The role of serine/threonine protein kinases in cardiovascular disease and potential therapeutic methods.

Protein phosphorylation is an important link in a variety of signaling pathways, and most of the important life processes in cells involve protein phosphorylation. Based on the amino acid residues of phosphorylated proteins, protein kinases can be categorized into the following families: serine/threonine protein kinases, tyrosine-specific protein kinases, histidine-specific protein kinases, tryptophan kinases, and aspartate/glutamyl protein kinases. Of all the protein kinases, most are serine/threonine kinases, where serine/threonine protein kinases are protein kinases that catalyze the phosphorylation of serine or threonine residues on target proteins using ATP as a phosphate donor. The current socially accepted classification of serine/threonine kinases is to divide them into seven major groups: protein kinase A, G, C (AGC), CMGC, Calmodulin-dependent protein kinase (CAMK), Casein kinase (CK1), STE, Tyrosine kinase (TKL) and others. After decades of research, a preliminary understanding of the specific classification and respective functions of serine/threonine kinases has entered a new period of exploration. In this paper, we review the literature of the previous years and introduce the specific signaling pathways and related therapeutic modalities played by each of the small protein kinases in the serine/threonine protein kinase family, respectively, in some common cardiovascular system diseases such as heart failure, myocardial infarction, ischemia-reperfusion injury, and diabetic cardiomyopathy. To a certain extent, the current research results, including molecular mechanisms and therapeutic methods, are fully summarized and a systematic report is made for the prevention and treatment of cardiovascular diseases in the future.

Multi-functional nanozyme-based colorimetric, fluorescence dual-mode assay for Salmonella typhimurium detection in milk.

Rapid and high-sensitive Salmonella detection in milk is important for preventing foodborne disease eruption. To overcome the influence of the complex ingredients in milk on the sensitive detection of Salmonella, a dual-signal reporter red fluorescence nanosphere (RNs)-Pt was designed by combining RNs and Pt nanoparticles. After being equipped with antibodies, the immune RNs-Pt (IRNs-Pt) provide an ultra-strong fluorescence signal when excited by UV light. With the assistance of the H2O2/TMB system, a visible color change appeared that was attributed to the strong peroxidase-like catalytic activity derived from Pt nanoparticles. The IRNs-Pt in conjunction with immune magnetic beads can realize that Salmonella typhimurium (S. typhi) was captured, labeled, and separated effectively from untreated reduced-fat pure milk samples. Under the optimal experimental conditions, with the assay, as low as 50 CFU S. typhi can be converted to detectable fluorescence and absorbance signals within 2 h, suggesting the feasibility of practical application of the assay. Meanwhile, dual-signal modes of quantitative detection were realized. For fluorescence signal detection (emission at 615 nm), the linear correlation between signal intensity and the concentration of S. typhi was Y = 83C-3321 (R2 = 0.9941), ranging from 103 to 105 CFU/mL, while for colorimetric detection (absorbamce at 450 nm), the relationship between signal intensity and the concentration of S. typhi was Y = 2.9logC-10.2 (R2 = 0.9875), ranging from 5 × 103 to 105 CFU/mL. For suspect food contamination by foodborne pathogens, this dual-mode signal readout assay is promising for achieving the aim of convenient preliminary screening and accurate quantification simultaneously.

Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches.

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

SERT and OCT mediate 5-HT1B receptor regulation of immobility behavior and uptake of 5-HT and HIS.

5-HT clearance, commonly mediated by transporters in the uptake-1 and uptake-2 families, has been linked to 5-HT1B receptor's action on behaviors. Since no specific transporters identified yet, effects of serotonin transporter (SERT) and organic cation transporter (OCTs) on 5-HT1B-elicited immobility phenotype, and 5-HT and HIS uptake were then investigated. Intraperitoneal injections of SERT inhibitor fluoxetine (FLX) and/or OCTs inhibitor decynium (D22) were used prior to local perfusion of 5-HT1B agonist CP93129 into the ventral hippocampus to measure immobility times in the FST and TST, to measure 5-HT uptake efficiencies and HIS uptake efficiencies derived from linear regressions using the transient no-net-flux quantitative microdialysis in C57BL/6 mice. Exogenous 5-HT and HIS uptake were measured following incubation of FLX and/or D22 with CP93129 in the RBL-2H3 cells. Moreover, surface membrane levels of SERT and OCT were detected in response to CP93129. Local CP93129 prolonged immobility times, which were attenuated following pretreatment of either inhibitor. Local CP93129 lowered the slopes obtained from the lineal regressions for 5-HT and HIS (slope is reciprocal to uptake efficiency), which were then weakened following pretreatment of either inhibitor. Similar findings were obtained following CP93129 incubation, and co-incubation of CP93129 with either inhibitor in the RBL-2H3. Moreover, CP93129 dose-dependently moved SERT and OCT3 in the cytosol to the surface membrane. Both SERT and OCT are the target effectors mediating 5-HT1B regulation of immobility time and 5-HT uptake, OCT mediates 5-HT1B regulation of HIS uptake. Their underlying signal transductions need to be further explored.

