Downregulation of Splicing Factor PTBP1 Curtails FBXO5 Expression to Promote Cellular Senescence in Lung Adenocarcinoma.

Polypyrimidine tract-binding protein 1 (PTBP1) plays an essential role in splicing and post-transcriptional regulation. Moreover, PTBP1 has been implicated as a causal factor in tumorigenesis. However, the involvement of PTBP1 in cellular senescence, a key biological process in aging and cancer suppression, remains to be clarified. Here, it is shown that PTBP1 is associated with the facilitation of tumor growth and the prognosis in lung adenocarcinoma (LUAD). PTBP1 exhibited significantly increased expression in various cancer types including LUAD and showed consistently decreased expression in multiple cellular senescence models. Suppression of PTBP1 induced cellular senescence in LUAD cells. In terms of molecular mechanisms, the silencing of PTBP1 enhanced the skipping of exon 3 in F-box protein 5 (FBXO5), resulting in the generation of a less stable RNA splice variant, FBXO5-S, which subsequently reduces the overall FBXO5 expression. Additionally, downregulation of FBXO5 was found to induce senescence in LUAD. Collectively, these findings illustrate that PTBP1 possesses an oncogenic function in LUAD through inhibiting senescence, and that targeting aberrant splicing mediated by PTBP1 has therapeutic potential in cancer treatment.

Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines.

BACKGROUND: Information is limited regarding the effectiveness of the two-dose messenger RNA (mRNA) vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in attenuating coronavirus disease 2019 (Covid-19) when administered in real-world conditions. METHODS: We conducted a prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers. From December 14, 2020, to April 10, 2021, the participants completed weekly SARS-CoV-2 testing by providing mid-turbinate nasal swabs for qualitative and quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) analysis. The formula for calculating vaccine effectiveness was 100% × (1 - hazard ratio for SARS-CoV-2 infection in vaccinated vs. unvaccinated participants), with adjustments for the propensity to be vaccinated, study site, occupation, and local viral circulation. RESULTS: SARS-CoV-2 was detected in 204 participants (5%), of whom 5 were fully vaccinated (≥14 days after dose 2), 11 partially vaccinated (≥14 days after dose 1 and <14 days after dose 2), and 156 unvaccinated; the 32 participants with indeterminate vaccination status (<14 days after dose 1) were excluded. Adjusted vaccine effectiveness was 91% (95% confidence interval [CI], 76 to 97) with full vaccination and 81% (95% CI, 64 to 90) with partial vaccination. Among participants with SARS-CoV-2 infection, the mean viral RNA load was 40% lower (95% CI, 16 to 57) in partially or fully vaccinated participants than in unvaccinated participants. In addition, the risk of febrile symptoms was 58% lower (relative risk, 0.42; 95% CI, 0.18 to 0.98) and the duration of illness was shorter, with 2.3 fewer days spent sick in bed (95% CI, 0.8 to 3.7). CONCLUSIONS: Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infection when administered in real-world conditions, and the vaccines attenuated the viral RNA load, risk of febrile symptoms, and duration of illness among those who had breakthrough infection despite vaccination. (Funded by the National Center for Immunization and Respiratory Diseases and the Centers for Disease Control and Prevention.).

Sex-dependent associations of serum BDNF, glycolipid metabolism and cognitive impairments in Parkinson's disease with depression: a comprehensive analysis.

