COVID-19 in the Tibet, China, the roof of the world: a comparative analysis of high-altitude residents and newcomers.

BACKGROUND: After a 920-day hiatus, COVID-19 resurged in the Tibet Autonomous Region of China in August 2022. This study compares the characteristics of COVID-19 between high-altitude residents and newcomers, as well as between newcomers and lowlanders. METHODS: This multi-center cohort study conducted at the Third People's Hospital of Tibet Autonomous Region and Beijing University Shenzhen Hospital, included 520 high-altitude resident patients, 53 high-altitude newcomer patients, and 265 lowlander patients infected with the Omicron variant. Initially, we documented epidemiological, clinical, and treatment data across varying residency at admission. We compared the severity of COVID-19 and various laboratory indicators, including hemoglobin concentration and SpO2%, over a 14-day period from the date of the first positive nucleic acid test, as well as the differences in treatment methods and disease outcomes between highlanders and high-altitude newcomers. We also compared several characteristics of COVID-19 between high-altitude newcomers and lowlanders. Univariate analysis, multivariable logistic regression, and the generalized linear mixed model were utilized for the analysis. RESULTS: No fatalities were observed. The study found no significant differences in COVID-19 severity or in the physiological measures of hemoglobin concentration and SpO2% between high-altitude and lowland residents. Similarly, there were no statistically significant differences in the values or trends of hemoglobin and SpO2% between high-altitude residents and newcomers throughout the 14-day observation period. However, compared to age- and sex-matched lowlander patients (1:5 ratio), high-altitude newcomers exhibited higher heart rates, respiratory rates, and average hemoglobin concentrations, along with lower platelet counts. There were no significant differences in hospital stays between the two groups. CONCLUSIONS: High-altitude residents and newcomer patients exhibit clinical similarities. However, the clinical characteristics of high-altitude newcomers and lowlander patients differ due to the impact of the high-altitude environment. These results highlight potential considerations for public health strategies in high-altitude regions such as Tibet.

Relationship between waist-to-height ratio and heart failure outcome: A single-centre prospective cohort study.

AIMS: This study sought to evaluate the correlation between waist-to-height ratio (WHtR) and heart failure (HF) outcomes across different ejection fraction (EF) categories. METHODS AND RESULTS: A prospective cohort study was conducted at a comprehensive tertiary hospital in China. The participants were categorized by WHtR and EF quartiles. Outpatient or telephone follow-up occurred every 6 months after the diagnosis of heart failure. The primary endpoint was all-cause mortality at 48 months. Cox proportional hazard regression analyses were employed to evaluate the association between WHtR and all-cause mortality. Among 859 enrolled participants, 545 (63.4%) were male, and the mean age was 65.2 ± 11.1 years. After adjusting for age and sex, WHtR demonstrated a strong correlation with both BMI (correlation = 0.703, P = 0.000) and WHR (correlation = 0.609, P = 0.000). Individuals with a high WHtR (≥0.50) had a higher prevalence of hypertension (56.4% vs. 39.6%) and diabetes (26.5% vs. 13.7%), higher levels of TC (3.61 ± 1.55 vs. 3.36 ± 0.90 mmol/L), TG (1.40 ± 0.81 vs. 1.06 ± 0.59 mmol/L), and LDL-C (2.03 ± 0.85 vs. 1.86 ± 0.76 mmol/L) compared with patients with low WHtR (<0.50). NT-proBNP levels were inversely correlated with EF values in both low and high WHtR groups. A total of 149 (18.9%) patients died at the conclusion of the follow-up period. The incidence of all-cause and cardiovascular death was higher in the low WHtR group compared with the high WHtR group [HRs = 1.83 (1.30-2.58), 1.96 (1.34-2.88), respectively]. There was no significant difference in noncardiovascular mortality or rehospitalization rates between the two groups. Patients with HFrEF/low WHtR exhibited a markedly elevated risk of all-cause mortality [HR = 2.31; (95% CI: 1.24-4.30)], heart failure mortality [HR = 3.52; (95% CI: 2.92-8.80)], and noncardiovascular mortality [HR = 4.59; (95% CI: 1.19-17.76)] compared with patients with HFrEF/high WHtR. WHtR has a negligible effect on the risk of all-cause and cardiovascular mortality in heart failure patients with preserved EFs. CONCLUSIONS: The obesity paradox, as delineated by WHtR, is observed in patients with HFrEF, yet absent in those with HFpEF.

