbiota compared to the control group. Characteristic genera in PCOS patients with hyperandrogenism include Bifidobacterium, Enterobacteriaceae&#95;unclassified, Streptococcus, Saccharimonadaceae, Enterococcus , and Eubacterium&#95;nodatum&#95;group . Five hormones, including 5β-androsterone, deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, and cortexolone, emerge as potential serum biomarkers for identifying patients with hyperandrogenic-PCOS (HA-PCOS). Furthermore, a lower vitamin D3 level may act as a susceptibility factor, suggesting that vitamin D3 supplementation could serve as a potential intervention for PCOS with hyperandrogenism. Conclusion: Specific fecal microbiota and serum steroids may be used as characteristic markers for clinical diagnosis of hyperandrogenic-PCOS. This research enhances our understanding of the intricate interplay among hormones, gut microbiota, and hyperandrogenemia in patients with PCOS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Chang, Luo, Pan, Hu, Liu, Ma, Wang, Guo and Wang.)

Low testosterone (T) levels are associated with many common diseases, such as obesity, male infertility, depression, and cardiovascular disease. It is well known that environmental cadmium (Cd) exposure can induce T decline, but the exact mechanism remains unclear. We established a murine model in which Cd exposure induced testicular T decline. Based on the model, we found Cd caused mitochondrial fusion disorder and Parkin mitochondrial translocation in mouse testes. MFN1 overexpression confirmed that MFN1-dependent mitochondrial fusion disorder mediated the Cd-induced T synthesis suppression in Leydig cells. Further data confirmed Cd induced the decrease of MFN1 protein by increasing ubiquitin degradation. Testicular specific Parkin knockdown confirmed Cd induced the ubiquitin-dependent degradation of MFN1 protein through promoting Parkin mitochondrial translocation in mouse testes. Expectedly, testicular specific Parkin knockdown also mitigated testicular T decline. Mito-TEMPO, a targeted inhibitor for mitochondrial reactive oxygen species (mtROS), alleviated Cd-caused Parkin mitochondrial translocation and mitochondrial fusion disorder. As above, Parkin mitochondrial translocation induced mitochondrial fusion disorder and the following T synthesis repression in Cd-exposed Leydig cells. Collectively, our study elucidates a novel mechanism through which Cd induces T decline and provides a new treatment strategy for patients with androgen disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Insulin-like growth factor-I (IGF-I) facilitates mitotic and anabolic actions in all tissues. In skeletal muscle, IGF-I can promote growth and resolution of damage by promoting satellite cell proliferation and differentiation, suppressing inflammation, and enhancing fiber formation. While the most well-characterized form of IGF-I is the mature protein, alternative splicing and post-translational modification complexity lead to several additional forms of IGF-I. Previous studies showed muscle efficiently stores glycosylated pro-IGF-I. However, non-glycosylated forms display more efficient IGF-I receptor activation in vitro, suggesting that the removal of the glycosylated C terminus is a necessary step to enable increased activity. We employed CRISPR-Cas9 gene editing to ablate IGF-I glycosylation sites (2ND) or its cleavage site (3RA) in mice to determine the necessity of glycosylation or cleavage for IGF-I function in postnatal growth and during muscle regeneration. 3RA mice had the highest circulating and muscle IGF-I content, whereas 2ND mice had the lowest levels compared to wild-type mice. After weaning, 4-week-old 2ND mice exhibited higher body and skeletal muscle mass than other strains. However, by 16 weeks of age, muscle and body size differences disappeared. Even though 3RA mice had more IGF-I stored in muscle in homeostatic conditions, regeneration was delayed after cardiotoxin-induced injury, with prolonged necrosis most evident at 5 days post injury (dpi). In contrast, 2ND displayed improved regeneration with reduced necrosis, and greater fiber size and muscle mass at 11 and 21 dpi. Overall, these results demonstrate that while IGF-I glycosylation may be important for storage, cleavage is needed to enable IGF-I to be used for efficient activity in postnatal growth and following acute injury., (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Understanding the motion characteristics of cervical spine through biomechanical analysis aids in the identification of abnormal joint movements. This knowledge is essential for the prevention, diagnosis, and treatment of related disorders. However, the anatomical structure of the cervical spine is complex, and traditional medical imaging techniques have certain limitations. Capturing the movement characteristics of various parts of the cervical spine in vivo during motion is challenging. The dual fluoroscopic imaging system (DFIS) is able to quantify the motion and motion patterns of individual segments. In recent years, DFIS has achieved accurate non-invasive measurements of dynamic joint movements in humans. This review assesses the research findings of DFIS about the cervical spine in healthy and pathological individuals. Relevant study search was conducted up to October 2023 in Web of Science, PubMed, and EBSCO databases. After the search, a total of 30 studies were ultimately included. Among them, 13 studies focused on healthy cervical spines, while 17 studies focused on pathological cervical spines. These studies mainly centered on exploring the vertebral bodies and associated structures of the cervical spine, including intervertebral discs, intervertebral foramina, and zygapophyseal joints. Further research could utilize DFIS to investigate cervical spine motion in different populations and under pathological conditions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In recent years, many students have faced economic hardship and experienced food insecurity, even as universities strive to create more equitable pathways to college. There is a need for a more holistic perspective that addresses the complexity of food insecurity amongst college students. To this end, we examined the relationship between the social determinants of health, including college food insecurity (CoFI) and childhood food insecurity (ChFI), and their relationship with well-being measures. The study sample was a convenience sample that included 372 students at a public university who responded to an online survey in fall 2021. Students were asked to report their food security status in the previous 30 days. We used the following analytical strategies: chi-square tests to determine differences between food secure (FS) and food insecure (FI) students; binary logistic regression of CoFI on student demographics and ChFI; and ordinal or binary logistic regression for well-being measures. Black students, off-campus students, first-generation students, in-state students, and humanities/behavioral/social/health sciences majors were more likely to report CoFI. FI students were more likely to have experienced ChFI and to have lower scores on all well-being measures. ChFI was associated with four well-being measures and its effects were mediated by CoFI. College student health initiatives would benefit from accounting for SDOH, including ChFI experiences and its subsequent cumulative disadvantages experienced during college.

