A MicroRNA Linking Human Positive Selection and Metabolic Disorders.

Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.

Plant immunity suppression via PHR1-RALF-FERONIA shapes the root microbiome to alleviate phosphate starvation.

The microbiome plays an important role in shaping plant growth and immunity, but few plant genes and pathways impacting plant microbiome composition have been reported. In Arabidopsis thaliana, the phosphate starvation response (PSR) was recently found to modulate the root microbiome upon phosphate (Pi) starvation through the transcriptional regulator PHR1. Here, we report that A. thaliana PHR1 directly binds to the promoters of rapid alkalinization factor (RALF) genes, and activates their expression under phosphate-starvation conditions. RALFs in turn suppress complex formation of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) receptor through FERONIA, a previously-identified PTI modulator that increases resistance to certain detrimental microorganisms. Suppression of immunity via the PHR1-RALF-FERONIA axis allows colonization by specialized root microbiota that help to alleviate phosphate starvation by upregulating the expression of PSR genes. These findings provide a new paradigm for coordination of host-microbe homeostasis through modulating plant innate immunity after environmental perturbations.

Kynurenine 3-monooxygenase limits de novo NAD+ synthesis through dietary tryptophan in renal proximal tubule epithelial cell models.

Nicotinamide adenine dinucleotide (NAD+) is a pivotal coenzyme, essential for cellular reactions, metabolism, and mitochondrial function. Depletion of kidney NAD+ levels and reduced de novo NAD+ synthesis through the tryptophan-kynurenine pathway are linked to acute kidney injury (AKI), whereas augmenting NAD+ shows promise in reducing AKI. We investigated de novo NAD+ biosynthesis using in vitro, ex vivo, and in vivo models to understand its role in AKI. Two-dimensional (2-D) cultures of human primary renal proximal tubule epithelial cells (RPTECs) and HK-2 cells showed limited de novo NAD+ synthesis, likely due to low pathway enzyme gene expression. Using three-dimensional (3-D) spheroid culture model improved the expression of tubular-specific markers and enzymes involved in de novo NAD+ synthesis. However, de novo NAD+ synthesis remained elusive in the 3-D spheroid culture, regardless of injury conditions. Further investigation revealed that 3-D cultured cells could not metabolize tryptophan (Trp) beyond kynurenine (KYN). Intriguingly, supplementation of 3-hydroxyanthranilic acid into RPTEC spheroids was readily incorporated into NAD+. In a human precision-cut kidney slice (PCKS) ex vivo model, de novo NAD+ synthesis was limited due to substantially downregulated kynurenine 3-monooxygenase (KMO), which is responsible for KYN to 3-hydroxykynurenine conversion. KMO overexpression in RPTEC 3-D spheroids successfully reinstated de novo NAD+ synthesis from Trp. In addition, in vivo study demonstrated that de novo NAD+ synthesis is intact in the kidney of the healthy adult mice. Our findings highlight disrupted tryptophan-kynurenine NAD+ synthesis in in vitro cellular models and an ex vivo kidney model, primarily attributed to KMO downregulation.NEW & NOTEWORTHY Nicotinamide adenine dinucleotide (NAD+) is essential in regulating mitochondrial function. Reduced NAD+ synthesis through the de novo pathway is associated with acute kidney injury (AKI). Our study reveals a disruption in de novo NAD+ synthesis in proximal tubular models, but not in vivo, attributed to downregulation of enzyme kynurenine 3-monooxygenase (KMO). These findings highlight a crucial role of KMO in governing de novo NAD+ biosynthesis within the kidney, shedding light on potential AKI interventions.

Predictive value of peripheral blood biomarkers in patients with non-small-cell lung cancer responding to anti-PD-1-based treatment.

