Effects of denitrification on speciation and redistribution of arsenic in estuarine sediments.

Microbially-mediated redox processes involving arsenic (As) and its host minerals significantly contribute to the mobilization of As in estuarine sediments. Despite its significance, the coupling between As dynamics and denitrification processes in these sediments is not well understood. This study employed sequential sediment extractions and simultaneous monitoring of dissolved iron (Fe), nitrogen (N), and sulfur (S) to investigate the impact of nitrate (NO3-) on the speciation and redistribution of As, alongside changes in microbial community composition. Our results indicated that NO3- additions significantly enhance anaerobic arsenite (As(III)) oxidation, facilitating its immobilization by increased adsorption onto sediment matrices in As-contaminated estuarine settings. Furthermore, NO3- promoted the conversion of As bound to troilite (FeS) and pyrite (FeS2) into forms associated with Fe oxides, challenging the previously assumed stability of FeS/FeS2-bound As in such environments. Continuous NO3- additions ensured As and Fe oxidation, thereby preventing their reductive dissolution and stabilizing the process that reduces As mobility. Changes in the abundance of bacterial communities and correlation analyses revealed that uncultured Anaerolineaceae and Thioalkalispira may be the main genus involved in these transformations. This study underscores the critical role of NO3- availability in modulating the biogeochemical cycle of As in estuarine sediments, offering profound insights for enhancing As immobilization techniques and informing environmental management and remediation strategies in As-contaminated coastal regions.

Hydrogen Embrittlement as a Conspicuous Material Challenge─Comprehensive Review and Future Directions.

Hydrogen is considered a clean and efficient energy carrier crucial for shaping the net-zero future. Large-scale production, transportation, storage, and use of green hydrogen are expected to be undertaken in the coming decades. As the smallest element in the universe, however, hydrogen can adsorb on, diffuse into, and interact with many metallic materials, degrading their mechanical properties. This multifaceted phenomenon is generically categorized as hydrogen embrittlement (HE). HE is one of the most complex material problems that arises as an outcome of the intricate interplay across specific spatial and temporal scales between the mechanical driving force and the material resistance fingerprinted by the microstructures and subsequently weakened by the presence of hydrogen. Based on recent developments in the field as well as our collective understanding, this Review is devoted to treating HE as a whole and providing a constructive and systematic discussion on hydrogen entry, diffusion, trapping, hydrogen-microstructure interaction mechanisms, and consequences of HE in steels, nickel alloys, and aluminum alloys used for energy transport and storage. HE in emerging material systems, such as high entropy alloys and additively manufactured materials, is also discussed. Priority has been particularly given to these less understood aspects. Combining perspectives of materials chemistry, materials science, mechanics, and artificial intelligence, this Review aspires to present a comprehensive and impartial viewpoint on the existing knowledge and conclude with our forecasts of various paths forward meant to fuel the exploration of future research regarding hydrogen-induced material challenges.

Synthesis of selenophene-containing flavonols and 2-styrylchromones: Evaluation of their activities compared with selenophene-containing chalcones as potential anticancer agents.

Previously, we documented the synthesis and assessed the biological effects of chalcones containing selenium against HT-29 human colorectal adenocarcinoma cells, demonstrating their significant potential. As research on selenium-containing flavonoids remains limited, this article outlines our design and synthesis of three selenium-based flavonols and three 2-styrylchromones. We conducted evaluations of these compounds to determine their impact on human lung cancer cells (A549, H1975, CL1-0, and CL1-5) and their influence on normal lung fibroblast MRC5 cells. Additionally, we included selenium-based chalcones in our testing for comparative purposes. Our findings highlight that the simplest compound, designated as compound 1, exhibited the most promising performance among the tested molecules.

In vitro studies on the effects of cryopreserved platelet-rich plasma on cells related to wound healing.

