Peripheral Immune Profiles Predict ALS Progression in an Age- and Sex-Dependent Manner.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose pathobiology associates with peripheral blood immune cell levels and activation patterns in an age and sex-dependent manner. This study's objective was to identify immune profile associations with ALS progression, whether the associations are age and sex-specific, and whether immune profiles can predict a future disease course. METHODS: Flow cytometry immune profiles (a combination of 22 peripheral blood immune markers) were generated for 241 participants with ALS and linked to ALS progression, using progression-free survival, which is a composite combining the revised ALS Functional Rating Scale and survival. Participants were first grouped by immune profiles using unsupervised hierarchical clustering, and clusters were associated with subsequent progression-free survival. Next, individual immune markers were associated with progression-free survival using least absolute shrinkage and selection operator-Cox regression. Analyses were stratified by age and sex to identify demographic-specific immune mechanisms. Finally, random forest determined the predictive power of immune profiles on ALS progression in the whole population and again stratified by age and sex. RESULTS: Progression-free survival differed between clusters of participants with similar immune profiles, particularly reduced natural killer (NK)-cell activation associated with slower progression. Individual markers such as neutrophil levels and NK-cell NKp46 expression associated with faster ALS progression while overall NK-cell levels and NK-cell subpopulations associated with slower progression; the strength of these associations varied by age and sex. Adding these immune markers to prediction models dramatically increased short-term prediction compared with routine clinical prognostic variables alone, and the addition of NK-cell markers further improved the prediction accuracy in female participants. DISCUSSION: Specific immune profiles likely contribute to ALS progression in an age and sex-dependent manner, and peripheral immune markers enhance the prediction of short-term clinical outcomes. These findings suggest a complex milieu of immune profiles associated with ALS progression, and more detailed immunophenotyping in ALS will facilitate personalized immunotherapeutics in ALS.

Optimizing the Structure and Optical Properties of Lanthanum Aluminate Perovskite through Nb5+ Doping.

This work involves the introduction of niobium oxide into lanthanum aluminate (LaAlO3) via a conventional solid-state reaction technique to yield LaAlO3:Nb (LaNbxAl1-xO3+δ) samples with Nb5+ doping levels ranging from 0.00 to 0.25 mol%. This study presents a comprehensive investigation of the effects of niobium doping on the phase evolution, defect control, and reflectance of LaNbxAl1-xO3+δ powder. Powder X-ray diffraction (XRD) analysis confirms the perovskite structure in all powders, and XRD and transmission electron microscopy (TEM) reveal successful doping of Nb5+ into LaNbxAl1-xO3+δ. The surface morphology was analyzed by scanning electron microscopy (SEM), and the results show that increasing the doping concentration of niobium leads to fewer microstructural defects. Oxygen vacancy defects in different compositions are analyzed at 300 K, and as the doping level increases, a clear trend of defect reduction is observed. Notably, LaNbxAl1-xO3+δ with 0.15 mol% Nb5+ exhibits excellent reflectance properties, with a maximum infrared reflectance of 99.7%. This study shows that LaNbxAl1-xO3+δ powder materials have wide application potential in the field of high reflectivity coating materials due to their extremely low microstructural defects and oxygen vacancy defects.

Impact of the Pre-Dehydration and Drying Methods on the Mass Transfer and Quality Attributes of Yak Milk Casein.

Drying is an important preservation method of casein. Traditional natural draining and drying processes have low efficiency, long processing time, and poor product quality, which urgently need to be improved. This study investigated the effects of pre-dehydration intensities (30 N 30 min (PreD1) and 50 N 30 min (PreD2)) and drying methods (including pulsed vacuum drying (PVD), infrared drying (IRD), and hot air drying (HAD)) on the drying kinetics, drying modeling, and quality of yak milk casein. These findings reveal that PreD2 and PVD both had a positive impact on shortening the drying time. Compared to other combined treatments, PreD2-PVD had the shortest drying time of 6 h. The Midilli-Kucuk mathematical model effectively predicted the drying of casein. The yak milk casein powder treated with PreD2-PVD possessed a higher content of gross compositions, superior color, lower levels of fat oxidation and 5-hydroxymethylfurfural (5-HMF), and higher emulsifying activity index (EAI) and emulsion stability index (ESI) values. Overall, combining pre-dehydration with PVD proved effective in improving the drying rate and maintaining a good quality of yak milk casein, showing promising potential for industrial applications.

