Tumor suppressor function of RBMS3 overexpression in EOC associated with immune cell infiltration.

Objectives: Epithelial ovarian cancer (EOC) is considered to be a prevalent female malignancy with both high incidence and mortality. It is reported that RNA-binding protein 3 (RBMS3) executives a tumor suppressor function in different cancers. This investigation was designed to examine the expression of RBMS3 in epithelial ovarian cancer, the effects on EOC cells, and its connection to immune cells that infiltrate tumors in the EOC microenvironment. Methods: The expression levels of RBMS3 in EOC tissues as well as their correlations with immune cell infiltration and clinical outcome were examined using bioinformatics approaches. Western blotting as well as immunohistochemistry were carried out to determine the protein levels in EOC tissues. In addition, qRT-PCR was employed to look at the expression of the mRNA. The role of RBMS3 in EOC cells was investigated, and an RBMS3 lentiviral vector was developed. The effects of RBMS3 on subcutaneous tumor development, the proliferation protein Ki-67, the tumor angiogenesis indicator CD31, and its function in controlling the tumor immune microenvironment were evaluated by in vivo tests. Results: There was a considerable decrease in RBMS3 expression in EOC tissues, which was linked to a poor prognosis for patients and the infiltration of multiple immune cell. Given immunohistochemical studies, tissues with increased RBMS3 expression had decreased markers of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages, whereas M1 macrophage markers were elevated. RBMS3 appears to suppress the capabilities of proliferating, invading, and migrating in EOC cells according to in vitro tests, whereas tumors overexpressing RBMS3 developed more slowly in syngeneic mouse models. The overexpression of RBMS3 led to a decline in the levels of Ki-67 protein and CD31. Additionally, it showed a negatively correlation with markers of regulatory T cell, myeloid-derived suppressor cell, and M2 macrophage but a positive correlation with markers of M1 macrophage. Conclusions: The findings revealed that elevated RBMS3 expression plays a tumor suppressor role in EOC and was connected to patient survival in EOC. The studies conducted in vitro and in vivo demonstrated a link between RBMS3 expression and the infiltration of certain immune cells, indicating a function for RBMS3 in the immunosuppressive tumor microenvironment and its promising efficiency as a novel target for immunotherapy against EOC.

Association between primary angle closure glaucoma and uric acid levels in serum and aqueous humor.

Purpose: To evaluate abnormalities in serum and aqueous humor uric acid (UA) levels in primary angle closure glaucoma (PACG). Methods: Patients with PACG and age-similar and gender-similar controls (patients scheduled for cataract extraction) were enrolled prospectively. Serum UA levels were determined by enzymatic colorimetry; aqueous humor UA levels by Enzyme-Linked ImmunoSorbent Assay. A t-test was used to compare UA levels between PACG patients and controls, with one-way ANOVA used to compare levels across PACG subgroups with differing disease severity. Comparisons between PACG patients and controls were adjusted for systemic and ocular confounding factors using binary logistic regression. Results: In all, 131 PACG patients and 112 controls were included. The serum UA level was 266 ± 69 µmol/L in the PACG group and 269 ± 73 µmol/L in the control group (p = 0.71). The aqueous humor UA level was 35.4 ± 8.2 µmol/L in the PACG group and 53.9 ± 18.6 µmol/L in the control group (p < 0.001). This difference remained significant after adjusting for age, gender, systolic blood pressure, diastolic blood pressure, body mass index, axial length, central corneal thickness, anterior chamber depth, lens thickness, white-to-white distance, corneal endothelial cell density, and serum UA level (odds ratio: 0.88, 95 % confidence interval: 0.83-0.93, p < 0.001). Conclusion: Aqueous humor UA levels differ between PACG patients and controls, but serum UA levels do not. This indicates that local UA plays a role in the pathogenesis of PACG, but systemic UA does not.

Impact of light on protective fractions of Cu in white wine: Influence of oxygen and bottle colour.