Platelet-rich plasma (PRP) holds promise as a therapeutic modality for wound healing; however, immediate utilization encounters challenges related to volume, concentration, and consistency. Cryopreservation emerges as a viable solution, preserving PRP's bioactive components and extending its shelf life. This study explores the practicality and efficacy of cryopreserved platelet-rich plasma (cPRP) in wound healing, scrutinizing both cellular mechanisms and clinical implications. Fresh PRP and cPRP post freeze-thaw underwent assessment in macrophage, fibroblast, and endothelial cell cultures. The impact of cPRP on active component release and cell behavior pertinent to wound healing was evaluated. Varied concentrations of cPRP (1%, 5%, 10%) were examined for their influence on cell polarization, migration, and proliferation. The results showed minimal changes in cPRP's IL-1ß levels, a slight decrease in PDGF-BB, and superior effects on macrophage M2 polarization and fibroblast migration, while no statistical significance was observed in endothelial cell angiogenesis and proliferation. Remarkably, 5% PRP exhibited the most significant stimulation among all cPRP concentrations, notably impacting cell proliferation, angiogenesis, and migration. The discussion underscores that cPRP maintains platelet phenotype and function over extended periods, with 5% cPRP offering the most favorable outcomes, providing a pragmatic approach for cold storage to extend post-thaw viability and amplify therapeutic effects.

What is the context? Platelet-rich plasma (PRP) is a potential bioactive material for wound healing, but using it immediately faces issues like volume, concentration, and consistency.Low-temperature freezing is a method employed to preserve PRP. However, the current understanding of the effects of the freezing-thawing process on the components of PRP and its impact on cells relevant to wound healing remains unclear.What is new? This study explores the feasibility and effectiveness of using cryopreserved PRP at −80°C for promoting wound healing. This research stands out for its focus on cellular responses and practical implications in therapeutic contexts.To understand their distinct impact on different cell types relevant to wound healing, the study meticulously examined various final concentrations of cPRP (1%, 5%, 10%).The study identified the superior effects of 5% cPRP on crucial cellular activities, notably in cell polarization, proliferation, angiogenesis, and migration.What is the impact? Low-temperature freezing can be considered an effective method for PRP preservation.Some bioactive components in cPRP exhibit subtle changes; however, these changes result in better effects on certain cell types related to healing.The study illustrates that all concentrations of cPRP effectively enhance cell proliferation, migration, and differentiation, emphasizing the comparable efficacy of cryopreserved PRP to non-cryopreserved PRP.

Palmitic acid impairs human and mouse placental function by inhibiting trophoblast autophagy through induction of acyl-coenzyme A-binding protein (ACBP) upregulation.

