LOF variants identifying candidate genes of laterality defects patients with congenital heart disease.

Defects in laterality pattern can result in abnormal positioning of the internal organs during the early stages of embryogenesis, as manifested in heterotaxy syndrome and situs inversus, while laterality defects account for 3~7% of all congenital heart defects (CHDs). However, the pathogenic mechanism underlying most laterality defects remains unknown. In this study, we recruited 70 laterality defect patients with CHDs to identify candidate disease genes by exome sequencing. We then evaluated rare, loss-of-function (LOF) variants, identifying candidates by referring to previous literature. We chose TRIP11, DNHD1, CFAP74, and EGR4 as candidates from 776 LOF variants that met the initial screening criteria. After the variants-to-gene mapping, we performed function research on these candidate genes. The expression patterns and functions of these four candidate genes were studied by whole-mount in situ hybridization, gene knockdown, and gene rescue methods in zebrafish models. Among the four genes, trip11, dnhd1, and cfap74 morphant zebrafish displayed abnormalities in both cardiac looping and expression patterns of early signaling molecules, suggesting that these genes play important roles in the establishment of laterality patterns. Furthermore, we performed immunostaining and high-speed cilia video microscopy to investigate Kupffer's vesicle organogenesis and ciliogenesis of morphant zebrafish. Impairments of Kupffer's vesicle organogenesis or ciliogenesis were found in trip11, dnhd1, and cfap74 morphant zebrafish, which revealed the possible pathogenic mechanism of their LOF variants in laterality defects. These results highlight the importance of rare, LOF variants in identifying disease-related genes and identifying new roles for TRIP11, DNHD1, and CFAP74 in left-right patterning. Additionally, these findings are consistent with the complex genetics of laterality defects.

In-silico assessment of high-risk non-synonymous SNPs in ADAMTS3 gene associated with Hennekam syndrome and their impact on protein stability and function.

Hennekam Lymphangiectasia-Lymphedema Syndrome 3 (HKLLS3) is a rare genetical disorder caused by mutations in a few genes including ADAMTS3. It is characterized by lymphatic dysplasia, intestinal lymphangiectasia, severe lymphedema and distinctive facial appearance. Up till now, no extensive studies have been conducted to elucidate the mechanism of the disease caused by various mutations. As a preliminary investigation of HKLLS3, we sorted out the most deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) that might affect the structure and function of ADAMTS3 protein by using a variety of in silico tools. A total of 919 nsSNPs in the ADAMTS3 gene were identified. 50 nsSNPs were predicted to be deleterious by multiple computational tools. 5 nsSNPs (G298R, C567Y, A370T, C567R and G374S) were found to be the most dangerous and can be associated with the disease as predicted by different bioinformatics tools. Modelling of the protein shows it can be divided into segments 1, 2 and 3, which are connected by short loops. Segment 3 mainly consists of loops without substantial secondary structures. With prediction tools and molecular dynamics simulation, some SNPs were found to significantly destabilize the protein structure and disrupt the secondary structures, especially in segment 2. The deleterious effects of mutations in segment 1 are possibly not from destabilization but from other factors such as the change in phosphorylation as suggested by post-translational modification (PTM) studies. This is the first-ever study of ADAMTS3 gene polymorphism, and the predicted nsSNPs in ADAMST3, some of which have not been reported yet in patients, will serve for diagnostic purposes and further therapeutic implications in Hennekam syndrome, contributing to better diagnosis and treatment.

The association of gestational age and birthweight with blood pressure, cardiac structure, and function in 4 years old: a prospective birth cohort study.

