Hypomorphic and hypermorphic mouse models of Fsip2 indicate its dosage-dependent roles in sperm tail and acrosome formation.

Loss-of-function mutations in multiple morphological abnormalities of the sperm flagella (MMAF)-associated genes lead to decreased sperm motility and impaired male fertility. As an MMAF gene, the function of fibrous sheath-interacting protein 2 (FSIP2) remains largely unknown. In this work, we identified a homozygous truncating mutation of FSIP2 in an infertile patient. Accordingly, we constructed a knock-in (KI) mouse model with this mutation. In parallel, we established an Fsip2 overexpression (OE) mouse model. Remarkably, KI mice presented with the typical MMAF phenotype, whereas OE mice showed no gross anomaly except for sperm tails with increased length. Single-cell RNA sequencing of the testes uncovered altered expression of genes related to sperm flagellum, acrosomal vesicle and spermatid development. We confirmed the expression of Fsip2 at the acrosome and the physical interaction of this gene with Acrv1, an acrosomal marker. Proteomic analysis of the testes revealed changes in proteins sited at the fibrous sheath, mitochondrial sheath and acrosomal vesicle. We also pinpointed the crucial motifs of Fsip2 that are evolutionarily conserved in species with internal fertilization. Thus, this work reveals the dosage-dependent roles of Fsip2 in sperm tail and acrosome formation.

Functional connectome hierarchy dysfunction in Alzheimer's disease and its relationship with cognition and gene expression profiling.

Numerous researches have shown that the human brain organizes as a continuum axis crossing from sensory motor to transmodal cortex. Functional network alterations were commonly found in Alzheimer's disease (AD). Whether the hierarchy of AD brain networks has changed and how these changes related to gene expression profiling and cognition is unclear. Using resting-state functional magnetic resonance imaging data from 233 subjects (185 AD patients and 48 healthy controls), we studied the changes in the functional network gradients in AD. Moreover, we investigated the relationships between gradient alterations and cognition, and gene expression profiling, respectively. We found that the second gradient organizes as a continuum axis crossing from the sensory motor to the transmodal cortex. Compared to the healthy controls, the secondary gradient scores of the visual and somatomotor network (SOM) increased significantly in AD, and the secondary gradient scores of default mode and frontoparietal network decreased significantly in AD. The secondary gradient scores of SOM and salience network (SAL) significantly positively correlated with memory function in AD. The secondary gradient in SAL also significantly positively correlated with language function. The AD-related second gradient alterations were spatially associated with the gene expression and the relevant genes enriched in neurobiology-related pathways, specially expressed in various tissues, cell types, and developmental stages. These findings suggested the changes in the functional network gradients in AD and deepened our understanding of the correlation between macroscopic gradient structure and microscopic gene expression profiling in AD.

Transmembrane modification of tumor vascular targeting peptide A7R as molecular cargo delivery tool.

In recent years, targeting tumor angiogenesis has emerged as a prominent research focus in the treatment and prevention of tumor expansion. A7R (ATWLPPR) exhibits high affinity and specificity for VEGFR-2, which is overexpressed in various tumors. To enhance the tumor tissue and cell penetration capabilities of A7R, we substituted its non-critical amino acid with Arginine (R) and Glutamic acid (E), cyclized the mutant peptide, and linked it to the membrane permeation sequence using coordination principles. We designed and synthesized fifteen novel penetrating peptides that target tumor blood vessels and cells, followed by conducting various biological evaluations and cell imaging experiments. The results demonstrated that Cyclo-A7R-RRR and A7R-RLLRLLR exhibited excellent permeability towards tumor cells, with Cyclo-A7R-RRR showing superior serum stability compared to A7R. Furthermore, the modified peptides showed no toxicity towards HeLa cells, U251 cells, HuH-7 cells, and HEK293 cells under 10 µmol/L. Utilizing Cyclo-A7R-RRR or A7R-RLLRLLR for transmembrane delivery of drug molecules could significantly improve their efficacy. Our findings broaden the potential application scenarios of A7R in targeted tumor angiogenesis.

How do species richness and its component dependence vary along the natural restoration in extremely heterogeneous forest ecosystems?