STUDY QUESTION: Can exposure to palmitic acid (PA), a common saturated fatty acid, modulate autophagy in both human and mouse trophoblast cells through the regulation of acyl-coenzyme A-binding protein (ACBP)? SUMMARY ANSWER: PA exposure before and during pregnancy impairs placental development through mechanisms involving placental autophagy and ACBP expression. WHAT IS KNOWN ALREADY: High-fat diets, including PA, have been implicated in adverse effects on human placental and fetal development. Despite this recognition, the precise molecular mechanisms underlying these effects are not fully understood. STUDY DESIGN, SIZE, DURATION: Extravillous trophoblast (EVT) cell line HTR-8/SVneo and human trophoblast stem cell (hTSC)-derived EVT (hTSCs-EVT) were exposed to PA or vehicle control for 24 h. Female wild-type C57BL/6 mice were divided into PA and control groups (n = 10 per group) and subjected to a 12-week dietary intervention. Afterward, they were mated with male wild-type C57BL/6 mice and euthanized on Day 14 of gestation. Female ACBPflox/flox mice were also randomly assigned to control and PA-exposed groups (each with 10 mice), undergoing the same dietary intervention and mating with ACBPflox/floxELF5-Cre male mice, followed by euthanasia on Day 14 of gestation. The study assessed the effects of PA on mouse embryonic development and placental autophagy. Additionally, the role of ACBP in the pathogenesis of PA-induced placental toxicity was investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS: The findings were validated using real-time PCR, Western blot, immunofluorescence, transmission electron microscopy, and shRNA knockdown approaches. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to PA-upregulated ACBP expression in both human HTR-8/SVneo cells and hTSCs-EVT, as well as in mouse placenta. PA exposure also induced autophagic dysfunction in HTR-8/SVneo cells, hTSCs-EVT, and mouse placenta. Through studies on ACBP placental conditional knockout mice and ACBP knockdown human trophoblast cells, it was revealed that reduced ACBP expression led to trophoblast malfunction and affected the expression of autophagy-related proteins LC3B-II and P62, thereby impacting embryonic development. Conversely, ACBP knockdown partially mitigated PA-induced impairment of placental trophoblast autophagy, observed both in vitro in human trophoblast cells and in vivo in mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Primary EVT cells from early pregnancy are fragile, limiting research use. Maintaining their viability is tough, affecting data reliability. The study lacks depth to explore PA diet cessation effects after 12 weeks. Without follow-up, understanding postdiet impacts on pregnancy stages is incomplete. Placental abnormalities linked to elevated PA diet in embryos lack confirmation due to absence of control groups. Clarifying if issues stem solely from PA exposure is difficult without proper controls. WIDER IMPLICATIONS OF THE FINDINGS: Consuming a high-fat diet before and during pregnancy may result in complications or challenges in successfully carrying the pregnancy to term. It suggests that such dietary habits can have detrimental effects on the health of both the mother and the developing fetus. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the National Natural Science Foundation of China (82171664, 82301909) and the Natural Science Foundation of Chongqing Municipality of China (CSTB2022NS·CQ-LZX0062, cstc2019jcyj-msxmX0749, and cstc2021jcyj-msxmX0236). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Odd Response-Induced Phase Separation of Active Spinners.

Due to the breaking of time-reversal and parity symmetries and the presence of non-conservative microscopic interactions, active spinner fluids and solids respectively exhibit nondissipative odd viscosity and nonstorage odd elasticity, engendering phenomena unattainable in traditional passive or active systems. Here, we study the effects of odd viscosity and elasticity on phase behaviors of active spinner systems. We find the spinner fluid under a simple shear experiences an anisotropic gas-liquid phase separation driven by the odd-viscosity stress. This phase separation exhibits equilibrium-like behavior, with both binodal-like and spinodal curves and critical point. However, the formed dense liquid phase is unstable, since the odd elasticity instantly takes over the odd viscosity to condense the liquid into a solid-like phase. The unusual phase behavior essentially arises from the competition between thermal fluctuations and the odd response-induced effective attraction. Our results demonstrate that the cooperation of odd viscosity and elasticity can lead to exotic phase behavior, revealing their fundamental roles in phase transition.

P53 upregulation by USP7-engaging molecular glues.

Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation. Identifying molecular glues is challenging. There is a scarcity of target-specific upregulating molecular glues, which are highly anticipated for numerous targets, including P53. P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases, whereas deubiquitinases (DUBs) remove polyubiquitination conjugates to counteract these E3 ligases. Thus, small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination. Here, using small-molecule microarray-based technology and unbiased screening, we identified three potential molecular glues that may tether P53 to the DUB, USP7, and elevate the P53 level. Among the molecular glues, bromocriptine (BC) is an FDA-approved drug with the most robust effects. BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7. Consistent with P53 upregulation in cancer cells, BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model. In summary, we established a potential screening platform and identified potential molecular glues upregulating P53. Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.

When the one true faith trumps all: Low religious diversity, religious intolerance, and science denial.

Past theories have linked science denial to religiosity but have not explained its geographic variability. We hypothesize that it springs not only from religious intensity but also from religious intolerance, which depends greatly on the experience of religious diversity and hence on geography. The belief that one's religion trumps other faiths precipitates the stance that it trumps science too. This psychological process is most likely to operate in regions or countries with low religious heterogeneity. We measure the rejection of science not only in people's refusal to follow specific health recommendations, such as taking COVID-19 vaccines, but also in general measures of scientific engagement and attainment. We rule out alternative explanations, including reverse causality and spurious correlations, by conducting controlled experiments and running robustness checks on our statistical models.