Background: Landing from heights is a common movement for active-duty military personnel during training. And the additional load they carry while performing these tasks can affect the kinetics and ankle kinematic of the landing. Traditional motion capture techniques are limited in accurately capturing the in vivo kinematics of the talus. This study aims to investigate the effect of additional trunk load on the kinematics of the talocrural and subtalar joints during landing, using a dual fluoroscopic imaging system (DFIS)., Methods: Fourteen healthy male participants were recruited. Magnetic resonance imaging was performed on the right ankle of each participant to create three-dimensional (3D) models of the talus, tibia, and calcaneus. High-speed DFIS was used to capture the images of participants performing single-leg landing jumps from a height of 40 cm. A weighted vest was used to apply additional load, with a weight of 16 kg. Fluoroscopic images were acquired with or without additional loading condition. Kinematic data were obtained by importing the DFIS data and the 3D models in virtual environment software for 2D-3D registration. The kinematics and kinetics were compared between with or without additional loading conditions., Results: During added trunk loading condition, the medial-lateral translation range of motion (ROM) at the talocrural joint significantly increased (p < 0.05). The subtalar joint showed more extension at 44-56 ms (p < 0.05) after contact. The subtalar joint was more eversion at 40-48 ms (p < 0.05) after contact under the added trunk load condition. The peak vertical ground reaction force (vGRF) significantly increased (p < 0.05)., Conclusions: With the added trunk load, there is a significant increase in peak vGRF during landing. The medial-lateral translation ROM of the talocrural joint increases. And the kinematics of the subtalar joint are affected. The observed biomechanical changes may be associated with the high incidence of stress fractures in training with added load., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Natural data typically exhibits a long-tailed distribution, presenting great challenges for recognition tasks. Due to the extreme scarcity of training instances, tail classes often show inferior performance. In this paper, we investigate the problem within the trendy visual-language (VL) framework and find that the performance bottleneck mainly arises from the recognition confusion between tail classes and their highly correlated head classes. Building upon this observation, unlike previous research primarily emphasizing class frequency in addressing long-tailed issues, we take a novel perspective by incorporating a crucial additional factor namely class correlation. Specifically, we model the representation learning procedure for each sample as two parts, i.e., a special part that learns the unique properties of its own class and a common part that learns shared characteristics among classes. By analysis, we discover that the learning process of common representation is easily biased toward head classes. Because of the bias, the network may lean towards the biased common representation as classification criteria, rather than prioritizing the crucial information encapsulated within the specific representation, ultimately leading to recognition confusion. To solve the problem, based on the VL framework, we introduce the rectification contrastive term (ReCT) to rectify the representation bias, according to semantic hints and training status. Extensive experiments on three widely-used long-tailed datasets demonstrate the effectiveness of ReCT. On iNaturalist2018, it achieves an overall accuracy of 75.4%, surpassing the baseline by 3.6 points in a ResNet-50 visual backbone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9 (CRISPR/Cas9) is a new generation of gene editing technology, which relies on single guide RNA to identify specific gene sites and guide Cas9 nuclease to edit specific location in the genome. However, the off-target effect of this technology hampers its development. In recent years, several deep learning models have been developed for predicting the CRISPR/Cas9 off-target activity, which contributes to more efficient and safe gene editing and gene therapy. However, the prediction accuracy remains to be improved. In this paper, we proposed a multi-scale convolutional neural network-based method, designated as CnnCRISPR, for CRISPR/Cas9 off-target prediction. First, we used one-hot encoding method to encode the sgRNA-DNA sequence pair, followed by a bitwise or operation on the two binary matrices. Second, the encoded sequence was fed into the Inception-based network for training and evaluating. Third, the well-trained model was applied to evaluate the off-target situation of the sgRNA-DNA sequence pair. Experiments on public datasets showed CnnCRISPR outperforms existing deep learning-based methods, which provides an effective and feasible method for addressing the off-target problems.