Inhibition of circ_0073932 attenuates myocardial ischemia‒reperfusion injury via miR-493-3p/FAF1/JNK.

Oxidative stress and apoptosis play crucial roles in myocardial ischemia‒reperfusion injury (MIRI). In this study, we investigated the role of circ_0073932 in MIRI as well as its molecular mechanism. A hypoxia/reoxygenation (H/R) cardiomyocyte model was established with H9C2 cardiomyocytes, and RT-qPCR was used to measure gene expression. We observed that circ_0073932 expression was abnormally increased in the H/R cardiomyocyte model and in blood samples from MIRI patients. Inhibition of circ_0073932 suppressed H/R-induced cell apoptosis, oxidative stress (ROS, LDH and MDA), and p-JNK expression. Dual luciferase reporter assays showed that circ_0073932 targeted the downregulation of miR-493-3p, and miR-493-3p targeted the downregulation of FAF1. Furthermore, si-circ_0073932, an miR-493-3p inhibitor, oe-FAF1, or si-FAF1 were transfected into H9C2 cardiomyocytes to investigate the roles of these factors in MIRI. Our results showed that compared with the H/R group, si-circ_0073932 inhibited H/R-induced cell apoptosis, oxidative stress (ROS, LDH and MDA), and p-JNK expression. These results were reversed by the miR-493-3p inhibitor or oe-FAF1. Finally, a rat model of MIRI was established, and si-circ_0073932 was administered. Inhibition of circ_0073932 reduced the area of myocardial infarction and decreased the levels of apoptosis and oxidative stress by inhibiting the JNK signaling pathway. Our study indicated that circ_0073932 mediates MIRI via miR-493-3p/FAF1/JNK in vivo and in vitro, revealing novel insights into the pathogenesis of MIRI and providing a new target for the clinical treatment of MIRI.

Antihypertensive prescription is associated with improved 30-day outcomes for discharged hypertensive emergency department patients.

Background: Hypertension (HTN) is common in discharged emergency department (ED) patients, yet the short-term outcomes of treating HTN at ED discharge are unclear. This study aimed to investigate whether emergency physician (EP) prescription of oral antihypertensive therapy at ED discharge for hypertensive patients is associated with a decreased 30-day risk of the severe adverse events (AEs), death, and revisits to the ED. Methods: We conducted an observational cohort study assessing the 30-day outcomes of discharged ED patients with HTN, comparing outcomes based on whether antihypertensive therapy was prescribed. All discharged adult ED patients from an eight-hospital system with a diagnosis of HTN from January 2016 to February 2020 were screened, and consisted of a mix of suburban and urban patients with broad ethnic and socioeconomic backgrounds. Patients were categorized into the treatment group if they received a prescription for antihypertensive medication at ED discharge. The primary outcome was severe composite AEs from HTN (aortic catastrophe, heart failure, myocardial infarction, hemorrhagic and ischemic stroke, or hypertensive encephalopathy) within 30 days of ED discharge. The secondary outcomes were death or ED revisit over the same period. Results: The study sample consisted of 93,512 ED visits; 57.5% were female, and mean age was 59.3 years. 4.7% of patients were prescribed antihypertensive treatment at ED discharge. Within 30 days, 0.7% of patients experienced an AE, 0.1% died, and 15.2% had an ED revisit. The treatment group had significantly lower odds of AE (adjusted odds ratio [aOR]: 0.224, 95%CI 0.106-0.416, p < 0.001), and ED revisits (aOR: 0.610, 95%CI 0.547-0.678, p < 0.001), adjusting for age, race, degree of HTN, ED treatment for elevated HTN, Elixhauser comorbidity index, and heart failure history. There was no difference in odds of death 30 days after discharge. Conclusion and relevance: Prescription antihypertensive therapy for discharged ED patients is associated with a 30-day decrease in severe adverse events and ED revisit rate.