Brain-derived neurotrophic factor (BDNF) and glycolipid metabolism have been implicated in cognitive impairments and depression among Parkinson's disease (PD). However, the role of sex differences in this relationship remains elusive. This study aimed to investigate the potential sex differences in the link between serum BDNF levels, glycolipid metabolism and cognitive performance among depressive PD patients. PD patients comprising 108 individuals with depression and 108 without depression were recruited for this study. Cognitive function was assessed using the Montreal Cognitive Assessment Beijing version (MOCA-BJ). The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HAMD-17), while motor symptoms were evaluated using the Revised Hoehn and Yahr rating scale (H-Y) and the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). Laboratory testing and enzyme-linked immunosorbent assay (ELISA) are used to measure serum levels of glycolipid metabolism and BDNF. Females showed superior performance in delayed recall (all p < 0.05), male PD patients exhibited higher scores in naming tasks compared to females in non-depression group. There was no sex differences in serum BDNF levels between depression and non-depression groups. Liner regression analysis indicated BDNF as an independent risk factor for language deficits in male PD patients with depression (p < 0.05), while cholesterol (CHOL) emerged as a cognitive influencing factor, particularly in delayed recall among male PD patients with depression (p < 0.05). Our study reveals extensive cognitive impairments in PD patients with depression. Moreover, BDNF and CHOL may contribute to the pathological mechanisms underlying cognitive deficits, particularly in male patients with depression.

Autophagy markers, cognitive deficits and depressive symptoms in Parkinson's disease.

Depressive symptoms are common in Parkinson's disease (PD). The relationships between autophagy and PD or depression have been documented. However, no studies explored the role of autophagy markers associated with depressive symptoms in PD. Our study aimed to investigate the relationships between autophagy markers, cognitive impairments and depressive symptoms in PD patients. A total of 163 PD patients aged 50-80 years were recruited. Plasma concentrations of autophagy markers (LC3-I, LC3-II and p62/SQSTM1) and glycolipid parameters were measured. Depressive symptoms, cognitive impairments, and motor function were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MoCA), and the Movement Disorders Society Unified Parkinson's Rating Scale Part III (MDS-UPDRS-III), respectively. There were no significant differences between depressed and non-depressed PD patients for LC3-I, LC3-II, LC3-II/LC3-I and p62/SQSTM1. After controlling confounding variables, LC3-II/LC3-I showed an independent relationship with depressive symptoms in PD patients (Beta = 10.082, t = 2.483, p = 0.014). Moreover, in depressive PD patients, p62/SQSTM1 was associated with MoCA score (Beta = - 0.002, t = - 2.380, p = 0.020); Further, p62/SQSTM1 was related to naming ability; in addition, p62/SQSTM1 was independently associated with delayed recall (Beta = - 0.001, t = - 2.452, p = 0.017). LC3-II/LC3-I was related to depressive symptoms in PD patients. In depressive PD patients, p62/SQSTM1 was associated with cognitive function, especially naming ability and delayed recall.

High myoglobin level as an independent risk factor for death in elderly patients with critical COVID-19 infection: a retrospective case-control study.

AIM: This study aimed to discover risk factors for death in patients with critical COVID-19 infection in order to identify patients with a higher risk of death at an early stage. METHODS: We retrospectively analyzed the clinical data of patients with critical COVID-19 infection from April 2022 to June 2022. Data were collected from the electronic medical records. Propensity matching scores were used to reduce the effect of confounding factors, such as patient baseline variables. Independent risk factors affecting patient prognosis were assessed using univariate logistic regression and multivariate logistic regression analysis. Restricted cubic spline curves were used to assess the relationship between independent and dependent variables. RESULTS: The data of 132 patients with critical COVID-19 infection were included in the study. Of the 132 patients, 79 survived and 53 died. Among laboratory indicators, patients who died had higher proportions of abnormalities in procalcitonin, aspartate aminotransferase (AST), creatinine, cardiac troponin I, and myoglobin. Univariate and multivariate logistic regression analyses suggested that abnormal AST (OR = 4.98, P = 0.02), creatinine (OR = 7.93, P = 0.021), and myoglobin (OR = 103.08, P = 0.002) were independent risk factors for death. After correction for AST and creatinine, a linear relationship between myoglobin and risk of death in patients was found using restricted cubic splines. CONCLUSION: High myoglobin level is an independent risk factor for death and is therefore a prognostic marker in elderly patients with severe COVID-19 infection.

A novel lncRNA TCONS_00071187 upregulated by activated GSK3ß promotes high glucose-induced mesangial cell proliferation in the diabetic nephropathy.

