Carbon-Extraction-Induced Biaxial Strain Tuning of Carbon-Intercalated Iridium Metallene for Hydrogen Evolution Catalysis.

Metallene materials with atomic thicknesses are receiving increasing attention in electrocatalysis due to ultrahigh surface areas and distinctive surface strain. However, the continuous strain regulation of metallene remains a grand challenge. Herein, taking advantage of autocatalytic reduction of Cu2+ on biaxially strained, carbon-intercalated Ir metallene, we achieve control over the carbon extraction kinetics, enabling fine regulation of carbon intercalation concentration and continuous tuning of (111) in-plane (-2.0%-2.6%) and interplanar (3.5%-8.8%) strains over unprecedentedly wide ranges. Electrocatalysis measurements reveal the strain-dependent activity toward hydrogen evolution reaction (HER), where weakly strained Ir metallene (w-Ir metallene) with the smallest lattice constant presents the highest mass activity of 2.89 A mg-1Ir at -0.02 V vs reversible hydrogen electrode (RHE). Theoretical calculations validated the pivotal role of lattice compression in optimizing H binding on carbon-intercalated Ir metallene surfaces by downshifting the d-band center, further highlighting the significance of strain engineering for boosted electrocatalysis.

JSNMF enables effective and accurate integrative analysis of single-cell multiomics data.

The single-cell multiomics technologies provide an unprecedented opportunity to study the cellular heterogeneity from different layers of transcriptional regulation. However, the datasets generated from these technologies tend to have high levels of noise, making data analysis challenging. Here, we propose jointly semi-orthogonal nonnegative matrix factorization (JSNMF), which is a versatile toolkit for the integrative analysis of transcriptomic and epigenomic data profiled from the same cell. JSNMF enables data visualization and clustering of the cells and also facilitates downstream analysis, including the characterization of markers and functional pathway enrichment analysis. The core of JSNMF is an unsupervised method based on JSNMF, where it assumes different latent variables for the two molecular modalities, and integrates the information of transcriptomic and epigenomic data with consensus graph fusion, which better tackles the distinct characteristics and levels of noise across different molecular modalities in single-cell multiomics data. We applied JSNMF to single-cell multiomics datasets from different tissues and different technologies. The results demonstrate the superior performance of JSNMF in clustering and data visualization of the cells. JSNMF also allows joint analysis of multiple single-cell multiomics experiments and single-cell multiomics data with more than two modalities profiled on the same cell. JSNMF also provides rich biological insight on the markers, cell-type-specific region-gene associations and the functions of the identified cell subpopulation.

Regulatory networks of senescence-associated gene-transcription factors promote degradation in Moso bamboo shoots.

Bamboo cultivation, particularly Moso bamboo (Phyllostachys edulis), holds significant economic importance in various regions worldwide. Bamboo shoot degradation (BSD) severely affects productivity and economic viability. However, despite its agricultural consequences, the molecular mechanisms underlying BSD remain unclear. Consequently, we explored the dynamic changes of BSD through anatomy, physiology and the transcriptome. Our findings reveal ruptured protoxylem cells, reduced cell wall thickness and the accumulation of sucrose and reactive oxygen species (ROS) during BSD. Transcriptomic analysis underscored the importance of genes related to plant hormone signal transduction, sugar metabolism and ROS homoeostasis in this process. Furthermore, BSD appears to be driven by the coexpression regulatory network of senescence-associated gene transcription factors (SAG-TFs), specifically PeSAG39, PeWRKY22 and PeWRKY75, primarily located in the protoxylem of vascular bundles. Yeast one-hybrid and dual-luciferase assays demonstrated that PeWRKY22 and PeWRKY75 activate PeSAG39 expression by binding to its promoter. This study advanced our understanding of the molecular regulatory mechanisms governing BSD, offering a valuable reference for enhancing Moso bamboo forest productivity.