Giant habitat heterogeneity is an important factor contributing to the high species richness (SR) in karst forests. Yet, the driving factor behind the alterations in SR patterns during natural restoration remains unclear. In this study, we established the forest dynamics plots along the natural restoration sequence (including shrub-tree mixed forest stage (SC), secondary forest stage (SG) and old-growth forest sage (OG)) in degraded karst forests to compare the SR and the dependence on its components (including total community abundance, species abundance distribution (SAD), and conspecific spatial aggregation (CSA)) among stages of natural restoration. By evaluating the degree of contribution of the components to local SR and rarefied SR, we found that the SG exhibited the highest local SR, while the rarefied SR remained increasing along the restoration sequence after controlling the sample size. At SC-SG stage, SAD and CSA contributed negatively to the differences in SR, while abundance made a positive contribution to SR differences. At SG-OG, abundance contributed positively to the difference in SR at all scales, while SAD contributed negatively at small scales. No significant contribution of CSA was found at observed scales. In addition, local SR varied more significantly with PIE than with abundance. Our research emphasizes the importance of eliminating the influence of abundance on species richness in forest ecology and management, as well as the significance of separately evaluating the components that shape the diversity patterns.

[Effect of Intensive Insulin Therapy on Prognosis in Patients With Acute Myocardial Infarction].

Objective To evaluate the clinical efficacy and safety of intensive insulin therapy in the patients with acute myocardial infarction and provide guidance for improving the prognosis. Methods The articles involving the randomized controlled trials(RCT)focusing on the effects of intensive versus conventional insulin therapy on the clinical outcomes of the patients with acute myocardial infarction were retrieved from Cochrane,Embase,PubMed,CNKI,Wanfang Data,VIP,and CBM with the time interval from inception to October 2022.The data of each RCT were extracted and used for meta-analysis in RevMan5.4. Results A total of 8 articles were included in this study,involving 726 patients(372 in the intensive insulin group and 354 in the normal insulin group).The meta-analysis results showed that the intensive insulin group had lower incidence of major cardiovascular adverse events (RR=0.53, 95%CI=0.44-0.64, P<0.001), lower all-cause mortality (RR=0.51, 95%CI=0.33-0.78, P=0.002),lower high-sensitivity C-reactive protein level on day 7(WMD=-2.00,95%CI=-2.17- -1.83,P<0.001),higher left ventricular ejection fraction on day 30 (WMD=3.94, 95%CI=2.45-5.43,P<0.001), and higher incidence of hypoglycemia events (RR=2.96, 95%CI=1.12-7.83,P=0.030) than the normal insulin group.There was no significant difference between the two groups in terms of no-reflow event after percutaneous coronary intervention(RR=0.39,95%CI=0.14-1.13,P=0.080). Conclusion Intensive insulin therapy might be associated with more clinical benefits in the patients with acute myocardial infarction,while the conclusion remains to be confirmed by more studies.

3D OPC method for controlling the morphology of micro structures in laser direct writing.

A 3D optical proximity correction (OPC) method for controlling the morphology of micro-structures in laser direct writing is proposed, considering both the optical proximity effect and nonlinear response of a thick-film photoresist. This method can improve the manufacturability and optical performance of devices, and can be used for most 3D micro\nano structures. Its application in the fabrication of a quadratic curvature microlens array shows that the shape of the lens is well controlled; that is, when the height of the lens is 5.25 µm, the average height error of the lens shape is less than 5.22%.

Associations between polygenic risk scores and accelerated brain ageing in smokers.

BACKGROUND: Smoking contributes to a variety of neurodegenerative diseases and neurobiological abnormalities, suggesting that smoking is associated with accelerated brain aging. However, the neurobiological mechanisms affected by smoking, and whether they are genetically influenced, remain to be investigated. METHODS: Using structural magnetic resonance imaging data from the UK Biobank (n = 33 293), a brain age predictor was trained on non-smoking healthy groups and tested on smokers to obtain the BrainAge Gap (BAG). The cumulative effect of multiple common genetic variants associated with smoking was then calculated to acquire a polygenic risk score (PRS). The relationship between PRS, BAG, total gray matter volume (tGMV), and smoking parameters was explored and further genes included in the PRS were annotated to identify potential molecular mechanisms affected by smoking. RESULTS: The BrainAge in smokers was predicted with very high accuracy (r = 0.725, MAE = 4.16). Smokers had a greater BAG (Cohen's d = 0.074, p < 0.0001) and higher PRS (Cohen's d = 0.63, p < 0.0001) than non-smokers. A higher PRS was associated with increased amount of smoking, mediated by BAG and tGMV. Several neurotransmitters and ion channel pathways were enriched in the group of smoking-related genes involved in addiction, brain synaptic plasticity, and some neurological disorders. CONCLUSION: By using a simplified single indicator of the entire brain (BAG) in combination with the PRS, this study highlights the greater BAG in smokers and its linkage with genes and smoking behavior, providing insight into the neurobiological underpinnings and potential features of smoking-related aging.