BACKGROUND: The introduction of the anti-PD-1 antibody has greatly improved the clinical outcomes of patients with non-small cell lung cancer (NSCLC). In this study, we retrospectively analyzed the efficacy of PD-1 antibody-based therapy in patients with locally advanced inoperable or metastatic NSCLC and reported an association between peripheral blood biomarkers and clinical response in these patients. METHODS: This single-center study included medical record data of patients with NSCLC treated with the PD-1 antibody as a first-line or subsequent line of treatment, either as monotherapy or in combination with chemotherapy. The patients were enrolled from 2020 to 2022. We dynamically evaluated multiple Th1 and Th2 cytokines in the blood serum and analyzed the phenotype of T cells from the peripheral blood to explore the correlation between cytokine levels, T cell phenotypes, and clinical response. RESULTS: A total of 88 patients with stage IIIA-IV NSCLC were enrolled, out of which 60 (68.18%) achieved a partial response (PR), 13 (14.77%) had stable disease (SD), and 15 (17.05%) experienced disease progression (PD). The disease control rate was 82.95%. Our results suggested a significant reduction (P = 0.002, P < 0.005) in lymphocyte absolute counts after treatment in patients with PD. Higher levels of IFN-γ (P = 0.023, P < 0.05), TNF-α (P = 0.00098, P < 0.005), IL-4 (P = 0.0031, P < 0.005), IL-5 (P = 0.0015, P < 0.005), and IL-10 (P = 0.036, P < 0.05) were detected in the peripheral blood before treatment in the PR group compared to the PD group. Moreover, patients with high levels of IL-5, IL-13, IL-4, IL-6, IFN-γ, and TNF-α (> 10 ng/mL) had superior progression-free survival compared to those with low levels (< 10 ng/mL). Furthermore, PD-1 expression on CD8+ T cells was higher in patients who showed a PR than in those who did not show a response (SD + PD; P = 0.042, P < 0.05). CONCLUSIONS: The findings of this study imply that the decrease in absolute blood lymphocyte counts after treatment is correlated with disease progression. Serum cytokine levels may predict the effectiveness and survival rates of anti-PD-1 blockade therapy in patients with NSCLC. In addition, PD-1 expression on CD8+ T cells was positively associated with better clinical response. Our findings highlight the potential of peripheral blood biomarkers to predict the effectiveness of PD-1-targeted treatments in patients with NSCLC. Larger prospective studies are warranted to further clarify the value of these biomarkers.

Tailoring Stress-Relieved Structure for SnSe Toward High Performance Potassium Ion Batteries.

Metal chalcogenides as an ideal family of anode materials demonstrate a high theoretical specific capacity for potassium ion batteries (PIBs), but the huge volume variance and poor cyclic stability hinder their practical applications. In this study, a design of a stress self-adaptive structure with ultrafine SnSe nanoparticles embedded in carbon nanofiber (SnSe@CNF) via the electrospinning technology is presented. Such an architecture delivers a record high specific capacity (272 mAh g-1 at 50 mA g-1) and high-rate performance (125 mAh g-1 at 1 A g-1) as a PIB anode. It is decoded that the fundamental understanding for this great performance is that the ultrafine SnSe particles enhance the full utilization of the active material and achieve stress relief as the stored strain energy from cycling is insufficient to drive crack propagation and thus alleviates the intrinsic chemo-mechanical degradation of metal chalcogenides.

Tunable Surface Charge of Layered Double Hydroxide Membranes Enabling Osmotic Energy Harvesting from Anion Transport.

Membrane-based osmotic energy harvesting is a promising technology with zero carbon footprint. High-performance ion-selective membranes (ISMs) are the core components in such applications. Recent advancement in 2D nanomaterials opens new avenues for building highly efficient ISMs. However, the majority of the explored 2D nanomaterials have a negative surface charge, which selectively enhances cation transport, resulting in the underutilization of half of the available ions. In this study, ISMs based on layered double hydroxide (LDH) with tunable positive surface charge are studied. The membranes preferentially facilitate anion transport with high selectivity. Osmotic energy harvesting device based on these membranes reached a power density of 2.31 W m-2 under simulated river/sea water, about eight times versus that of a commercial membrane tested under the same conditions, and up to 7.05 W m-2 under elevated temperature and simulated brine/sea water, and long-term stability with consistent performance over a 40-day period. A prototype reverse electrodialysis energy harvesting device, comprising a pair of LDH membranes and commercial cation-selective membranes, is able to simultaneously harvest energy from both cations and anions achieving a power density of 6.38 W m-2 in simulated river/sea water, demonstrating its potential as building blocks for future energy harvesting systems.