Hypersecretory production of glucose oxidase in Pichia pastoris through combinatorial engineering of protein properties, synthesis, and secretion.

Glucose oxidase (EC 1.1.3.4, GOD) is a widely used industrial enzyme. To construct a GOD-hyperproducing Pichia pastoris strain, combinatorial strategies have been applied to improve GOD activity, synthesis, and secretion. First, wild-type GOD was subjected to saturation mutagenesis to obtain an improved variant, MGOD1 (V20W/T30S), with 1.7-fold higher kcat /KM . Subsequently, efficient signal peptides were screened, and the copy number of MGOD1 was optimized to generate a high-producing strain, 8GM1, containing eight copies of AOX1 promoter-GAS1 signal peptide-MGOD1 expression cassette. Finally, the vesicle trafficking of 8GM1 was engineered to obtain the hyperproducing strain G1EeSe co-expressing the trafficking components EES and SEC. 22, and the EES gene (PAS_chr3_0685) was found to facilitate both protein secretion and production for the first time. Using these strategies, GOD secretion was enhanced 65.2-fold. In the 5-L bioreactor, conventional fed-batch fermentation without any process optimization resulted in up to 7223.0 U/mL extracellular GOD activity (3.3-fold higher than the highest level reported to date), with almost only GOD in the fermentation supernatant at a protein concentration of 30.7 g/L. Therefore, a GOD hyperproducing strain for industrial applications was developed, and this successful case can provide a valuable reference for the construction of high-producing strains for other industrial enzymes.

Rational design of NiO/Ti3C2Tx nanocomposites with enhanced triethylamine sensing performance.

MXenes with excellent conductivity and abundant surface functional groups have displayed great advantages as platforms for sensing materials. NiO also has drawn much attention for gas detection due to its unique merits of excellent catalytic activity. Herein, NiO nanoparticles are incorporated with multilayer Ti3C2Tx-MXene to develop excellent triethylamine sensors. Due to the larger specific surface area and formed p-p heterojunctions, the response of the NiO/Ti3C2Tx gas sensor is endowed with a response value of 950% to 50 ppm triethylamine gas and is much higher than that of the pristine NiO sensor. Moreover, the NiO/Ti3C2Tx sensor displays a fast response time of 8 s (50 ppm triethylamine), excellent reproducibility, and reliable long-term stability. This study proves that NiO/Ti3C2Tx sensors have potential for the effective detection of triethylamine gas.

Peritoneal Phosphate Clearance: Determinants and Association With Mortality.

BACKGROUND: Dialytic phosphate removal is a cornerstone of the management of hyperphosphatemia in peritoneal dialysis (PD) patients, but the influencing factors on peritoneal phosphate clearance (PPC) are incompletely understood. Our objective was to explore clinically relevant factors associated with PPC in patients with different PD modality and peritoneal transport status and the association of PPC with mortality. METHODS: This is a cross-sectional and prospective observational study. Four hundred eighty-five PD patients were enrolled and divided into 2 groups according to PPC. All-cause mortality was evaluated after followed-up for at least 3 months. RESULTS: High PPC group showed lower mortality compared with Low PPC group by Kaplan-Meier analysis and log-rank test. Both multivariate linear regression and multivariate logistic regression revealed that high transport status, total effluent dialysate volume per day, continuous ambulatory PD (CAPD), and protein in total effluent dialysate volume appeared to be positively correlated with PPC; body mass index (BMI) and the normalized protein equivalent of total nitrogen appearance (nPNA) were negatively correlated with PPC. Besides PD modality and membrane transport status, total effluent dialysate volume showed a strong relationship with PPC, but the correlation differed among PD modalities. CONCLUSIONS: Higher PPC was associated with lower all-cause mortality risk in PD patients. Higher PPC correlated with CAPD modality, fast transport status, higher effluent dialysate volume and protein content, and with lower BMI and nPNA.

The mutational load in natural populations is significantly affected by high primary rates of retroposition.