Endoplasmic Reticulum Stress Contributes to Intestinal Injury in Intrauterine Growth Restriction Newborn Piglets.

Intrauterine growth retardation (IUGR) in piglets is associated with a high rate of morbidity and mortality after birth due to gut dysfunction, and the underlying mechanisms remain poorly understood. This study selected six pairs of IUGR newborn male piglets and normal birth weight newborn piglets (Large White × Landrace) to investigate differences in intestinal structure and digestive functions, intestinal ERS and apoptosis, intestinal barrier function, and inflammatory response. The results showed that IUGR significantly reduced the jejunal villi height (p < 0.05) and the ratio of villus-height-to-crypt-depth (p = 0.05) in neonatal piglets. Additionally, the microvilli in the jejunum of IUGR neonatal piglets were shorter than those in normal-weight piglets, and swelling of the mitochondria and expansion of the endoplasmic reticulum were observed. IUGR also significantly reduced serum glucose and lactase levels (p < 0.05) while significantly increasing mRNA levels of jejunal IRE1α, EIF2α, CHOP, Bax, Caspase9, Mucin2, Claudin-1, Occludin, ZO-1, Bcl-2, IL-6, and IFN-γ (p < 0.05), as well as GRP78 protein levels in neonatal piglets (p < 0.05). These findings suggest that IUGR impairs intestinal structure and barrier function in newborn piglets by enhancing intestinal inflammatory responses, activating intestinal ERS and the signaling pathways related to the unfolded protein response, thereby inducing ERS-related apoptosis.

The microbiota and metabolome dynamics and their interactions modulate solid-state fermentation process and enhance clean recycling of brewers' spent grain.

The massive yield of brewers' spent grain (BSG) waste inevitably threaten environmental health. Here, solid-state fermentation (SSF) technology featuring multi-strain (MS) inoculation and high-throughput sequencing technology were employed to facilitate the sustainable and clean recycling of BSG waste while revealing the associated underlying microbiological and metabolic mechanisms. MS inoculation displayed a lower pH value (3.91 vs. 4.12) and neutral detergent fiber content (446.24 vs. 476.23 g/kg DM), a higher levels of lactic acid (86.64 vs. 33.07 g/kg DM), acetic acid (6.13 vs. 4.87 g/kg DM), propionic acid (2.78 vs. 2.18 g/kg DM) and crude protein (307.5 vs. 289.15 g/kg DM) than those in the control group. Moreover, MS inoculation inhibited the formation of non-protein-N and ammonia-N, and spoilage microorganism resuscitation, while enhanced substrate preservation. Microbiologically, during the SSF, the group treated with MS inoculation exhibited an increase in the relative abundance of Leuconostoc (0.58%∼6.60%), Weissella (6.22%∼15.42%), Enterococcus (3.15%∼9.08%), Bacillus (17.63%∼31.29%), Lactobacillus (12.89%∼8.29%), Pseudoalteromonas (12.87%∼16.29%), and a decrease in the relative abundance of Acinetobacter (0.79%∼0.02%) and Enterobacteriaceae (0.78%∼0.24%). Metabolically, starch and sucrose metabolism, arginine and proline metabolism, and phenylalanine metabolism significantly influenced the quality of extruded BSG fermented by MS during SSF. The examination of the correlation between the microbiota, metabolites, and fermentation parameters revealed that complex interactions between microbes and the environment factors impact metabolite production. Collectively, inoculating with MS improved fermentation quality and stability, facilitated the clean recycling of BSG, which is linked to complex interactions among microbes, the environment factors and metabolite production.