This study investigates the impact of COVID-19 pandemic on perceived everyday discrimination using data from the 2018 and 2021 General Social Survey. The study included representative samples of 1,499 adults in 2018 and 2,361 adults in 2021 in the United States. The study found that the overall level of perceived everyday discrimination had a slight decline from 2018 to 2021. However, frequency of being threatened/harassed increased in all racial/ethnic groups and more substantially among Asian Americans and people in the "other race" category. Most social statuses had a similar association with perceived everyday discrimination in 2018 and 2021 (e.g., higher among younger age, homo/bisexual, non-Hispanic Black, U.S. born, divorced/separated). In 2018, perceived discrimination was also higher among Hispanics, people of multiple races, Jews and people of "other religions." In 2021, it was also higher among "other races" and parents who were never married. Perceived everyday discrimination was associated with all health and well-being outcomes. Also, the negative association between perceived discrimination and health and well-being appears to be stronger in 2021 than in 2018. These findings suggest that the pandemic intensified the relationship between perceived everyday discrimination and health and well-being. They point to an urgent need to develop effective efforts to mitigate the harmful impact of discrimination., (© 2024. W. Montague Cobb-NMA Health Institute.)

Off-target effects of CRISPR/Cas9 can lead to suboptimal genome editing outcomes. Numerous deep learning-based approaches have achieved excellent performance for off-target prediction; however, few can predict the off-target activities with both mismatches and indels between single guide RNA (sgRNA) and target DNA sequence pair. In addition, data imbalance is a common pitfall for off-target prediction. Moreover, due to the complexity of genomic contexts, generating an interpretable model also remains challenged. To address these issues, firstly we developed a BERT-based model called CRISPR-BERT for enhancing the prediction of off-target activities with both mismatches and indels. Secondly, we proposed an adaptive batch-wise class balancing strategy to combat the noise exists in imbalanced off-target data. Finally, we applied a visualization approach for investigating the generalizable nucleotide position-dependent patterns of sgRNA-DNA pair for off-target activity. In our comprehensive comparison to existing methods on five mismatches-only datasets and two mismatches-and-indels datasets, CRISPR-BERT achieved the best performance in terms of AUROC and PRAUC. Besides, the visualization analysis demonstrated how implicit knowledge learned by CRISPR-BERT facilitates off-target prediction, which shows potential in model interpretability. Collectively, CRISPR-BERT provides an accurate and interpretable framework for off-target prediction, further contributes to sgRNA optimization in practical use for improved target specificity in CRISPR/Cas9 genome editing. The source code is available at https://github.com/BrokenStringx/CRISPR-BERT., Competing Interests: Declaration of competing interest All the authors have read and agree with the contents of the manuscript, and there is no conflict of interest in the submission of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Increased incidence of anterior cruciate ligament injuries has amplified the need for quantitative research in clinical and academic settings. We used a novel digital arthrometer to measure knee laxity in healthy people and patients with anterior cruciate ligament injuries. Changes in stiffness were also assessed to develop new indicators for detecting anterior cruciate ligament injury. The purpose of this study was to use arthrometer to measure the quantitative indicator of knee laxity, bringing clinicians a new perspective on how to identify injury to the ACL. Methods: In this cross-sectional study, anterior tibial displacement under continuous loading was measured using a novel digital arthrometer in 30 patients with unilateral anterior cruciate ligament injury and 30 healthy controls. Load-displacement curves were plotted, using real-time load and displacement changes. Stiffness was defined by the slope of the applied load to tibial displacement. Anterior tibial displacement and instantaneous stiffness values under different loads were compared. The restricting contribution of the anterior cruciate ligament transformed the displacement-stiffness curve from a sharp decrease to a stable increase, resulting in a minimum stiffness value. Using the minimum stiffness as the turning point, the load-displacement curve was divided into regions 1 and 2. The two regions' stiffness changes were compared. Based on the findings, receiver operating characteristic curves were plotted and the area under the curve was calculated to estimate the diagnostic accuracy. Results: Anterior tibial displacement was significantly greater in the anterior cruciate ligament injury group than in the controls under each 10-N increase load ( p < 0.05). In the anterior cruciate ligament injury group, instantaneous stiffness was significantly lower on the injured side than on the healthy side ( p < 0.05). In the two regions of the load-displacement curve, stiffness was significantly lower in the anterior cruciate ligament injury group than in the control group (all, p < 0.05). Receiver operating characteristic curves were plotted, using changes in stiffness under the two regions in both groups. Stiffness in region 2 had the largest area under the curve (0.94; 95% CI, 0.88-0.99). Using the cut-off value of 9.62 N/mm to detect ACL injury, the sensitivity and specificity were 93% and 82%, respectively. Conclusion: Our investigation of ligament stiffness provides novel insights into the properties of knee laxity. Stiffness in the later stages of increased loading <9.62 N/mm could be a valid indicator for identifying knee laxity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Zhao, Wu, Zhou, Luo, Huang, Xu and Wang.)