Gene retroposition is known to contribute to patterns of gene evolution and adaptations. However, possible negative effects of gene retroposition remain largely unexplored since most previous studies have focused on between-species comparisons where negatively selected copies are mostly not observed, as they are quickly lost from populations. Here, we show for natural house mouse populations that the primary rate of retroposition is orders of magnitude higher than the long-term rate. Comparisons with single-nucleotide polymorphism distribution patterns in the same populations show that most retroposition events are deleterious. Transcriptomic profiling analysis shows that new retroposed copies become easily subject to transcription and have an influence on the expression levels of their parental genes, especially when transcribed in the antisense direction. Our results imply that the impact of retroposition on the mutational load has been highly underestimated in natural populations. This has additional implications for strategies of disease allele detection in humans.

Tracing the Origin and Evolutionary Fate of Recent Gene Retrocopies in Natural Populations of the House Mouse.

Although the contribution of retrogenes to the evolution of genes and genomes has long been recognized, the evolutionary patterns of very recently derived retrocopies that are still polymorphic within natural populations have not been much studied so far. We use here a set of 2,025 such retrocopies in nine house mouse populations from three subspecies (Mus musculus domesticus, M. m. musculus, and M. m. castaneus) to trace their origin and evolutionary fate. We find that ancient house-keeping genes are significantly more likely to generate retrocopies than younger genes and that the propensity to generate a retrocopy depends on its level of expression in the germline. Although most retrocopies are detrimental and quickly purged, we focus here on the subset that appears to be neutral or even adaptive. We show that retrocopies from X-chromosomal parental genes have a higher likelihood to reach elevated frequencies in the populations, confirming the notion of adaptive effects for "out-of-X" retrogenes. Also, retrocopies in intergenic regions are more likely to reach higher population frequencies than those in introns of genes, implying a more detrimental effect when they land within transcribed regions. For a small subset of retrocopies, we find signatures of positive selection, indicating they were involved in a recent adaptation process. We show that the population-specific distribution pattern of retrocopies is phylogenetically informative and can be used to infer population history with a better resolution than with SNP markers.

Combination therapy with dendritic cell loaded-exosomes supplemented with PD-1 inhibition at different time points have superior antitumor effect in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a prevalent cause of cancer-related deaths, is insensitive to traditional treatments. At different time intervals, the combined antitumor effects of DC-TEX and the programmed death protein 1 (PD-1) antibody (Ab) have not been investigated. In this study, HCC models were established and treated at different time intervals with DC-TEX alone or in combination with PD-1 Ab. In addition, we developed an orthotopic HCC model in BALB/c nude mice and restored T cells. Results demonstrated that the PD-1 + CD8 + T-cell population also increased significantly after DC-TEX treatment, in addition to the increased number of CD8 + T cells. The number of CD8 + T cells increased 72 h after DC-TEX administration. Similar observations were made for PD-1 + CD8 + T cells. Subsequently, PD-1 Ab was administered in combination with DC-TEX at different time points (0, 24, 72, 96, 120, or 168 h). Surprisingly, the combination treatment demonstrated a strong antitumor effect, which was very prominent when PD-1 Ab was administered at 72 h. PD-1 Ab significantly reversed the proliferative ability of PD-1 + CD8 + T cells at 72 h in vitro. The combined antitumor effects of PD-1 Ab and DC-TEX occurred mainly by stimulating CD8 + T cell proliferation and inhibiting T cell exhaustion. In conclusion, our results indicate that the combination of DC-TEX and PD-1 Ab significantly inhibits tumor growth in a murine HCC model and that the timing of PD-1 Ab administration impacts the antitumor effect.

Solution Self-Assembly of Amphiphilic Tadpole-like Giant Molecules Constructed by Monotethering Diblock Copolymer Chain onto a Nanoparticle.