Artificial parasin I protein (API) supplementation improves growth performance and intestinal health in weaned piglets challenged with enterotoxigenic Escherichia coli.

Diarrheas are common risks faced by piglets during the weaning period. This study investigated the alleviating effects of artificial parasin I protein (API) on growth performance and intestinal health of weaned pigs upon enterotoxigenic Escherichia coli (ETEC) challenge. Sixty piglets were randomly divided into five groups and fed a basal diet (CON) or basal diet supplemented with API at 0, 750, and 1500 mg/kg or antibiotics for 5 weeks. On d 15 and 25, piglets were challenged with ETEC K88 except for the CON group. Before the ETEC challenge (d 1-14), dietary API supplementation improved growth performance, and 750 mg API increased (P < 0.05) the average daily gain (ADG), decreased (P < 0.05) feed to gain ratio (F/G) and diarrhea index of weaned piglets. ETEC challenge (during d 15-35) reduced growth performance and increased (P < 0.01) the F/G, diarrhea rate, and diarrhea index. This event was accompanied by the numerically increased malondialdehyde (MDA) levels in serum and ileum, the decreased (P < 0.05) zonula-occludens-1 (ZO-1) and interleukin-6 (IL-6) in the ileum, and the increased (P = 0.04) secretory immunoglobulin A (sIgA) protein in the ileum. Artificial parasin I protein supplementation alleviated the negative impact of ETEC. The 750 mg/kg API inclusion elevated (P < 0.05) ADG and decreased (P < 0.05) F/G. Two levels of API decreased (P < 0.01) the diarrhea rate and diarrhea index. Meanwhile, API inclusion decreased (P < 0.01) the crypt depth in the jejunum, elevated (P < 0.05) villus height in the duodenum and villus height to crypt depth ratio in the duodenum and ileum, up-regulated (P < 0.05) ZO-1 gene, and down-regulated (P < 0.05) mucin-2 gene in the jejunum, and 1500 mg/kg API decreased (P < 0.01) sIgA level and down-regulated (P < 0.05) IL-1ß gene in the ileum. Furthermore, 750 mg/kg API elevated (P < 0.01) Bifidobacteria population and acetic acid concentrations in the cecal chyme. In conclusion, API supplementation alleviates the negative impact of ETEC on growth performance and intestinal health, thus can be applied as an antibiotic alternative in weaned piglets.

Distinguishing Quantum Phases through Cusps in Full Counting Statistics.

Measuring physical observables requires averaging experimental outcomes over numerous identical measurements. The complete distribution function of possible outcomes or its Fourier transform, known as the full counting statistics, provides a more detailed description. This method captures the fundamental quantum fluctuations in many-body systems and has gained significant attention in quantum transport research. In this Letter, we propose that cusp singularities in the full counting statistics are a novel tool for distinguishing between ordered and disordered phases. As a specific example, we focus on the superfluid-to-Mott transition in the Bose-Hubbard model. Through both analytical analysis and numerical simulations, we demonstrate that the full counting statistics exhibit a cusp singularity as a function of the phase angle in the superfluid phase when the subsystem size is sufficiently large, while it remains smooth in the Mott phase. This discontinuity can be interpreted as a first-order transition between different semiclassical configurations of vortices. We anticipate that our discoveries can be readily tested using state-of-the-art ultracold atom and superconducting qubit platforms.

Analysis of prognostic risk factors and development of a predictive model for fetuses with right aortic arch with mirror-image branching: a prognostic evaluation method based on ultrasound parameter features.