Reduction of Backward Scatterings at the Low-Coherence Kunwu Laser Facility.

We report the first experimental observation on the reduction of backward scatterings by an instantaneous broadband laser with 0.6% bandwidth in conditions of interest for inertial confinement fusion at the low-coherence Kunwu laser facility. The backscatter of stimulated Brillouin scattering (SBS) was robustly reduced by half at intensities of 1-5×10^{14} W/cm^{2} with the 0.53-µm broadband laser in comparison with the monochromatic laser. As SBS dominates energy loss of laser-plasma interactions, the reduction of that demonstrates the enhancement of laser-target coupling by the use of broadband laser. The mitigation of filamentation leads to the reduction of stimulated Raman backscattering at low intensities. In addition, the three-halves harmonic emission was reduced with the broadband laser as well.

A Review of Cerebrospinal Fluid Circulation and the Pathogenesis of Congenital Hydrocephalus.

The brain's ventricles are filled with a colorless fluid known as cerebrospinal fluid (CSF). When there is an excessive accumulation of CSF in the ventricles, it can result in high intracranial pressure, ventricular enlargement, and compression of the surrounding brain tissue, leading to potential damage. This condition is referred to as hydrocephalus. Hydrocephalus is classified into two categories: congenital and acquired. Congenital hydrocephalus (CH) poses significant challenges for affected children and their families, particularly in resource-poor countries. Recognizing the psychological and economic impacts is crucial for developing interventions and support systems that can help alleviate the distress and burden faced by these families. As our understanding of CSF production and circulation improves, we are gaining clearer insights into the causes of CH. In this article, we will summarize the current knowledge regarding CSF circulation pathways and the underlying causes of CH. The main causes of CH include abnormalities in the FoxJ1 pathway of ventricular cilia, dysfunctions in the choroid plexus transporter Na+-K+-2Cl- contransporter isoform 1, developmental abnormalities in the cerebral cortex, and structural abnormalities within the brain. Understanding the causes of CH is indeed crucial for advancing research and developing effective treatment strategies. In this review, we will summarize the findings from existing studies on the causes of CH and propose potential research directions to further our understanding of this condition.

Encapsulation of phenolic acids within food-grade carriers systems: a systematic review.

Phenolic acids are natural compounds with potential therapeutic effects against various diseases. However, their incorporation into food and pharmaceutical products is limited by challenges such as instability, low solubility, and reduced bioavailability. This systematic review summarizes recent advances in phenolic acid encapsulation using food-grade carrier systems, focusing on proteins, lipids, and polysaccharides. Encapsulation efficiency, release behavior, and bioavailability are examined, as well as the potential health benefits of encapsulated phenolic acids in food products. Strategies to address limitations of current encapsulation systems are also proposed. Encapsulation has emerged as a promising method to enhance the stability and bioavailability of phenolic acids in food products, and various encapsulation technologies have been developed for this purpose. The use of proteins, lipids, and carbohydrates as carriers in food-grade encapsulation systems remains a common approach, but it is associated with certain limitations. Future research on phenolic acid encapsulation should focus on developing environmentally friendly, organic solvent-free, low-energy, scalable, and stable encapsulation systems, as well as co-encapsulation methods that combine multiple phenolic acids or phenolic acids with other bioactive substances to produce synergistic effects.

OxLDL enhances procoagulant activity of endothelial cells by TMEM16F-mediated phosphatidylserine exposure.

