Atrial Natriuretic Peptide Alleviates Motion Sickness Potentially through Regulating Endolymph Volume in the Inner Ear Increased by Arginine Vasopressin.

INTRODUCTION: Dimenhydrinate and scopolamine are frequently used drugs, but they cause drowsiness and performance decrement. Therefore, it is crucial to find peripheral targets and develop new drugs without central side effects. This study aimed to investigate the anti-motion sickness action and inner ear-related mechanisms of atrial natriuretic peptide (ANP). METHODS: Endolymph volume in the inner ear was measured with magnetic resonance imaging and expression of AQP2 and p-AQP2 was detected with Western blot analysis and immunofluorescence method. RESULTS: Both rotational stimulus and intraperitoneal arginine vasopressin (AVP) injection induced conditioned taste aversion (CTA) to 0.15% sodium saccharin solution and an increase in the endolymph volume of the inner ear. However, intraperitoneal injection of ANP effectively alleviated the CTA behaviour and reduced the increase in the endolymph volume after rotational stimulus. Intratympanic injection of ANP also inhibited rotational stimulus-induced CTA behaviour, but anantin peptide, an inhibitor of ANP receptor A (NPR-A), blocked this inhibitory effect of ANP. Both rotational stimulus and intraperitoneal AVP injection increased the expression of AQP2 and p-AQP2 in the inner ear of rats, but these increases were blunted by ANP injection. In in vitro experiments, ANP addition decreased AVP-induced increases in the expression and phosphorylation of AQP2 in cultured endolymphatic sac epithelial cells. CONCLUSION: Therefore, the present study suggests that ANP could alleviate motion sickness through regulating endolymph volume of the inner ear increased by AVP, and this action of ANP is potentially mediated by activating NPR-A and antagonising the increasing effect of AVP on AQP2 expression and phosphorylation.

Malignant melanoma with liver, stomach, and duodenal metastasis.

Malignant melanoma (MM) is a common and highly invasive malignant tumor in clinical practice that is prone to occur in the skin and mucosa and prone to early metastasis. The common sites of metastasis are the liver, lungs, brain, etc. Metastatic gastrointestinal mucosa is relatively rare. Once metastasis occurs, the prognosis of patients is significantly worse. This article reports a case diagnosed as MM with liver, stomach, and duodenal metastasis by ultrasound-guided endoscopic puncture at Fengdu People's Hospital in Chongqing, with gastrointestinal discomfort as the initial symptom and a history of melanoma. Therefore, when a patient has a history of melanoma surgery and presents with digestive symptoms, it is necessary to consider the disease. Regular endoscopic screening should be performed, and early surgical treatment and postoperative chemotherapy combined with targeted therapy may improve patient prognosis and prolong patient survival.

Potential Embolic Sources in Embolic Stroke of Undetermined Source Patients with Patent Foramen Ovale.

INTRODUCTION: A patent foramen ovale (PFO) may coexist with other potential embolic sources (PESs) in patients with embolic stroke of undetermined source (ESUS), leading to difficulty in attributing the stroke to either the PFO or other PESs. We aimed to investigate the prevalence and predictors of concomitant PESs in ESUS patients with PFOs. METHODS: A retrospective cohort study was conducted in a tertiary stroke centre. Consecutive patients with ESUS and a concomitant PFO admitted between 2012 and 2021 were included in the study. Baseline characteristics and investigations as a part of stroke workup including echocardiographic and neuroimaging data were collected. PESs were adjudicated by 2 independent neurologists after reviewing the relevant workup. RESULTS: Out of 1,487 ESUS patients, a total of 309 patients who had a concomitant PFO with mean age of 48.8 ± 13.2 years were identified during the study period. The median Risk of Paradoxical Embolism (RoPE) score for the study cohort was 6 (IQR 5-7.5). Of the 309 patients, 154 (49.8%) only had PFO, 105 (34.0%) patients had 1 other PES, 34 (11.0%) had 2 PES, and 16 (5.2%) had 3 or more PES. The most common PESs were atrial cardiopathy (23.9%), left ventricular dysfunction (22.0%), and cardiac valve disease (12.9%). The presence of additional PESs was associated with age ≥60 years (p < 0.001), RoPE score ≤6 (p ≤0.001), and the presence of comorbidities including diabetes mellitus (p = 0.004), hypertension (p≤ 0.001), and ischaemic heart disease (p = 0.011). CONCLUSION: A large proportion of ESUS patients with PFOs had concomitant PESs. The presence of concomitant PESs was associated with older age and a lower RoPE score. Further, large cohort studies are warranted to investigate the significance of the PES and their overlap with PFOs in ESUS.