Background: Prenatal ultrasound plays a crucial role in the diagnosis and classification of right aortic arch (AO) with mirror-image branching (RAA-MB). The recent research in this area has primarily focused on qualitative diagnosis, neglecting the quantitative analysis of ultrasound factors that impact RAA-MB outcomes. This study used echocardiography to measure prenatal ultrasound parameters for vascular ring and trachea in fetuses with RAA-MB, employing a nomogram model to evaluate factors influencing their prognosis, thereby providing a comprehensive characterization of potential outcomes. Methods: A retrospective case-control study was conducted from March 2019 to March 2023. A systematic gathering of prenatal echocardiograms and clinical data was completed for a cohort comprising 92 cases of fetal RAA-MB at the Ultrasound Medicine Center of Gansu Provincial Maternity and Child Care Hospital. Participant recruitment was executed through random selection from among those receiving outpatient medical care. Within the cohort, 42 cases were categorized as fetuses with isolated RAA-MB, while the remaining 50 cases were characterized as fetuses with RAA-MB and associated anomalies. Measurements were taken of the angle between the right AO and the ductus arteriosus (DA) (AO-DA), the distance between the AO and DA, the diameter of AO and DA, and the distance growth rate (DGR) of the AO-DA distance. Additionally, measurements were taken of the tracheal anterior-posterior diameter, tracheal left-right diameter, and tracheal circumference in the three-vessel tracheal view. In the AO view, measurements were taken of the tracheal cross-sectional area (TA) and the vessel ring cross-sectional area (VRA). The relationship between these parameters and the prognosis of fetuses with RAA-MB was assessed using logistic regression analysis. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic performance of the predictive model based on these factors. Results: The multivariate logistic regression analysis revealed that the independent predictive factors for the prognosis of fetuses with RAA-MB were the AO-DA distance [odds ratio (OR) =0.012], TA (OR =0.401), and VRA (OR =1.103) (all P values <0.001). The area under the ROC curve was 0.891 [95% confidence interval (CI): 0.789-0.914; P<0.001], indicating a high accuracy of the model's predictions. Conclusions: The AO-DA distance, TA, and VRA are factors that influence the prognosis of fetuses with RAA-MB. The column chart model constructed based on these parameters can effectively provide a reference for predicting the risk of adverse outcomes in fetuses with RAA-MB.

Evaluation and analysis of influencing factors of placental mesenchymal dysplasia diagnosed using prenatal ultrasonography and pregnancy outcomes: case series.

Background: Placental mesenchymal dysplasia (PMD) is a rare placental vascular malformation of unknown etiology. PMD may coexist with a healthy fetus, and its ultrasound appearance is similar to that of a hydatidiform mole, especially the partial type. Prenatal ultrasonography is vital for accurate diagnosis of these conditions. This study aimed to summarize the characteristics of prenatal ultrasonographic images across different gestational weeks (W) for PMD and evaluate and analyze factors that influence pregnancy outcomes related to PMD. The goal is to improve the diagnosis of PMD, effectively assess fetal prognosis, and provide a reference for prenatal consultations and clinical management. Case Description: Of the 15 included patients, 4, 8, and 3 had PMD in early pregnancy (<13+6 W), mid-pregnancy (approximately 14-27+6 W), and late pregnancy (>28 W), respectively. Among the 15 patients, 5 successfully underwent delivery, thereby resulting in fetal survival; 3 experienced intrauterine death, 1 had a miscarriage, and 6 pregnancies were terminated. During early pregnancy, ultrasonographic manifestations of PMD included microscopic anechoic cystic areas in the placental parenchyma. In the second trimester, the placenta exhibited diffuse enlargement and thickening, with the placental parenchyma showing cellular anechoic cystic areas clearly separated from the surrounding normal placental tissue. As the pregnancy progressed, the cystic areas gradually reduced in the third trimester. Additionally, localized umbilical blood vessels showed tumorous lesions, sometimes accompanied by intravascular thrombosis. Some cases exhibited tortuosity and dilation in the umbilical vein. Conclusions: PMD exhibited varying ultrasonographic characteristics across different gestational stages and demonstrated regular disease evolution corresponding to gestational W. This condition is associated with adverse pregnancy outcomes, with the location, extent, and severity of lesions being crucial factors affecting fetal development in utero.