Inhibiting mesangial cell proliferation is one of the strategies to control the early progression of diabetic nephropathy (DN). GSK3ß is closely related to cell apoptosis as well as the development of DN, but whether it acts on the proliferation of mesangial cells is unclear. This study aimed to elucidate the role and mechanism of GSK3ß-mediated lncRNA in high glucose-induced mesangial cell proliferation. HBZY-1 cells were used to establish the cell model of DN. The automatic cell counter was applied to assess cell proliferation. Flow cytometry was used to detect cell apoptosis and intracellular ROS levels. High-throughput transcriptomics sequencing was performed to detect the different expressions of long noncoding RNAs (lncRNAs) in the cell model of DN after knocking down the expression of GSK3ß by the transfection of siRNA. The expression of RNA was detected by real-time PCR. In the cell model of DN using HBZY-1 cells, cell proliferation was enhanced accompanied by GSK3ß activation and elevated apoptosis rate and reactive oxygen species (ROS) levels. A panel of novel lncRNAs, which were differentially expressed after GSK3ß knockdown in the cell model of DN, were identified by high-throughput transcriptomics sequencing. Among them, the expression of TCONS_00071187 was upregulated under high glucose conditions while the knockdown of the GSK3ß expression led to the downregulation of TCONS_00071187. The knockdown of TCONS_00071187 resulted in reduced mesangial cell proliferation, and decreased apoptosis rates and ROS levels. In conclusion, GSK3ß promoted mesangial cell proliferation by upregulating TCONS_00071187, which led to enhanced ROS production under high glucose conditions in the cell model of DN. This study revealed the role of GSK3ß medicated lncRNAs in the development of DN.

The Diagnostic Value of Carnett's Test with Chronic Abdominal Pain: A Narrative Review.

PURPOSE OF REVIEW: Chronic abdominal wall pain is a poorly recognized cause of chronic abdominal pain, and patients frequently go misdiagnosed despite a battery of medical tests. The Carnett's test is a diagnostic tool used to distinguish between abdominal wall pain and visceral pain. This review synthesizes the current literature on the Carnett's test, merges the viewpoints of diverse writers, and evaluates and reports on the Carnett's test's applicability. RECENT FINDINGS: Several clinical investigations have established the usefulness of the Carnett's test in the diagnosis of chronic abdominal wall pain. Furthermore, the Carnett's test is quite useful in determining the depth of the mass and detecting psychogenic abdominal pain. However, its diagnostic use for acute abdominal pain is limited. The Carnett's test is a simple and safe point-of-care diagnostic technique, with several studies supporting its usefulness. Early detection of abdominal wall pain is critical for chronic abdominal wall pain therapy. Carnett's test is very useful in patients with chronic, unexplained local abdominal discomfort who are compliant and do not have a clear rationale for surgery.

Discharge preparation experiences and needs of intergenerational caregivers of neonatal intensive care unit preterm: A qualitative study.

PURPOSE: This study aimed to explore the real experiences and needs of neonatal intensive care unit (NICU) preterm intergenerational caregivers for discharge preparation and provide a basis for nursing staff to formulate systemic and personalized health education plans and continuous nursing plans for preterm discharge. DESIGN AND METHODS: This was a descriptive qualitative study. An objective sampling method was used to select 16 intergenerational caregivers of preterm infants admitted to the NICU of tertiary obstetrics and gynecology hospitals in Zhejiang and Jilin provinces from December 2023 to February 2024. Semi-structured interviews were conducted on the day of discharge of the preterm infants and six weeks after discharge. Colaizzi's seven-step analysis method was used to analyze the interview data. RESULTS: Based on the existence, relatedness, and growth (ERG) theory, the discharge preparation experiences and needs of neonatal intergenerational caregivers in the NICU were summarized into three themes: psychological condition, care capacity condition, and multi-party support needs. CONCLUSIONS: In the process of hospital discharge preparation, intergenerational caregivers of premature infants in NICU have multiple needs, including enhancing nursing ability and obtaining psychological and multi-party support. It is helpful to take effective interventions to improve their readiness for discharge. PRACTICE IMPLICATIONS: The nursing staff should develop personalized discharge health education plans and continuous nursing plans to improve the level of discharge preparation. PATIENT OR PUBLIC CONTRIBUTIONS: There were no patient or public contributions.