Oxidized low-density lipoprotein (oxLDL), a key component in atherosclerosis and hyperlipidemia, is a risk factor for atherothrombosis in dyslipidemia, yet its mechanism is poorly understood. In this study, we used oxLDL-induced human aortic endothelial cells (HAECs) and high-fat diet (HFD)-fed mice as a hyperlipidemia model. Phosphatidylserine (PS) exposure, cytosolic Ca2+, reactive oxygen species (ROS), and lipid peroxidation were measured by flow cytometer. TMEM16F expression was detected by immunofluorescence, western blot, and reverse transcription polymerase chain reaction. Procoagulant activity (PCA) was measured by coagulation time, intrinsic/extrinsic factor Xase, and thrombin generation. We found that oxLDL-induced PS exposure and the corresponding PCA of HAECs were increased significantly compared with control, which could be inhibited over 90% by lactadherin. Importantly, TMEM16F expression in oxLDL-induced HAECs was upregulated by enhanced intracellular Ca2+ concentration, ROS, and lipid peroxidation, which led to PS exposure. Meanwhile, the knockdown of TMEM16F by short hairpin RNA significantly inhibited PS exposure in oxLDL-induced HAECs. Moreover, we observed that HFD-fed mice dramatically increased the progress of thrombus formation and accompanied upregulated TMEM16F expression by thromboelastography analysis, FeCl3-induced carotid artery thrombosis model, and western blot. Collectively, these results demonstrate that TMEM16F-mediated PS exposure may contribute to prothrombotic status under hyperlipidemic conditions, which may serve as a novel therapeutic target for the prevention of thrombosis in hyperlipidemia.

Deficiency of P2RY11 causes narcolepsy and attenuates the recruitment of neutrophils and macrophages in the inflammatory response in zebrafish.

Purinergic receptor P2Y11, a G protein-coupled receptor that is stimulated by extracellular ATP, has been demonstrated to be related to the chemotaxis of granulocytes, apoptosis of neutrophils, and secretion of cytokines in vitro. P2Y11 mutations were associated with narcolepsy. However, little is known about the roles of P2RY11 in the occurrence of narcolepsy and inflammatory response in vivo. In this study, we generated a zebrafish P2Y11 mutant using CRISPR/Cas9 genome editing and demonstrated that the P2Y11 mutant replicated the narcolepsy-like features including reduced HCRT expression and excessive daytime sleepiness, suggesting that P2Y11 is essential for HCRT expression. Furthermore, we accessed the cytokine expression in the mutant and revealed that the P2RY11 mutation disrupted the systemic inflammatory balance by reducing il4, il10 and tgfb, and increasing il6, tnfa, and il1b. In addition, the P2RY11-deficient larvae with caudal fin injuries exhibited significantly slower migration and less recruitment of neutrophils and macrophages at damaged site, and lower expression of anti-inflammatory cytokines during tissue damage. All these findings highlight the vital roles of P2RY11 in maintaining HCRT production and secreting anti-inflammatory cytokines in the native environment, and suggested that P2RY11-deficient zebrafish can serve as a reliable and unique model to further explore narcolepsy and inflammatory-related diseases with impaired neutrophil and macrophage responses.

First report of Giardia duodenalis in dairy cattle and beef cattle in Shanxi, China.

BACKGROUND: Giardia duodenalis is an important intestinal parasitic protozoan that infects several vertebrates, including humans. Cattle are considered the major source of giardiasis outbreak in humans. This study aimed to investigate the prevalence and multilocus genotype (MLG) of G. duodenalis in Shanxi, and lay the foundation for the prevention and control of Giardiosis. METHODS AND RESULTS: DNA extraction, nested polymerase chain reaction, sequence analysis, MLG analysis, and statistical analysis were performed using 858 bovine fecal samples from Shanxi based on three gene loci: ß-giardin (bg), glutamate dehydrogenase (gdh), and triosephosphate isomerase (tpi). The overall prevalence of G. duodenalis was 28.3%, while its prevalence in Yingxian and Lingqiu was 28.1% and 28.5%, respectively. The overall prevalence of G. duodenalis in dairy cattle and beef cattle was 28.0% and 28.5%, respectively. G. duodenalis infection was detected in all age groups evaluated in this study. The overall prevalence of G. duodenalis in diarrhea and nondiarrhea samples was 32.4% and 27.5%, respectively, whereas that in intensively farmed and free-range cattle was 35.0% and 19.9%, respectively. We obtained 83, 53, and 59 sequences of bg, gdh, and tpi in G. duodenalis, respectively. Moreover, assemblage A (n = 2) and assemblage E (n = 81) by bg, assemblage A (n = 1) and assemblage E (n = 52) by gdh, and assemblage A (n = 2) and assemblage E (n = 57) by tpi were identified. Multilocus genotyping yielded 29 assemblage E MLGs, which formed 10 subgroups. CONCLUSIONS: To the best of our knowledge, this is the first study to report cattle infected with G. duodenalis in Shanxi, China. Livestock-specific G. duodenalis assemblage E was the dominant assemblage genotype, and zoonotic sub-assemblage AI was also detected in this region.

