A penta-component mpox mRNA vaccine induces protective immunity in nonhuman primates.

The recent worldwide outbreaks of mpox prioritize the development of a safe and effective mRNA vaccine. The contemporary mpox virus (MPXV) exhibits changing virological and epidemiological features, notably affecting populations already vulnerable to human immunodeficiency virus (HIV). Herein, we profile the immunogenicity of AR-MPXV5, a penta-component mRNA vaccine targeting five specific proteins (M1R, E8L, A29L, A35R, and B6R) from the representative contemporary MPXV clade II strain, in both naive and simian immunodeficiency virus (SIV)-infected nonhuman primates.

Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4, and mediate potent PTPN2/N1 degradation in cells and mice.

Reconfiguration of the reductive TCA cycle enables high-level succinic acid production by Yarrowia lipolytica.

Succinic acid (SA) is an important C4-dicarboxylic acid. Microbial production of SA at low pH results in low purification costs and hence good overall process economics. However, redox imbalances limited SA biosynthesis from glucose via the reductive tricarboxylic acid (TCA) cycle in yeast.

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable.

NDRG1 Signaling Is Essential for Endothelial Inflammation and Vascular Remodeling.

Background: NDRG-1 (N-myc downstream-regulated gene 1) is a member of NDRG family that plays essential roles in cell differentiation, proliferation, and stress responses. Although the expression of NDRG1 is regulated by fluid shear stress, its roles in vascular biology remain poorly understood. The purpose of the study is to determine the functional significance of NDRG1 in vascular inflammation and remodeling.

Association of Lifestyle With Incidence of Heart Failure According to Metabolic and Genetic Risk Status: A Population-Based Prospective Study.

Background: Whether lifestyle factors are similarly associated with risk of heart failure (HF) for individuals with different metabolic or genetic risk status remains unclear.

Methods: We included 464 483 participants from UK Biobank who were free of major cardiovascular disease or HF during baseline recruitment. Healthy lifestyle factors included avoidance of smoking, no obesity, regular physical activity, and healthy diet.

Lipidomic Signatures of Dairy Consumption and Associated Changes in Blood Pressure and Other Cardiovascular Risk Factors Among Chinese Adults.

Background: Omics data may provide a unique opportunity to discover dairy-related biomarkers and their linked cardiovascular health.

Methods: Dairy-related lipidomic signatures were discovered in baseline data from a Chinese cohort study (n=2140) and replicated in another Chinese study (n=212). Dairy intake was estimated by a validated food-frequency questionnaire.

YVO cascaded Raman laser for five-visible-wavelength switchable emission.

We report switchable emission of visible light at five wavelengths generated in a $\text{YVO}_4$YVO cascaded Raman cavity driven by an acousto-optic ${Q}$Q-switched Nd:YAP laser at 1080 nm. The second-harmonic generation and sum-frequency generation of the fundamental, first-Stokes, and second-Stokes waves were realized based on the angle-tuned BBO crystal. The phase-match angle tuning span of a BBO crystal is only approximately 2.

Evolution of the Raman beam quality in a folded-coupled-cavity Nd:YVO/YVO Raman laser.

An end-pumped actively $Q$Q-switched ${\rm Nd}\!:\!{{\rm YVO}_4}/{{\rm YVO}_4}$Nd:YVO/YVO Raman laser with a folded coupled cavity is demonstrated to study the evolution of Raman beam quality. The theoretical mechanism of the beam cleanup effect of stimulated Raman scattering is analyzed. The beam quality ($M^2$M) of the Raman beam and the fundamental beams before and after the Raman conversion are measured experimentally.

Additional common loci associated with stroke and obesity identified using pleiotropic analytical approach.

Stroke is a complex disease with multiple etiologies. Numerous studies suggest an established association between obesity and stroke, which may partly arise from the shared genetic components between the two phenotypes. Despite genome-wide association studies (GWASs) have identified some loci associated with stroke and obesity individually, the estimated genetic variability explained by these loci is limited (especially for stroke) and the pleiotropic loci between them are largely unknown.

Improved detection of common variants in coronary artery disease and blood pressure using a pleiotropy cFDR method.

Plenty of genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms (SNPs) for coronary artery disease (CAD) and blood pressure (BP). However, these SNPs only explain a small proportion of the heritability of two traits/diseases. Although high BP is a major risk factor for CAD, the genetic intercommunity between them remain largely unknown.

Down-regulated expression of microRNA-338-5p contributes to neuropathology in Alzheimer's disease.

Alzheimer's disease (AD) is a leading cause of dementia. However, the mechanisms responsible for development of AD, especially for the sporadic variant, are still not clear. In our previous study, we discovered that a small noncoding RNA (miR-188-3p) targeting β-site amyloid precursor protein cleaving enzyme (BACE)-1, a key enzyme responsible for Aβ formation, plays an important role in the development of neuropathology in AD.