Discovery of novel cholinesterase inhibitors easily crossing the blood-brain barrier via structure-property relationship investigation: Methylenedioxy-cinnamicamides containing tertiary amine side chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 µmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72 ± 93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

The clinical characteristics of cerebral small vessel disease patients with motoric cognitive risk syndrome during single- and dual-task walking.

Objective: We aimed to (1) identify neuroimaging biomarkers of distinguishing motoric cognitive risk syndrome (MCRS) risk among older Chinese adults with cerebral small vessel disease (CSVD) and (2) detect differences in gait parameters and neuroimaging biomarkers between CSVD individual with and without MCRS, especially during dual-task walking (DTW). Methods: We enrolled 126 inpatients with CSVD who were divided into two groups according to MCRS status. Data on basic parameters, variability, asymmetry, and coordination were collected during single-task walking (STW) and DTW. Neuroimaging features (white matter hyperintensities, lacunes, and microbleeds) and total disease burden were calculated. Analysis of variance and logistic regression analyses were applied to assess the role of STW, DTW, and neuroimaging biomarkers in MCRS. Results: In total, 126 consecutive inpatients with CSVD were included (84 and 42 patients were classified as MCRS-negative and MCRS-positive, respectively). The MCRS-positive group showed poorer performance for nearly all gait parameters compared with the MCRS-negative group during cognitive DTW. Meanwhile, all gait parameters except asymmetry were assessed in participants with MCRS for significant deterioration during cognitive DTW compared with that during STW. However, only basic parameters differed between STW and cognitive DTW in participants without MCRS. A significant independent association between total CSVD scores and MCRS was also detected. Conclusions: For CSVD patients, with higher total CSVD burden rather than any single neuroimaging marker, was linked to a greater risk of MCRS. In addition, CSVD individuals with MCRS had higher variability and phase coordination index (PCI), especially in cognitive DTW. Thus, they should concentrate more on their gait variability or coordination and reduce secondary task loads while walking in daily life, especially in cognitive secondary tasks.

Advances in systemic immune inflammatory indices in non-small cell lung cancer: A review.

Lung cancer is one of the most prevalent cancers globally, with non-small cell lung cancers constituting the majority. These cancers have a high incidence and mortality rate. In recent years, a growing body of research has demonstrated the intricate link between inflammation and cancer, highlighting that inflammation and cancer are inextricably linked and that inflammation plays a pivotal role in cancer development, progression, and prognosis of cancer. The Systemic Immunoinflammatory Index (SII), comprising neutrophil, lymphocyte, and platelet counts, is a more comprehensive indicator of the host's systemic inflammation and immune status than a single inflammatory index. It is widely used in clinical practice due to its cost-effectiveness, simplicity, noninvasiveness, and ease of acquisition. This paper reviews the impact of SII on the development, progression, and prognosis of non-small cell lung cancer.

Metabolic landscape and pathogenic insights: a comprehensive analysis of high ovarian response in infertile women undergoing in vitro fertilization.