Unexpected reduction in thermal conductivity observed in graphene/h-BN heterostructures.

Heterostructures find wide-ranging applications in fields such as thermal management, thermoelectric energy conversion, and nanoelectronics. This study provides new insights into the thermal conductivity of parallel heterointerfaces by investigating a longitudinal heterostructure composed of graphene and hexagonal boron nitride (h-BN) using molecular dynamics simulations. Interestingly, it is observed that this unique heterostructure possesses a lower thermal conductivity compared to pure h-BN. The analysis reveals that phonon scattering is enhanced by stress at the interface of the heterostructure and the mass distribution through it. The heterostructure model introduced in this study presents new insights for controlling phonon transportation in nanoscale structures.

Effects of 90 dB pure tone exposure on auditory and cardio-cerebral system functions in macaque monkeys.

Excessive noise exposure presents significant health risks to humans, affecting not just the auditory system but also the cardiovascular and central nervous systems. This study focused on three male macaque monkeys as subjects. 90 dB sound pressure level (SPL) pure tone exposure (frequency: 500Hz, repetition rate: 40Hz, 1 min per day, continuously exposed for 5 days) was administered. Assessments were performed before exposure, during exposure, immediately after exposure, and at 7-, 14-, and 28-days post-exposure, employing auditory brainstem response (ABR) tests, electrocardiograms (ECG), and electroencephalograms (EEG). The study found that the average threshold for the Ⅴ wave in the right ear increased by around 30 dB SPL right after exposure (P < 0.01) compared to pre-exposure. This elevation returned to normal within 7 days. The ECG results indicated that one of the macaque monkeys exhibited an RS-type QRS wave, and inverted T waves from immediately after exposure to 14 days, which normalized at 28 days. The other two monkeys showed no significant changes in their ECG parameters. Changes in EEG parameters demonstrated that main brain regions exhibited significant activation at 40Hz during noise exposure. After noise exposure, the power spectral density (PSD) in main brain regions, particularly those represented by the temporal lobe, exhibited a decreasing trend across all frequency bands, with no clear recovery over time. In summary, exposure to 90 dB SPL noise results in impaired auditory systems, aberrant brain functionality, and abnormal electrocardiographic indicators, albeit with individual variations. It has implications for establishing noise protection standards, although the precise mechanisms require further exploration by integrating pathological and behavioral indicators.

TFEB SUMOylation in macrophages accelerates atherosclerosis by promoting the formation of foam cells through inhibiting lysosomal activity.

Atherosclerosis (AS) is a serious cardiovascular disease. One of its hallmarks is hyperlipidemia. Inhibiting the formation of macrophage foam cells is critical for alleviating AS. Transcription factor EB (TFEB) can limit the formation of macrophage foam cells by upregulating lysosomal activity. We examined whether TFEB SUMOylation is involved in this progress during AS. In this study, we investigated the role of TFEB SUMOylation in macrophages in AS using TFEB SUMOylation deficiency Ldlr-/- (TFEB-KR: Ldlr-/-) transgenic mice and TFEB-KR bone marrow-derived macrophages. We observed that TFEB-KR: Ldlr-/- atherosclerotic mice had thinner plaques and macrophages with higher lysosomal activity when compared to WT: Ldlr-/- mice. TFEB SUMOylation in macrophages decreased after oxidized low-density lipoprotein (OxLDL) treatment in vitro. Compared with wild type macrophages, TFEB-KR macrophages exhibited less lipid deposition after OxLDL treatment. Our study demonstrated that in AS, deSUMOylation of TFEB could inhibit the formation of macrophage foam cells through enhancing lysosomal biogenesis and autophagy, further reducing the accumulation of lipids in macrophages, and ultimately alleviating the development of AS. Thus, TFEB SUMOylation can be a switch to modulate macrophage foam cells formation and used as a potential target for AS therapy.