Wound healing can be improved by (-)-epigallocatechin gallate through targeting Notch in streptozotocin-induced diabetic mice.

Delayed wound healing is one of the most prominent clinical manifestations of diabetes and lacks satisfactory treatment options. Persistent inflammation occurs in the late phase of wound healing and impairs the healing process in mice with diabetes mellitus (DM). In this study, we observed that the late wound healing in streptozotocin (STZ)-induced DM mice could be improved by (-)-epigallocatechin gallate (EGCG).

Development of Quenching-qPCR (Q-Q) assay for measuring absolute intracellular cleavage efficiency of ribozyme.

Ribozyme (Rz) is a very attractive RNA molecule in metabolic engineering and synthetic biology fields where RNA processing is required as a control unit or ON/OFF signal for its cleavage reaction. In order to use Rz for such RNA processing, Rz must have highly active and specific catalytic activity. However, current methods for assessing the intracellular activity of Rz have limitations such as difficulty in handling and inaccuracies in the evaluation of correct cleavage activity.

Novel Common Variants Associated with Obesity and Type 2 Diabetes Detected Using a cFDR Method.

Genome-wide association studies (GWASs) have been performed extensively in diverse populations to identify single nucleotide polymorphisms (SNPs) associated with complex diseases or traits. However, to date, the SNPs identified fail to explain a large proportion of the variance of the traits/diseases. GWASs on type 2 diabetes (T2D) and obesity are generally focused on individual traits independently, and genetic intercommunity (common genetic contributions or the product of over correlated phenotypic world) between them are largely unknown, despite extensive data showing that these two phenotypes share both genetic and environmental risk factors.

Novel common variants associated with body mass index and coronary artery disease detected using a pleiotropic cFDR method.

Genome-wide association studies (GWAS) have been successfully applied in identifying single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and coronary heart disease (CAD). However, the SNPs to date can only explain a small percentage of the genetic variances of traits. Here, we applied a genetic pleiotropic conditional false discovery rate (cFDR) method that combines summary statistic p values from different multi-center GWAS datasets, to detect common genetic variants associated with these two traits.

DNA Hydroxymethylation by Ten-eleven Translocation Methylcytosine Dioxygenase 1 and 3 Regulates Nociceptive Sensitization in a Chronic Inflammatory Pain Model.

Background: Ten-eleven translocation methylcytosine dioxygenase converts 5-methylcytosine in DNA to 5-hydroxymethylcytosine, which plays an important role in gene transcription. Although 5-hydroxymethylcytosine is enriched in mammalian neurons, its regulatory function in nociceptive information processing is unknown.

Methods: The global levels of 5-hydroxymethylcytosine and ten-eleven translocation methylcytosine dioxygenase were measured in spinal cords in mice treated with complete Freund's adjuvant.

Quercetin-nanostructured lipid carriers: characteristics and anti-breast cancer activities in vitro.

Quercetin (Q), a common dietary flavonoid, has gained research attention in cancer chemo-prevention, but its low level of aqueous solubility, stability, cellular bioavailability has limited its application. We have synthesized biocompatible and biodegradable Q-nanostructured lipid carriers (Q-NLC) using a novel phase inversion-based process method. The average size of Q-NLC was 32 nm in diameter.

Polymerlike statistical characterization of two-dimensional granular chains.

Statistical behaviors of packing collections of granular chains in a two-dimensional container have been investigated experimentally. On compaction from their own gravity, the longer chains pack into a structure with lower packing density due to the prevalence of backbone loops. The packing of chains can be considered as the jamming of the granular system.

Sandwich-like compounds based on the all-metal aromatic unit Al(4)2- and the main-group metals M (M=Li, Na, K, Be, Mg, Ca).

Inspired by the pioneering experimental characterisation of the all-metal aromatic unit Al(4)2- in the bimetallic molecules MAl4- (M=Li, Na, Cu) and by the very recent theoretical design of sandwich-type transition-metal complexes [Al4MAl4]q- (q=0-2; M=Ti, V, Cr, Zr, Nb, Mo, Hf, Ta, W), we used density functional theory (DFT) calculations (B3LYP/6-311+G(d) to design a series of novel non-transition-metal sandwich complexes based on the all-metal aromatic unit Al4(2-) and the main-group metals M (M=Li, Na, K, Be, Mg, Ca). The traditional homo-decked sandwich compounds [Al4MAl4]q- (without counterions) and (nM)q+[Al4MAl4]q- (with counterions M) (q=2-3, M=Li, Na, K, Be, Mg, Ca), although some of them are truly energy minima, have a much higher energy than many fused isomers. We thus concluded that it seems unlikely for Al4(2-) to sandwich the main-group metal atoms in the homo-decked sandwich form.