BACKGROUND: Current evidence relating birthweight and gestational age to cardiovascular risk is conflicting. Whether these factors have independent or interactive impacts on cardiovascular parameters during early childhood remains unclear. The goal of this study was to explore whether there were any independent and interactive effects of gestational age and birthweight on blood pressure, left ventricle (LV) structure, and function in 4 years old. METHODS: This study included 1194 children in the Shanghai Birth Cohort from 2013 to 2016. Information about the mothers and children was recorded at time of birth using a questionnaire. Follow-up measurements, including anthropometric, blood pressure, and echocardiography, were taken between 2018 and 2021, when the children were 4 years old. Multiple linear or logistic regressions and restricted cubic spline were used to explore the association of birthweight and gestational age with cardiovascular measurements. RESULTS: Gestational age had a significant negative correlation with both systolic blood pressure [ß = - 0.41, 95% CI: (- 0.76, - 0.07)] and mean arterial pressure [ß = - 0.36, 95%CI: (- 0.66, - 0.07)]. The risk of prehypertension decreased with increased gestational age [OR = 0.54, 95% CI: (0.32, 0.93)]. The relationship between birthweight with blood pressure was U-shape (P for non-linear < 0.001). The wall thickness, volume, mass, and cardiac output of LV increased with birthweight, though the ejection fraction [ß = - 1.02, 95% CI: (- 1.76, - 0.27)] and shorten fraction [ß = 0.72, 95% CI: (- 1.31, - 0.14)] decreased with birthweight. The risk of LV hypertrophy was not associated with birthweight [OR = 1.59, 95% CI: (0.68, 3.73)]. CONCLUSIONS: In this study, we found different associations of birthweight and gestational age with cardiovascular measurements in the offspring at 4 years old. Gestational age influenced blood pressure independent of birthweight. Heart size and function at 4 years old was influenced mostly by birthweight and not by gestational age.

De novo disruptive heterozygous MMP21 variants are potential predisposing genetic risk factors in Chinese Han heterotaxy children.

BACKGROUND: Heterotaxy syndrome (HTX) is caused by aberrant left-right patterning early in embryonic development, which results in abnormal positioning and morphology of the thoracic and abdominal organs. Currently, genetic testing discerns the underlying genetic cause in less than 20% of sporadic HTX cases, indicating that genetic pathogenesis remains poorly understood. In this study, we aim to garner a deeper understanding of the genetic factors of this disease by documenting the effect of different matrix metalloproteinase 21 (MMP21) variants on disease occurrence and pathogenesis. METHODS: Eighty-one HTX patients with complex congenital heart defects and 89 healthy children were enrolled, and we investigated the pathogenetic variants related to patients with HTX by exome sequencing. Zebrafish splice-blocking Morpholino oligo-mediated transient suppression assays were performed to confirm the potential pathogenicity of missense variants found in these patients with HTX. RESULTS: Three MMP21 heterozygous non-synonymous variants (c.731G > A (p.G244E), c.829C > T (p.L277F), and c.1459A > G (p.K487E)) were identified in three unrelated Chinese Han patients with HTX and complex congenital heart defects. Sanger sequencing confirmed that all variants were de novo. Cell transfection assay showed that none of the variants affect mRNA and protein expression levels of MMP21. Knockdown expression of mmp21 by splice-blocking Morpholino oligo in zebrafish embryos revealed a heart looping disorder, and mutant human MMP21 mRNA (c.731G > A, c.1459A > G, heterozygous mRNA (wild-type&c.731G > A), as well as heterozygous mRNA (wild-type& c.1459A > G) could not effectively rescue the heart looping defects. A patient with the MMP21 p.G244E variant was identified with other potential HTX-causing missense mutations, whereas the patient with the MMP21 p.K487E variant had no genetic mutations in other causative genes related to HTX. CONCLUSION: Our study highlights the role of the disruptive heterozygous MMP21 variant (p.K487E) in the etiology of HTX with complex cardiac malformations and expands the current mutation spectrum of MMP21 in HTX.

Predictive value of fetal echocardiographic parameters in surgical strategy for Tetralogy of Fallot.

OBJECTIVES: This study aimed to evaluate whether fetal echocardiographic parameters were predictive of the postnatal surgical treatment required for fetuses with Tetralogy of Fallot (TOF). METHODS: The fetal echocardiographic and postnatal clinical data of all cases of prenatal TOF at Xinhua Hospital from 2016 to 2020 were reviewed. Patients were categorized based on the operation type, and cardiac parameters were compared between groups. RESULTS: Of the 37 fetuses assessed, the development of the pulmonary valve annulus (PVA) was significantly poorer in the transannular patch group. Patients with a prenatal PVA z-score (Schneider's method) ≥ -2.645, a PVA z-score (Lee's method) ≥ -2.805, a PVA/aortic valve annulus diameter ratio ≥ .697, and a pulmonary annulus index ≥ .823 were more likely to undergo pulmonary valve-sparing surgery. There was a strong correlation between prenatal and postnatal PVA z-scores. The PVA growth potential was greater in the pulmonary valve-sparing surgery group. CONCLUSIONS: PVA-related parameters evaluated by fetal echocardiography can predict the type of surgical intervention required and are valuable in improving prenatal counseling in fetal cases of TOF.