A rapid procedure to generate stably transfected HEK293 suspension cells for recombinant protein manufacturing: Yield improvements, bioreactor production and downstream processing.

The human cell line HEK293 is one of the preferred choices for manufacturing therapeutic proteins and viral vectors for human applications. Despite its increased use, it is still considered in disadvantage in production aspects compared to cell lines such as the CHO cell line. We provide here a simple workflow for the rapid generation of stably transfected HEK293 cells expressing an engineered variant of the SARS-CoV-2 Receptor Binding Domain (RBD) carrying a coupling domain for linkage to VLPs through a bacterial transpeptidase-sortase (SrtA). To generate stable suspension cells expressing the RBD-SrtA, a single two plasmids transfection was performed, with hygromycin selection. The suspension HEK293 were grown in adherent conditions, with 20% FBS supplementation. These transfection conditions increased cell survival, allowing the selection of stable cell pools, which was otherwise not possible with standard procedures in suspension. Six pools were isolated, expanded and successfully re-adapted to suspension with a gradual increase of serum-free media and agitation. The complete process lasted four weeks. Stable expression with viability over 98% was verified for over two months in culture, with cell passages every 4-5 days. With process intensification, RBD-SrtA yields reached 6.4 µg/mL and 13.4 µg/mL in fed-batch and perfusion-like cultures, respectively. RBD-SrtA was further produced in fed-batch stirred tank 1L-bioreactors, reaching 10-fold higher yields than perfusion flasks. The trimeric antigen displayed the conformational structure and functionality expected. This work provides a series of steps for stable cell pool development using suspension HEK293 cells aimed at the scalable production of recombinant proteins.

Chemical Weathering Patterns of Diluted Bitumen Spilled into Freshwater Limnocorrals.

Due to the sudden nature of oil spills, few controlled studies have documented how oil weathers immediately following accidental release into a natural lake environment. Here, we evaluated the weathering patterns of Cold Lake Winter Blend, a diluted bitumen (dilbit) product, by performing a series of controlled spills into limnocorrals installed in a freshwater lake in Northern Ontario, Canada. Using a regression-based design, we added seven different dilbit volumes, ranging from 1.5 to 180 L, resulting in oil-to-water ratios between 1:71,000 (v/v) and 1:500 (v/v). We monitored changes in the composition of various petroleum hydrocarbons (PHCs), including n-alkanes, polycyclic aromatic hydrocarbons (PAHs), and oil biomarkers in dilbit over time, as it naturally weathered for 70 days. Depletion rate constants (kD) of n-alkanes and PAHs ranged from 0.0009 to 0.41 d-1 and 0.0008 to 0.38 d-1, respectively. There was no significant relationship between kD and spill volume, suggesting that spill size did not influence the depletion of petroleum hydrocarbons from the slick. Diagnostic ratios calculated from concentrations of n-alkanes, isoprenoids, and PAHs indicated that evaporation and photooxidation were major processes contributing to dilbit weathering, whereas dissolution and biodegradation were less important. These results demonstrate the usefulness of large scale field studies carried out under realistic environmental conditions to elucidate the role of different weathering processes following a dilbit spill.

Salmonella typhimurium may support cancer treatment: a review.

Antitumour treatments are evolving, including bacteria-mediated cancer therapy which is concurrently an ancient and cutting-edge approach. Salmonella typhimurium is a widely studied bacterial species that colonizes tumor tissues, showing oncolytic and immune system-regulating properties. It can be used as a delivery vector for genes and drugs, supporting conventional treatments that lack tumor-targeting abilities. This article summarizes recent evidence on the anticancer mechanisms of S. typhimurium alone and in combination with other anticancer treatments, suggesting that it may be a suitable approach to disease management.

Arsenic interferes with spermatogenesis involving Rictor/mTORC2-mediated blood-testis barrier disruption in mice.

