A pyruvate transporter in the apicoplast of apicomplexan parasites.

Pyruvate lies at a pivotal node of carbon metabolism in eukaryotes. It is involved in diverse metabolic pathways in multiple organelles, and its interorganelle shuttling is crucial for cell fitness. Many apicomplexan parasites harbor a unique organelle called the apicoplast that houses metabolic pathways like fatty acid and isoprenoid precursor biosyntheses, requiring pyruvate as a substrate. However, how pyruvate is supplied in the apicoplast remains enigmatic. Here, deploying the zoonotic parasite Toxoplasma gondii as a model apicomplexan, we identified two proteins residing in the apicoplast membranes that together constitute a functional apicoplast pyruvate carrier (APC) to mediate the import of cytosolic pyruvate. Depletion of APC results in reduced activities of metabolic pathways in the apicoplast and impaired integrity of this organelle, leading to parasite growth arrest. APC is a pyruvate transporter in diverse apicomplexan parasites, suggesting a common strategy for pyruvate acquisition by the apicoplast in these clinically relevant intracellular pathogens.

Non-CG DNA hypomethylation promotes photosynthesis and nitrogen fixation in soybean.

Non-CG DNA methylation, a plant-specific epigenetic mark mainly regulated by chromomethylase (CMT), is known to play important roles in Arabidopsis thaliana. However, whether and to what extent non-CG DNA methylation modulates agronomic traits in crops remain to be explored. Here, we describe the consequences of non-CG DNA hypomethylation on development, seed composition, and yield in soybean (Glycine max). We created a Gmcmt mutant line lacking function of all four CMT genes. This line exhibited substantial hypomethylation of non-CG (CHG and CHH) sites. Non-CG hypomethylation enhanced chromatin accessibility and promoted or repressed the expression of hundreds of functionally relevant genes, including upregulation of GOLDEN-LIKE 10 (GmGLK10), which led to enhanced photosynthesis and, unexpectedly, improved nitrogen fixation efficiency. The Gmcmt line produced larger seeds with increased protein content. This study provides insights into the mechanisms of non-CG methylation-based epigenetic regulation of soybean development and suggests viable epigenetic strategies for improving soybean yield and nutritional value.

Control of homologous recombination by the HROB-MCM8-MCM9 pathway.

DNA repair by homologous recombination (HR) is essential for genomic integrity, tumor suppression, and the formation of gametes. HR uses DNA synthesis to repair lesions such as DNA double-strand breaks and stalled DNA replication forks, but despite having a good understanding of the steps leading to homology search and strand invasion, we know much less of the mechanisms that establish recombination-associated DNA polymerization. Here, we report that C17orf53/HROB is an OB-fold-containing factor involved in HR that acts by recruiting the MCM8-MCM9 helicase to sites of DNA damage to promote DNA synthesis. Mice with targeted mutations in Hrob are infertile due to depletion of germ cells and display phenotypes consistent with a prophase I meiotic arrest. The HROB-MCM8-MCM9 pathway acts redundantly with the HELQ helicase, and cells lacking both HROB and HELQ have severely impaired HR, suggesting that they underpin two major routes for the completion of HR downstream from RAD51. The function of HROB in HR is reminiscent of that of gp59, which acts as the replicative helicase loader during bacteriophage T4 recombination-dependent DNA replication. We therefore propose that the loading of MCM8-MCM9 by HROB may similarly be a key step in the establishment of mammalian recombination-associated DNA synthesis.

Human neutralizing antibodies elicited by SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global health emergency that is in urgent need of intervention1-3. The entry of SARS-CoV-2 into its target cells depends on binding between the receptor-binding domain (RBD) of the viral spike protein and its cellular receptor, angiotensin-converting enzyme 2 (ACE2)2,4-6. Here we report the isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells from 8 individuals infected with SARS-CoV-2. We identified antibodies that potently neutralize SARS-CoV-2; this activity correlates with competition with ACE2 for binding to RBD. Unexpectedly, the anti-SARS-CoV-2 antibodies and the infected plasma did not cross-react with the RBDs of SARS-CoV or Middle East respiratory syndrome-related coronavirus (MERS-CoV), although there was substantial plasma cross-reactivity to their trimeric spike proteins. Analysis of the crystal structure of RBD-bound antibody revealed that steric hindrance inhibits viral engagement with ACE2, thereby blocking viral entry. These findings suggest that anti-RBD antibodies are largely viral-species-specific inhibitors. The antibodies identified here may be candidates for development of clinical interventions against SARS-CoV-2.