Performance of heart rate adjusted heart rate variability for risk stratification of sudden cardiac death.

PURPOSE: As a non-invasive tool for the assessment of cardiovascular autonomic function, the predictive value of heart rate variability (HRV) for sudden cardiac death (SCD) risk stratification remains unclear. In this study, we investigated the performance of the individualized heart rate (HR) adjusted HRV (HRVI) for SCD risk stratification in subjects with diverse risks. METHODS: A total of 11 commonly used HRV metrics were analyzed in 192 subjects, including 88 healthy controls (low risk group), 82 hypertrophic cardiomyopathy (HCM) patients (medium risk group), and 22 SCD victims (high risk group). The relationship between HRV metrics and HR was examined with long-term and short-term analysis. The performance HRVI was evaluated by area under the receiver operating characteristic curve (AUC) and covariance of variation (CV). RESULTS: Most of the HRV metrics were exponentially decayed with the increase of HR, while the exponential power coefficients were significantly different among groups. The HRVI metrics discriminated low, medium and high risk subjects with a median AUC of 0.72[0.11], which was considerably higher than that of the traditional long-term (0.63[0.04]) and short-term (0.58[0.05]) HRV without adjustment. The average CV of the HRVI metrics was also significantly lower than traditional short-term HRV metrics (0.09 ± 0.02 vs. 0.24 ± 0.13, p < 0.01). CONCLUSIONS: Subjects with diverse risks of SCD had similar exponential decay relationship between HRV metrics and HR, but with different decaying rates. HRVI provides reliable and robust estimation for risk stratification of SCD.

Ratiometric optical detection of pyrophosphate based on aggregation-caused dual-signal response of gold nanoclusters.

Sensing of pyrophosphate ion (PPi) has received much attention due to the strong demand for clinical diagnostics. Here, based on gold nanoclusters (Au NCs), a ratiometric optical detection method for PPi is developed by simultaneously detecting the dual signals of fluorescence (FL) and second-order scattering (SOS). The PPi is detected by inhibiting the formation of aggregates of Fe3+ with Au NCs. Binding of Fe3+ to Au NCs causes aggregation of Au NCs, which leads to fluorescence quenching and scattering increasing. The presence of PPi can competitively bind Fe3+ to re-disperse the Au NCs and finally recover the fluorescence and reduce the scattering signal. The designed PPi sensor shows a high sensitivity with a linear range 5-50 µM and a detection limit of 1.2 µM. In addition, the assay has excellent selectivity for PPi, which makes its application in real biological samples extremely valuable.

Propensity-score matched analysis of patent foramen ovale closure in real-world study cohort with cryptogenic ischemic stroke.