Ingestion of arsenic interferes with spermatogenesis and increases the risk of male infertility, but the underlying mechanism remines unclear. In this study, we investigated spermatogenic injury with a focus on blood-testis barrier (BTB) disruption by administrating 5 mg/L and 15 mg/L arsenic orally to adult male mice for 60 d. Our results showed that arsenic exposure reduced sperm quality, altered testicular architecture, and impaired Sertoli cell junctions at the BTB. Analysis of BTB junctional proteins revealed that arsenic intake downregulated Claudin-11 expression and increased protein levels of ß-catenin, N-cadherin, and Connexin-43. Aberrant localization of these membrane proteins was also observed in arsenic-treated mice. Meanwhile, arsenic exposure altered the components of Rictor/mTORC2 pathway in mouse testis, including inhibition of Rictor expression, reduced phosphorylation of protein kinase Cα (PKCα) and protein kinase B (PKB), and elevated matrix metalloproteinase-9 (MMP-9) levels. Furthermore, arsenic also induced testicular lipid peroxidative damage, inhibited antioxidant enzyme (T-SOD) activity, and caused glutathione (GSH) depletion. Our findings suggest that disruption of BTB integrity is one of the main factors responsible for the decline in sperm quality caused by arsenic. PKCα-mediated rearrangement of actin filaments and PKB/MMP-9-increased barrier permeability jointly contribute to arsenic-induced BTB disruption.

Prediction of Fetal Biliary Atresia Based on Second and Third-Trimester Ultrasound Characteristics.

OBJECTIVE: To explore the diagnostic performance of prenatal ultrasound in the prediction of biliary atresia (BA). METHODS: We prospectively collected cases of suspected biliary abnormalities in the 2nd trimester of pregnancy and performed a series (at least 3) of prenatal ultrasound examinations in the 2nd and 3rd trimester. The presence of the gallbladder was examined each time, and its size and shape were assessed if the gallbladder was visible. The existence of other abnormalities was carefully evaluated. Neonatal ultrasound examination was conducted within 1 month after birth, and clinical data were followed-up for 6 months after birth. RESULTS: Among the 41 895 patients, 298 were suspected to have biliary abnormalities, while 82 patients were excluded due to loss to follow-up or induced labor caused by other abnormalities. A total of 216 patients were included in this study, and 15 were diagnosed with BA. We summarized the ultrasound findings of the gallbladders and defined a high-risk gallbladder for the prenatal diagnosis of BA. This was demonstrated to have the best diagnostic performance as a single parameter, with an area under the curve of 0.914 (95 %CI: 0.869-0.948). In addition, higher incidences of biliary cysts, right hepatic artery dilation, echogenic bowel, and ascites were observed in BA fetuses. Logistic regression analysis showed that the combination of 5 parameters had better diagnostic performance, with an area under the curve of 0.995 (95 %CI: 0.973-0.999). CONCLUSION: The fetal gallbladder was found to be a critical feature for the identification of BA. Concomitant abnormalities could be helpful to improve the accuracy of the diagnosis.

Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library.

There have been outbreaks of SARS-CoV-2 around the world for over three years, and its variants continue to evolve. This has become a major global health threat. The main protease (Mpro, also called 3CLpro) plays a key role in viral replication and proliferation, making it an attractive drug target. Here, we have identified a novel potential inhibitor of Mpro, by applying the virtual screening of hundreds of nilotinib-structure-like compounds that we designed and synthesized. The screened compounds were assessed using SP docking, XP docking, MM-GBSA analysis, IFD docking, MD simulation, ADME/T prediction, and then an enzymatic assay in vitro. We finally identified the compound V291 as a potential SARS-CoV-2 Mpro inhibitor, with a high docking affinity and enzyme inhibitory activity. Moreover, the docking results indicate that His41 is a favorable amino acid for pi-pi interactions, while Glu166 can participate in salt-bridge formation with the protonated primary or secondary amines in the screened molecules. Thus, the compounds reported here are capable of engaging the key amino acids His41 and Glu166 in ligand-receptor interactions. A pharmacophore analysis further validates this assertion.

On-treatment blood TMB as predictors for camrelizumab plus chemotherapy in advanced lung squamous cell carcinoma: biomarker analysis of a phase III trial.

BACKGROUND: Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown. METHODS: Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values. RESULTS: Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, P < 0.001), PFS (median, 9.1 vs 4.1 months; P < 0.001) and OS (median, not reached vs 8.0 months; P < 0.001) in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy (low vs high, median OS, 18.2 vs 7.8 months; P = 0.001). Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy. CONCLUSION: On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03668496.