Cu(II)-organic acid (fraction I) and Cu(I)-thiol (fraction II) complexes can suppress sulfhydryl off-aromas in wine. This study investigated the impact of light exposure on the protective fractions of Cu of bottled white wine. Fluorescent light-exposed Chardonnay with two initial concentrations of dissolved oxygen (0.5 and 10 mg/L) was stored in different coloured bottles and concentrations of Cu fractions and riboflavin, a photo-initiator at 370-440 nm, were measured during 110 days storage. Light-exposed wines with lower oxygen concentrations resulted in a 100-fold decrease in the Cu fraction I half-life, and a 60-fold decrease for Cu fractions I and II combined. The half-life for Cu fraction I decay during light exposure was extended 30-fold with the use of brown compared to flint glass. Light exposure can rapidly exhaust the protective Cu fractions in wine, and bottles with less light transmission below 440 nm can slow this loss.

Comparison of Techniques for the Quantitation of Reductive Aroma Compounds in White Wine: Links to Sensory Analysis and Cu Fractions.

Multiple analytical methodologies allow quantitation of H2S and methanethiol (MeSH) in wine, but confirmation that the determined concentrations are related to perceived off-aromas, or "reductive" faults, is yet to be provided. Fifty white wines underwent sensory evaluation and measurement of free and salt-treated H2S and MeSH concentrations by gas chromatography with sulfur chemiluminescence detection and/or gas detection tubes. The determined concentrations were compared across techniques and different analysis laboratories. Sulfhydryl off-odors in the wines were best described by boiled and rotten egg and natural gas/sewerage/durian aroma attributes. The wines with the highest ratings for both aromas had high concentrations of free H2S, free MeSH, and/or salt-treated MeSH but were unrelated to salt-treated H2S. The free sulfhydryl concentrations and their associated aromas appeared to be suppressed by specific Cu fractions in the wines. This study provides evidence of the relevant measures of reductive aroma compounds and their relation to off-odors and Cu fractions.

Association between biological aging and diabetic retinopathy.

The impact of aging on diabetic retinopathy (DR) remains underestimated. The current study aimed to investigate the association between biological aging and DR, in contrast to chronological age (CA). Using the National Health and Nutrition Survey data from 2005 to 2008. Biological aging was evaluated through the biological age (BA) and phenotypic age (PA), which were calculated from clinical markers. DR was identified in participants with diabetes mellitus (DM) when they exhibited one or more retinal microaneurysms or retinal blot hemorrhages under retinal imaging, with or without the presence of more severe lesions. Survey-weighted multivariable logistic regression was performed, and the regression model was further fitted using restricted cubic splines. The discriminatory capability and clinical utility of the model were evaluated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Based on weighted analyses, of the 3100 participants included in this study, of which 162 had DR. In the adjusted model, BA (odds ratio [OR] = 1.12, 95% CI, 1.06-1.18) and PA (OR = 1.11, 95% CI, 1.07-1.14) were associated with DR, while CA was not significantly (OR = 1.01, 95% CI, 0.99-1.03). Narrowing the analysis to DM participants and adjusting for factors like insulin showed similar results. ROC and DCA analyses indicate that BA/PA predicted DR better than CA and offer greater clinical utility. The positive association between BA/PA and DR was consistent across subgroups despite potential interactions. Biological aging heightens DR risk, with BA/PA showing a stronger association than CA. Our findings underscored the importance of timely anti-aging interventions for preventing DR.

Nonsense-mediated mRNA decay of metal-binding activator MAC1 is dependent on copper levels and 3'-UTR length in Saccharomyces cerevisiae.

The nonsense-mediated mRNA decay (NMD) pathway was initially identified as a surveillance pathway that degrades mRNAs containing premature termination codons (PTCs). NMD is now also recognized as a post-transcriptional regulatory pathway that regulates the expression of natural mRNAs. Earlier studies demonstrated that regulation of functionally related natural mRNAs by NMD can be differential and condition-specific in Saccharomyces cerevisiae. Here, we investigated the regulation of MAC1 mRNAs by NMD in response to copper as well as the role the MAC1 3'-UTR plays in this regulation. MAC1 is a copper-sensing transcription factor that regulates the high-affinity copper uptake system. MAC1 expression is activated upon copper deprivation. We found that MAC1 mRNAs are regulated by NMD under complete minimal (CM) but escaped NMD under low and high copper conditions. Mac1 protein regulated gene, CTR1 is not regulated by NMD in conditions where MAC1 mRNAs are NMD sensitive. We also found that the MAC1 3'-UTR is the NMD targeting feature on the mRNAs, and that MAC1 mRNAs lacking 3'-UTRs were stabilized during copper deprivation. Our results demonstrate a mechanism of regulation for a metal-sensing transcription factor, at both the post-transcriptional and post-translational levels, where MAC1 mRNA levels are regulated by NMD and copper, while the activity of Mac1p is controlled by copper levels.