Cryptococcus gattii strains with a high phagocytosis phenotype by macrophages display high pathogenicity at the early stage of infection in vivo.

Cryptococcus gattii (Cg) is a facultative intracellular pathogen that can replicate and disseminate in mammalian macrophages, causing life-threatening cryptococcosis in both immunocompetent and immunocompromised individuals. Cryptococcus-macrophage interactions are crucial for cryptococcosis prognosis. However, the relationship between Cg pathogenicity and phagocytosis by macrophages has not yet been investigated in depth. In this study, a series of in vitro and in vivo experiments were conducted to investigate the interaction between macrophages and Cg. Flow cytometry was used to detect the phagocytic phenotypes of the Cg strains within macrophages. Scanning electron microscopy, transmission electron microscopy, and immunofluorescence were used to observe phagocytosis and proliferation, respectively. Survival and lung fungal burden tests were also performed. Our results show that Cg cells display different phagocytosis phenotypes, which are independent of the molecular type. Within macrophages, the high phagocytosis phenotype (HP) strains obtain higher intracellular proliferation than the low phagocytosis phenotype (LP) strains. At the early stage of infection in vivo, HP-inducing permissive granulomas within the lungs seldom limit the dissemination of cryptococci. In addition, HP strains could inhibit the formation of M1-type macrophages, proliferate intracellularly and disseminate extracellularly, and cause hypoxia induced by mucus and acidic polysaccharide accumulation in pulmonary alveoli much earlier than LP strains in vivo. Our work reveals that Cg displays diverse interactions with macrophages, which may enhance our understanding of the pathogenicity of this life-threatening pathogen.

Microscopic origins of the crystallographically preferred growth in evaporation-induced colloidal crystals.

Unlike crystalline atomic and ionic solids, texture development due to crystallographically preferred growth in colloidal crystals is less studied. Here we investigate the underlying mechanisms of the texture evolution in an evaporation-induced colloidal assembly process through experiments, modeling, and theoretical analysis. In this widely used approach to obtain large-area colloidal crystals, the colloidal particles are driven to the meniscus via the evaporation of a solvent or matrix precursor solution where they close-pack to form a face-centered cubic colloidal assembly. Via two-dimensional large-area crystallographic mapping, we show that the initial crystal orientation is dominated by the interaction of particles with the meniscus, resulting in the expected coalignment of the close-packed direction with the local meniscus geometry. By combining with crystal structure analysis at a single-particle level, we further reveal that, at the later stage of self-assembly, however, the colloidal crystal undergoes a gradual rotation facilitated by geometrically necessary dislocations (GNDs) and achieves a large-area uniform crystallographic orientation with the close-packed direction perpendicular to the meniscus and parallel to the growth direction. Classical slip analysis, finite element-based mechanical simulation, computational colloidal assembly modeling, and continuum theory unequivocally show that these GNDs result from the tensile stress field along the meniscus direction due to the constrained shrinkage of the colloidal crystal during drying. The generation of GNDs with specific slip systems within individual grains leads to crystallographic rotation to accommodate the mechanical stress. The mechanistic understanding reported here can be utilized to control crystallographic features of colloidal assemblies, and may provide further insights into crystallographically preferred growth in synthetic, biological, and geological crystals.

Down-regulated Wnt7a and GPR124 in early-onset preeclampsia placentas reduce invasion and migration of trophoblast cells.