An ascidian Polycarpa aurata-derived pan-inhibitor against coronaviruses targeting Mpro.

Coronaviruses (CoVs) are responsible for a wide range of illnesses in both animals and human. The main protease (Mpro) of CoVs is an attractive drug target, owing its critical and highly conserved role in viral replication. Here, we developed and refined an enzymatic technique to identify putative Mpro inhibitors from 189 marine chemicals and 46 terrestrial natural products. The IC50 values of Polycarpine (1a), a marine natural substance we studied and synthesized, are 30.0 ± 2.5 nM for SARS-CoV-2 Mpro and 0.12 ± 0.05 µM for PEDV Mpro. Our research further demonstrated that pretreatment with Polycarpine (1a) inhibited the betacoronavirus SARS-CoV-2 and alphacoronavirus PEDV multiplication in Vero-E6 cells. As a result, Polycarpine (1a), a pan-inhibitor of Mpro, will function as an effective and promising antiviral option to combat CoVs infection and as a foundation for further therapeutic research.

Metal mixtures associate with higher amyotrophic lateral sclerosis risk and mortality independent of genetic risk and correlate to self-reported exposures: a case-control study.

Background: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival, and exposure sources. Methods: Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. Odds and hazard ratios for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected SNPs. Results: Plasma and urine samples from 454 ALS and 294 control participants were analyzed. Elevated levels of individual metals, including copper, selenium, and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.42, CI=1.24-1.63, p<0.001; urine, HR=1.52, CI=1.31-1.76, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures associated with measured plasma and urine metals. Conclusion: Metals in plasma and urine associated with increased ALS risk and reduced survival, independent of genetic risk, and correlated with occupational and non-occupational metal exposures. These data underscore the significance of metal exposure in ALS risk and progression.

Untargeted metabolomics uncovers metabolic dysregulation and tissue sensitivity in ACE2 knockout mice.

Angiotensin-converting enzyme 2 (ACE2) polymorphisms are associated with increased risk of type 2 diabetes mellitus (T2DM), obesity and dyslipidemia, which have been determined in various populations. Consistently, ACE2 knockout (ACE2 KO) mice display damaged energy metabolism in multiple tissues, especially the key metabolic tissues such as liver, skeletal muscle and epididymal white adipose tissue (eWAT) and show even more severe phenotype under high-fat diet (HFD) induced metabolic stress. However, the effects of ACE2 on global metabolomics profiling and the tissue sensitivity remain unclear. To understand how tissues independently and collectively respond to ACE2, we performed untargeted metabolomics in serum in ACE2 KO and control wild type (WT) mice both on normal diet (ND) and HFD, and in three key metabolic tissues (liver, skeletal muscle and eWAT) after HFD treatment. The results showed significant alterations in metabolic profiling in ACE2 KO mice. We identified 275 and 168 serum metabolites differing significantly between WT and ACE2 KO mice fed on ND and HFD, respectively. And the altered metabolites in the ACE2 KO group varied from 90 to 196 in liver, muscle and eWAT. The alterations in ND and HFD serum were most similar. Compared with WT mice, ACE2 KO mice showed an increase in N-phenylacetylglutamine (PAGln), methyl indole-3-acetate, 5-hydroxytryptophol, cholic acid, deoxycholic acid and 12(S)-HETE, while LPC (19:0) and LPE (16:1) decreased. Moreover, LPC (20:0), LPC (20:1) and PC (14:0e/6:0) were reduced in both ND and HFD serum, paralleling the decreases identified in HFD skeletal muscle. Interestingly, DL-tryptophan, indole and Gly-Phe decreased in both ND and HFD serum but were elevated in HFD liver of ACE2 KO mice. A low level of l-ergothioneine was observed among liver, muscle, and epididymal fat tissue of ACE2 KO mice. Pathway analysis demonstrated that different tissues exhibited different dysregulated metabolic pathways. In conclusion, these results revealed that ACE2 deficiency leads to an overall state of metabolic distress, which may provide a new insight into the underlying pathogenesis in metabolic disorders in both ACE2 KO mice and in patients with certain genetic variant of ACE2 gene.

Effects of acid and aluminum stress on seed germination and physiological characteristics of seedling growth in Sophora davidii.