Objective: Intrathyroid thymic carcinoma (ITTC) is a rare malignancy. The current understanding of ITTC is inadequate, and there is no standard treatment for ITTC. In the present study, we aimed to explore the clinicopathological characteristics of ITTC and identify potential therapeutic targets., Methods: The clinicopathological characteristics of 22 ITTC patients at our institution were reviewed. The expression of DNA mismatch repair (MMR) proteins and PD-L1 in ITTC were assessed by immunohistochemistry (IHC)., Results: All patients underwent surgery. There were nine females and 13 males, with a slight male predominance. Their ages ranged from 42 to 79 years (average, 54. 1 years). The diameters of the neck masses ranged from 10 to 100 mm (average, 39 mm). Ipsilateral lymph node (LN) dissection was performed in 18 patients: 12 demonstrated LN metastasis, six showed no LN metastasis, and no lymph nodes were dissected in four. One patient had liver metastasis. CK5/6, P63, CD5, and CD117 were expressed in all cases. All cases were negative for TTF1, PAX8, thyroglobulin, and BRAF V600E. DNA MMR protein expression was retained in all tested tumors, and EBV-encoded small RNA (EBER) in situ hybridization was consistently negative. The Ki67 proliferation index ranged from 10 to 70 %. All patients were followed-up for 14-134 months, four died, six were lost to follow-up, and the remaining patients survived without disease. The PD-L1 combined positive score ranged from 10 to 80 (average: 40)., Conclusion: Our results confirm that CD5 and CD117 co-expression support a diagnosis of ITTC. All tumors in this cohort were DNA MMR-proficient and were not associated with Epstein-Barr virus (EBV) infection. A high CPS for PD-L1 suggests that immune checkpoint inhibitor therapy may be worthy of further exploration in patients with ITTC., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is a malignant tumor of the gastrointestinal tract that significantly impacts the health of patients and lacks promising methods of diagnosis. Tumor-associated macrophages (TAMs) are involved in CRC progression, and their function is regulated by long non-coding RNAs (lncRNAs). The lncRNA NBR2 was recently reported as an oncogene, whose function in CRC remains uncertain. The present study aimed to investigate the biological function of lncRNA NBR2 in the progression of CRC and its underlying molecular mechanisms. Ten pairs of clinical CRC and para-carcinoma tissues were collected to determine the expression levels of lncRNA NBR2 and miR-19a, and the polarization state of TAMs. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate the expression of miR-19a, and western blotting was used to determine the expression levels of tumor necrosis factor-α, human leukocyte antigen-DR, arginase-1, CD163, CD206, interleukin-4, AMP-activated protein kinase (AMPK), p-AMPK, hypoxia-inducible factor-1α (HIF-1α), protein kinase B (AKT), p-AKT, mechanistic target of rapamycin (mTOR), and p-mTOR in TAMs. The proliferative ability of HCT-116 cells was detected using the CCK8 assay, and the migratory ability of HCT-116 cells was evaluated using the Transwell assay. The interaction between lncRNA NBR2 and miR-19a was determined using the luciferase assay. The lncRNA NBR2 was downregulated and miR-19a was highly expressed in CRC cells, accompanied by a high M2 polarization. Downregulated miR-19a promoted M1 polarization, activated AMPK, suppressed HIF-1α and AKT/mTOR signaling pathways, and promoted antitumor properties in NBR2-overexpressed TAMs, which were all reversed by the introduction of the miR-19a mimic. LncRNA NBR2 was verified to target miR-19a in macrophages according to the results of the luciferase assay. Collectively, lncRNA NBR2 may suppress the progression of CRC by downregulating miR-19a to regulate M2 macrophage polarization., Competing Interests: None