Association between maternal exposure to indoor air pollution and offspring congenital heart disease: a case-control study in East China.

BACKGROUND: Previous research suggested an association between maternal exposure to ambient air pollutants and the risk of congenital heart disease (CHD). However, the effect of individual prenatal exposure to indoor air pollutants on CHD occurrence was not reported. METHODS: We performed a hospital-based case-control study to investigate the association between personal air pollution exposure during pregnancy and the risk of CHD in offspring. A total of 44 cases and 75 controls were included from two hospitals in East China. We investigated maternal and residential environmental characteristics using a questionnaire and obtained personal indoor air samples to assess particulate matter (PM) and volatile organic compounds (VOCs) from 22-30 gestational weeks. Formaldehyde, benzene, toluene, xylene, total volatile organic compounds (TVOCs), PM2.5, and PM10 were assessed. Logistic regression was performed to assess associations and interactions between individual indoor air pollutants and CHD after adjusting for confounders. The potential residential environmental factors affecting the risks of indoor air pollutants on CHD were also assessed. RESULTS: Median TVOC (0.400 vs. 0.005 mg/m3, P < 0.001) exposure levels in cases were significantly higher than controls. A logistic regression model adjusted for confounders revealed that exposure to high levels of indoor TVOCs (AOR 7.09, 95% CI 2.10-23.88) during pregnancy was associated with risks for CHD and the occurrence of some major CHD subtype in offspring. These risk effects were enhanced in pregnant women living in a newly renovated house but were mitigated by household use of smoke ventilators when cooking. We observed a positive interaction of maternal exposure to TVOCs and PM2.5 and the risk for CHD. CONCLUSIONS: Maternal exposure to indoor VOCs and PMs may increase the risk of giving birth to foetuses with CHD.

Absorption characteristics of ilexgenin A and ilexsaponin B1 in human umbilical vein endothelial cells after administration of the total triterpenoid saponins from Ilex pubescens.

Ilex pubescens is a famous Chinese herbal medicine, frequently used to treat cardiovascular disease in South China. In this study, we aim to explore the absorption properties of ilexgenin A (C1) and ilexsaponin B1 (C3) in vascular endothelial cells after administration of the total triterpenoid saponins from Ilex pubescens (IPTS) and clarify the possible transport mechanisms. A UPLC-qTOF-MS/MS system was used to identify the components in IPTS that could be intracellularly transported by human umbilical vein endothelial cells (HUVECs). Afterwards, a rapid, highly selective and sensitive method was established to simultaneously quantify the concentration of C1 and C3 in HUVECs after administration of IPTS. The results demonstrate that pretreatment with IPTS could promote the survival of HUVECs and reduce the damage caused by TNF-α to HUVECs. Among the main 11 components in IPTS, eight components could be absorbed by HUVECs, including seven triterpenoids and one phenolic acid. The uptake of C1 and C3 by HUVECs occurred in a time-, temperature- and concentration-dependent manner, indicating the participation of passive diffusion and active transportation mechanisms. The two triterpenoid saponins all exhibited rapid absorption and a bimodal phenomenon in their concentration-time profiles, and equilibrium could be achieved after 6 h. Furthermore, C1 and C3 intracellular transportation was regulated by serum proteins, sodium-dependent glucose transporter 1 and P-glycoprotein. The current research for the first time demonstrates the in vitro pharmacokinetics characteristics of C1 and C3 in HUVECs lines, which could supply a new way of understanding the treatment of cardiovascular diseases.

Growth patterns in early childhood and cardiovascular structure and function at 4 years old: A prospective cohort study.