Comparison of evaluation metrics of deep learning for imbalanced imaging data in osteoarthritis studies.

PURPOSE: To compare the evaluation metrics for deep learning methods that were developed using imbalanced imaging data in osteoarthritis studies. MATERIALS AND METHODS: This retrospective study utilized 2996 sagittal intermediate-weighted fat-suppressed knee MRIs with MRI Osteoarthritis Knee Score readings from 2467 participants in the Osteoarthritis Initiative study. We obtained probabilities of the presence of bone marrow lesions (BMLs) from MRIs in the testing dataset at the sub-region (15 sub-regions), compartment, and whole-knee levels based on the trained deep learning models. We compared different evaluation metrics (e.g., receiver operating characteristic (ROC) and precision-recall (PR) curves) in the testing dataset with various class ratios (presence of BMLs vs. absence of BMLs) at these three data levels to assess the model's performance. RESULTS: In a subregion with an extremely high imbalance ratio, the model achieved a ROC-AUC of 0.84, a PR-AUC of 0.10, a sensitivity of 0, and a specificity of 1. CONCLUSION: The commonly used ROC curve is not sufficiently informative, especially in the case of imbalanced data. We provide the following practical suggestions based on our data analysis: 1) ROC-AUC is recommended for balanced data, 2) PR-AUC should be used for moderately imbalanced data (i.e., when the proportion of the minor class is above 5% and less than 50%), and 3) for severely imbalanced data (i.e., when the proportion of the minor class is below 5%), it is not practical to apply a deep learning model, even with the application of techniques addressing imbalanced data issues.

Sex- and age-specific prevalence and risk factors of depressive symptoms in Parkinson's disease.

Although depressive symptoms are common in PD, few studies investigated sex and age differences in depressive symptoms. Our study aimed to explore the sex and age differences in the clinical correlates of depressive symptoms in patients with PD. 210 PD patients aged 50-80 were recruited. Levels of glucose and lipid profiles were measured. The Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MoCA) and the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) assessed depressive symptom, cognition and motor function, respectively. Male depressive PD participants had higher fasting plasma glucose (FPG) levels. Regarding the 50-59 years group, depressive patients had higher TG levels. Moreover, there were sex and age differences in the factors associated with severity of depressive symptoms. In male PD patients, FPG was an independent contributor to HAMD-17 (Beta = 0.412, t = 4.118, p < 0.001), and UPDRS-III score was still associated with HAMD-17 in female patients after controlling for confounding factors (Beta = 0.304, t = 2.961, p = 0.004). Regarding the different age groups, UPDRS-III (Beta = 0.426, t = 2.986, p = 0.005) and TG (Beta = 0.366, t = 2.561, p = 0.015) were independent contributors to HAMD-17 in PD patients aged 50-59. Furthermore, non-depressive PD patients demonstrated better performance with respect to visuospatial/executive function among the 70-80 years group. These findings suggest that sex and age are crucial non-specific factors to consider when assessing the relationship between glycolipid metabolism, PD-specific factors and depression.

The relationship between inflammatory markers, clinical characteristics, and cognitive performance in drug-naïve patients with schizophrenia.