OBJECTIVES: Preeclampsia (PE) is a disease specific to pregnancy that causes 9-10 % of maternal deaths. Early-onset PE (<34 weeks' gestation) is the most dangerous category of PE. Wnt7a and GPR124 (G protein-coupled receptor 124) are widely expressed in the human reproductive process. Especially during embryogenesis and tumorigenesis, Wnt7a plays a crucial role. However, few studies have examined the association between Wnt7a-GPR124 and early-onset PE. The aim of this study was to examine the significance of Wnt7a and GPR124 in early-onset PE as well as Wnt7a's role in trophoblast cells. METHODS: Immunohistochemistry (IHC), real-time PCR, and western blotting (WB) were used to investigate Wnt7a and GPR124 expression in normal and early-onset PE placentas. Additionally, FACS, Transwell, and CCK-8 assays were used to diagnose Wnt7a involvement in migration, invasion, and proliferation. RESULTS: In the early-onset PE group, Wnt7a and GPR124 expression was significantly lower than in the normal group, especially in the area of syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). A negative correlation was found between Wnt7a RNA and GPR124 expression (r=-0.42, p<0.01). However, the Wnt7a RNA expression level was positive correlated with PE severity. In further cellular functional experiments, knockdown of Wnt7a inhibits HTR8/SVeno cells invasion and migration but has little effect on proliferation and apoptosis. CONCLUSIONS: Through the Wnt pathway, Wnt7a regulates trophoblast cell invasion and migration, and may contribute to early-onset preeclampsia pathogenesis. A molecular level study of Wnt7a will be needed to find downstream proteins and mechanisms of interaction.

Quantitative Proteomics Provided Insights into the Protective Effects of Heat Acclimation on the Rat Hypothalamus after Exertional Heatstroke.

BACKGROUND: The effects of heat acclimation (HA) on the hypothalamus after exertional heatstroke (EHS) and the specific mechanism have not been fully elucidated, and this study aimed to address these questions. METHODS: In the present study, rats were randomly assigned to the control, EHS, HA, or HA + EHS groups (n = 9). Hematoxylin and eosin (H&E) staining was used to examine pathology. Tandem mass tag (TMT)-based proteomic analysis was utilized to explore the impact of HA on the protein expression profile of the hypothalamus after EHS. Bioinformatics analysis was used to predict the functions of the differentially expressed proteins. The differential proteins were validated by western blotting. An enzyme-linked immunosorbent assay was used to measure the expression levels of inflammatory cytokines in the serum. RESULTS: The H&E staining (n = 5) results revealed that there were less structural changes in hypothalamus in the HA + EHS group compared with the EHS group. Proteomic analysis (n = 4) revealed that proinflammatory proteins such as argininosuccinate synthetase (ASS1), high mobility group protein B2 (HMGB2) and vimentin were evidently downregulated in the HA + EHS group. The levels of interleukin (IL)-1ß, IL-1, and IL-8 were decreased in the serum samples (n = 3) from HA + EHS rats. CONCLUSIONS: HA may alleviate hypothalamic damage caused by heat attack by inhibiting inflammatory activities, and ASS1, HMGB2 and vimentin could be candidate factors involved in the exact mechanism.

Testing the generalizability of cfDNA fragmentomic features across different studies for cancer early detection.

cfDNA fragmentomic features have been used in cancer detection models; however, the generalizability of the models needs to be tested. We proposed a type of cfDNA fragmentomic feature named chromosomal arm-level fragment size distribution (ARM-FSD), evaluated and compared its performance and generalizability for lung cancer and pan-cancer detection with existing cfDNA fragmentomic features (as reference) by using cohorts from different institutions. The ARM-FSD lung cancer model outperformed the reference model by ∼10% when being tested by two external cohorts (AUC: 0.97 vs. 0.86; 0.87 vs. 0.76). For pan-cancer detection, the performance of the ARM-FSD based model is consistently higher than the reference (AUC: 0.88 vs. 0.75, 0.98 vs. 0.63) in a pan-cancer and a lung cancer external validation cohort, indicating that ARM-FSD model produces stable performance across multiple cohorts. Our study reveals ARM-FSD based models have a higher generalizability, and highlights the necessity of cross-study validation for predictive model development.