BACKGROUND AND AIMS: Childhood overweight and obesity are lifetime risk factors for cardiovascular disease but the relationship between dynamic body mass index (BMI) change and cardiovascular structure and function in early childhood remains unclear. METHODS AND RESULTS: This cohort study consisted 525 participants with 6 distinct representative growth patterns to examine the associations between BMI growth patterns and subsequent cardiovascular structure and function at age 4. BMIs were obtained at birth, 2 and 4 years old. Cardiovascular assessments were performed, including blood pressure (BP), cardiac geometric parameters, left ventricular (LV) function, speckle-tracking, integrated backscatter analysis and carotid intima-media thickness. Compared to the stable normal BMI pattern, children with the stable overweight (OW) pattern had significantly greater LV anatomic parameters in fully adjusted models. Children with the catch-up (CU) pattern revealed a uniform trend and had poorer strain. LV diameters and integrated backscatter signals were larger for those with BMI gain and lose pattern. Children with BMI lose pattern showed improved tendency involving LV mass index and BP. Both OW and CU patterns were associated with high systolic BP [odds ratio (95% CI): OW: 3.67 (1.08, 12.47); CU: 4.24 (1.75, 10.28)]. Compared to static BMI measurements at birth, 2 and 4 years old, dynamic BMI growth patterns were more predictive of cardiovascular structure and function at 4. CONCLUSIONS: Children with overweight-related BMI growth patterns in early childhood experienced undesirable cardiovascular functional or structural changes as early as 4 years old, indicating that early intervention is needed and potentially beneficial.

Role of Site-Specific Glycosylation in the I-Like Domain of Integrin ß1 in Small Extracellular Vesicle-Mediated Malignant Behavior and FAK Activation.

Integrin ß1 plays an essential role in the crosstalk between tumor cells and their microenvironment. Aberrant N-glycosylation of integrin ß1 was documented to alter integrin ß1 expression, dimerization, and biological function. However, the biological function of site-specific N-glycosylation of integrin ß1 on extracellular vesicles is not fully understood. In this study, we mutated putative N-glycosylation sites in different domains of integrin ß1. Removal of the N-glycosylation sites on the I-like domain of integrin ß1 (termed the Δ4-6 ß1 mutant) suppressed focal adhesion kinase (FAK) signaling, cell migration, and adhesion compared with other ß1 mutants. Cell adhesion, migration, and activation of FAK were suppressed in recipient MCF7 cells co-cultured with Δ4-6 mutant cells and treated with small extracellular vesicles (sEVs) from Δ4-6 mutant cells. Notably, the wild-type and ß1 mutant were both present in sEVs, and could be transferred to recipient cells via sEVs, resulting in changes of cell behavior. Our findings demonstrate the important roles of N-glycosylation of the I-like domain of integrin ß1. Moreover, the vesicular Δ4-6 ß1 mutant can regulate integrin-mediated functions in recipient cells via sEVs.

A Study on Hair Mercury Levels of University Students.

Total mercury (THg) and methylmercury (MeHg) concentrations were measured in hair of 98 Chinese university students to study their levels of Hg exposure and influencing factors. The results showed that Hg exposure for university students was at a low level with concentrations lower than the USEPA recommended reference level (1 µg/g) across all hair samples. The percentage of MeHg to THg (%MeHg) in hair was about 50%, lower than the previously reported value of 70-100%, probably associated with the low %MeHg in the diet of university students. Fish and rice consumption were not a primary factor affecting hair Hg levels of university students, while smoking could be one main pathway of Hg exposure. In addition, the similarly dietary structure in the studied university narrowed the difference of Hg exposure levels among students.

Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiac disease and is characterised by unexplained ventricular myocardial hypertrophy. HCM is highly heterogeneous and is primarily caused by the mutation of genes encoding sarcomere proteins. As a result of its genetic basis, we investigated the underlying cause of HCM in a Chinese family by whole-exome sequencing. METHODS: Whole-exome sequencing was performed for seven clinically diagnosed HCM family members and the resulting single nucleotide variants associated with cardiac hypertrophy or heart development were analysed by a polymerase chain reaction and Sanger sequencing. RESULTS: A non-frameshift deletion mutation (p.S527del) of Formin Homology 2 Domain Containing 3 (FHOD3) was detected in all of the affected family members and was absent in all unaffected members, with the exception of one young member. Moreover, three single nucleotide variants associated with heart development and morphogenesis were identified in the proband but were absent in the other affected subjects. CONCLUSIONS: This is the first HCM family case of FHOD3 (p.S527del) variation in Asia. Additionally, RNF207 (p.Q268P), CCM2 (p. E233K) and SGCZ (p.Q134X) may be related to the clinical heterogeneity of the family. The present study could enable the provision of genetic counseling for this family and provide a basis for future genetic and functional studies.