Optical neural networks (ONNs) herald a new era in information and communication technologies and have implemented various intelligent applications. In an ONN, the activation function (AF) is a crucial component determining the network performances and on-chip AF devices are still in development. Here, we first demonstrate on-chip reconfigurable AF devices with phase activation fulfilled by dual-functional graphene/silicon (Gra/Si) heterojunctions. With optical modulation and detection in one device, time delays are shorter, energy consumption is lower, reconfigurability is higher and the device footprint is smaller than other on-chip AF strategies. The experimental modulation voltage (power) of our Gra/Si heterojunction achieves as low as 1 V (0.5 mW), superior to many pure silicon counterparts. In the photodetection aspect, a high responsivity of over 200 mA/W is realized. Special nonlinear functions generated are fed into a complex-valued ONN to challenge handwritten letters and image recognition tasks, showing improved accuracy and potential of high-efficient, all-component-integration on-chip ONN. Our results offer new insights for on-chip ONN devices and pave the way to high-performance integrated optoelectronic computing circuits., (© 2023. The Author(s).)

Objective: Ankle braces can affect the kinematics of the ankle joint during landing tasks. Previous studies were primarily relied on traditional marker-based motion capture systems, which pose limitations in non-invasively capturing the motion of the talus bone. The effect of ankle braces on the in vivo kinematics of the tibiotalar and subtalar joints during landing remains unknown. This study used a high-speed dual fluoroscopic imaging system (DFIS) and magnetic resonance imaging (MRI) to investigate effect of ankle braces on the in vivo kinematics of the tibiotalar and subtalar joints during landing. Methods: Fourteen healthy participants were recruited for this study. During the experiment, static three-dimensional MRI data were collected for each participant, and 3D ankle joint models for the calcaneus, talus, and tibia were constructed. The DFIS was used to capture the images of each participant performing a single-leg landing-jump task at a height of 40 cm. The images were captured once with and without a brace in the fatigue condition, which was induced by running. The six-degree-of-freedom (6DOF) kinematic data were obtained by 2D-3D registration. Results: The flexion-extension range of motion (ROM) (42.73 ± 4.76° vs. 38.74 ± 5.43°, p = 0.049) and anterior-posterior translation ROM (16.86 ± 1.74 mm vs. 15.03 ± 1.73 mm, p = 0.009) of the tibiotalar joint were decreased. The maximum inversion angle (-3.71 ± 2.25° vs. 2.11 ± 1.83°, p = 0.047) of the subtalar joint was decreased. Conclusion: The ankle brace limited the flexion-extension ROM of the tibiotalar joints and the inversion angle of the subtalar joint during landing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Hu, Li, Huang, Wu, Li and Wang.)

Photonic mechanical sensors offer several advantages over their electronic counterparts, including immunity to electromagnetic interference, increased sensitivity, and measurement accuracy. Exploring flexible mechanical sensors on deformable substrates provides new opportunities for strain-optical coupling operations. Nevertheless, existing flexible photonics strategies often require cumbersome signal collection and analysis with bulky setups, limiting their portability and affordability. To address these challenges, we propose a waveguide-integrated flexible mechanical sensor based on cascaded photonic crystal microcavities with inherent deformation and biaxial tensile state analysis. Leveraging the advanced multiplexing capability of the sensor, for the first time, we successfully demonstrate 2D shape reconstruction and quasi-distributed strain sensing with 110 μm spatial resolution. Our microscale mechanical sensor also exhibits exceptional sensitivity with a detected force level as low as 13.6 μN in real-time measurements. This sensing platform has potential applications in various fields, including biomedical sensing, surgical catheters, aircraft and spacecraft engineering, and robotic photonic skin development.

We correct the error in [Opt. Express30, 3866 (2022)10.1364/OE.450092], Fig. 6(c). The unit of the vertical axis in the figure should be arbitrary units, not dB. All the conclusions are unchanged after the correction.

We correct the error in [Opt. Express31, 1103(2023)10.1364/OE.478613] Fig. 5(c). The unit of the vertical axis in the figure should be arbitrary units, not dB. All the conclusions are not changed after the correction.