Genotype-phenotype association and functional analysis of hnRNPA1 mutations in amyotrophic lateral sclerosis.

BACKGROUND: Pathogenic variants in hnRNPA1 have been reported in amyotrophic lateral sclerosis (ALS) patients. However, studies on hnRNPA1 mutant spectrum and pathogenicity of variants were rare. METHODS: We performed whole exome sequencing of ALS-associated genes and subsequent verification of rare variants in hnRNPA1 in our ALS patients. The hnRNPA1 mutations reported in literature were reviewed and combined with our results to determine the genotype-phenotype relationship. Functional analysis of the novel variant p.G195A was performed in vitro by transfection of mutant hnRNPA1 into 293T cell. RESULTS: Among 207 ALS patients recruited, 3 rare hnRNPA1 variants were identified (mutant frequency 1.45%), including two recurrent mutations (p.P340S and p.G283R), and a novel rare variant p.G195A. In combination with previous reports, there are 27 ALS patients with 15 hnRNPA1 mutations identified. Disease onset age was 47.90 ± 1.52 years with predominant limb onset. The p.P340S mutation caused flail arm syndrome (FAS) in two independent families with extended life expectancy. The newly identified p.G195A mutation, lying at the start of the PrLD ("prion-like" domain)/LCD (low-complexity domain), causes local structural changes in 3D protein prediction. Upon sodium arsenite exposure, mutant hnRNPA1 retained in the nucleus but deficit of cytoplasmic G3BP1-positive stress granule clearance was observed. This is different from the p.P340S mutation which caused both cytoplasmic translocation and stress granule formation. No cytoplasmic TDP-43 translocation was observed. CONCLUSION: Mutations in hnRNPA1 are overall minor in ALS patients. The p.P340S mutation is associated with manifestation of FAS. Mutations in LCD of hnRNPA1 cause stress granule misprocessing.

Effective immobilization and biosafety assessment of antimony in soil with zeolite-supported nanoscale zero-valent iron.

Antimony (Sb) contamination in certain areas caused by activities such as antimony mining and smelting poses significant risks to human health and ecosystems. In this study, a stable composite material consisting of natural zeolite-supported nanoscale zero-valent iron (Z-ZVI) was successfully prepared. The immobilization effect of Z-ZVI on Sb in contaminated soil was investigated. Experimental results showed that Z-ZVI exhibited superior performance compared to pure nano zero-valent iron (nZVI) in terms of stability, with a lower zeta potential (-25.16 mV) at a pH of 7 and a higher specific surface area (54.54 m2/g). It can be easily applied and dispersed in contaminated soils. Additionally, Z-ZVI demonstrated a more abundant porous structure. After 60 days of treatment with 3% Z-ZVI, the leaching concentration of Sb in the contaminated soil decreased from 1.32 mg/L to 0.31 mg/L (a reduction of 76%), and the concentration of available Sb species decreased from 19.84 mg/kg to 0.71 mg/kg, achieving a fixation efficiency of up to 90%. X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) analysis confirmed the effective immobilization of Sb in the soil through reduction of antimonate to antimonite, precipitation, and adsorption processes facilitated by Z-ZVI. Moreover, the addition of Z-ZVI effectively reduced the bioavailability of Sb in the contaminated soil, thereby mitigating its toxicity to earthworms. In conclusion, Z-ZVI can be utilized as a promising material for the safe remediation and antimony and other heavy metal-contaminated soils.

Comparative transcriptome analysis of longissimus dorsi muscle reveal potential genes affecting meat trait in Chinese indigenous Xiang pig.