The self-assembly behavior of a tadpole-like giant molecule (TGM) constructed from a hydrophobic nanoparticle (NP) monotethered by a single amphiphilic AB diblock copolymer chain was investigated by combining self-consistent field theory and density functional theory in solution. The effects of the hydrophobicities of the B blocks and NPs (i.e., solvent properties) on the self-assembly behavior of the TGMs were investigated in the cases of weak and strong intramolecular interactions (i.e., incompatibilities) between the components of giant molecules, respectively. Besides conventional ordered aggregates (such as spheres, rings, and vesicles) with hydrophobic B-cores covered by NP shells, several aggregates with novel hierarchical structures, including vesicles with NP-inserted hydrophobic walls, bead-string-like micelles, and long cylindrical micelles with NP bumps, were obtained by tuning the solvent properties under different intramolecular interactions. Noteworthy that the simulation results show that the arrangement of the NP bumps on the long cylindrical micelles may have a certain degree of helicity, which means that these micelles may have some unique electromagnetic features such as circular dichroism. Phase diagrams as a function of the hydrophobicities of the B blocks and NPs were constructed to show the formation conditions of these novel structures. These findings can not only offer new insights into understanding of the self-assembly behavior of the TGM in solution but also provide useful guidance for simple and efficient regulation of the morphology, as well as the NP distribution and arrangement of the ordered aggregates in experiments.

Enhancing enzymatic resistance of starch through strategic application of food physical processing technologies.

The demand for clean-label starch, perceived as environmentally friendly in terms of production and less hazardous to health, has driven the advancement of food physical processing technologies aimed at modifying starch. One of the key objectives of these modifications has been to reduce the glycaemic potency and increase resistant starch content of starch, as these properties have the potential to positively impact metabolic health. This review provides a comprehensive overview of recent updates in typical physical processing techniques, including annealing, heat-moisture, microwave and ultrasonication, and a brief discussion of several promising recent-developed methods. The focus is on evaluating the molecular, supramolecular and microstructural changes resulting from these modifications and identifying targeted structures that can foster enzyme-digestion resistance in native starch and its forms relevant to food applications. After a comprehensive search and assessment, the current physical modifications have not consistently improved starch enzymatic resistance. The opportunities for enhancing the effectiveness of modifications lie in (1) identifying modification conditions that avoid the intensive disruption of the granular and supramolecular structure of starch and (2) exploring novel strategies that incorporate multi-type modifications.

Brønsted Acid-Catalyzed Reaction of N-arylnaphthalen-2-amines with Quinone Esters for the Construction of Carbazole and C-N Axially Chiral Carbazole Derivatives.

We demonstrated here an efficient synthetic method of carbazole derivatives from readily available N-arylnaphthalen-2-amines and quinone esters catalyzed by Brønsted acid. With this strategy, a series of carbazole derivatives were obtained in good to excellent yields (76 to >99) under mild conditions. Large scale reaction illustrated the synthetic utility of this protocol. Meanwhile, a series of C-N axially chiral carbazole derivatives were also constructed in moderate to good yields (36-89% yield) with moderate to excellent atroposelectivities (44-94% ee) by using chiral phosphoric acid as a catalyst, which provides a novel strategy for the atroposelective construction of C-N axially chiral compounds and a new member of the C-N atropisomers.

Effects of diet and gender on the pharmacokinetics of oral lenvatinib: A clinical trial in healthy Chinese participants.