In silico design of single guide RNA (sgRNA) plays a critical role in clustered regularly interspaced, short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system. Continuous efforts are aimed at improving sgRNA design with efficient on-target activity and reduced off-target mutations. In the last 5 years, an increasing number of deep learning-based methods have achieved breakthrough performance in predicting sgRNA on- and off-target activities. Nevertheless, it is worthwhile to systematically evaluate these methods for their predictive abilities. In this review, we conducted a systematic survey on the progress in prediction of on- and off-target editing. We investigated the performances of 10 mainstream deep learning-based on-target predictors using nine public datasets with different sample sizes. We found that in most scenarios, these methods showed superior predictive power on large- and medium-scale datasets than on small-scale datasets. In addition, we performed unbiased experiments to provide in-depth comparison of eight representative approaches for off-target prediction on 12 publicly available datasets with various imbalanced ratios of positive/negative samples. Most methods showed excellent performance on balanced datasets but have much room for improvement on moderate- and severe-imbalanced datasets. This study provides comprehensive perspectives on CRISPR/Cas9 sgRNA on- and off-target activity prediction and improvement for method development., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Fatigue can affect the ankle kinematic characteristics of landing movements. Traditional marker-based motion capture techniques have difficulty in accurately obtaining the kinematics of the talocrural and subtalar joints. This study aimed to investigate the effects of fatigue on the talocrural and subtalar joints during the landing using dual fluoroscopic imaging system (DFIS). Methods: This study included fourteen healthy participants. The foot of each participant was scanned using magnetic resonance imaging to create 3D models. High-speed DFIS was used to capture images of the ankle joint during participants performing a single-leg landing jump from a height of 40 cm. Fatigue was induced by running and fluoroscopic images were captured before and after fatigue. Kinematic data were obtained by 3D/2D registration in virtual environment software. The joint kinematics in six degrees of freedom and range of motion (ROM) were compared between the unfatigued and fatigued conditions. Results: During landing, after the initial contact with the ground, the main movement of the talocrural joint is extension and abduction, while the subtalar joint mainly performs extension, eversion, and abduction. Compared to unfatigued, during fatigue the maximum medial translation (1.35 ± 0.45 mm vs. 1.86 ± 0.69 mm, p = 0.032) and medial-lateral ROM (3.19 ± 0.60 mm vs. 3.89 ± 0.96 mm, p = 0.029) of the talocrural joint significantly increased, the maximum flexion angle (0.83 ± 1.24° vs. 2.11 ± 1.80°, p = 0.037) of the subtalar joint significantly increased, and the flexion-extension ROM (6.17 ± 2.21° vs. 7.97 ± 2.52°, p = 0.043) of the subtalar joint significantly increased. Conclusion: This study contributes to the quantitative understanding of the normal function of the talocrural and subtalar joints during high-demand activities. During landing, the main movement of the talocrural joint is extension and abduction, while the subtalar joint mainly performs extension, eversion, and abduction. Under fatigue conditions, the partial ROM of the talocrural and subtalar joints increases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Li, Hu, Zhang, Li and Wang.)

Objectives: This study pursued 3 goals: (1) to determine how depressive symptoms among U.S. older adults changed in 2018-2020, a period transitioning to the first wave of coronavirus disease (COVID) pandemic, compared to in prepandemic periods, (2) to determine whether physical disability predicts change in depressive symptoms in 2018-2020, and (3) to assess whether psychological resilience moderates the association between physical disability and change in depressive symptoms in 2018-2020., Methods: Based on biennial longitudinal data of the Health and Retirement Study from 2010 to 2020, we used a before-after design and latent change score model to examine whether depressive symptoms change in 2018-2020 represents a continuation or departure from the overall trend of between-wave changes in 2010-2018. We also used physical disability in 2018 and psychological resilience in 2016-2018 to predict depressive symptoms change score in 2018-2020., Results: In contrast to the relatively stable between-wave change trend in 2010-2018, there was an abrupt elevation in the latent change score of depressive symptoms in 2018-2020, which was primarily driven by increased affective symptoms (e.g., depressed mood, loneliness, unhappiness, and sadness). Increase in depressive symptoms in 2018-2020 was associated positively with physical disability but negatively with psychological resilience. Moderation effect of psychological resilience, however, was not significant., Discussion: Our findings reveal heavier COVID-related mental health burden for older adults with physical disabilities and the potential benefits of enhancing individual psychological resilience. They also suggest that health interventions addressing the COVID impacts need to particularly focus on the affective aspects of depressive symptoms., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Food insecurity is linked with poor physical and mental health outcomes, including anxiety, depression and stress. Rural residents in particular face unique challenges obtaining healthy food; the COVID-19 pandemic exacerbated the relationship between food insecurity and mental health outcomes. This study examines the relationship between food insecurity and stress, and the moderating influence of household characteristics, neighborhood social environment and food environment on this relationship, using a sample of 630 rural South Carolina (SC) residents during COVID-19. Two measures of stress were used in this study: current levels of stress and changes in stress since COVID-19. Results showed a gradient pattern between food insecurity and stress: rural residents with high food insecurity were 6.1 times more likely and those with moderate food insecurity were 3.4 times more likely to report higher level of general stress than those with low food insecurity; rural residents with high food insecurity were 3.3 times more likely and those with moderate food insecurity were 2.0 times more likely to report greater increase in stress after COVID-19 than those with low food insecurity. Neighborhood social environment and food environment provided a buffering effect on the relationship between food insecurity and stress. A stronger social environment after COVID-19 and higher levels of easiness in food access mitigated the negative impacts of food insecurity on stress. Efforts to ameliorate food insecurity should address these broader contextual variables, involving community-level factors., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