In this study, we compared the transcriptome of longissimus dorsi muscle between Guizhou Xiang pigs (XP) and Western commercial Large White pigs (LW), which show diffirent meat quality between them. In terms of meat quality traits, the pH 45 min, color score, backfat thickness, and intramuscular fat (IMF) content were higher in Xiang pigs than in Large White pigs (P < 0.01), while the drip loss, lean meat percentage, shear force, and longissimus dorsi muscle area of Xiang pigs were lower than that of Large White pigs (P < 0.01). Nutrients such as monounsaturated fatty acid (MUFA), total amino acids (TAA), delicious amino acids (DAA) and essential amino acids (EAA) in Xiang pigs were higher than that in Large White pigs, and the proportion of polyunsaturated fatty acid (PUFA) of Xiang pigs was significantly lower than Large White pigs (P < 0.01). Transcriptome analysis identified 163 up-regulated genes and 88 genes down-regulated in Xiang pigs longissimus dorsi muscle. Combined with the correlation analysis and quantitative trait locis (QTLs) affecting meat quality, a total of 227 DEGs were screened to be significantly associated with meat quality values. Enrichment analysis indicated that numerous members of genes were gathered in muscle development, adipogenesis, amino acid metabolism, fatty acid metabolism and synthesis. Of those, 29 genes were identified to be hub genes that might be related with the meat quality of Xiang pig, such as MYOD1, ACTB, ASNS, FOXO1, ARG2, SLC2A4, PLIN2, and SCD. Thus, we screened and identified the potential functional genes for the formation of meat quality in Xiang pigs, which provides a corresponding theoretical basis for the study of the molecular regulatory mechanism of pork quality and the improvement of pork quality.

A Multifunctional Herb-Derived Glycopeptide Hydrogel for Chronic Wound Healing.

Chronic wounds constitute an increasingly prevalent global healthcare issue, characterized by recurring bacterial infections, pronounced oxidative stress, compromised functionality of immune cells, unrelenting inflammatory reactions, and deficits in angiogenesis. In response to these multifaceted challenges, the study introduced a stimulus-responsive glycopeptide hydrogel constructed by oxidized Bletilla striata polysaccharide (OBSP), gallic acid-grafted ε-Polylysine (PLY-GA), and paeoniflorin-loaded micelles (MIC@Pae), called OBPG&MP. The hydrogel emulates the structure of glycoprotein fibers of the extracellular matrix (ECM), exhibiting exceptional injectability, self-healing, and biocompatibility. It adapts responsively to the inflammatory microenvironment of chronic wounds, sequentially releasing therapeutic agents to eradicate bacterial infection, neutralize reactive oxygen species (ROS), modulate macrophage polarization, suppress inflammation, and encourage vascular regeneration and ECM remodeling, playing a critical role across the inflammatory, proliferative, and remodeling phases of wound healing. Both in vitro and in vivo studies confirmed the efficacy of OBPG&MP hydrogel in regulating the wound microenvironment and enhancing the regeneration and remodeling of chronic wound skin tissue. This research supports the vast potential for herb-derived multifunctional hydrogels in tissue engineering and regenerative medicine.

Direct and rapid thermal shock for recycling spent graphite in lithium-ion batteries.

Due to the rapid increase in the number of spent lithium-ion batteries, there has been a growing interest in the recovery of degraded graphite. In this work, a rapid thermal shock (RTS) strategy is proposed to regenerate spent graphite for use in lithium-ion batteries. The results of structural and morphological characterization demonstrate that the graphite is well regenerated by the RTS process. Additionally, an amorphous carbon layer forms and coats onto the surface of the graphite, contributing to excellent rate performance. The regenerated graphite (RG-1000) displays excellent rate performance, with capacities of 413 mAh g-1 at 50 mA g-1 and 102.1 mAh g-1 at 1000 mA g-1, respectively. Furthermore, it demonstrates long-term cycle stability, maintaining a capacity of 80 mAh g-1 at 1000 mA g-1 with a capacity retention of 78.4 % after 600 cycles. This RTS method enables rapid and efficient regeneration of spent graphite anodes for lithium-ion batteries, providing a facile and environmentally friendly strategy for their direct regeneration.

Reaction Environment Regulation for Electrocatalytic CO2 Reduction in Acids.