Increasing evidence implicates that inflammatory factors do play a crucial role in the pathophysiology of schizophrenia. However, the association between inflammatory markers and different symptom dimensions and cognitive function of schizophrenia remains unclear. A total of 140 drug-naïve patients with schizophrenia and 69 healthy controls matched for age and gender were enrolled. Peripheral blood plasma concentrations of S-100 calcium-binding protein B (S100B), neutrophil gelatinase-associated lipocalin (NGAL), and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assay (ELISA). Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Compared with healthy controls, patients with schizophrenia had significantly worse cognitive function and lower levels of NGAL and IFN-γ (P < 0.001). In schizophrenia, plasma NGAL and IFN-γ levels negatively correlated with positive symptom scores (all P < 0.05). There was a positive correlation between plasma levels of NGAL and IFN-γ with visual learning, neurocognition, and MCCB total score (all P < 0.05). We found that NGAL levels (ß = 0.352, t = 5.553, 95% CI 0.228-0.477, P < 0.001) and negative symptoms subscale scores (ß = - 0.321, OR = 0.725, 95% CI 648-0.811, P < 0.001) were independently associated with the MCCB total score. Further, binary logistic regression analysis indicated that the concentrations of NGAL (ß = - 0.246, OR = 0.782, 95% CI 0.651-0.939, P = 0.008) were independently associated with the diagnosis of schizophrenia. There was a positive correlation between NGAL and IFN-γ levels and MCCB total score in schizophrenia. NGAL level was an independent protective factor for cognitive function and an independent risk factor for the diagnosis of schizophrenia.

Negative symptoms and neurocognition in drug-naïve schizophrenia: moderating role of plasma neutrophil gelatinase-associated lipocalin (NGAL) and interferon-gamma (INF-γ).

Previous studies reported that peripheral inflammation was associated with cognitive performance and brain structure in schizophrenia. However, the moderating effect of inflammation has not been extensively studied. This study investigated whether inflammation markers moderated the association between negative symptoms and neurocognition in schizophrenia. This cross-sectional study included 137 drug-naïve schizophrenia patients (DNS) and 67 healthy controls (HC). We performed the Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for cognitive assessment and the Positive and Negative Syndrome Scale (PANSS) for psychiatric symptoms. Plasma concentrations of interferon-gamma (IFN-γ), neutrophil gelatinase-associated lipocalin (NGAL), and nuclear factor kappa B (NF-κB) were measured. The MCCB neurocognition score, social cognition score, and total score; the plasma concentrations of NGAL, IFN-γ, and NF-κB were significantly decreased in DNS than in HC (all P's < 0.001). PANSS negative subscale (PNS), PANSS reduced expressive subdomain (RES) negatively correlated with neurocognition score (P = 0.007; P = 0.011, respectively). Plasma concentrations of IFN-γ and NGAL positively correlated with neurocognition score (P = 0.043; P = 0.008, relatively). The interactions of PNS × NGAL; PNS × IFN-γ; RES × IFN-γ accounted for significant neurocognition variance (P = 0.025; P = 0.029, P = 0.007, respectively). Simple slope analysis showed that all the above moderating effects only occurred in patients with near normal IFN-γ and NGAL levels. Plasma concentrations of IFN-γ and NGAL moderated the relationship between negative symptoms (especially RES) and neurocognition in schizophrenia. Treatment targeting inflammation may contribute to neurocognition improvement in schizophrenia.

Mitochondrial Methionyl-tRNA Formyltransferase Deficiency Alleviates Metaflammation by Modulating Mitochondrial Activity in Mice.

Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-κB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases.

Cognition, motor symptoms, and glycolipid metabolism in Parkinson's disease with depressive symptoms.

Depressive symptoms and abnormal glycolipid metabolisms are common in patients with Parkinson's disease (PD), but their relationship has not been fully reported. It is not clear whether glycolipid impairments lead to poor cognitive and motor function, and aggravate depressive symptoms. Therefore, we aimed to explore the relationships between glycolipid variables, cognition, motor and depressive symptoms in PD patients cross-sectionally. Two hundred ten PD patients were recruited. Glycolipid parameters and Uric acid (UA) were measured. Depressive symptoms, cognitive function and motor symptoms were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MOCA) and the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part-III (UPDRS-III). Depressive PD patients had significantly worse motor symptoms and higher levels of fasting plasma glucose (FPG) than those in non-depressive patients (F = 24.145, P < 0.001). Further, logistic regression analysis indicated that UPDRS-III (OR = 1.039, 95% CI 1.019-1.057, P = 0.044), FPG (OR = 1.447, 95% CI 1.050-1.994, P = 0.024) were independently associated with depression. In PD patients without depression, UA (ß = - 0.068, t = - 2.913, P = 0.005) and cholesterol (CHOL) (ß = - 3.941, t = - 2.518, P = 0.014) were independent predictors of the UPDRS-III score; in addition, UPDRS-III score was negatively associated with MOCA score (ß = - 0.092, t = - 2.791, P = 0.007). FPG levels and motor symptoms were related to depressive symptoms in PD patients. Further, in non-depressive PD patients, UA and CHOL showed putative biomarkers of motor symptoms.