BACKGROUND: In the realm of assisted reproduction, a subset of infertile patients demonstrates high ovarian response following controlled ovarian stimulation (COS), with approximately 29.7% facing the risk of Ovarian Hyperstimulation Syndrome (OHSS). Management of OHSS risk often necessitates embryo transfer cancellation, leading to delayed prospects of successful pregnancy and significant psychological distress. Regrettably, these patients have received limited research attention, particularly regarding their metabolic profile. In this study, we aim to utilize gas chromatography-mass spectrometry (GC-MS) to reveal these patients' unique serum metabolic profiles and provide insights into the disease's pathogenesis. METHODS: We categorized 145 infertile women into two main groups: the CON infertility group from tubal infertility patients and the Polycystic Ovary Syndrome (PCOS) infertility group. Within these groups, we further subdivided them into four categories: patients with normal ovarian response (CON-NOR group), patients with high ovarian response and at risk for OHSS (CON-HOR group) within the CON group, as well as patients with normal ovarian response (PCOS-NOR group) and patients with high ovarian response and at risk for OHSS (PCOS-HOR group) within the PCOS group. Serum metabolic profiles were analyzed using GC-MS. The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL. RESULTS: The serum metabolomics analysis revealed four different metabolites within the CON group and 14 within the PCOS group. Remarkably, 10-pentadecenoic acid emerged as a discernible risk metabolite for the CON-HOR, also found to be a differential metabolite between CON-NOR and PCOS groups. cysteine and 5-methoxytryptamine were also identified as risk metabolites for the PCOS-HOR. Furthermore, KEGG analysis unveiled significant enrichment of the aminoacyl-tRNA biosynthesis pathway among the metabolites differing between PCOS-NOR and PCOS-HOR. CONCLUSION: Our study highlights significant metabolite differences between patients with normal ovarian response and those with high ovarian response and at risk for OHSS within both the tubal infertility control group and PCOS infertility group. Importantly, we observe metabolic similarities between patients with PCOS and those with a high ovarian response but without PCOS, suggesting potential parallels in their underlying causes.

A Conceptual Framework to Understand the Self-Assembly of Chemically Active Colloids.

Colloids that generate chemicals, or "chemically active colloids", can interact with their neighbors and generate patterns via forces arising from such chemical gradients. Examples of such assemblies of chemically active colloids are abundant in the literature, but a unified theoretical framework is needed to rationalize the scattered results. Combining experiments, theory, Brownian dynamics, and finite element simulations, we present here a conceptual framework for understanding how immotile, yet chemically active, colloids assemble. This framework is based on the principle of ionic diffusiophoresis and diffusioosmosis and predicts that a chemically active colloid interacts with its neighbors through short- and long-range interactions that can be either repulsive or attractive, depending on the relative diffusivity of the released cations and anions, and the relative zeta potential of a colloidal particle and the planar surface on which it resides. As a result, 4 types of pairwise interactions arise, leading to 4 different types of colloidal assemblies with distinct patterns. Using short-range attraction and long-range attraction (SALR) systems as an example, we show quantitative agreement between the framework and experiments. The framework is then applied to rationalize a wide range of patterns assembled from chemically active colloids in the literature exhibiting other types of pairwise interactions. In addition, the framework can predict what the assembly looks like with minimal experimental information and help infer ionic diffusivity and zeta potential values in systems where these values are inaccessible. Our results represent a solid step toward building a complete theory for understanding and controlling chemically active colloids, from the molecular level to their mesoscopic superstructures and ultimately to the macroscopic properties of the assembled materials.

Identification of congenital aortic valve malformations in juvenile natriuretic peptide receptor 2 deficient (Npr2+/-) mice using high frequency ultrasound.

Mouse models of congenital aortic valve malformations are useful for studying disease pathobiology, but most models have incomplete penetrance (e.g., ~2 to 77% prevalence of bicuspid aortic valves (BAVs) across multiple models). For longitudinal studies of pathologies associated with BAVs and other congenital valve malformations, which manifest over months in mice, it is operationally inefficient, economically burdensome, and ethically challenging to enroll large numbers of mice in studies without first identifying those with valvular abnormalities. To address this need, we established and validated a novel in vivo high frequency (30 MHz) ultrasound imaging protocol capable of detecting aortic valvular malformations in juvenile mice. Fifty natriuretic peptide receptor 2 heterozygous mice on a low density lipoprotein receptor deficient background (Npr2+/-;Ldlr-/-; 32 male, 18 female) were imaged at 4- and 8-weeks of age. Fourteen percent of the Npr2+/-;Ldlr-/- mice exhibited features associated with aortic valve malformations, including: i) abnormal trans-aortic flow patterns on color Doppler (recirculation and regurgitation); ii) peak systolic flow velocities distal to the aortic valves reaching or surpassing ~1250 mm/s by pulsed wave Doppler; and iii) putative fusion of cusps along commissures and abnormal movement elucidated by 2D imaging with ultra-high temporal resolution. Valves with these features were confirmed by ex vivo gross anatomy and histological visualization to have thickened cusps, partial fusions, or Sievers type 0 bicuspid valves. This ultrasound imaging protocol will enable efficient, cost-effective and humane implementation of studies of congenital aortic valvular abnormalities and associated pathologies in a wide range of mouse models.