Variations in the persistence of 5'-end genomic and subgenomic SARS-CoV-2 RNAs in wastewater from aircraft, airports and wastewater treatment plants.

Wastewater sequencing has become a powerful supplement to clinical testing in monitoring SARS-CoV-2 infections in the post-COVID-19 pandemic era. While its applications in measuring the viral burden and main circulating lineages in the community have proved their efficacy, the variations in sequencing quality and coverage across the different regions of the SARS-CoV-2 genome are not well understood. Furthermore, it is unclear how different sample origins, viral extraction and concentration methods and environmental factors impact the reads sequenced from wastewater. Using high-coverage, amplicon-based, paired-end read sequencing of viral RNA extracted from wastewater collected directly from aircraft, pooled from different aircraft and airport buildings or from regular wastewater plants, we assessed the genome coverage across the sample groups with a focus on the 5'-end region covering the leader sequence and investigated whether it was possible to detect subgenomic RNA from viral material recovered from wastewater. We identified distinct patterns in the persistence of the different genomic regions across the different types of wastewaters and the existence of chimeric reads mapping to non-amplified regions. Our findings suggest that preservation of the 5'-end of the genome and the ability to detect subgenomic RNA reads, though highly susceptible to environment and sample processing conditions, may be indicative of the quality and amount of the viral RNA present in wastewater.

Azathioprine/hydroxyurea preconditioning prior to nonmyeloablative matched sibling donor hematopoietic stem cell transplantation in adults with sickle cell disease: A prospective observational cohort study.

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.

Polymorphic markers of several immune regulatory genes modulate the susceptibility for eczema and related phenotypes in children.

Background: Eczema is associated with multiple genes regulating epidermal barrier functions and immunological pathways. However, their epistatic interactions are not well studied. This cross-sectional study investigated the relationship between childhood eczema phenotypes and single-nucleotide polymorphisms (SNPs) of immune regulatory genes. Methods: One thousand three hundred and twenty-nine Chinese eczematous children and 1,179 non-allergic controls were recruited. Nine SNPs of immune regulatory genes signal transducer and activator of transcription 3 (STAT3), interleukin-10 (IL10), transforming growth factor-beta 1 (TGFB1), and IL-6 receptor (IL6R) were genotyped by TaqMan genotyping assays. Logistic regression was used to analyze the associations between SNPs and eczema phenotypes. Generalized multifactor dimensionality reduction (GMDR) was used to examine epistatic interactions among these SNPs as well as those reported by our group [filaggrin (FLG) and 11q13] for eczema phenotypes. Results: TGFB1_rs1800469 was found to be associated with eczema [odds ratio (OR), 0.82; 95% confidence interval (CI): 0.73-0.92; P=0.001], atopic eczema (OR, 0.83; 95% CI: 0.72-0.95; P=0.009) and allergic rhinitis (OR, 0.84; 95% CI: 0.74-0.95; P=0.005). We also found a trend between IL10_rs1800872 and increased total immunoglobulin E (IgE) levels (P=0.009). Epistatic interaction among IL10_rs3021094, TGFB1_rs1800469, IL6R_rs2228145, and STAT3_rs4796793 were found for total IgE [testing accuracy (TA), 0.551; cross-validation consistency (CVC), 10; P=0.014]. Mean log-transformed total IgE (logIgE) levels in high-risk cases, low-risk cases, high-risk controls, and low-risk controls were 2.75, 2.60, 1.90, and 1.81 respectively (P=0.019 for trend). Conclusions: Functional TGFB1 polymorphism is associated with both eczema and allergic rhinitis, suggesting the role of TGF-ß1 in allergy susceptibility. IL10 may be associated with increased total IgE levels. Interaction among immune regulatory genes modulates total IgE levels.