Extrusion can ameliorate negative effects of molecular structures of brewer's spent grain on energy contents and amino acid digestibility in growing pigs.

The objectives of this study were to investigate the effects of extrusion on the chemical compositions, surface structure, and molecular structure of brewer's spent grain (BSG), as well as to determine the digestible energy (DE), metabolizable energy (ME), apparent total tract digestibility (ATTD) of nutrients and energy, and amino acid (AA) digestibility of extruded BSG when fed to growing pigs. Firstly, we determined the changes in chemical compositions and molecular structure of both non-extruded and extruded BSG. In Exp. 1, eighteen growing pigs were fed three different diets including one corn-soybean meal basal diet and two experimental diets containing 20% BSG with or without extrusion. Feces and urine were collected to determine the ATTD of nutrients and energy, DE, and ME of extruded or non-extruded BSG. In Exp. 2, eighteen growing pigs were fed three different diets including 30% BSG with or without extrusion, and an N-free diet. Ileal digesta was collected through the slaughter method to determine the apparent ileal digestibility (AID) and standardized ileal digestibility (SID) of AA of extruded or non-extruded BSG. The results showed that extrusion reduced the neutral detergent fiber, hemicellulose and cellulose contents in BSG, and increased the Arg, Asp, Glu, Ser, Tyr, total indispensable AA and total AA contents of BSG, altered the surface structure of BSG, increased the peak absorbance in amide I and amide II height, amide II and amide (I+II) area, α-helix height, decreased ß-sheet height, and weakened band intensities in cellulosic compounds (CELC) area, structural carbohydrates (SCHO) area, carbohydrates area (CHO) peak 2 and 3 height, the area ratio of CELC: CHO and CELC: SCHO. Moreover, DE and ME values and ATTD of energy, dry matter, crude protein, acid detergent fiber, neutral detergent fiber, cellulose and hemicellulose increased (P < 0.05) when pigs were fed extruded BSG diets. The AID and SID of Arg, His, Lys, Val and Gly increased, whereas the AID and SID of Ile and Leu decreased when pigs were fed extrusion diets (P < 0.05). Our study found that the ATTD of nutrients and AA digestibility in pigs were positively correlated with the molecular structure of proteins, and negatively correlated with the molecular structure of carbohydrates (P < 0.05). These findings suggested that extrusion had the potential to improve the nutrient digestibility of BSG by altering its chemical compositions, surface structure, and molecular structure.

Qiliqiangxin Alleviates Imbalance of Inflammatory Cytokines in Patients with Dilated Cardiomyopathy: A Randomized Controlled Trial.

OBJECTIVE: Qiliqiangxin (QLQX) capsule- a traditional Chinese medicine used for treating heart failure (HF), can modulate inflammatory cytokines in rats with myocardial infarction. However, its immune-regulating effect on dilated cardiomyopathy (DCM) remains unknown. The aim of this study was to investigate whether QLQX has a unique regulatory role in the imbalance of pro- and anti-inflammatory cytokines in patients with DCM. METHODS: The QLQX-DCM is a randomized- double-blind trial conducted at 24 tertiary hospitals in China. A total of 345 patients with newly diagnosed virus-induced DCM were randomly assigned to receive QLQX capsules or placebo while receiving optimal medical therapy for HF. The primary endpoints were changes in plasma inflammatory cytokines and improvements in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) over the 12-month treatment. RESULTS: At the 12-month follow-up, the levels of IFN-γ, IL-17, TNF-α, and IL-4 decreased significantly, while the level of IL-10 increased in both groups compared with baselines (all P<0.0001). Furthermore-these changes, coupled with improvements in LVEF, NT-proBNP and New York Heart Association (NYHA) functional classification, excluding the LVEDd in the QLQX group, were greater than those in the placebo group (all P<0.001). Additionally, compared with placebo, QLQX treatment also reduced all-cause mortality and rehospitalization rates by 2.17% and 2.28%, respectively, but the difference was not statistically significant. CONCLUSION: QLQX has the potential to alleviate the imbalance of inflammatory cytokines in patients with DCM, potentially leading to further improvements in cardiac function when combined with anti-HF standard medications.