Heme metabolism and HO-1 in the pathogenesis and potential intervention of endometriosis.

Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase-1 (HO-1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO-1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti-inflammatory, and anti-proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

Ventricular Netrin-1 deficiency leads to defective pyramidal decussation and mirror movement in mice.

The corticospinal tract (CST) is the principal neural pathway responsible for conducting voluntary movement in the vertebrate nervous system. Netrin-1 is a well-known guidance molecule for midline crossing of commissural axons during embryonic development. Families with inherited Netrin-1 mutations display congenital mirror movements (CMM), which are associated with malformations of pyramidal decussation in most cases. Here, we investigated the role of Netrin-1 in CST formation by generating conditional knockout (CKO) mice using a Gfap-driven Cre line. A large proportion of CST axons spread laterally in the ventral medulla oblongata, failed to decussate and descended in the ipsilateral spinal white matter of Ntn1Gfap CKO mice. Netrin-1 mRNA was expressed in the ventral ventricular zone (VZ) and midline, while Netrin-1 protein was transported by radial glial cells to the ventral medulla, through which CST axons pass. The level of transported Netrin-1 protein was significantly reduced in Ntn1Gfap CKO mice. In addition, Ntn1Gfap CKO mice displayed increased symmetric movements. Our findings indicate that VZ-derived Netrin-1 deletion leads to an abnormal trajectory of the CST in the spinal cord due to the failure of CST midline crossing and provides novel evidence supporting the idea that the Netrin-1 signalling pathway is involved in the pathogenesis of CMM.

Bismuth-Containing Quadruple Therapy for Helicobacter pylori Eradication: A Randomized Clinical Trial of 10 and 14 Days.

BACKGROUND: Bismuth-containing quadruple therapy is the first-line treatment for eradicating Helicobacter pylori (H. pylori). The optimal duration for H. pylori eradication using bismuth-containing quadruple therapy remains controversial. Therefore, we aimed to compare the clinical effects of the 10- and 14-day bismuth-containing quadruple treatment regimen to eradicate H. pylori. METHODS: Treatment-naïve patients with H. pylori infection (n = 1300) were enrolled in this multicenter randomized controlled study across five hospitals in China. They were randomized into 10- or 14-day treatment groups to receive bismuth-containing quadruple therapy as follows: vonoprazan 20 mg twice daily; bismuth 220 mg twice daily; amoxicillin 1000 mg twice daily; and either clarithromycin 500 mg twice daily or tetracycline 500 mg four times daily. At least 6 weeks after treatment, we performed a 13C-urea breath test to evaluate H. pylori eradication. RESULTS: The per-protocol eradication rates were 93.22% (564/605) and 93.74% (569/607) (p < 0.001) and the intention-to-treat eradication rates were 88.62% (576/650) and 89.38% (581/650) (p = 0.007) for the 10- and 14-day regimens, respectively. Incidence of adverse effects was lower in patients who received 10- vs. 14 days of treatment (22.59% vs. 28.50%, p = 0.016). We observed no significant differences in the compliance to treatment or the discontinuation of therapy because of severe adverse effects between the groups. CONCLUSION: Compared with the 14-day bismuth-containing quadruple regimens, the 10-day regimen demonstrated a non-inferior efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and tolerated and could be recommended for H. pylori eradication (NCT05049902).

The association and underlying mechanism of the digit ratio (2D:4D) in hypospadias.