Rapid Spread of Severe Fever with Thrombocytopenia Syndrome Virus by Parthenogenetic Asian Longhorned Ticks.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is spreading rapidly in Asia. This virus is transmitted by the Asian longhorned tick (Haemaphysalis longicornis), which has parthenogenetically and sexually reproducing populations. Parthenogenetic populations were found in ≥15 provinces in China and strongly correlated with the distribution of severe fever with thrombocytopenia syndrome cases. However, distribution of these cases was poorly correlated with the distribution of populations of bisexual ticks. Phylogeographic analysis suggested that the parthenogenetic population spread much faster than bisexual population because colonization is independent of sexual reproduction. A higher proportion of parthenogenetic ticks was collected from migratory birds captured at an SFTSV-endemic area, implicating the contribution to the long-range movement of these ticks in China. The SFTSV susceptibility of parthenogenetic females was similar to that of bisexual females under laboratory conditions. These results suggest that parthenogenetic Asian longhorned ticks, probably transported by migratory birds, play a major role in the rapid spread of SFTSV.

The association between assisted reproductive technology and cardiac remodeling in fetuses and early infants: a prospective cohort study.

BACKGROUND: Limited data exist regarding the potential impact of assisted reproductive technology (ART) on cardiac remodeling. In particular, whether different ART techniques are related to different cardiac alterations remains unclear. We aimed to evaluate cardiac changes in fetuses and infants arising from ART and fetal cardiac alterations in fetuses conceived by specific ART procedures. METHODS: This prospective and observational cohort study recruited 111 fetuses conceived by ART and 106 spontaneously conceived controls between December 2017 and April 2019. Echocardiography was performed between 28+0 and 32+6 weeks-of-gestation and at 0-2 and 6 months after birth. RESULTS: A total of 88 ART fetuses and 85 controls were included in the final analysis. Compared to controls, ART fetuses demonstrated a globular enlarged left ventricle (LV) (LV sphericity index of mid-section, 2.29 ± 0.34 vs. 2.45 ± 0.39, P = 0.006; LV area, 262.33 ± 45.96 mm2 vs. 244.25 ± 47.13 mm2, P = 0.002), a larger right ventricle (RV) (RV area, 236.10 ± 38.63 mm2 vs. 221.14 ± 42.60 mm2, P = 0.003) and reduced LV systolic deformation (LV global longitudinal strain (GLS), -19.56% ± 1.90% vs. -20.65% ± 1.88%, P = 0.013; LV GLS rate S, -3.32 ± 0.36 s-1 vs. -3.58 ± 0.39 s-1, P = 0.023). There were no significant differences between the ART and control groups at postnatal follow-ups. Furthermore, we found fetal cardiac morphometry and function were comparable between different ART procedures. Compared to controls, the fetuses derived from various ART procedures all exhibited impairments in the LV GLS and the LV GLS rate S. CONCLUSIONS: Our analysis demonstrated that subclinical cardiac remodeling and dysfunction were evident in ART fetuses, although these alterations did not persist in early infancy. In addition, various ART procedures may cause the same unfavorable changes in the fetal heart. TRIAL REGISTRATION: This trial was registered at the Chinese Clinical Trial Registry ( www.chictr.org.cn ) ( ChiCTR1900021672 ) on March 4, 2019, retrospectively registered.

Using deep learning and electronic health records to detect Noonan syndrome in pediatric patients.

PURPOSE: The variable expressivity and multisystem features of Noonan syndrome (NS) make it difficult for patients to obtain a timely diagnosis. Genetic testing can confirm a diagnosis, but underdiagnosis is prevalent owing to a lack of recognition and referral for testing. Our study investigated the utility of using electronic health records (EHRs) to identify patients at high risk of NS. METHODS: Using diagnosis texts extracted from Cincinnati Children's Hospital's EHR database, we constructed deep learning models from 162 NS cases and 16,200 putative controls. Performance was evaluated on 2 independent test sets, one containing patients with NS who were previously diagnosed and the other containing patients with undiagnosed NS. RESULTS: Our novel method performed significantly better than the previous method, with the convolutional neural network model achieving the highest area under the precision-recall curve in both test sets (diagnosed: 0.43, undiagnosed: 0.16). CONCLUSION: The results suggested the validity of using text-based deep learning methods to analyze EHR and showed the value of this approach as a potential tool to identify patients with features of rare diseases. Given the paucity of medical geneticists, this has the potential to reduce disease underdiagnosis by prioritizing patients who will benefit most from a genetics referral.