OBJECTIVE: Lenvatinib is a tyrosine kinase inhibitor that helps prevent angiogenesis. In this study, we investigated the potential influencing factors on lenvatinib pharmacokinetics to provide a reference for clinical application. MATERIALS AND METHODS: All healthy participants received a single dose of 4 mg lenvatinib mesylate capsules with a high-fat meal or fasted conditions. Lenvatinib plasma concentrations were determined via high-performance liquid chromatography-mass spectrometry/mass spectrometry, and the pharmacokinetic parameters were calculated using WinNonlin 8.1 software. A mixed effect model analysis was adopted to explore the influence factor for the pharmacokinetic parameters of lenvatinib. RESULTS: After a single oral dose of 4 mg lenvatinib mesylate, the pharmacokinetic parameters for the fasted and fed groups were as follows: tmax was 2.0 hours and 4.5 hours, Cmax was 53.60 ng/mL and 45.54 ng/mL, AUC0-t was 597.44 h×ng/mL and 561.51 h×ng/mL, CL was 6.82 L/h and 7.26 L/h, and Vd was 82.82 L and 94.04 L, respectively. Compared with those in the fasted group, decreased Cmax and increased tmax were observed in the fed group. The geometric mean ratios of fed/fasted for Cmax, AUC0-t, and AUC0-∞ were 86.9%, 94.0%, and 93.9%, respectively, and the pharmacokinetics of lenvatinib were significantly influenced by food intake. Gender influenced the pharmacokinetics of lenvatinib; females had higher Cmax and AUC0-t levels after 4 mg lenvatinib. Lenvatinib was well tolerated in healthy Chinese subjects. CONCLUSION: High-fat diet altered the pharmacokinetic profile of lenvatinib, but not sufficient to significantly impact its clinical efficacy. Therefore, lenvatinib is suitable for administration under fasted or fed conditions.

A longitudinal study on the effect of extreme temperature on non-accidental deaths in Hulunbuir City based on DLNM model.

OBJECTIVE: To explore the frequency and effect of extreme temperature on the non-accidental death rate in Hulunbuir, a Chinese ice city. METHODS: From 2014 to 2018, mortality data of residents residing in Hulunbuir City were collected. The lag and cumulative effects of extreme temperature conditions on non-accidental death and respiratory and circulatory diseases were analyzed by distributed lag non-linear models (DLNM). RESULTS: The risk of death was the highest during high-temperature conditions, the RR value was 1.111 (95% CI 1.031 ~ 1.198). The effect was severe and acute. The risk of death during extreme low-temperature conditions peaked on the fifth day, (RR 1.057; 95% CI 1.012 ~ 1.112), then decreased and was maintained for 12 days. The cumulative RR value was 1.289 (95% CI 1.045 ~ 1.589). Heat significantly influenced the incidence of non-accidental death in both men (RR 1.187; 95% CI 1.059-1.331) and women (RR 1.252; 95% CI 1.085-1.445). CONCLUSIONS: Regardless of the temperature effect, the risk of death in the elderly group (≥ 65 years) was significantly higher than that of the young group (0-64 years). High-temperature and low-temperature conditions can contribute to the increased number of deaths in Hulunbei. While high-temperature has an acute effect, low-temperature has a lagging effect. Elderly and women, as well as people with circulatory diseases, are more sensitive to extreme temperatures.

Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of baloxavir in rat plasma and its application to pharmacokinetic studies.

In this study, an ultra-performance liquid chromatography-tandem mass spectrometry method was established for the development and validation of baloxavir acid (BXA) concentrations and the active ingredients of the antiviral drug baloxavir marboxil (BXM). Further, the method was applied to study the pharmacokinetics of BXA. BXA was determined by the electrospray ionization multiple reaction monitoring positive ion mode, and the mass-to-charge ratios (m/z) of BXA and internal standard baloxavir-d4 were 484.2 → 247.2 and 488.1 → 247.2. An Oasis max online column (2.1 × 20 mm, 30 µm) was used with 1% formic acid in water (A) and 2% formic acid in acetonitrile (B) as mobile phases at a flow rate of 0.5 mL·min-1 for chromatographic separation. The linearity was good in the range of 3-200 ng·mL-1 (r = 0.9994), with 3.00 ng·mL-1 lower limit of quantification. The relative standard deviation of the inter-assay precision was less than or equal to 6.51%, and the accuracy was in the range of 91.28%-104.29%. This method is suitable for the determination of BXA and for performing pharmacokinetic studies in clinical research.