Genome Mining of a Fungal Polyketide Synthase-Nonribosomal Peptide Synthetase Hybrid Megasynthetase Pathway to Synthesize a Phytotoxic N-Acyl Amino Acid.

Guided by the retrobiosynthesis hypothesis, we characterized a fungal polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrid megasynthetase pathway to generate 2-trans-4-trans-2-methylsorbyl-d-leucine (1), a polyketide amino acid conjugate that inhibits Arabidopsis root growth. The biosynthesis of 1 includes a PKS-NRPS enzyme to assemble an N-acyl amino alcohol intermediate, which is further oxidized to an N-acyl amino acid (NAAA), demonstrating a new biosynthetic logic for synthesizing NAAAs and expanding the chemical space of products encoded by fungal PKS-NRPS clusters.

Bayesian analysis of joint quantile regression for multi-response longitudinal data with application to primary biliary cirrhosis sequential cohort study.

This article proposes a Bayesian approach for jointly estimating marginal conditional quantiles of multi-response longitudinal data with multivariate mixed effects model. The multivariate asymmetric Laplace distribution is employed to construct the working likelihood of the considered model. Penalization priors on regression parameters are incorporated into the working likelihood to conduct Bayesian high-dimensional inference. Markov chain Monte Carlo algorithm is used to obtain the fully conditional posterior distributions of all parameters and latent variables. Monte Carlo simulations are conducted to evaluate the sample performance of the proposed joint quantile regression approach. Finally, we analyze a longitudinal medical dataset of the primary biliary cirrhosis sequential cohort study to illustrate the real application of the proposed modeling method.

Water and Air Stable Copper(I) Complexes of Tetracationic Catenane Ligands for Oxidative C-C Cross-Coupling.

Aqueous soluble and stable Cu(I) molecular catalysts featuring a catenane ligand composed of two dicationic, mutually repelling but mechanically interlocked macrocycles are reported. The ligand interlocking not only fine-tunes the coordination sphere and kinetically stabilizes the Cu(I) against air oxidation and disproportionation, but also buries the hydrophobic portions of the ligands and prevents their dissociation which are necessary for their good water solubility and a sustained activity. These catenane Cu(I) complexes can catalyze the oxidative C-C coupling of indoles and tetrahydroisoquinolines in water, using H2O2 as a green oxidant with a good substrate scope. The successful use of catenane ligands in exploiting aqueous Cu(I) catalysis thus highlights the many unexplored potential of mechanical bond as a design element for exploring transition metal catalysis under challenging conditions.

Optimization system for training efficiency and load balance based on the fusion of heart rate and inertial sensors.

Objectives: To enhance the daily training quality of athletes without inducing significant physiological fatigue, aiming to achieve a balance between training efficiency and load. Design methods: Firstly, we developed an activity classification training model using the random forest algorithm and introduced the "effective training rate" (the ratio of effective activity time to total time) as a metric for assessing athlete training efficiency. Secondly, a method for rating athlete training load was established, involving qualitative and quantitative analyses of physiological fatigue through subjective fatigue scores and heart rate data. Lastly, an optimization system for training efficiency and load balance, utilizing multiple inertial sensors, was created. Athlete states were categorized into nine types based on the training load and efficiency ratings, with corresponding management recommendations provided. Results: Overall, this study, combining a sports activity recognition model with a physiological fatigue assessment model, has developed a training efficiency and load balance optimization system with excellent performance. The results indicate that the prediction accuracy of the sports activity recognition model is as high as 94.70%. Additionally, the physiological fatigue assessment model, utilizing average relative heart rate and average RPE score as evaluation metrics, demonstrates a good overall fit, validating the feasibility of this model. Conclusions: This study, based on relative heart rate and wearable devices to monitor athlete physiological fatigue, has developed a balanced optimization system for training efficiency and load. It provides a reference for athletes' physical health and fatigue levels, offering corresponding management recommendations for coaches and relevant professionals.

Prevalence of autoimmune diseases in patients with sickle cell disease: a single center retrospective analysis.

Not available.

Deuteration-enhanced neutron contrasts to probe amorphous domain sizes in organic photovoltaic bulk heterojunction films.