Divergent amplifications of CYP9A cytochrome P450 genes provide two noctuid pests with differential protection against xenobiotics.

Here, we provide mechanistic support for the involvement of the CYP9A subfamily of cytochrome P450 monooxygenases in the detoxification of host plant defense compounds and chemical insecticides in Spodoptera exigua and Spodoptera frugiperda. Our comparative genomics shows that a large cluster of CYP9A genes occurs in the two species but with significant differences in its contents, including several species-specific duplicates and substantial sequence divergence, both between orthologs and between duplicates. Bioassays of CRISPR-Cas9 knockouts of the clusters show that, collectively, the CYP9As can detoxify two furanocoumarin plant defense compounds (imperatorin and xanthotoxin) and insecticides representing three different chemotypes (pyrethroids, avermectins, and oxadiazines). However, in vitro metabolic assays of heterologously expressed products of individual genes show several differences between the species in the particular CYP9As with activities against these compounds. We also find that the clusters show tight genetic linkage with high levels of pyrethroid resistance in field strains of the two species. We propose that their divergent amplifications of the CYP9A subfamily have not only contributed to the development of the broad host ranges of these species over long evolutionary timeframes but also supplied them with diverse genetic options for evolving resistance to chemical insecticides in the very recent past.

The inhibitory mechanism of a small protein reveals its role in antimicrobial peptide sensing.

A large number of small membrane proteins have been uncovered in bacteria, but their mechanism of action has remained mostly elusive. Here, we investigate the mechanism of a physiologically important small protein, MgrB, which represses the activity of the sensor kinase PhoQ and is widely distributed among enterobacteria. The PhoQ/PhoP two-component system is a master regulator of the bacterial virulence program and interacts with MgrB to modulate bacterial virulence, fitness, and drug resistance. A combination of cross-linking approaches with functional assays and protein dynamic simulations revealed structural rearrangements due to interactions between MgrB and PhoQ near the membrane/periplasm interface and along the transmembrane helices. These interactions induce the movement of the PhoQ catalytic domain and the repression of its activity. Without MgrB, PhoQ appears to be much less sensitive to antimicrobial peptides, including the commonly used C18G. In the presence of MgrB, C18G promotes MgrB to dissociate from PhoQ, thus activating PhoQ via derepression. Our findings reveal the inhibitory mechanism of the small protein MgrB and uncover its importance in antimicrobial peptide sensing.

A cell-free system for functional studies of small membrane proteins.

Numerous small proteins have been discovered across all domains of life, among which many are hydrophobic and predicted to localize to the cell membrane. Based on a few that are well-studied, small membrane proteins are regulators involved in various biological processes, such as cell signaling, nutrient transport, drug resistance, and stress response. However, the function of most identified small membrane proteins remains elusive. Their small size and hydrophobicity make protein production challenging, hindering function discovery. Here, we combined a cell-free system with lipid sponge droplets and synthesized small membrane proteins in vitro. Lipid sponge droplets contain a dense network of lipid bilayers, which accommodates and extracts newly synthesized small membrane proteins from the aqueous surroundings. Using small bacterial membrane proteins MgrB, SafA, and AcrZ as proof of principle, we showed that the in vitro-produced membrane proteins were functionally active, for example, modulating the activity of their target kinase as expected. The cell-free system produced small membrane proteins, including one from human, up to micromolar concentrations, indicating its high level of versatility and productivity. Furthermore, AcrZ produced in this system was used successfully for in vitro co-immunoprecipitations to identify interaction partners. This work presents a robust alternative approach for producing small membrane proteins, which opens a door to their function discovery in different domains of life.

α-Ketoglutarate plays an inflammatory inhibitory role by regulating scavenger receptor class a expression through N6-methyladenine methylation during sepsis.