Neonatal outcome of cases with isolated prenatal ventricular disproportion with a dominant right ventricle.

OBJECTIVES: Isolated prenatal ventricular disproportion with a dominant right ventricle represents a challenge in decision-making for both physicians and pregnant women. In the current study, we sought to delineate the postnatal outcomes of these cases. METHODS: This retrospective analysis included consecutive cases of isolated ventricular disproportion identified using complete fetal echocardiography at the Fetal Heart Center of Xinhua Hospital from January 2014 to October 2017. Postnatal cardiac outcome was examined using transthoracic echocardiography within the first 6 months after birth. RESULTS: A total of 90 fetuses were included in the final analysis. The median gestational age (GA) at diagnosis was 29 weeks (range 24 to 36). At postnatal examination, cardiac malformations were detected in 39 cases (43.3%), including 25 (27.8%) cases of congenital cardiac septal defects, eight (8.9%) of persistent left superior vena cava, four (4.4%) of left-sided obstructive diseases, and one (1.1%) case of coronary fistula. Nineteen cases (21.1%) with fetal cardiac malformations had significant lower GA at diagnosis (P = .01) and greater right to left ventricle ratio (1.38 vs 1.30, P = .02). Neonatal surgical intervention was not required in any of the cases. CONCLUSIONS: Isolated prenatal ventricular disproportion with a dominant right ventricle comprises minor postnatal cardiac malformations and doesn't require neonatal intervention.

Is echocardiography necessary for all single umbilical artery fetuses? A retrospective study in a selected Chinese population.

AIM: Previous evidence on the relationship between single umbilical artery (SUA) and congenital heart disease (CHD) is controversial. We thus conducted a retrospective study to explore the potential risk factors associated with CHD in SUA fetuses, and verify if all these SUA fetuses should be referred for detail fetal echocardiography. METHODS: We reviewed medical records of SUA fetuses referred to Xinhua Hospital for fetal echocardiography between September 2009 and February 2014. All the pregnancies were divided into two groups of CHD and non-CHD according to the results of fetal echocardiography. The maternal and fetal characteristics were compared via χ2 test and Fishers' test. Furthermore, Poisson regression was used to analyze the risk factors associated with CHD in SUA pregnancies. RESULTS: Nineteen CHD cases (12.5%) were detected among 152 SUA fetuses, all with abnormal cardiac views during obstetric screening ultrasound (P < 0.001). χ2 test showed that abnormal cardiac screening findings, extracardiac abnormality and infection or threatened abortion during first trimester were significantly associated with prenatal detection of CHD (P < 0.001). Multivariable Poisson regression after adjustment found that SUA fetuses with extracardiac abnormality had 4.74 (95% confidence interval: 1.89, 11.90) times higher risk of CHD. CONCLUSION: Incidence of CHD was higher in SUA cases, and CHD fetuses could be screened efficiently by abnormal cardiac screening during obstetric screening ultrasound. SUA fetuses with extracardiac abnormality and maternal risk factors have higher risk of CHD, and should be strongly recommended for fetal echocardiography. In contrast, SUA fetuses without above situations might only need routine obstetric follow-up.

Assessment of longitudinal systolic ventricular dysfunction and asynchrony using velocity vector imaging in children with a single right ventricle.

Assessment of ventricular dysfunction and asynchrony is very important in predicting the outcome for children with a single right ventricle. However, the assessment is inaccurate and subjective because of the unusual ventricular shape. This study aimed to evaluate the feasibility and clinical value of velocity vector imaging for assessing longitudinal systolic ventricular dysfunction and intraventricular asynchrony in children with a single right ventricle. The study enrolled 36 children with a single right ventricle and 36 age-matched children with a normal heart. Peak systolic velocity, peak displacement, strain, strain rate, time to peak systolic velocity, and time to peak systolic strain were measured via velocity vector imaging using the Siemens Sequoia C512 echocardiography instrument. The maximum positive rate of ventricular pressure change (Max [dp/dt]) was obtained by cardiac catheterization for all the children with a single right ventricle. In the children with a single right ventricle, the maximal temporal differences and the standard deviations of the times to peak systolic velocity and peak systolic strain were higher (P < 0.01) than in the children with a normal heart. Moreover, the strain and strain rate values were significantly lower in all six segments (P < 0.05). The strain rate of the basal segment adjacent to the rudimentary chamber correlated best with Max (dp/dt) (r = 0.86; P < 0.01). Longitudinal systolic dysfunction and intraventricular asynchrony could be assessed accurately using velocity vector imaging in children with a single right ventricle.