Sophora davidii, a vital forage species, predominantly thrives in the subtropical karst mountains of Southwest China. Its resilience to poor soil conditions and arid environments renders it an ideal pioneer species for ecological restoration in these regions. This study investigates the influence of acidic, aluminum-rich local soil on the germination and seedling growth physiology of S. davidii. Experiments were conducted under varying degrees of acidity and aluminum stress, employing three pH levels (3.5 to 5.5) and four aluminum concentrations (0.5 to 2.0 mmol·L-1). The results showed that germination rate, germination index, and vigor index of S. davidii seeds were decreased but not significantly under slightly acidic conditions (pH 4.5-5.5), while strong acid (pH = 3.5) significantly inhibited the germination rate, germination index, and vigor index of white spurge seeds compared with the control group. Aluminum stress (≥0.5 mmol·L-1) significantly inhibited the germination rate, germination index, and vigor index of S. davidii seed. Moreover, the seedlings' root systems were sensitive to the changes of aluminum concentration, evident from significant root growth inhibition, characterized by root shortening and color deepening. Notably, under aluminum stress (pH = 4.3), the levels of malondialdehyde and proline in S. davidii escalated with increasing aluminum concentration, while antioxidant enzyme activities demonstrated an initial increase followed by a decline. The study underscores the pivotal role of cellular osmoregulatory substances and protective enzymes in combating aluminum toxicity in S. davidii, a key factor exacerbating growth inhibition in acidic environments. These findings offer preliminary theoretical insights for the practical agricultural utilization of S. davidii in challenging soil conditions.

Analysis of the composition and influencing factors of hospitalization expenses for 1517 patients with lung malignant tumors in Beijing.

This study aimed to analyze the composition of the total hospitalization expenses of patients with lung cancer in Beijing TongRen Hospital from January 2018 to December 2020 before and after the implementation of the "Beijing Medical Consumption Linkage Comprehensive Reform Implementation Plan" (hereinafter referred to as "Reform"). The SPSS 25.0 statistical software was used to perform descriptive statistics on the total hospitalization costs of selected 1517 patients with lung malignant tumors, and single factor and multivariate regression analysis were used to clarify the influencing factors of the patients' total hospitalization costs. From 2018 to 2020, the total hospitalization costs of patients with lung malignant tumors increased year by year (P < .05), and the average length of hospital stay decreased year by year (P < .05). The total hospitalization expenses of patients with lung malignant tumors mainly include material expenses, surgical expenses, inspection expenses, inspection expenses and medicine expenses. After the implementation of the "Reform," the proportion of medicine, inspection, nursing and other expenses in the total hospitalization expenses of patients with lung malignant tumors has been significantly reduced (P < .05), and the proportion of surgical expenses has been significantly increased (P < .05). The results of the univariate analysis showed that gender, age, length of stay in the hospital, surgery, and tumor location were the main factors affecting the total hospitalization expenses of patients (P < .05). The results of multivariate analysis showed that gender (female), age (<40 years old), length of stay (≥15 days), surgery (yes), and tumor location (right lung) are the main factors affecting the total hospitalization cost of patients with malignant tumors (P < .05). Under the premise of ensuring the efficacy of patients, the economic burden of patients is reduced by reducing the cost of materials, shortening the length of hospitalization, strengthening hospital management, and controlling the continuous growth of hospitalization costs.

Sensory properties of rehydrated Toona sinensis shoots after dehydrated by different drying methods and association with gamma-glutamyl transferase reaction.

Sulfur-containing compounds are responsible for the aroma of Toona sinensis shoot (TS). In this study, vacuum-freeze-drying (VFD), microwave-drying (MD), and hot-air-drying at 100 and 40 °C (HAD100 and HAD40, respectively), were applied to dehydrate perishable TS for preservation. VFD-TS retained most aroma of fresh/raw TS after rehydration. The content of sulfur-containing compounds reached to 118.00 µg/g with leading by methyl thiirane, (E,E)/(E,Z)/(Z,Z)-bis-(1-propenyl) disulfides, and (Z)/(E)-2-mercapto-3,4-dimethyl-2,3-dihydrothiophenes accounting for 86.33 %. They were undetected in the rehydrated MD-TS and HAD100-TS, as the indigenous enzymes in TS were deactivated under their dehydration conditions. Interestingly, the sulfur-containing compounds was restored by 77.47 % after the TS was treated by gamma-glutamyl transferase (GGT). Thus, the release of sulfur-containing compounds from TS could depend on GGT reaction. It was different from alliaceous vegetables relying on alliinase reaction. The results revealed the aroma formation in TS and provided an approach to enhance the aroma of TS dried by different methods.