Sepsis arises from an uncontrolled inflammatory response triggered by infection or stress, accompanied by alteration in cellular energy metabolism, and a strong correlation exists between these factors. Alpha-ketoglutarate (α-KG), an intermediate product of the TCA cycle, has the potential to modulate the inflammatory response and is considered a crucial link between energy metabolism and inflammation. The scavenger receptor (SR-A5), a significant pattern recognition receptor, assumes a vital function in anti-inflammatory reactions. In the current investigation, we have successfully illustrated the ability of α-KG to mitigate inflammatory factors in the serum of septic mice and ameliorate tissue damage. Additionally, α-KG has been shown to modulate metabolic reprogramming and macrophage polarization. Moreover, our findings indicate that the regulatory influence of α-KG on sepsis is mediated through SR-A5. We also elucidated the mechanism by which α-KG regulates SR-A5 expression and found that α-KG reduced the N6-methyladenosine level of macrophages by up-regulating the m6A demethylase ALKBH5. α-KG plays a crucial role in inhibiting inflammation by regulating SR-A5 expression through m6A demethylation during sepsis. The outcomes of this research provide valuable insights into the relationship between energy metabolism and inflammation regulation, as well as the underlying molecular regulatory mechanism.

Kinesin motor KIFC1 is required for tubulin acetylation and actin-dependent spindle migration in mouse oocyte meiosis.

Mammalian oocyte maturation is a unique asymmetric division, which is mainly because of actin-based spindle migration to the cortex. In the present study, we report that a kinesin motor KIFC1, which is associated with microtubules for the maintenance of spindle poles in mitosis, is also involved in actin dynamics in murine oocyte meiosis, co-localizing with microtubules during mouse oocyte maturation. Depletion of KIFC1 caused the failure of polar body extrusion, and we found that meiotic spindle formation and chromosome alignment were disrupted. This might be because of the effects of KIFC1 on HDAC6 and NAT10-based tubulin acetylation, which further affected microtubule stability. Mass spectroscopy analysis revealed that KIFC1 also associated with several actin nucleation factors and we found that KIFC1 was essential for the distribution of actin filaments, which further affected spindle migration. Depletion of KIFC1 leaded to aberrant expression of formin 2 and the ARP2/3 complex, and endoplasmic reticulum distribution was also disturbed. Exogenous KIFC1 mRNA supplement could rescue these defects. Taken together, as well as its roles in tubulin acetylation, our study reported a previously undescribed role of kinesin KIFC1 on the regulation of actin dynamics for spindle migration in mouse oocytes.

The Relationship between Framingham Stroke Risk Profile on Incident Dementia and Alzheimer's Disease: A 40-Year Follow-Up Study Highlighting Female Vulnerability.

OBJECTIVE: Sex differences in the association between cardiovascular risk factors and the incident all-cause dementia and the subtype Alzheimer's disease (AD) risk are unclear. METHODS: Framingham Heart Study (FHS) participants (n = 4,171, 54% women, aged 55 to 69 years) were included at baseline and followed up to 40 years. The Framingham Stroke Risk Profile (FSRP) was dichotomized into 2 levels (cutoff: 75th percentile of the FSRP z-scores). Cause-specific hazard models, with death as a competing event, and restricted mean survival time (RMST) model were used to analyze the association between FSRP levels and incident all-cause dementia and AD. Interactions between FSRP and sex were estimated, followed by a sex-stratified analysis to examine the sex modification effect. RESULTS: High FSRP was significantly associated with all-cause dementia (hazard ratio [HR] = 1.25, robust 95% confidence interval [CI] = 1.21 to 1.29, p < 0.001) and AD (HR = 1.58, robust 95% CI = 1.57 to 1.59, p < 0.001) in cause-specific hazard models. High FSRP was significantly associated with incident dementia (HR = 2.81, robust 95% CI = 2.75 to 2.87, p < 0.001) and AD (HR = 2.96, robust 95% CI = 2.36 to 3.71, p < 0.001) in women, but not in men. Results were consistent in the RMST models. Current diabetes and high systolic blood pressure as FSRP components were significantly associated with dementia and AD in women but not in men. INTERPRETATION: High FSRP in mid- to early late life is a critical risk factor for all-cause dementia and AD, particularly in women. Sex-specific interventions and further research to elucidate underlying mechanisms are warranted. ANN NEUROL 2024.

Kinesin KIF3A regulates meiotic progression and spindle assembly in oocyte meiosis.