Effect of chirp on pulse reflection and refraction at a moving temporal boundary.

The reflection and refraction of chirped Gaussian pulse at a moving step refractive-index boundary are investigated. When a chirped Gaussian pulse crosses a temporal boundary, the shape of the reflected spectra is distorted by adjusting chirp parameters. However, the transmitted spectra retain the Gaussian shape. The shape of the final output spectra is the same if the absolute values of the chirp are the same. By changing the chirp values, we can control the energy of the reflected and transmitted pulses, and the splitting distance of the pulse at the temporal boundary. By adjusting the time-dependent refractive index, chirped Gaussian pulses can experience total internal reflection at the temporal boundary. When pulse splitting occurs in an anomalous dispersion region, the velocity of the transmitted pulse decreases.

Modulation of cardiac thin filament structure by phosphorylated troponin-I analyzed by protein-protein docking and molecular dynamics simulation.

Tropomyosin, controlled by troponin-linked Ca2+-binding, regulates muscle contraction by a macromolecular scale steric-mechanism that governs myosin-crossbridge-actin interactions. At low-Ca2+, C-terminal domains of troponin-I (TnI) trap tropomyosin in a position on thin filaments that interferes with myosin-binding, thus causing muscle relaxation. Steric inhibition is reversed at high-Ca2+ when TnI releases from F-actin-tropomyosin as Ca2+ and the TnI switch-peptide bind to the N-lobe of troponin-C (TnC). The opposite end of cardiac TnI contains a phosphorylation-sensitive ∼30 residue-long N-terminal peptide that is absent in skeletal muscle, and likely modifies these interactions in hearts. Here, PKA-dependent phosphorylation of serine 23 and 24 modulates Ca2+ and possibly switch-peptide binding to TnC, causing faster relaxation during the cardiac-cycle (lusitropy). The cardiac-specific N-terminal TnI domain is not captured in crystal structures of troponin or in cryo-EM reconstructions of thin filaments; thus, its global impact on thin filament structure and function is uncertain. Here, we used protein-protein docking and molecular dynamics simulation-based protocols to build a troponin model that was guided by and hence consistent with the recent seminal Yamada structure of Ca2+-activated thin filaments. We find that when present on thin filaments, phosphorylated Ser23/24 along with adjacent polar TnI residues interact closely with both tropomyosin and the N-lobe of TnC during our simulations. These interactions would likely bias tropomyosin to an off-state positioning on actin. In situ, such enhanced relaxation kinetics would promote cardiac lusitropy.

The modification of air particulate matter on the relationship between temperature and childhood asthma hospitalization: An exploration based on different interaction strategies.

The influence of temperature on childhood asthma was self-evident, yet the issue of whether the relationship will be synergized by air pollution remains unclear. The study aimed to investigate whether the relationship between short-term temperature exposure and childhood asthma hospitalization was modified by particulate matter (PM). Data on childhood asthma hospitalization, meteorological factors, and air pollutants during 2013-2016 in Hefei, China, were collected. First, a basic Poisson regression model combined with a distributed lag nonlinear model was used to assess the temperature-childhood asthma hospitalization relationship. Then, two interactive strategies were applied to explore the modification effect of PM on the temperature-childhood asthma hospitalization association. We found a greater effect of cold (5th percentile of temperature) on asthma during days with higher PM2.5 (RR: 2.16, 95% CI: 1.38, 3.38) or PM10 (RR: 1.87, 95% CI:1.20, 2.91) than that during days with lower PM2.5 (RR: 1.64, 95% CI: 1.06, 2.54) or PM10 (RR: 1.52, 95% CI: 0.98, 2.36). In addition, we observed a greater modification effect of PM2.5 on the cold-asthma association than did PM10, with a per 10 µg/m3 increase in PM2.5 and PM10 associated with increases of 0.065 and 0.025 for the RR corresponding to the 5th temperature percentile, respectively. For the temperature-related AF, moderate cold showed the largest change magnitude with the PM levels rising compared with other temperature ranges. For the subgroup, Females and those aged 6-18 years were more sensitive to the modification effect of PM2.5 or PM10 on the cold-asthma association. Our findings demonstrated that particulate matter could modify the associations between temperature and childhood asthma hospitalization.