Prognostic Value of Pre-Treatment Neutrophil-To-Lymphocyte Ratio and Platelet-To-Lymphocyte Ratio in Patients With Brain Metastasis From Lung Cancer: A systematic Review and Meta-Analysis.

In modern clinical medicine, lung cancer is one of the most common types of cancer, and the brain is a routine organ of metastasis. Recently, researchers have evaluated hematologic indicators, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), and confirmed that they are valid indices for predicting the outcome of patients with lung cancer. However, their prognostic significance for patients with lung cancer who have progressed to brain metastasis (BM) has not been clarified. Our study performed and reported a meta-analysis focusing on the association of pre-treatment NLR, PLR, and overall survival (OS) in lung cancer patients with BM. We searched the PubMed, Embase, and China National Knowledge Infrastructure databases using the PRISMA strategy. Meta-analyses of OS were performed using random-effects models because of the significant heterogeneity. We included 11 articles to evaluate NLR and PLR in 1,977 eligible patients. The NLR group consisted of 11 studies whose meta-analysis showed that OS was significantly shorter in patients with high NLR than in those with low NLR (pooled HR=1.84 (95% CI: 1.47-2.31). Five studies were included in the PLR group, and the results suggested that OS was significantly shorter in patients with high PLR than in those with low PLR (pooled HR=1.53 (95% CI: 1.07-2.20). Our meta-analysis showed a statistically significant association between NLR, PLR, and OS. Lower pre-treatment NLR and PLR predicted a better OS.

Cobalt and nitrogen co-doped monolithic carbon foam for ultrafast degradation of emerging organic pollutants via peroxymonosulfate activation.

Cobalt-based catalysts are expected as one of the most promising peroxymonosulfate (PMS) activators for the removal of organic pollutants from industrial wastewater. However, the easy agglomeration, difficult separation, and secondary pollution of cobalt ions limit their practical application. In this study, a novel, highly efficient, reusable cobalt and nitrogen co-doped monolithic carbon foam (Co-N-CMF) was utilized to activate PMS for ultrafast pollutant degradation. Co-N-CMF (0.2 g/L) showed ultrafast catalytic kinetics and higher total organic carbon (TOC) removal efficiency. Bisphenol A, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, and 2,4-dichlorophenol could be completely degraded after 2, 4, 5, and 5 min, and the TOC removal efficiencies were 77.4 %, 68.9 %, 72.8 %, and 79.8 %, respectively, corresponding to the above pollution. The sulfate radical (SO4•-) was the main reactive oxygen species in Co-N-CMF/PMS based on electron paramagnetic resonance. The ecological structure-activity relationship program analysis via the quantitative structure activity relationship analysis and phytotoxicity assessment revealed that the Co-N-CMF/PMS system demonstrates good ecological safety and ecological compatibility. The Co-N-CMF catalyst has good catalytic activity and facile recycling, which provides a fine method with excellent PMS activation capacity for 2,4-dichlorophenol elimination from simulated industrial wastewater. This study provides new insights into the development of monolithic catalysts for ultrafast wastewater treatment via PMS activation.

Effectiveness of Tai Chi exercise on fear of falling and balance in older adults: A meta-analysis.