A machine learning-based hybrid recommender framework for smart medical systems.

This article presents a hybrid recommender framework for smart medical systems by introducing two methods to improve service level evaluations and doctor recommendations for patients. The first method uses big data techniques and deep learning algorithms to develop a registration review system in medical institutions. This system outperforms conventional evaluation methods, thus achieving higher accuracy. The second method implements the term frequency and inverse document frequency (TF-IDF) algorithm to construct a model based on the patient's symptom vector space, incorporating score weighting, modified cosine similarity, and K-means clustering. Then, the alternating least squares (ALS) matrix decomposition and user collaborative filtering algorithm are applied to calculate patients' predicted scores for doctors and recommend top-performing doctors. Experimental results show significant improvements in metrics called precision and recall rates compared to conventional methods, making the proposed approach a practical solution for department triage and doctor recommendation in medical appointment platforms.

Cell Heterogeneity and Variability in Peripheral Nerve after Injury.

With the development of single-cell sequencing technology, the cellular composition of more and more tissues is being elucidated. As the whole nervous system has been extensively studied, the cellular composition of the peripheral nerve has gradually been revealed. By summarizing the current sequencing data, we compile the heterogeneities of cells that have been reported in the peripheral nerves, mainly the sciatic nerve. The cellular variability of Schwann cells, fibroblasts, immune cells, and endothelial cells during development and disease has been discussed in this review. The discovery of the architecture of peripheral nerves after injury benefits the understanding of cellular complexity in the nervous system, as well as the construction of tissue engineering nerves for nerve repair and axon regeneration.

Resistance role of Lactobacillus sp. and Lactococcus sp. to copper ions in healthy children's intestinal microorganisms.

Heavy metal exposure is closely associated with gut microbe function and tolerance. However, intestinal microbe responses in children to different copper ion (Cu2+) concentrations have not yet been clarified. Here, in vitro cultivation systems were established for fecal microbe control and Cu2+-treated groups in healthy children. 16S rDNA high-throughput sequencing, meta-transcriptomics and metabolomics were used here to identify toxicity resistance mechanisms at microbiome levels. The results showed that Lactobacillus sp. and Lactococcus sp. exerted protective effects against Cu2+ toxicity, but these effects were limited by Cu2+ concentration. When the Cu2+ concentration was ≥ 4 mg/L, the abundance of Lactobacillus sp. and Lactococcus sp. significantly decreased, and the pathways of antioxidant activity and detoxification processes were enriched at 2 mg/L Cu2+, and beneficial metabolites accumulated. However, at high concentrations of Cu2+ (≥4 mg/L), the abundance of potential pathogen increased, and was accompanied by a downregulation of genes in metabolism and detoxification pathways, which meant that the balance of gut microbiota was disrupted and toxicity resistance decreased. From these observations, we identified some probiotics that are tolerant to heavy metal Cu2+, and warn that only when the concentration limit of Cu2+ in food is 2 mg/L, then a balanced gut microbiota can be guaranteed in children, thereby providing protection for their health.

Berberine Metabolites Stimulate GLP-1 Secretion by Alleviating Oxidative Stress and Mitochondrial Dysfunction.