ABSTRACT: The second-to-fourth digit (2D:4D) ratio is thought to be associated with prenatal androgen exposure. However, the relationship between the 2D:4D ratio and hypospadias is poorly understood, and its molecular mechanism is not clear. In this study, by analyzing the hand digit length of 142 boys with hypospadias (23 distal, 68 middle, and 51 proximal) and 196 controls enrolled in Shanghai Children's Hospital (Shanghai, China) from December 2020 to December 2021, we found that the 2D:4D ratio was significantly increased in boys with hypospadias (P < 0.001) and it was positively correlated with the severity of the hypospadias. This was further verified by the comparison of control mice and prenatal low testosterone mice model obtained by knocking out the risk gene (dynein axonemal heavy chain 8 [DNAH8]) associated with hypospadias. Furthermore, the discrepancy was mainly caused by a shift in 4D. Proteomic characterization of a mouse model validated that low testosterone levels during pregnancy can impair the growth and development of 4D. Comprehensive mechanistic explorations revealed that during the androgen-sensitive window, the downregulation of the androgen receptor (AR) caused by low testosterone levels, as well as the suppressed expression of chondrocyte proliferation-related genes such as Wnt family member 5a (Wnt5a), Wnt5b, Smad family member 2 (Smad2), and Smad3; mitochondrial function-related genes in cartilage such as AMP-activated protein kinase (AMPK) and nuclear respiratory factor 1 (Nrf-1); and vascular development-related genes such as myosin light chain (MLC), notch receptor 3 (Notch3), and sphingosine kinase 1 (Sphk1), are responsible for the limitation of 4D growth, which results in a higher 2D:4D ratio in boys with hypospadias via decreased endochondral ossification. This study indicates that the ratio of 2D:4D is a risk marker of hypospadias and provides a potential molecular mechanism.

The Association Between Mitochondrial tRNAGlu Variants and Hearing Loss: A Case-Control Study.

Purpose: This study aimed to examine the frequencies of mt-tRNAGlu variants in 180 pediatric patients with non-syndromic hearing loss (NSHL) and 100 controls. Methods: Sanger sequencing was performed to screen for mt-tRNAGlu variants. These mitochondrial DNA (mtDNA) pathogenic mutations were further assessed using phylogenetic conservation and haplogroup analyses. We also traced the origins of the family history of probands carrying potential pathogenic mtDNA mutations. Mitochondrial functions including mtDNA content, ATP and reactive oxygen species (ROS) were examined in cells derived from patients carrying the mt-tRNAGlu A14692G and CO1/tRNASer(UCN) G7444A variants and controls. Results: We identified four possible pathogenic variants: m.T14709C, m.A14683G, m.A14692G and m.A14693G, which were found in NSHL patients but not in controls. Genetic counseling suggested that one child with the m.A14692G variant had a family history of NSHL. Sequence analysis of mtDNA suggested the presence of the CO1/tRNASer(UCN) G7444A and mt-tRNAGlu A14692G variants. Molecular analysis suggested that, compared with the controls, patients with these variants exhibited much lower mtDNA copy numbers, ATP production, whereas ROS levels increased (p<0.05 for all), suggesting that the m.A14692G and m.G7444A variants led to mitochondrial dysfunction. Conclusion: mt-tRNAGlu variants are important risk factors for NSHL.

The main aim of our study was to explore the association between the mt-tRNA^Glu variants and hearing loss. We found that m.T14709C, m.A14683G, m.A14692G and m.A14693G variants were associated with hearing impairments, these variants localized at extremely conserved nucleotides of mt-tRNA^Glu and may result a failure in tRNA metabolism, furthermore, patients with mt-tRNA^Glu variants exhibited much lower levels of mtDNA copy number, ATP as compared with controls, whereas ROS increased. As a result, mt-tRNA^Glu variants may serve as biomarkers for mitochondrial deafness, and screening for tRNA^Glu variants is recommended for early detection and diagnosis of mitochondrial deafness.

Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy.

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvß3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.