Single-Atom Catalysts on Covalent Organic Frameworks for Energy Applications.

Single-atom catalysts (SACs) have been investigated and applied to energy conversion devices. However, issues of metal agglomeration, low metal loading, and substrate stability have hindered realization of the SACs' full potential. Recently, covalent organic framework (COF)-based SACs have emerged as promising materials to enable highly efficient catalytic reactions. Here, we summarize the representative COF-based SACs and their wide application in clean energy devices and conversion reactions, such as hydrogen evolution reaction, carbon dioxide reduction reaction, nitrogen reduction reaction, oxygen reduction reaction, and oxygen evolution reaction. Based on their catalysis conditions, these reactions are categorized into photocatalyzed and electrocatalyzed reactions. We also summarize their design strategies, including heteroatom inclusion, donor-acceptor pairs, pore engineering, interface engineering, etc. Although COF-based SACs are promising, more efforts, such as linkage engineering, functional groups, ionization, multifunctional sites for cocatalyzed systems, etc., could improve them to be the ideal SAC materials. At the end, we provide our perspectives on where the field will proceed in the next 5 years.

Exposure to volatile organic compounds induces cardiovascular toxicity that may involve DNA methylation.

Volatile organic compounds (VOCs) are common air pollutants and water contaminants. We previously found maternal exposure to VOCs was associated with offspring congenital heart disease (CHD). However, little information is available about the effects of VOCs on cardiovascular development at embryonic stage and the underlying mechanism remains unclear. In this study, we aimed to investigate the effects of a mixture of six VOCs on cardiovascular development in zebrafish embryos. Embryos were exposed to different concentrations of VOCs mixture (32 mg/L, 64 mg/L and 128 mg/L) for 96 h, cardiovascular abnormalities including elongated heart shape, increased distance between sinus venosus and bulbus arteriosus, slowed circulation and altered heart rate were observed in a dose- and time-dependent manner. Meanwhile, VOCs exposure increased global DNA methylation levels in embryos. Analysis identified hundreds of differentially methylated sites and the enrichment of differentially methylated sites on cardiovascular development. Two differentially methylated-associated genes involved in MAPK pathway, hgfa and ntrk1, were identified to be the potential genes mediating the effects of VOCs. By enzyme-linked immunosorbent assay, altered human serum hgf and ntrk1 levels were detected in abnormal pregnancies exposed to higher VOCs levels with fetal CHD. For the first time, our study revealed exposure to VOCs induced severe cardiovascular abnormalities in zebrafish embryos. The toxicity might result from alterations in DNA methylation and corresponding expression levels of genes involved in MAPK pathway. Our study provides important information for the risk of VOCs exposure on embryonic cardiovascular development.

Preparation of Ultrafine Co- and Ni-Coated (Ti,W,Mo,Ta)(C,N) Powders and Their Influence on the Microstructure of Ti(C,N)-Based Cermets.

The use of metal-coated ceramic powders not only effectively enhances the wettability of the metal-ceramic interface but also promotes a more uniform microstructure in Ti(C,N)-based cermets, which is advantageous for improving their mechanical properties. In this study, ultrafine Co- and Ni-coated (Ti,W,Mo,Ta)(C,N) powders were synthesized via the spray-drying-in-situ carbothermal reduction method. Subsequently, Ti(C,N)-based cermets were effectively fabricated using the as-prepared ultrafine Co- and Ni-coated (Ti,W,Mo,Ta)(C,N) powders. The impact of reaction temperature, heating rate, and isothermal time on the phase and microstructure of prepared powders was analyzed using X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Additionally, the microstructure of the as-sintered cermets was experimentally investigated. The findings reveal that the complete reduction of Co and Ni metal salts, pre-coated on the surface of (Ti,W,Mo,Ta)(C,N) particles, can be achieved through rapid heating (10 °C/min) in a specific temperature range (600-1000 °C) with an isothermal time of 3 h at a lower reduction temperature (1000 °C). The synthesized powders have only two phases: the (Ti,W,Mo,Ta)(C,N) phase and Co/Ni phase, and no other heterogeneous phases were observed with an oxygen content of 0.261 wt.%. Notably, the conventional core-rim structure was not dominant in the cermets obtained from the prepared Co- and Ni-coated (Ti,W,Mo,Ta)(C,N) powders. Moreover, the heterogeneous segregation effect of the Co/Ni coating on the ultrafine powder particles resulted in a finer microstructure than the traditional cermets with the same composition. However, the grain size is mainly in the range of 0.5-0.8 µm. The weaker residual stresses at the core and rim interfaces and the finer particle distributions could theoretically enhance the toughness of Ti(C,N)-based cermets, simultaneously.