Kinesin family member 3A (KIF3A) is a microtubule-oriented motor protein that belongs to the kinesin-2 family for regulating intracellular transport and microtubule movement. In this study, we characterized the critical roles of KIF3A during mouse oocyte meiosis. We found that KIF3A associated with microtubules during meiosis and depletion of KIF3A resulted in oocyte maturation defects. LC-MS data indicated that KIF3A associated with cell cycle regulation, cytoskeleton, mitochondrial function and intracellular transport-related molecules. Depletion of KIF3A activated the spindle assembly checkpoint, leading to metaphase I arrest of the first meiosis. In addition, KIF3A depletion caused aberrant spindle pole organization based on its association with KIFC1 to regulate expression and polar localization of NuMA and γ-tubulin; and KIF3A knockdown also reduced microtubule stability due to the altered microtubule deacetylation by histone deacetylase 6 (HDAC6). Exogenous Kif3a mRNA supplementation rescued the maturation defects caused by KIF3A depletion. Moreover, KIF3A was also essential for the distribution and function of mitochondria, Golgi apparatus and endoplasmic reticulum in oocytes. Conditional knockout of epithelial splicing regulatory protein 1 (ESRP1) disrupted the expression and localization of KIF3A in oocytes. Overall, our results suggest that KIF3A regulates cell cycle progression, spindle assembly and organelle distribution during mouse oocyte meiosis.

5-methylcytosine modification by Plasmodium NSUN2 stabilizes mRNA and mediates the development of gametocytes.

5-methylcytosine (m5C) is an important epitranscriptomic modification involved in messenger RNA (mRNA) stability and translation efficiency in various biological processes. However, it remains unclear if m5C modification contributes to the dynamic regulation of the transcriptome during the developmental cycles of Plasmodium parasites. Here, we characterize the landscape of m5C mRNA modifications at single nucleotide resolution in the asexual replication stages and gametocyte sexual stages of rodent (Plasmodium yoelii) and human (Plasmodium falciparum) malaria parasites. While different representations of m5C-modified mRNAs are associated with the different stages, the abundance of the m5C marker is strikingly enhanced in the transcriptomes of gametocytes. Our results show that m5C modifications confer stability to the Plasmodium transcripts and that a Plasmodium ortholog of NSUN2 is a major mRNA m5C methyltransferase in malaria parasites. Upon knockout of P. yoelii nsun2 (pynsun2), marked reductions of m5C modification were observed in a panel of gametocytogenesis-associated transcripts. These reductions correlated with impaired gametocyte production in the knockout rodent malaria parasites. Restoration of the nsun2 gene in the knockout parasites rescued the gametocyte production phenotype as well as m5C modification of the gametocytogenesis-associated transcripts. Together with the mRNA m5C profiles for two species of Plasmodium, our findings demonstrate a major role for NSUN2-mediated m5C modifications in mRNA transcript stability and sexual differentiation in malaria parasites.

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced cervical cancer constitutes around 37% of cervical cancer cases globally and has a poor prognosis due to limited therapeutic options. Immune checkpoint inhibitors in the neoadjuvant setting could address these challenges. We aimed to investigate the efficacy and safety of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer. METHODS: In this single-arm, phase 2 trial, which was done across eight tertiary hospitals in China, we enrolled patients aged 18-70 years with untreated cervical cancer (IB3, IIA2, or IIB/IIIC1r with a tumour diameter ≥4 cm [International Federation of Gynecology and Obstetrics, 2018]) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients underwent one cycle of priming doublet chemotherapy (75-80 mg/m2 cisplatin, intravenously, plus 260 mg/m2 nab-paclitaxel, intravenously), followed by two cycles of a combination of chemotherapy (cisplatin plus nab-paclitaxel) on day 1 with camrelizumab (200 mg, intravenously) on day 2, with a 3-week interval between treatment cycles. Patients with stable disease or progressive disease received concurrent chemoradiotherapy, and patients with a complete response or partial response proceeded to radical surgery. The primary endpoint was the objective response rate, by independent central reviewer according to Response Evaluation Criteria in Solid Tumours, version 1.1. Activity and safety were analysed in patients who received at least one dose of camrelizumab. This study is registered with ClinicalTrials.gov, NCT04516616, and is ongoing. FINDINGS: Between Dec 1, 2020, and Feb 10, 2023, 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46-57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0-14·5). An objective response was noted in 83 (98% [95% CI 92-100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. The most common grade 3-4 treatment-related adverse events during neoadjuvant chemo-immunotherapy were lymphopenia (21 [25%] of 85), neutropenia (ten [12%]), and leukopenia (seven [8%]). No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer. FUNDING: National Key Technology Research and Development Program of China and the National Clinical Research Center of Obstetrics and Gynecology.

New insights on the evolution of nucleolar dominance in newly resynthesized hexaploid wheat Triticum zhukovskyi.