OBJECTIVE: To assess the effect of Tai Chi exercise on fear of falling (FOF) and balance in older adults. METHOD: Chinese and English databases were searched for randomized controlled trials (RCTs) on the effect of Tai Chi on the fear of falling and balance of older adults. The search time limit was from inception until 13 December 2022. RESULTS: A total of 13 RCTs were included and the overall quality was moderate. The results showed that Tai Chi exercise could significantly improve fear of falling [SMD = -0.54, 95%CI(-1.09, 0.01), Z =1.94, P = 0.05], dynamic balance [SMD = -2.23, 95%CI(-3.89, -0.75), Z=2.90, P = 0.004] and fall incidence [RR = 0.48, 95%CI(0.35, 0.65), Z =4.67, P <0.001] in older adults. However, its significant benefits in improving the static balance [MD = 4.16, 95%CI(-3.71, 12.04), Z =1.04, P = 0.30] in older adults were not found. The results of the subgroup analysis showed that the short-term effect of Tai Chi in reducing the fear of falling was more significant (P = 0.002). CONCLUSION: Tai Chi could alleviate the FOF of older adults, improve balance and reduce fall incidence. However, large-sample, multi-center, high-quality randomized controlled studies are still verified in the future.

[Genetic analysis of a Chinese pedigree with Cohen syndrome due to compound heterozygous variants of VPS13B gene].

OBJECTIVE: To investigate the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Cohen syndrome. METHODS: A proband who was admitted to Zhengzhou People's Hospital on June 2, 2021 due to intellectual disability and developmental delay, in addition with her younger sister and other family members, were selected as the study subjects. Clinical data of the proband and her younger sister were collected. Genomic DNA was extracted from peripheral venous blood and chorionic villi samples. Chromosomal abnormalities were detected with chromosomal microarray analysis (CMA). Whole exome sequencing (WES) and Sanger sequencing were carried out to detect candidate variants in the proband. With RNA extracted from the peripheral blood samples, VPS13B gene transcripts and expression were analyzed by PCR and real-time quantitative PCR. Prenatal diagnosis was carried out at 12 weeks' gestation. RESULTS: The proband was a 10-year-old female with clinical manifestations including development delay, obesity, severe myopia and peculiar facial features. Her sister was 3 years old with a similar phenotype. CMA revealed no chromosomal abnormality in the proband, while WES results revealed that the proband and her sister had both harbored compound heterozygous variants of the VPS13B gene, namely c.10076_10077delCA (p.T3359fs*29) and c.6940+1G>T, which were respectively inherited from their mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+PS4+PM4+PP1; PVS1+PM2_Supporting+PM3+PP1). In vivo splicing assay confirmed that the c.6940+1G>T variant has produced a frameshift transcript with skipping of exon 38. Compared with the control group, the expression of RNA in the peripheral blood of the proband's parents has decreased to 65% ~ 70% (P < 0.01), whilst that in the proband and her sister has decreased to 40% (P < 0.001). Prenatal diagnosis at 12 weeks of gestation has found that the fetus only harbored the heterozygous c.10076_ 10077delCA variant. CONCLUSION: The c.10076_10077delCA (p.T3359fs*29) frameshift variant and c.6940+1G>T splicing variant probably underlay the Cohen syndrome in this pedigree. Genetic testing has facilitated the diagnosis of this disease.

Improvement in hemodynamics of amlodipine besylate combined with metoprolol in patients with hypertension complicated by heart failure.

To observe the effect of amlodipine besylate combined with metoprolol in treating hypertension and heart failure. Total number of patients with hypertension combined with HF admitted to our hospital was One hundred and fifty from May 2017 to May 2022 selected for the study and they were distributed into single drug group and combination group by the method of random number table, with the total number of 75 cases in every group. Metoprolol treatment was given to the single drug group and metoprolol combined with amlodipine besylate treatment was given to the combination group. Both groups' scientific outcomes were compared, including their ventricular function, inflammatory factors, hemodynamics and liver and kidney function. Adverse treatment-related side events for patients were also tallied. Compared to the single drug group, the combination group's overall treatment effectiveness was higher (P<0.05). The combined group had better ventricular function, improved hemodynamics and lower levels of inflammatory factors (P<0.05). The liver, kidney function and adverse effects outcomes were the same in both groups (P>0.05). Amlodipine besylate combined with metoprolol has a better clinical effect in treating hypertension combined with heart failure, which can more effectively improve patients' cardiac function, inflammation and hemodynamics.