Prenatal Diagnosis of Persistent Left Superior Vena Cava Using High-Definition Flow Render Mode and Spatiotemporal Image Correlation.

OBJECTIVE: This study aimed to assess the use of two-dimensional (2D) ultrasound combined with high-definition flow (HD-flow) render mode and spatiotemporal image correlation (STIC) in diagnosing and classifying fetal persistent left superior vena cava (PLSVC). METHODS: Overall, 114 cases of fetal PLSVC were diagnosed using 2D ultrasound combined with STIC, and 114 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to evaluate the effectiveness of the diagnostic approach. RESULTS: All 114 PLSVC cases were diagnosed using 2D ultrasound combined with STIC. Although the diagnostic coincidence rate of PLSVC in the HD-flow combined with STIC was similar to that in the 2D ultrasound combined with HD-flow (96.8 vs 96.2%), 2D ultrasound with STIC enabled dynamic visualization of the PLSVC, furthering prenatal diagnosis. These cases were classified as type I PLSVC: 80 cases of type Ia, 29 cases of type Ib, and 5 cases of type Ic. Seventy isolated PLSVC cases (61.4%) were noted, whereas 44 cases (35.6%) were associated with concomitant structural abnormalities. Intracardiac structural malformations accounted for the highest proportion (n = 53, 58.89%), followed by single umbilical artery and facial/bodily abnormalities (n = 10, 11.11%). CONCLUSION: Combining HD-flow and STIC complements 2D ultrasound in diagnosing and classifying fetal PLSVC, demonstrating significant clinical relevance.

Nano-Se exhibits limited protective effect against heat stress induced poor breast muscle meat quality of broilers compared with other selenium sources.

BACKGROUND: At present, heat stress (HS) has become a key factor that impairs broiler breeding industry, which causes growth restriction and poor meat quality of broilers. Selenium (Se) is an excellent antioxidant and plays a unique role in meat quality improvement. Recent years, nano-selenium (NanoSe) has received tremendous attention in livestock production, due to its characteristic and good antibacterial performance in vitro. Here, we developed the heat stressed-broiler model to investigate the protective effects of NanoSe on growth performance and meat quality of broilers and compare whether there are differences with that of other Se sources (Sodium selenite, SS; Selenoyeast, SeY; Selenomethionine, SeMet). RESULTS: HS jeopardized the growth performance and caused poor meat quality of breast muscle in broilers, which were accompanied by lowered antioxidant capacity, increased glycolysis, increased anaerobic metabolism of pyruvate, mitochondrial stress and abnormal mitochondrial tricarboxylic acid (TCA) cycle. All Se sources supplementation exhibited protective effects, which increased the Se concentration and promoted the expression of selenoproteins, improved the mitochondrial homeostasis and the antioxidant capacity, and promoted the TCA cycle and the aerobic metabolism of pyruvate, thus improved the breast muscle meat quality of broilers exposed to HS. However, unlike the other three Se sources, the protective effect of NanoSe on meat quality of heat stressed-broilers was not ideal, which exhibited limited impact on the pH value, drip loss and cooking loss of the breast muscle. Compared with the other Se sources, broilers received NanoSe showed the lowest levels of slow MyHC, the highest levels of fast MyHC and glycogen, the highest mRNA levels of glycolysis-related genes (PFKM and PKM), the highest protein expression of HSP60 and CLPP, and the lowest enzyme activities of GSH-Px, citroyl synthetase (CS) and isocitrate dehydrogenase (ICD) in breast muscle. Consistent with the SS, the Se deposition in breast muscle of broilers received NanoSe was lower than that of broilers received SeY or SeMet. Besides, the regulatory efficiency of NanoSe on the expression of key selenoproteins (such as SELENOS) in breast muscle of heat stressed-broilers was also worse than that of other Se sources. CONCLUSION: Through comparing the meat quality, Se deposition, muscle fiber type conversion, glycolysis, mitochondrial homeostasis, and mitochondrial TCA cycle-related indicators of breast muscle in heat stressed broilers, we found that the protective effects of organic Se (SeY and SeMet) are better than that of inorganic Se (SS) and NanoSe. As a new Se source, though NanoSe showed some protective effect on breast muscle meat quality of heat stressed broilers, the protective effect of NanoSe is not ideal, compared with other Se sources.