Berberine (BBR) is a principal component of Rhizoma coptidis known for its therapeutic potential in treating diseases such as type 2 diabetes mellitus (T2DM) and obesity. Despite the trace levels of BBR in plasma, it's believed that its metabolites play a pivotal role in its biological activities. While BBR is recognized to promote GLP-1 production in intestinal L cells, the cytoprotective effects of its metabolites on these cells are yet to be explored. The present study investigates the effects of BBR metabolites on GLP-1 secretion and the underlying mechanisms. Our results revealed that, out of six BBR metabolites, berberrubine (BBB) and palmatine (PMT) significantly increased the production and glucose-stimulated secretion of GLP-1 in GLUTag cells. Notably, both BBB and PMT could facilitate GLP-1 and insulin secretion and enhance glucose tolerance in standard mice. Moreover, a single dose of PMT could markedly increase plasma GLP-1 and improve glucose tolerance in mice with obesity induced by a high-fat diet. In palmitic acid or TNF[Formula: see text]-treated GLUTag cells, BBB and PMT alleviated cell death, oxidative stress, and mitochondrial dysfunction. Furthermore, they could effectively reverse inflammation-induced inhibition of the Akt signaling pathway. In general, these insights suggest that the beneficial effects of orally administered BBR on GLP-1 secretion are largely attributed to the pharmacological activity of BBB and PMT by their above cytoprotective effects on L cells, which provide important ideas for stimulating GLP-1 secretion and the treatment of T2DM.

Association between ABO blood type and coronavirus disease 2019 severe outcomes across dominant variant strains.

Objectives: Existing evidence suggests a link between ABO blood type and severe outcomes in coronavirus disease 2019 (COVID-19). We aimed to assess the relationship between blood type and severe outcomes across variant strains throughout the pandemic. Methods: This was a multicenter retrospective observational cohort analysis from a large health system in southeastern Michigan using electronic medical records to evaluate emergency encounters, hospitalization, and severe outcomes in COVID-19 based on ABO blood type. Consecutive adult patients presenting to the emergency department with a primary diagnosis of COVID-19 (U07.1) from March 1, 2020 through December 31, 2022 were assessed. Patients who presented during three distinct time intervals that coincided with Alpha, Delta, and Omicron variant predominance were included in the analysis. Exclusions included no record of ABO blood type, positive PCR COVID-19 test within the preceding 28 days, and if transferred from out of the health system. Severe outcomes were inclusive of intensive care unit admission, mechanical ventilation, or death, which, as a composite, represented our primary outcome. Secondary outcomes were hospital admission and length of stay. A logistic regression model was employed to test the association between ABO blood type and severe outcome, adjusting for age, sex, race, vaccination status, Elixhauser comorbidity indices, and the dominant variant time period in which the encounter occurred. Results: Of the 33,796 COVID-19 encounters, 9416 met inclusion criteria; 4071 (43.2%) were type O, 3417 (36.3%) were type A, 459 (4.9%) were type AB, and 1469 (15.6%) were type B blood. Note that 66.4% of the cohort was female (p = 0.18). The proportion of composite severe disease among the four blood types was similar and ranged between 8.6% and 8.9% (p = 0.98). Note that 53.0% of type A blood patients required hospital admission, compared to 51.9%, 50.4%, and 48.1% of type AB, B, and O blood, respectively (p < 0.001). Compared to patients with O blood type (43.2%), non-O blood type (58.8%; composite of A, AB, and B) exhibited no statistically significant difference in the proportion of composite severe disease (8.8% vs. 8.7%; p = 0.81) Multivariable regression analyses exhibited no significant difference regarding the presence of severe outcomes among the four blood types or O versus non-O blood types during T1, T2, and T3. Conclusions: ABO blood type was not associated with COVID-19 severe outcomes across the Delta, Alpha, and Omicron dominant COVID waves across a large health system in southeastern Michigan. Further research is needed to better understand if ABO blood type is a risk factor for severe disease among evolving COVID-19 variants and other viral upper respiratory infections.

Plasma proteome analysis and validation of patients with community-acquired pneumonia: A cohort study.