Nucleolar dominance (ND) is a widespread epigenetic phenomenon in hybridizations where nucleolus transcription fails at the nucleolus organizer region (NOR). However, the dynamics of NORs during the formation of Triticum zhukovskyi (GGAu Au Am Am ), another evolutionary branch of allohexaploid wheat, remains poorly understood. Here, we elucidated genetic and epigenetic changes occurring at the NOR loci within the Am , G, and D subgenomes during allopolyploidization by synthesizing hexaploid wheat GGAu Au Am Am and GGAu Au DD. In T. zhukovskyi, Au genome NORs from T. timopheevii (GGAu Au ) were lost, while the second incoming NORs from T. monococcum (Am Am ) were retained. Analysis of the synthesized T. zhukovskyi revealed that rRNA genes from the Am genome were silenced in F1 hybrids (GAu Am ) and remained inactive after genome doubling and subsequent self-pollinations. We observed increased DNA methylation accompanying the inactivation of NORs in the Am genome and found that silencing of NORs in the S1 generation could be reversed by a cytidine methylase inhibitor. Our findings provide insights into the ND process during the evolutionary period of T. zhukovskyi and highlight that inactive rDNA units may serve as a 'first reserve' in the form of R-loops, contributing to the successful evolution of T. zhukovskyi.

A protein palmitoylation cascade regulates microtubule cytoskeleton integrity in Plasmodium.

Morphogenesis of many protozoans depends on a polarized establishment of cytoskeletal structures. In malaria-causing parasites, this can be observed when a round zygote develops into an elongated motile ookinete within the mosquito stomach. This morphogenesis is mediated by the pellicle cytoskeletal structures, including the inner membrane complex (IMC) and the underlying subpellicular microtubules (SPMs). How the parasite maintains the IMC-SPM connection and establishes a dome-like structure of SPM to support cell elongation is unclear. Here, we show that palmitoylation of N-terminal cysteines of two IMC proteins (ISP1/ISP3) regulates the IMC localization of ISP1/ISP3 and zygote-to-ookinete differentiation. Palmitoylation of ISP1/ISP3 is catalyzed by an IMC-residing palmitoyl-S-acyl-transferase (PAT) DHHC2. Surprisingly, DHHC2 undergoes self-palmitoylation at C-terminal cysteines via its PAT activity, which controls DHHC2 localization in IMC after zygote formation. IMC-anchored ISP1 and ISP3 interact with microtubule component ß-tubulin, serving as tethers to maintain the proper structure of SPM during zygote elongation. This study identifies the first PAT-substrate pair in malaria parasites and uncovers a protein palmitoylation cascade regulating microtubule cytoskeleton.

Development of a Recombinase-Aided Amplification Assay for the Rapid Detection of Candida auris.

Candida auris (C. auris) was first discovered in Japan in 2009 and has since spread worldwide. It exhibits strong transmission ability, high multidrug resistance, blood infectivity, and mortality rates. Traditional diagnostic techniques for C. auris have shortcomings, leading to difficulty in its timely diagnosis and identification. Therefore, timely and accurate diagnostic assays for clinical samples are crucial. We developed a novel, rapid recombinase-aided amplification (RAA) assay targeting the 18S rRNA, ITS1, 5.8S rRNA, ITS2, and 28S rRNA genes for C. auris identification. This assay can rapidly amplify DNA at 39 °C in 20 min. The analytical sensitivity and specificity were evaluated. From 241 clinical samples collected from pediatric inpatients, none were detected as C. auris-positive. We then prepared simulated clinical samples by adding 10-fold serial dilutions of C. auris into the samples to test the RAA assay's efficacy and compared it with that of real-time PCR. The assay demonstrated an analytical sensitivity of 10 copies/µL and an analytical specificity of 100%. The lower detection limit of the RAA assay for simulated clinical samples was 101 CFU/mL, which was better than that of real-time PCR (102-103 CFU/mL), demonstrating that the RAA assay may have a better detection efficacy for clinical samples. In summary, the RAA assay has high sensitivity, specificity, and detection efficacy. This assay is a potential new method for detecting C. auris, with simple reaction condition requirements, thus helping to manage C. auris epidemics.

Prophylactic vitamin C supplementation regulates DNA demethylation to protect against cisplatin-induced acute kidney injury in mice.