High-fat diet (HFD)-induced obesity results in bone loss associated with an imbalanced gut microbiota and altered immune status. Probiotics are live microorganisms that are beneficial to the host and are important in maintaining bone health and gut homeostasis. In this study, the probiotic Lactobacillus coryniformis subsp . torquens (T3L) was isolated from traditional yak milk cheese produced in Lhasa and showed distinct acid and bile salt resistance as potential probiotics. Our data indicated that T3L not only reversed HFD-induced gut dysbiosis, as indicated by decreased Firmicutes-to-Bacteroidetes ratios but also reduced bone loss. The anti-obesity, microbiome-modulating, and bone-protective effects were transmissible via horizontal faeces transfer from T3L-treated mice to HFD-fed mice. The protective effects of T3L on bone mass were associated with regulatory T (Treg) cell-mediated inhibition of osteoclast differentiation. Our data indicate that T3L is a regulator of the gut microbiota and bone homeostasis in an animal model.

Background: Sleep-related problems are debilitating and long-lasting conditions in individuals with stroke. We aimed to estimate the prevalence of poor sleep quality after stroke by conducting a systematic review and meta-analysis., Methods: Five databases (PubMed, Embase, Web of Science, Scopus, and CINHAL) were searched for literature published before November 2022. Studies recruiting participants with stroke, using a validated scale to measure sleep quality and in English were included. We used the Agency for Healthcare Research and Quality Scale and Newcastle-Ottawa Scale to assess the quality of eligible studies. Pooled prevalence and subgroup analyses were performed to understand the variation in sleep quality among studies. We followed the PRISMA checklist to report the study., Results: Thirteen studies were included for analysis (n = 3886). The pooled prevalence of poor sleep quality was 53% (95% CI 41-65%). Studies using PSQI with a cutoff point of 7 had a prevalence of 49% (95% CI 26-71%), whereas those with a cutoff point of 5 had a higher prevalence of 66% (95% CI 63-69%) (P = .13). Geographical location could explain the prevalence variation between studies. The majority of included studies had a medium level quality of evidence (10/13)., Conclusion: Poor sleep quality appears to be common in patients with stroke. Considering its negative impact on health, effective measures should be taken to improve their quality of sleep. Longitudinal studies should be conducted to examine the contributing factors and investigate the mechanisms that lead to poor sleep quality., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a potentially novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (<15%) were sufficient to protect skeletal muscles in dystrophic mdx mice from stress injury. Longer-term treatment also decreased muscle fibrosis in key disease-implicated tissues. Importantly, therapeutic levels of myosin inhibition with EDG-5506 did not detrimentally affect strength or coordination. Finally, in dystrophic dogs, EDG-5506 reversibly reduced circulating muscle injury biomarkers and increased habitual activity. This unexpected biology may represent an important alternative treatment strategy for Duchenne and related myopathies.