The electrocatalytic CO2 reduction reaction (CO2RR) is a sustainable route for converting CO2 into value-added fuels and feedstocks, advancing a carbon-neutral economy. The electrolyte critically influences CO2 utilization, reaction rate and product selectivity. While typically conducted in neutral/alkaline aqueous electrolytes, the CO2RR faces challenges due to (bi)carbonate formation and its crossover to the anolyte, reducing efficiency and stability. Acidic media offer promise by suppressing these processes, but the low Faradaic efficiency, especially for multicarbon (C2+) products, and poor electrocatalyst stability persist. The effective regulation of the reaction environment at the cathode is essential to favor the CO2RR over the competitive hydrogen evolution reaction (HER) and improve long-term stability. This review examines progress in the acidic CO2RR, focusing on reaction environment regulation strategies such as electrocatalyst design, electrode modification and electrolyte engineering to promote the CO2RR. Insights into the reaction mechanisms via in situ/operando techniques and theoretical calculations are discussed, along with critical challenges and future directions in acidic CO2RR technology, offering guidance for developing practical systems for the carbon-neutral community.

miR-30a-5p mediates ferroptosis of hippocampal neurons in chronic cerebral hypoperfusion-induced cognitive dysfunction by modulating the SIRT1/NRF2 pathway.

OBJECTIVE: Chronic cerebral hypoperfusion (CCH) is a common cause of brain dysfunction. As a microRNA (also known as miRNAs or miRs), miR-30a-5p participates in neuronal damage and relates to ferroptosis. We explored the in vivo and in vitro effects and functional mechanism of miR-30a-5p in CCH-triggered cognitive impairment through the silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. METHODS: After 1 month of CCH modeling through bilateral common carotid artery stenosis, mice were injected with 2 µL antagomir (also known as anti-miRNAs) miR-30a-5p, with cognitive function evaluated by Morris water maze and novel object recognition tests. In vitro HT-22 cell oxygen glucose deprivation (OGD) model was established, followed by miR-30a-5p inhibitor and/or si-SIRT1 transfections, with Fe2+ concentration, malonaldehyde (MDA) and glutathione (GSH) contents, reactive oxygen species (ROS), miR-30a-5p and SIRT1 and glutathione peroxidase 4 (GPX4) protein levels, NRF2 nuclear translocation, and miR-30a-5p-SIRT1 targeting relationship assessed. RESULTS: CCH-induced mice showed obvious cognitive impairment, up-regulated miR-30a-5p, and down-regulated SIRT1. Ferroptosis occurred in hippocampal neurons, manifested by elevated Fe2+ concentration and ROS and MDA levels, mitochondrial atrophy, and diminished GSH content. Antagomir miR-30a-5p or miR-30a-5p inhibitor promoted SIRT1 expression and NRF2 nuclear translocation, increased GPX4, cell viability and GSH content, and reduced Fe2+ concentration and ROS and MDA levels. miR-30a-5p negatively regulated SIRT1. In vitro, miR-30a-5p knockout increased NRF2 nuclear translocation by up-regulating SIRT1, inhibiting OGD-induced ferroptosis in HT-22 cells. CONCLUSION: miR-30a-5p induces hippocampal neuronal ferroptosis and exacerbates post-CCH cognitive dysfunction by targeting SIRT1 and reducing NRF2 nuclear translocation.

Characterization of polyamine metabolism predicts prognosis, immune profile, and therapeutic efficacy in lung adenocarcinoma patients.

Background: Polyamine modification patterns in lung adenocarcinoma (LUAD) and their impact on prognosis, immune infiltration, and anti-tumor efficacy have not been systematically explored. Methods: Patients from The Cancer Genome Atlas (TCGA) were classified into subtypes according to polyamine metabolism-related genes using the consensus clustering method, and the survival outcomes and immune profile were compared. Meanwhile, the geneCluster was constructed according to the differentially expressed genes (DEGs) of the subtypes. Subsequently, the polyamine metabolism-related score (PMRS) system was established using the least absolute shrinkage and selection operator (LASSO) multivariate regression analysis in the TCGA training cohort (n = 245), which can be applied to characterize the prognosis. To verify the predictive performance of the PMRS, the internal cohort (n = 245) and the external cohort (n = 244) were recruited. The relationship between the PMRS and immune infiltration and antitumor responses was investigated. Results: Two distinct patterns (C1 and C2) were identified, in which the C1 subtype presented an adverse prognosis, high CD8+ T cell infiltration, tumor mutational burden (TMB), immune checkpoint, and low tumor immune dysfunction and exclusion (TIDE). Furthermore, two geneClusters were established, and similar findings were observed. The PMRS, including three genes (SMS, SMOX, and PSMC6), was then constructed to characterize the polyamine metabolic patterns, and the patients were divided into high- and low-PMRS groups. As confirmed by the validation cohort, the high-PMRS group possessed a poor prognosis. Moreover, external samples and immunohistochemistry confirmed that the three genes were highly expressed in tumor samples. Finally, immunotherapy and chemotherapy may be beneficial to the high-PMRS group based on the immunotherapy cohorts and low half-maximal inhibitory concentration (IC50) values. Conclusion: We identified distinct polyamine modification patterns and established a PMRS to provide new insights into the mechanism of polyamine action and improve the current anti-tumor strategy of LUAD.