Exploring optimal drug targets through subtractive proteomics analysis and pangenomic insights for tailored drug design in tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, ranks among the top causes of global human mortality, as reported by the World Health Organization's 2022 TB report. The prevalence of M. tuberculosis strains that are multiple and extensive-drug resistant represents a significant barrier to TB eradication. Fortunately, having many completely sequenced M. tuberculosis genomes available has made it possible to investigate the species pangenome, conduct a pan-phylogenetic investigation, and find potential new drug targets. The 442 complete genome dataset was used to estimate the pangenome of M. tuberculosis. This study involved phylogenomic classification and in-depth analyses. Sequential filters were applied to the conserved core genome containing 2754 proteins. These filters assessed non-human homology, virulence, essentiality, physiochemical properties, and pathway analysis. Through these intensive filtering approaches, promising broad-spectrum therapeutic targets were identified. These targets were docked with FDA-approved compounds readily available on the ZINC database. Selected highly ranked ligands with inhibitory potential include dihydroergotamine and abiraterone acetate. The effectiveness of the ligands has been supported by molecular dynamics simulation of the ligand-protein complexes, instilling optimism that the identified lead compounds may serve as a robust basis for the development of safe and efficient drugs for TB treatment, subject to further lead optimization and subsequent experimental validation.

From random coil polymers to helical structures induced by carbon nanotubes and supramolecular interactions.

A simple method is reported for the preparation of double-helical structures through a series of achiral random and block copolymers poly(styrene-co-4-vinylbenzyl triazolylmethyl methylthymine) (PS-co-PVBT) with various T units on the side chains through click reactions of poly(styrene-co-4-vinylbenzyl azide) (PS-co-PVBN(3)) with propargyl thymine (PT) and also the synthesis of the A-appended pyrene derivative (A-Py) through click chemistry. This double-helical structure is observed from achiral random-coil polystyrene (PS) main chains, stabilized through the combination of multiple A-T hydrogen bonds, and π-π stacking between pyrene units and single-walled carbon nanotubes (SWCNTs).

A nomogram to predict 28-day mortality in neonates with sepsis: a retrospective study based on the MIMIC-III database.

Background: Sepsis is the second-leading cause of death in neonates. We established a predictive nomogram to identify critically ill neonates early and reduce the time to treatment. Methods: It is a retrospective case-control study based on the MIMIC-III database. The study population comprised 924 neonates diagnosed with sepsis. Results: Neonates with sepsis included in the MIMIC-III database were enrolled, including 880 surviving neonates and 44 neonates who died. In the derivation dataset, stepwise regression and the Lasso algorithm were employed to select predictive variables, and the neonatal sequential organ failure assessment score (nSOFA) was calculated simultaneously. Bootstrap resampling was utilized to perform internal validation. The results indicated that the Lasso algorithm displayed superior discrimination, sensitivity, and specificity relative to stepwise regression and nSOFA scores. After 500 bootstrap resampling tests, the area under the receiver operating characteristic curve (AUC) of the Lasso algorithm was 0.912 (95% CI: 0.870-0.977). The nomogram based on the Lasso algorithm outperformed stepwise regression and nSOFA scores in terms of calibration and the clinical net benefit. This nomogram can assist in prognosticating neonatal severe sepsis and aid in guiding clinical practice while concurrently improving patient outcomes. Conclusions: The established nomogram revealed that jaundice, corticosteroid use, weight, serum calcium, inotropes and base excess are all important predictors of 28-day mortality in neonates with sepsis. This nomogram can facilitate the early identification of neonates with severe sepsis. However, it still requires further modification and external validation to make it widely available.