The search for optimal nocturnal diurnal heart rate Index targets in ICU patients: a retrospective observational study from large ICU database.

Background: Circadian rhythms play a crucial role in cardiovascular health, with the nocturnal diurnal heart rate index (NDHRI) reflecting significant circadian variations. However, the optimal NDHRI target in Intensive Care Unit (ICU) patients remains undefined. This study aims to establish an evidence-based NDHRI target range and assess its association with mortality. Methods: Data from the eICU Collaborative Research Database (n = 32,412) were analyzed. NDHRI was calculated by dividing cumulative nighttime heart rate area by daytime area. Generalized additive models (GAMs) explored the non-linear relationship between mean NDHRI and mortality, adjusting for confounders. Subgroup analyses were conducted based on ethnicity, ICU type, and comorbidities. Results: A U-shaped association was observed between hospital mortality and mean NDHRI (P < 0.001). The optimal NDHRI range (40.0%-45.0%) demonstrated the lowest mortality rates. The duration spent within this range correlated inversely with mortality (P < 0.001). Subgroup analyses consistently supported these findings across diverse patient profiles. Conclusions: Our findings suggest an association between maintaining NDHRI within the 40.0%-45.0% range and lower mortality rates in critically ill patients, highlighting the potential utility of monitoring circadian heart rate variations in the ICU. Further research and future randomized controlled trials are essential to confirm causality and should consider this NDHRI range as a pivotal reference target.

Large Piezoelectricity Induced by Internal Stress in (K,Na)NbO3 Single Crystals.

Achieving a high piezoelectric response and excellent stability is essential for practical applications of ferroelectric materials. Herein, large piezoelectricity of d33 = 167 pC/N and kt = 0.52 is found in a K0.7Na0.3NbO3 lead-free ferroelectric single crystal without poling, which is comparable to the artificially poled KNN crystals. The large piezoelectricity is maintained up to 196 °C, showing excellent thermal stability. It was demonstrated that the high piezoelectricity is associated with strong self-polarization in the crystals. The strong internal stress formed during crystal growth gives a preferred spontaneous polarization orientation, resulting in a net macro total polarization. In addition, the internal stress also pins domain wall motions and provides a "restoring force" for the domain switching. This work provides a strategy for designing and optimizing the piezoelectric performance of ferroelectric materials.

Neuroinflammation in Alzheimer's disease: insights from peripheral immune cells.

Alzheimer's disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and cerebrovascular dysfunction. The presence of chronic neuroinflammation, breaches in the blood-brain barrier (BBB), and increased levels of inflammatory mediators are central to the pathogenesis of AD. These factors promote the penetration of immune cells into the brain, potentially exacerbating clinical symptoms and neuronal death in AD patients. While microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD, recent evidence suggests the infiltration of cerebral vessels and parenchyma by peripheral immune cells, including neutrophils, T lymphocytes, B lymphocytes, NK cells, and monocytes in AD. These cells participate in the regulation of immunity and inflammation, which is expected to play a huge role in future immunotherapy. Given the crucial role of peripheral immune cells in AD, this article seeks to offer a comprehensive overview of their contributions to neuroinflammation in the disease. Understanding the role of these cells in the neuroinflammatory response is vital for developing new diagnostic markers and therapeutic targets to enhance the diagnosis and treatment of AD patients.

ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment.

BACKGROUND: The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. METHODS: Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. RESULTS: Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. CONCLUSION: Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.

Unsupervised domain adaptive segmentation algorithm based on two-level category alignment.

To enhance the model's generalization ability in unsupervised domain adaptive segmentation tasks, most approaches have primarily focused on pixel-level local features, but neglected the clue in category information. This limitation results in the segmentation network only learning global inter-domain invariant features but ignoring the category-specific inter-domain invariant features, which degenerates the segmentation performance. To address this issue, we present an Unsupervised Domain Adaptive algorithm based on two-level Category Alignment in two different spaces for semantic segmentation tasks, denoted as UDAca+. The first level is image-level category alignment based on class activation map (CAM), and the second one is pixel-level category alignment based on pseudo label. By utilizing category information, UDAca+ can effectively capture domain-invariant yet category-discriminative feature representations to improve segmentation accuracy. In addition, an adversarial learning-based strategy in mixed domain is designed to train the proposed network. Moreover, a confidence calculation method is introduced to mitigate the misleading issues of negative transfer and over-alignment caused by the noise in image-level pseudo labels. UDAca+ achieves the state-of-the-art (SOTA) performance on two synthetic-to-real adaptative tasks, and verifies its effectiveness for image segmentation.

Next-generation probiotic candidates targeting intestinal health in weaned piglets: Both live and heat-killed Akkermansia muciniphila prevent pathological changes induced by enterotoxigenic Escherichia coli in the gut.

The use of next-generation probiotics (NGP) in pigs for combating diseases has been subject to limited research. Here we explored the potential of a well-known NGP candidate Akkermansia muciniphila targeting pig gut health. In the first screening experiment, we found that the abundance of A. muciniphila peaked at 14 d old but decreased at weaning (21 d old; P < 0.05), suggesting the weaning period may be an effective window for A. muciniphila intervention. Following that, 48 crossbred weaned pigs at 28 d old were randomly assigned to five groups: control (CON), high/low live A. muciniphila (HA/LA), and high/low heat-killed A. muciniphila (HIA/LIA). From 1 to 28 d old, the CON group received gastric infusion of anaerobic sterile saline every other day; the HA and LA groups were gavaged every other day with 1 × 1010 CFU/5 mL and 5 × 108 CFU/5 mL live A. muciniphila, respectively; and the HIA and LIA groups were gavaged every other day with 1 × 1010 CFU/5 mL and 5 × 108 CFU/5 mL heat-killed A. muciniphila, respectively. At d 29, pigs in the CON group were randomly and equally divided into two groups, one of which was named the enterotoxigenic Escherichia coli (ETEC) group, and all groups except CON received a 5-d ETEC challenge. The supplementation of A. muciniphila numerically reduced the diarrhea rate of weaned pigs compared to the pigs that only received the ETEC challenge (P = 0.57), but the LIA group had a higher diarrhea rate than the CON group (P < 0.05). Consistent with this, the supplementation of A. muciniphila improved the small intestinal morphology and structure, proportion of CD4+ T lymphocytes in the blood, as well as the expression of genes related to intestinal barrier and antioxidant indices of pigs with ETEC challenge, especially for the LA group (P < 0.05). Meanwhile, A. muciniphila supplementation reduced the expression of ETEC virulence factor genes in the ileum and colon of pigs challenged by ETEC (P < 0.05). Therefore, A. muciniphila may protect the intestinal health of weaned piglets from damage caused by ETEC infection, but the effect may vary depending on the concentration and activity of A. muciniphila.