Recently, there has been significant progress in medical image segmentation utilizing deep learning techniques. However, these achievements largely rely on the supposition that the source and target domain data are identically distributed, and the direct application of related methods without addressing the distribution shift results in dramatic degradation in realistic clinical environments. Current approaches concerning the distribution shift either require the target domain data in advance for adaptation, or focus only on the distribution shift across domains while ignoring the intra-domain data variation. This paper proposes a domain-aware dual attention network for the generalized medical image segmentation task on unseen target domains. To alleviate the severe distribution shift between the source and target domains, an Extrinsic Attention (EA) module is designed to learn image features with knowledge originating from multi-source domains. Moreover, an Intrinsic Attention (IA) module is also proposed to handle the intra-domain variation by individually modeling the pixel-region relations derived from an image. The EA and IA modules complement each other well in terms of modeling the extrinsic and intrinsic domain relationships, respectively. To validate the model effectiveness, comprehensive experiments are conducted on various benchmark datasets, including the prostate segmentation in magnetic resonance imaging (MRI) scans and the optic cup/disc segmentation in fundus images. The experimental results demonstrate that our proposed model effectively generalizes to unseen domains and exceeds the existing advanced approaches.

The properties of [Formula: see text] (M: 3d transition metal) perovskite crystals are significantly dependent on point defects, whether introduced accidentally or intentionally. The most studied defects in La-based perovskites are the oxygen vacancies and doping impurities on the La and M sites. Here, we identify that intrinsic antisite defects, the replacement of La by the transition metal, M, can be formed under M-rich and O-poor growth conditions, based on results of an accurate many-body ab initio approach. Our fixed-node diffusion Monte Carlo (FNDMC) calculations of [Formula: see text] ([Formula: see text], Fe, and Co) find that such antisite defects can have low formation energies and are magnetized. Complementary density functional theory (DFT)-based calculations show that Mn antisite defects in [Formula: see text] may cause the p-type electronic conductivity. These features could affect spintronics, redox catalysis, and other broad applications. Our bulk validation studies establish that FNDMC reproduces the antiferromagnetic state of [Formula: see text], whereas DFT with PBE (Perdew-Burke-Ernzerhof), SCAN (strongly constrained and appropriately normed), and the LDA+U (local density approximation with Coulomb U) functionals all favor ferromagnetic states, at variance with experiment., (© 2023. The Author(s).)

Myocardial fibrosis is the most serious complication of viral myocarditis (VMC). This study aimed to investigate the therapeutic benefits and underlying mechanisms of lentivirus-mediated human tissue kallikrein gene transfer in myocardial fibrosis in VMC mice. We established VMC mouse model via intraperitoneal injection with Coxsackie B3 virus. The effect was then assessed after treatment with vehicle, the empty lentiviral vectors (EZ.null), and the vectors expressing hKLK1 (EZ.hKLK1) via tail vein injection for 30 days, respectively. The results showed that administering EZ.hKLK1 successfully induced hKLK1 overexpression in mouse heart. Compared with EZ.null treatment, EZ.hKLK1 administration significantly reduced the heart/weight ratio, improved cardiac function, and ameliorated myocardial inflammation in VMC mice, suggesting that hKLK1 overexpression alleviates VMC in mice. EZ.hKLK1 administration also significantly abrogated the increased myocardial collagen content, type I/III collagen ratio, TGF-β1 mRNA and protein expression in VMC mice, suggesting that hKLK1 overexpression reduces collagen accumulation and blunts TGF-β1 signaling in the hearts of VMC mice. In conclusion, our results suggest that hKLK1 alleviates myocardial fibrosis in VMC mice, possibly by downregulating TGF-β1 expression., Competing Interests: The authors report no conflicts of interest in this work.

Gastric carcinomas have high morbidity and mortality. It produces no noticeable symptoms in the early stage while causing complex complications in its advanced stage, making treatment difficult. Palliative therapy aims to relieve the symptoms of cancer patients and focuses on improving their quality of life. At present, five palliative therapies for advanced gastric carcinomas are offered: resection, gastrojejunostomy, stenting, chemotherapy, and radiotherapy. In recent years, palliative therapy has been used in the clinical treatment of advanced gastric carcinomas and related complications because of its efficacy in gastric outlet obstruction and gastric bleeding. In the future, multimodal and interdisciplinary palliative therapies can be applied to control general symptoms to improve patients' condition, prolong their lifespan and improve their quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Luo, Zhao, Lin, Li, Jie, Wu, Fang, Pang and Huang.)

Superoscillation refers to a phenomenon where a band-limited wave locally oscillates faster than its highest Fourier component. Current research on optical superoscillations predominantly lies on the basis of free-space waves. As the optical waveguides play a key role in energy and information transportation, guided waves with precisely controlled deep-subwavelength features offers unprecedented flexibility for applications. In this Letter, we numerically show that, by superimposing eigenmodes of a multimode SiO 2 waveguide and forcing the resultant field to pass through a set of predetermined points, superoscillatory fields in various shapes can be formed in preset cross-sectional planes. Furthermore, by padding prescribed intensities in multiple cross sections, we successfully create a persistent superoscillatory saddle.