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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-ß, 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.
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The Chinese government's reclassification of Classical Swine Fever (CSF) from a class â to a class â ¡ 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.
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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.
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Endometriosis , Estudio de Asociación del Genoma Completo , Lípidos , Análisis de la Aleatorización Mendeliana , Triglicéridos , Humanos , Femenino , Endometriosis/sangre , Endometriosis/genética , Análisis de la Aleatorización Mendeliana/métodos , Triglicéridos/sangre , Lípidos/sangre , Factores de Riesgo , Causalidad , Finlandia/epidemiología , Colesterol/sangreRESUMEN
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_unclassified, Streptococcus, Saccharimonadaceae, Enterococcus, and Eubacterium_nodatum_group. Five hormones, including 5ß-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.
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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.
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Reconstrucción del Ligamento Cruzado Anterior , Tibia , Humanos , Reconstrucción del Ligamento Cruzado Anterior/métodos , Tibia/cirugía , Masculino , Adulto , Adulto Joven , Femenino , Ligamento Cruzado Anterior/cirugíaRESUMEN
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 45â 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.
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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.
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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.
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Inseguridad Alimentaria , Determinantes Sociales de la Salud , Estudiantes , Humanos , Universidades , Femenino , Estudiantes/estadística & datos numéricos , Estudiantes/psicología , Masculino , Adulto Joven , Encuestas y Cuestionarios , Adulto , Adolescente , Abastecimiento de Alimentos/estadística & datos numéricosRESUMEN
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.
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Cadmio , Mitocondrias , Piroptosis , Testículo , Animales , Cadmio/toxicidad , Masculino , Ratones , Testículo/efectos de los fármacos , Testículo/metabolismo , Piroptosis/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Proteostasis , Proteínas Mitocondriales/metabolismo , Exposición a Riesgos Ambientales/efectos adversos , ADN Mitocondrial , Proteasas ATP-Dependientes/metabolismo , Estrés ProteotóxicoRESUMEN
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 40â¯cm. A weighted vest was used to apply additional load, with a weight of 16â¯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 44-56â¯ms (p < 0.05) after contact. The subtalar joint was more eversion at 40-48â¯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.
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Articulación Talocalcánea , Soporte de Peso , Humanos , Masculino , Fenómenos Biomecánicos , Articulación Talocalcánea/fisiología , Articulación Talocalcánea/diagnóstico por imagen , Soporte de Peso/fisiología , Adulto Joven , Fluoroscopía , Adulto , Imagen por Resonancia Magnética , Astrágalo/fisiología , Astrágalo/diagnóstico por imagen , Imagenología Tridimensional , Torso/fisiología , Rango del Movimiento Articular/fisiología , Articulación del Tobillo/fisiologíaRESUMEN
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.
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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.
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Cadmio , Contaminantes Ambientales , Células Intersticiales del Testículo , Testículo , Testosterona , Ubiquitina-Proteína Ligasas , Masculino , Animales , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Cadmio/toxicidad , Testosterona/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismo , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Contaminantes Ambientales/toxicidad , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones Endogámicos C57BL , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genéticaRESUMEN
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.
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Embarazo Heterotópico , Ultrasonografía Prenatal , Humanos , Femenino , Embarazo , Adulto , Estudios Retrospectivos , Ultrasonografía Prenatal/métodos , Embarazo Heterotópico/diagnóstico por imagen , Adulto Joven , Resultado del Embarazo , Estudios de SeguimientoRESUMEN
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.
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Sistemas CRISPR-Cas , ARN Guía de Sistemas CRISPR-Cas , Sistemas CRISPR-Cas/genética , Edición Génica , Redes Neurales de la Computación , GenomaRESUMEN
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.
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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.
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Lenguaje , Semántica , Sesgo , Aprendizaje , Reconocimiento en PsicologíaRESUMEN
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.
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Sistemas CRISPR-Cas , ARN Guía de Sistemas CRISPR-Cas , Edición Génica , Genoma , GenómicaRESUMEN
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.
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Neoplasias Colorrectales , MicroARNs , ARN Largo no Codificante , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Luciferasas/metabolismo , Macrófagos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
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.
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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.