Problematic utilization of online social networking site in Chinese college students: prediction of personality and dynamic mediators.

Utilization of online social networking sites (SNSs) is often problematic in young people. However, studies seldom seek to understand personal differences and deep-seated reasons in its problematic utilization. This study aims to explore the longstanding and recent psychosocial predictors of problematic utilization of WeChat friend center (PUWF) longitudinally. A total of 433 college students (17-25 years old, male/female ratio: 389/44) were investigated over 2 successive years (T1: first year; T2: second year) using the Sixteen Personality Factor Questionnaire, Adolescent Self-Rating Life Events Checklist, Social Support Scale, Patient Health Questionnaire, Connor-Davidson Resilience Scale, and the problematic utilization scale of the WeChat friend center which was developed in this study. Correlation, regression, and structural equation analyses were conducted. A problematic utilization scale of the WeChat friend center was developed with Cronbach's alpha of .836. 21.02% of students reported WeChat PUWF. Males utilized the WeChat friend center less than females, and females were at higher risk of PUWF, which was correlated with worse mental health. In the longitudinal prediction, regression and modeling analyses showed that apprehension of personality predicted PUWF consistently and directly, and this was partially mediated by T1 depression and T2 negative life events. Resultys suggest that females are at higher risk for PUWF. Apprehension personality has a direct and indirect effect on PUWF through recent depression and life events. The findings help to recognize individuals at risk for PUWF as well as to better prevent it, and provide suggestions as to the functional design of SNSs according to different need of users. Core tips: Utilization of SNSs is often problematic in young people. However, personal differences and deep-seated reasons in its problematic utilization has been poorly revealed. Through a longitudinal investigation, this study confirms that females are at higher risk for PUWF. Apprehension personality has a direct and indirect effect on PUWF through recent depression and life events. The findings help to recognize individuals at risk for PUWF and give theoretical evidence to the functional design of SNSs for diferent users. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-03150-7.

[Angiodynamic and optical coupling analysis of skin tissue model under finite pressure].

The pulse amplitude of fingertip volume could be improved by selecting the vascular dense area and applying appropriate pressure above it. In view of this phenomenon, this paper used Comsol Multiphysics 5.6 (Comsol, Sweden), the finite element analysis software of multi-physical field coupling simulation, to establish the vascular tissue model of a single small artery in fingertips for simulation. Three dimensional Navier-Stokes equations were solved by finite element method, the velocity field and pressure distribution of blood were calculated, and the deformation of blood vessels and surrounding tissues was analyzed. Based on Lambert Beer's Law, the influence of the longitudinal compression displacement of the lateral light surface region and the tissue model on the light intensity signal is investigated. The results show that the light intensity signal amplitude could be increased and its peak value could be reduced by selecting the area with dense blood vessels. Applying deep pressure to the tissue increased the amplitude and peak of the signal. It is expected that the simulation results combined with the previous experimental experience could provide a feasible scheme for improving the quality of finger volume pulse signal.

Dysfunction in Sertoli cells participates in glucocorticoid-induced impairment of spermatogenesis.

The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage-specific marker antigen F4/80 as well as inflammation-related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism-related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone-treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase-4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone-induced impairment of spermatogenesis.