Cisplatin-induced acute kidney injury (AKI) restricts the use of cisplatin as a first-line chemotherapeutic agent. Our previous study showed that prophylactic vitamin C supplementation may act as an epigenetic modulator in alleviating cisplatin-induced AKI in mice. However, the targets of vitamin C and the mechanisms underlying the epigenetics changes remain largely unknown. Herein, whole-genome bisulfite sequencing and bulk RNA sequencing were performed on the kidney tissues of mice treated with cisplatin with prophylactic vitamin C supplementation (treatment mice) or phosphate-buffered saline (control mice) at 24 h after cisplatin treatment. Ascorbyl phosphate magnesium (APM), an oxidation-resistant vitamin C derivative, was found that led to global hypomethylation in the kidney tissue and regulated different functional genes in the promoter region and gene body region. Integrated evidence suggested that APM enhanced renal ion transport and metabolism, and reduced apoptosis and inflammation in the kidney tissues. Strikingly, Mapk15, Slc22a6, Cxcl5, and Cd44 were the potential targets of APM that conferred protection against cisplatin-induced AKI. Moreover, APM was found to be difficult to rescue cell proliferation and apoptosis caused by cisplatin in the Slc22a6 knockdown cell line. These results elucidate the mechanism by which vitamin C as an epigenetic regulator to protects against cisplatin-induced AKI and provides a new perspective and evidence support for controlling the disease process through regulating DNA methylation.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

Spontaneous Formation of Ultrasmall Noble Metal Nanoparticles on Cobalt-Based Layered Double Hydroxide for Electrochemical and Environmental Catalysis.

Supported noble metal nanoparticles (NMNPs) are appealing for energy and environment catalysis. To facilitate the loading of NMNPs, in situ reduction of Mn+ on the support with extra reductants/surfactants is adopted, but typically results in aggregated NMNPs with uneven size distributions or blocked active sites of the NMNPs. Herein, the use of cobalt layered double hydroxide (Co-LDH) is proposed as both support and reductant for the preparation of supported NMNPs with ultrasmall sizes and even distributions. The resultant Co-LDH-supported NMNPs exhibit excellent catalytic performance and stability. For example, Ir/Co-LDH displays a low overpotential of 188 mV (10 mA cm-2) for electrocatalytic oxygen evolution reaction and a long-term stability over 100 h (100 mA cm-2) in overall water splitting. Ru/Co-LDH can achieve a 4-nitrophenol reduction with high rate of 0.36 min-1 and S2- detection with low limit of detection (LOD) of 0.34 µm. Overall, this work provides a green and effective strategy to fabricate supported NMNPs with greatly improved catalytic performances.

Design and rationale of the Comprehensive intelligent Hypertension managEment SyStem (CHESS) evaluation study: A cluster randomized controlled trial for hypertension management in primary care.

BACKGROUND: Hypertension management in China is suboptimal with high prevalence and low control rate due to various barriers, including lack of self-management awareness of patients and inadequate capacity of physicians. Digital therapeutic interventions including mobile health and computational device algorithms such as clinical decision support systems (CDSS) are scalable with the potential to improve blood pressure (BP) management and strengthen the healthcare system in resource-constrained areas, yet their effectiveness remains to be tested. The aim of this report is to describe the protocol of the Comprehensive intelligent Hypertension managEment SyStem (CHESS) evaluation study assessing the effect of a multifaceted hypertension management system for supporting patients and physicians on BP lowering in primary care settings. MATERIALS AND METHODS: The CHESS evaluation study is a parallel-group, cluster-randomized controlled trial conducted in primary care settings in China. Forty-one primary care sites from 3 counties of China are randomly assigned to either the usual care or the intervention group with the implementation of the CHESS system, more than 1,600 patients aged 35 to 80 years with uncontrolled hypertension and access to a smartphone by themselves or relatives are recruited into the study and followed up for 12 months. In the intervention group, participants receive patient-tailored reminders and alerts via messages or intelligent voice calls triggered by uploaded home blood pressure monitoring data and participants' characteristics, while physicians receive guideline-based prescription instructions according to updated individual data from each visit, and administrators receive auto-renewed feedback of hypertension management performance from the data analysis platform. The multiple components of the CHESS system can work synergistically and have undergone rigorous development and pilot evaluation using a theory-informed approach. The primary outcome is the mean change in 24-hour ambulatory systolic BP from baseline to 12 months. DISCUSSION: The CHESS trial will provide evidence and novel insight into the effectiveness and feasibility of an implementation strategy using a comprehensive digital BP management system for reducing hypertension burden in primary care settings. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov, NCT05605418.