A Novel Strain of Fusarium oxysporum Virus 1 Isolated from Fusarium oxysporum f. sp. niveum Strain X-GS16 Influences Phenotypes of F. oxysporum Strain HB-TS-YT-1hyg.

A novel strain of Fusarium oxysporum virus 1 (FoV1) was identified from the Fusarium oxysporum f. sp. niveum strain X-GS16 and designated as Fusarium oxysporum virus 1-FON (FoV1-FON). The full genome of FoV1-FON is 2902 bp in length and contains two non-overlapping open reading frames (ORFs), ORF1 and ORF2, encoding a protein with an unknown function (containing a typical -1 slippery motif G_GAU_UUU at the 3'-end) and a putative RNA-dependent RNA polymerase (RdRp), respectively. BLASTx search against the National Center for the Biotechnology Information (NCBI) non-redundant database showed that FoV1-FON had the highest identity (97.46%) with FoV1. Phylogenetic analysis further confirmed that FoV1-FON clustered with FoV1 in the proposed genus Unirnavirus. FoV1-FON could vertically transmit via spores. Moreover, FoV1-FON was transmitted horizontally from the F. oxysporum f. sp. niveum strain X-GS16 to the F. oxysporum strain HB-TS-YT-1hyg. This resulted in the acquisition of the F. oxysporum strain HB-TS-YT-1hyg-V carrying FoV1-FON. No significant differences were observed in the sporulation and dry weight of mycelial biomass between HB-TS-YT-1hyg and HB-TS-YT-1hyg-V. FoV1-FON infection significantly increased the mycelial growth of HB-TS-YT-1hyg, but decreased its virulence to potato tubers and sensitivity to difenoconazole, prochloraz, and pydiflumetofen. To our knowledge, this is the first report of hypovirulence and reduced sensitivity to difenoconazole, prochloraz, and pydiflumetofen in F. oxysporum due to FoV1-FON infection.

Rare earth elements induced electronic engineering in Rh cluster toward efficient alkaline hydrogen evolution reaction.

The unique electronic and crystal structures of rare earth metals (RE) offer promising opportunities for enhancing the hydrogen evolution reaction (HER) properties of materials. In this work, a series of RE (Sm, Nd, Pr and Ho)-doped Rh@NSPC (NSPC stands for N, S co-doped porous carbon nanosheets) with sizes less than 2 nm are prepared, utilizing a simple, rapid and solvent-free joule-heat pyrolysis method for the first time. The optimized Sm-Rh@NSPC achieves HER performance. The high-catalytic performance and stability of Sm-Rh@NSPC are attributed to the synergistic electronic interactions between Sm and Rh clusters, leading to an increase in the electron cloud density of Rh, which promotes the adsorption of H+, the dissociation of Rh-H bonds and the release of H2. Notably, the overpotential of the Sm-Rh@NSPC catalyst is a mere 18.1 mV at current density of 10 mAcm-2, with a Tafel slope of only 15.2 mV dec-1. Furthermore, it exhibits stable operation in a 1.0 M KOH electrolyte at 10 mA cm-2 for more than 100 h. This study provides new insights into the synthesis of composite RE hybrid cluster nanocatalysts and their RE-enhanced electrocatalytic performance. It also introduces fresh perspectives for the development of efficient electrocatalysts.

Absolute protein quantification based on calibrated particle counting using electrospray-differential mobility analysis.