PURPOSE: This study aimed to investigate the diagnostic potential of plasma biomarkers of community-acquired pneumonia (CAP) and their severity grading. EXPERIMENTAL DESIGN: Plasma proteomes from cohort I (n = 32) with CAP were analyzed by data-independent acquisition mass spectrometry (MS). MetaboAnalyst 5.0 was used to statistically evaluate significant differences in proteins from different samples, and demographic and clinical data were recorded for all enrolled patients. Cohort II (n = 80) was used to validate candidate biomarkers. Plasma protein levels were determined using quantitative enzyme-linked immunosorbent assay (ELISA). Correlations were assessed using Pearson's correlation coefficient. A receiver operating characteristic curve was used to verify the association between the variables, CAP diagnosis, and prognosis. RESULTS: 121 differentially expressed proteins (DEPs) were obtained between CAP and controls. These DEPs were mainly aggregated in pathways of phagosome(hsa04145) and complement and coagulation cascades (hsa04610). No significant differential proteins were detected in bacterial, viral, and mixed infection groups. The plasma levels of fetuin-A, alpha-1-antichymotrypsin (AACT), α1-acid glycoprotein (A1AG), and S100A8/S100A9 heterodimers detected by ELISA were consistent with those of MS. AACT, A1AG, S100A8/S100A9 heterodimer, and fetuin-A can potentially be used as diagnostic predictors, and fetuin-A and AACT are potential predictors of SCAP. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma protein profiling can successfully identify potential biomarkers for CAP diagnosis and disease severity assessment. These biomarkers should be further studied for their clinical application.

Quiescence enables unrestricted cell fate in naive embryonic stem cells.

Quiescence in stem cells is traditionally considered as a state of inactive dormancy or with poised potential. Naive mouse embryonic stem cells (ESCs) can enter quiescence spontaneously or upon inhibition of MYC or fatty acid oxidation, mimicking embryonic diapause in vivo. The molecular underpinning and developmental potential of quiescent ESCs (qESCs) are relatively unexplored. Here we show that qESCs possess an expanded or unrestricted cell fate, capable of generating both embryonic and extraembryonic cell types (e.g., trophoblast stem cells). These cells have a divergent metabolic landscape comparing to the cycling ESCs, with a notable decrease of the one-carbon metabolite S-adenosylmethionine. The metabolic changes are accompanied by a global reduction of H3K27me3, an increase of chromatin accessibility, as well as the de-repression of endogenous retrovirus MERVL and trophoblast master regulators. Depletion of methionine adenosyltransferase Mat2a or deletion of Eed in the polycomb repressive complex 2 results in removal of the developmental constraints towards the extraembryonic lineages. Our findings suggest that quiescent ESCs are not dormant but rather undergo an active transition towards an unrestricted cell fate.

Combined Replacement of Fishmeal and Fish Oil by Poultry Byproduct Meal and Mixed Oil: Effects on the Growth Performance, Body Composition, and Muscle Quality of Tiger Puffer.

This study aimed to evaluate the effects of combined replacement of fishmeal (FM) and fish oil (FO) with poultry byproduct meal (PBM) and mixed oil (MO, poultry oil: coconut oil = 1 : 1) on growth performance, body composition and muscle quality of tiger puffer (Takifugu rubripes). Fish with an average initial body weight of 14.29 g were selected for the feeding experiment. FM accounting for 0%, 5%, and 10% of the diet was replaced by PBM. For each grade of FM replacement, 5% FO or MO was used as added oil. The six experimental diets were designated as FO-FM, MO-FM, FO-5PBM, MO-5PBM, FO-10PBM, and MO-10PBM, respectively. Each treatment was performed in triplicate with 30 fish per replicate. The feeding period was 45 days. There was no significant difference in growth performance among the groups. Dietary supplementation of both PBM and MO had marginal effects on whole-fish proximate composition, except that dietary MO supplementation significantly increased the liver moisture content. In serum, there were no significant differences in contents of triglyceride, total cholesterol, total bile acid, and protein carbonyl among groups, but the malondialdehyde content was reduced by MO. The fatty acid composition in fish mirrored those in the diets, but the omega-3 sparing effects of saturated and monounsaturated fatty acid in MO can still be observed. Dietary PBM and MO had marginal effects on free amino acid composition and texture of fish muscle, but exerted complicated effects on the muscle volatile flavor compound composition. In conclusion, combined fishmeal (10% of the diet) and fish oil (5% of the diet) replacement with poultry byproduct and mixed oil (poultry oil + coconut oil) had no adverse effects on the growth performance and body proximate composition of farmed tiger puffer. However, these replacements changed the muscle flavor compound profile.