An organic photovoltaic bulk heterojunction comprises of a mixture of donor and acceptor materials, forming a semi-crystalline thin film with both crystalline and amorphous domains. Domain sizes critically impact the device performance; however, conventional X-ray scattering techniques cannot detect the contrast between donor and acceptor materials within the amorphous intermixing regions. In this study, we employ neutron scattering and targeted deuteration of acceptor materials to enhance the scattering contrast by nearly one order of magnitude. Remarkably, the PM6:deuterated Y6 system reveals a new length scale, indicating short-range aggregation of Y6 molecules in the amorphous intermixing regions. All-atom molecular dynamics simulations confirm that this short-range aggregation is an inherent morphological advantage of Y6 which effectively assists charge extraction and suppresses charge recombination as shown by capacitance spectroscopy. Our findings uncover the amorphous nanomorphology of organic photovoltaic thin films, providing crucial insights into the morphology-driven device performance.

Ultrasimple size encoded microfluidic chip for rapid simultaneous multiplex detection of DNA sequences.

Simultaneous multiplexed analysis can provide comprehensive information for disease diagnosis. However, the current multiplex methods rely on sophisticated barcode technology, which hinders its wider application. In this study, an ultrasimple size encoding method is proposed for multiplex detection using a wedge-shaped microfluidic chip. Driving by negative pressure, microparticles are naturally arranged in distinct stripes based on their sizes within the chip. This size encoding method demonstrates a high level of precision, allowing for accuracy in distinguishing 3-5 sizes of microparticles with a remarkable accuracy rate of up to 99%, even the microparticles with a size difference as small as 0.5 µm. The entire size encoding process is completed in less than 5 min, making it ultrasimple, reliable, and easy to operate. To evaluate the function of this size encoding microfluidic chip, three commonly co-infectious viruses' nucleic acid sequences (including complementary DNA sequences of HIV and HCV, and DNA sequence of HBV) are employed for multiplex detection. Results indicate that all three DNA sequences can be sensitively detected without any cross-interference. This size-encoding microfluidic chip-based multiplex detection method is simple, rapid, and high-resolution, its successful application in serum samples renders it highly promising for potential clinical promotion.

Sample size determination for interval estimation of the prevalence of a sensitive attribute under non-randomized response models.

A sufficient number of participants should be included to adequately address the research interest in the surveys with sensitive questions. In this paper, sample size formulas/iterative algorithms are developed from the perspective of controlling the confidence interval width of the prevalence of a sensitive attribute under four non-randomized response models: the crosswise model, parallel model, Poisson item count technique model and negative binomial item count technique model. In contrast to the conventional approach for sample size determination, our sample size formulas/algorithms explicitly incorporate an assurance probability of controlling the width of a confidence interval within the pre-specified range. The performance of the proposed methods is evaluated with respect to the empirical coverage probability, empirical assurance probability and confidence width. Simulation results show that all formulas/algorithms are effective and hence are recommended for practical applications. A real example is used to illustrate the proposed methods.

An Improved Nested U-Net Network for Fluorescence In Situ Hybridization Cell Image Segmentation.

Fluorescence in situ hybridization (FISH) is a powerful cytogenetic method used to precisely detect and localize nucleic acid sequences. This technique is proving to be an invaluable tool in medical diagnostics and has made significant contributions to biology and the life sciences. However, the number of cells is large and the nucleic acid sequences are disorganized in the FISH images taken using the microscope. Processing and analyzing images is a time-consuming and laborious task for researchers, as it can easily tire the human eyes and lead to errors in judgment. In recent years, deep learning has made significant progress in the field of medical imaging, especially the successful application of introducing the attention mechanism. The attention mechanism, as a key component of deep learning, improves the understanding and interpretation of medical images by giving different weights to different regions of the image, enabling the model to focus more on important features. To address the challenges in FISH image analysis, we combined medical imaging with deep learning to develop the SEAM-Unet++ automated cell contour segmentation algorithm with integrated attention mechanism. The significant advantage of this algorithm is that it improves the accuracy of cell contours in FISH images. Experiments have demonstrated that by introducing the attention mechanism, our method is able to segment cells that are adherent to each other more efficiently.

Creating pairs of exceptional points for arbitrary polarization control: asymmetric vectorial wavefront modulation.