The traceability of in vitro diagnostics or drug products is based on the accurate quantification of proteins. In this study, we developed an absolute quantification approach for proteins. This method is based on calibrated particle counting using electrospray-differential mobility analysis (ES-DMA) coupled with a condensation particle counter (CPC). The absolute concentration of proteins was quantified with the observed protein particle number measured with ES-DMA-CPC, and the detection efficiency was determined by calibrators. The measurement performance and quantitative level were verified using two certificated reference materials, BSA and NIMCmAb. The linear regression fit for the detection efficiency values of three reference materials and one highly purified protein (myoglobin, BSA, NIMCmAb and fibrinogen) indicated that the detection efficiency and the particle size distribution of these proteins exhibited a linear relationship. Moreover, to explore the suitability of the detection efficiency-particle size curve for protein quantification, the concentrations of three typical proteinaceous particles, including two high molecular weight proteins (NIST reference material 8671 and D-dimer) and one protein complex (glutathione S-transferase dimer), were determined. This work suggests that this calibrated particle counting method is an efficient approach for nondestructive, rapid and accurate quantification of proteins, especially for measuring proteinaceous particles with tremendous size and without reference standards.

Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. FINDINGS: 14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29). INTERPRETATION: In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. FUNDING: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Cerebrospinal fluid amyloid-ß and cerebral microbleed are associated with distinct neuropsychiatric sub-syndromes in cognitively impaired patients.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in cognitively impaired individuals including Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Whereas several studies have reported the associations between NPS with AD pathologic biomarkers and cerebral small vessel disease (SVD), but it remains unknown whether AD pathology and SVD contribute to different sub-syndromes independently or aggravate same symptoms synergistically. METHOD: We included 445 cognitively impaired individuals (including 316 MCI and 129 AD) with neuropsychiatric, cerebrospinal fluid (CSF) biomarkers (Aß42, p-tau, and t-tau) and multi-model MRI data. Psychiatric symptoms were accessed by using the Neuropsychiatric Inventory (NPI). Visual assessment of SVD (white matter hyperintensity, microbleed, perivascular space, lacune) on MRI images was performed by experienced radiologist. Linear regression analyses were conducted to test the association between neuropsychiatric symptoms with AD pathology and CSVD burden after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, and clinical diagnosis. RESULTS: The NPI total scores were related to microbleed (estimate 2.424; 95% CI [0.749, 4.099]; P =0.005). Considering the sub-syndromes, the hyperactivity was associated with microbleed (estimate 0.925; 95% CI [0.115, 1.735]; P =0.025), whereas the affective symptoms were correlated to CSF level of Aß42 (estimate -0.006; 95% CI [-0.011, -0.002]; P =0.005). Furthermore, we found the apathy sub-syndrome was associated with CSF t-tau/Aß42 (estimate 0.636; 95% CI [0.078, 1.194]; P =0.041) and microbleed (estimate 0.693; 95% CI [0.046, 1.340]; P =0.036). In addition, we found a significant interactive effect between CSF t-tau/Aß42 and microbleed (estimate 0.993; 95% CI [0.360, 1.626]; P =0.019) on severity of apathy sub-syndrome. CONCLUSION: Our study showed that CSF Aß42 was associated with affective symptoms, but microbleed was correlated with hyperactivity and apathy, suggesting the effect of AD pathology and SVD on different neuropsychiatric sub-syndromes.

Isotope engineering achieved by local coordination design in Ti-Pd co-doped ZrCo-based alloys.

Deuterium/Tritium (D/T) handling in defined proportions are pivotal to maintain steady-state operation for fusion reactors. However, the hydrogen isotope effect in metal-hydrogen systems always disturbs precise D/T ratio control. Here, we reveal the dominance of kinetic isotope effect during desorption. To reconcile the thermodynamic stability and isotope effect, we demonstrate a quantitative indicator of Tgap and further a local coordination design strategy that comprises thermodynamic destabilization with vibration enhancement of interstitial isotopes for isotope engineering. Based on theoretical screening analysis, an optimized Ti-Pd co-doped Zr0.8Ti0.2Co0.8Pd0.2 alloy is designed and prepared. Compared to ZrCo alloy, the optimal alloy enables consistent isotope delivery together with a three-fold lower Tgap, a five-fold lower energy barrier difference, a one-third lower isotopic composition deviation during desorption and an over two-fold higher cycling capacity. This work provides insights into the interaction between alloy and hydrogen isotopes, thus opening up feasible approaches to support high-performance fusion reactors.