A new screening strategy and whole-exome sequencing for the early diagnosis of maturity-onset diabetes of the young.

AIMS: This study aimed to establish a systematic screening strategy to select candidates for genetic testing among patients with maturity-onset diabetes of the young (MODY) and to accomplish early diagnosis of MODY. MATERIALS AND METHODS: We enrolled 1478 sporadic patients from the outpatient department of endocrinology. Out of the1478 patients, 1279 participants were successfully screened according to the "AACM" strategy, which includes the age of onset, autoantibody to islet antigen, C-peptide and metabolic syndrome. Another six probands and their families who fulfilled the common clinical criteria for MODY were also examined for causative gene mutations. Whole-exome sequencing (WES) was performed to examine the mutations. RESULTS: A total of 24 out of 1279 sporadic patients with newly diagnosed diabetes were eligible for genetic testing. Mutations were found in 4/24 participants in the cohort, as well as in 2/6 pedigrees. A likely pathogenic alteration, a likely benign alteration and three alterations with uncertain significance were identified with WES. Most of the mutant genes recognised in our trial were not the most common causative genes of MODY, and all of the mutations were specifically reported in Asian patients only, suggesting a unique genetic background of MODY in different ethnicities. CONCLUSIONS: In this systematic study of MODY in a new-onset diabetes cohort, MODY cases were incorrectly diagnosed as type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), suggesting that an observant clinician is necessary for early and correct MODY diagnosis. This systematic approach to screening is practical and specific enough to identify patients who are most appropriate for genetic testing.

Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers - Eight U.S. Locations, December 2020-March 2021.

Messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines have been shown to be effective in preventing symptomatic COVID-19 in randomized placebo-controlled Phase III trials (1,2); however, the benefits of these vaccines for preventing asymptomatic and symptomatic SARS-CoV-2 (the virus that causes COVID-19) infection, particularly when administered in real-world conditions, is less well understood. Using prospective cohorts of health care personnel, first responders, and other essential and frontline workers* in eight U.S. locations during December 14, 2020-March 13, 2021, CDC routinely tested for SARS-CoV-2 infections every week regardless of symptom status and at the onset of symptoms consistent with COVID-19-associated illness. Among 3,950 participants with no previous laboratory documentation of SARS-CoV-2 infection, 2,479 (62.8%) received both recommended mRNA doses and 477 (12.1%) received only one dose of mRNA vaccine.† Among unvaccinated participants, 1.38 SARS-CoV-2 infections were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) per 1,000 person-days.§ In contrast, among fully immunized (≥14 days after second dose) persons, 0.04 infections per 1,000 person-days were reported, and among partially immunized (≥14 days after first dose and before second dose) persons, 0.19 infections per 1,000 person-days were reported. Estimated mRNA vaccine effectiveness for prevention of infection, adjusted for study site, was 90% for full immunization and 80% for partial immunization. These findings indicate that authorized mRNA COVID-19 vaccines are effective for preventing SARS-CoV-2 infection, regardless of symptom status, among working-age adults in real-world conditions. COVID-19 vaccination is recommended for all eligible persons.

Transcriptional regulation of autophagy by an FXR-CREB axis.

Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions. Acute regulation of autophagy by nutrient-sensing kinases is well defined, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor farnesoid X receptor (FXR) and the fasting transcriptional activator cAMP response element-binding protein (CREB) coordinately regulate the hepatic autophagy gene network. Pharmacological activation of FXR repressed many autophagy genes and inhibited autophagy even in fasted mice, and feeding-mediated inhibition of macroautophagy was attenuated in FXR-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data, FXR and CREB binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted autophagic degradation of lipids, or lipophagy, under nutrient-deprived conditions, and FXR inhibited this response. Mechanistically, CREB upregulated autophagy genes, including Atg7, Ulk1 and Tfeb, by recruiting the coactivator CRTC2. After feeding or pharmacological activation, FXR trans-repressed these genes by disrupting the functional CREB-CRTC2 complex. This study identifies the new FXR-CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.