Exceptional points (EPs) can achieve intriguing asymmetric control in non-Hermitian systems due to the degeneracy of eigenstates. Here, we present a general method that extends this specific asymmetric response of EP photonic systems to address any arbitrary fully-polarized light. By rotating the meta-structures at EP, Pancharatnam-Berry (PB) phase can be exclusively encoded on one of the circular polarization-conversion channels. To address any arbitrary wavefront, we superpose the optical signals originating from two orthogonally polarized -yet degenerate- EP eigenmodes. The construction of such orthogonal EP eigenstates pairs is achieved by applying mirror-symmetry to the nanostructure geometry flipping thereby the EP eigenmode handedness from left to right circular polarization. Non-Hermitian reflective PB metasurfaces designed using such EP superposition enable arbitrary, yet unidirectional, vectorial wavefront shaping devices. Our results open new avenues for topological wave control and illustrate the capabilities of topological photonics to distinctively operate on arbitrary polarization-state with enhanced performances.

Potential Interaction between WNT16 and Vitamin D on Bone Qualities in Adolescent Idiopathic Scoliosis Patients and Healthy Controls.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal deformity that is associated with low bone mineral density (BMD). Vitamin D (Vit-D) supplementation has been suggested to improve BMD in AIS, and its outcomes may be related to genetic factors. The present study aimed to (a) investigate the synergistic effect between a low BMD-related gene (wingless-related integration site 16, WNT16) and two important Vit-D pathway genes (Vit-D receptor, VDR, and Vit-D binding protein, VDBP) on serum Vit-D and bone qualities in Chinese AIS patients and healthy adolescents, and (b) to further investigate the effect of ablating Wnt16 on the cortical bone quality and whether diets with different dosages of Vit-D would further influence bone quality during the rapid growth phase in mice in the absence of Wnt16. A total of 519 girls (318 AIS vs. 201 controls) were recruited, and three selected single-nucleotide polymorphisms (SNPs) (WNT16 rs3801387, VDBP rs2282679, and VDR rs2228570) were genotyped. The serum 25(OH)Vit-D level was significantly associated with VDBP rs2282679 alleles (OR = -4.844; 95% CI, -7.521 to -2.167, p < 0.001). Significant multi-locus models were identified by generalized multifactor dimensionality reduction (GMDR) analyses on the serum 25(OH)Vit-D level (p = 0.006) and trabecular area (p = 0.044). In the gene-edited animal study, Wnt16 global knockout (KO) and wildtype (WT) male mice were provided with different Vit-D diets (control chow (1000 IU/Kg) vs. Vit-D-deficient chow (Nil in Vit-D) vs. high-dose Vit-D chow (20,000 IU/Kg)) from 4 weeks to 10 weeks old. Wnt16 global KO mice had significantly lower serum 25(OH)Vit-D levels and higher liver Vdbp mRNA expression levels than WT mice. In addition, Wnt16 global KO mice showed a decrease in bone density, cortical thickness and cortical area compared with WT mice. Interestingly, high-dose Vit-D chow led to lower bone density, cortical thickness, and cortical area in WT mice, which were less obvious in Wnt16 global KO mice. In conclusion, WNT16 may regulate the serum 25(OH)Vit-D level and bone qualities, which might be associated with VDBP expression. Further investigations with a larger sample size and wider spectrum of scoliosis severity are required to validate our findings regarding the interaction between WNT16 and Vit-D status in patients with AIS.

Magnetic Microbead-Based Herringbone Chip for Sensitive Detection of Human Immunodeficiency Virus.

The microfluidic chip-based nucleic acid detection method significantly improves the sensitivity since it precisely controls the microfluidic flow in microchannels. Nonetheless, significant challenges still exist in improving the detection efficiency to meet the demand for rapid detection of trace substances. This work provides a novel magnetic herringbone (M-HB) structure in a microfluidic chip, and its advantage in rapid and sensitive detection is verified by taking complementary DNA (cDNA) sequences of human immunodeficiency virus (HIV) detection as an example. The M-HB structure is designed based on controlling the magnetic field distribution in the micrometer scale and is formed by accumulation of magnetic microbeads (MMBs). Hence, M-HB is similar to a nanopore microstructure, which has a higher contact area and probe density. All of the above is conducive to improving sensitivity in microfluidic chips. The M-HB chip is stable and easy to form, which can linearly detect cDNA sequences of HIV quantitatively ranging from 1 to 20 nM with a detection limit of 0.073 nM. Compared to the traditional herringbone structure, this structure is easier to form and release by controlling the magnetic field, which is flexible and helps in further study. Results show that this chip can sensitively detect the cDNA sequences of HIV in blood samples, demonstrating that it is a powerful platform to rapidly and sensitively detect multiple nucleic acid-related viruses of infectious diseases.