INTRODUCTION: Patent foramen ovale (PFO) occurs in 25% of the general population and in 40% of cryptogenic ischemic stroke patients. Recent trials support PFO closure in selected patients with cryptogenic stroke. We examined the outcomes of transcatheter PFO closure in a real-world study cohort with cryptogenic stroke. METHODS: Consecutive ischemic stroke patients who were classified as cryptogenic on the TOAST aetiology and diagnosed with a PFO were included. All patients underwent either transcatheter PFO closure or medical therapy. A 2:1 propensity score matching by sex and Risk-of-Paradoxical-Embolism (RoPE) score was performed. Multivariable regression models adjusted for sex and RoPE score. RESULTS: Our cohort comprised 232 patients with mean age 44.3 years (SD 10.8) and median follow-up 1486.5 days. 33.2% were female. PFO closure (n=84) and medical therapy (n=148) groups were well-matched with <10% mean-difference in sex and RoPE score. Two patients in the treated group (2.4%) and seven in the control group (4.7%) had a recurrent ischemic stroke event. Multivariable Cox regression demonstrated a hazard-ratio of 0.26 (95%CI 0.03-2.13, P=0.21) for PFO closure compared to control. The incidence of atrial fibrillation (AF) detected post-PFO closure was similar between the treated and control (1.19% vs 1.35%, multivariable logistic regression odds-ratio 0.90, 95%CI 0.04-9.81, P=0.94). There were no major periprocedural complications documented. The difference in restricted mean survival-time free from stroke at two years between treated and control was 26.2 days (95%CI 5.52-46.85, P=0.013). CONCLUSIONS: In this Asian cohort, we report a low incidence of ischemic stroke recurrence and new-onset AF in patients who underwent PFO closure. When compared to the medical therapy group, there was no significant difference in the incidence of stroke recurrence and new-onset AF. Further studies involving larger real-world cohorts are warranted to identify patients who are more likely to benefit from PFO closure.

Photochromic Coordination Compound: Oxygen-Assisted Photoinduced Color Change for Triplet Oxygen Detection.

Detection of oxygen though color change is highly desirable for rapid qualitative analysis like the case of pH test papers. This work demonstrates 3O2-assisted photoinduced color change of a new photochromic coordination compound [Zn(4-aminopyridine)2Cl2] (ZnaPyCl), which represents the first photochromic compound with a selective 3O2 detection ability. The compound underwent photoinduced intraligand charge separation and formed a stable diradical-like triplet species in the solid state or in frozen solution, accompanied by conversion of triplet oxygen to singlet oxygen.

Clinical predictors for nondiabetic kidney diseases in patients with type 2 diabetes mellitus: a retrospective study from 2017 to 2021.

BACKGROUND: Nondiabetic kidney disease (NDKD), which is prevalent among patients with diabetes mellitus (DM), is considerably different from diabetic kidney disease (DKD) in terms of the pathological features, treatment strategy and prognosis. Although renal biopsy is the current gold-standard diagnostic method, it cannot be routinely performed due to a range of risks. The aim of this study was to explore the predictors for differentiating NDKD from DKD to meet the urgent medical needs of patients who cannot afford kidney biopsy. METHODS: This is a retrospective study conducted by reviewing the medical records of patients with type 2 DM who underwent percutaneous renal biopsy at the Affiliated Hospital of Guizhou Medical University between January 2017 and May 2021. The demographic data, clinical data, blood test results, and pathological examination results of the patients were obtained from their medical records. Multivariate regression analysis was performed to evaluate the predictive factors for NDKD. RESULTS: A total of 244 patients were analyzed. The median age at biopsy was 55 (46, 62) years. Patients diagnosed with true DKD, those diagnosed with NDKD and those diagnosed with NDKD superimposed DKD represented 48.36% (118/244), 45.9% (112/244) and 5.74% (14/244), respectively, of the patient population. Immunoglobulin A nephropathy was the most common type of lesion in those with NDKD (59, 52.68%) and NDKD superimposed DKD (10, 71.43%). Independent predictive indicators for diagnosing NDKD included a DM duration of less than 5 years (odds ratio [OR] = 4.476; 95% confidence interval [CI]: 2.257-8.877; P < 0.001), an absence of diabetic retinopathy (OR = 4.174; 95% CI: 2.049-8.502; P < 0.001), a high RBC count (OR = 1.901; 95% CI: 1.251-2.889; P = 0.003), and a negative of urinary glucose excretion test result (OR = 2.985; 95% CI: 1.474-6.044; P = 0.002).. CONCLUSIONS: A DM duration less than 5 years, an absence of retinopathy, a high RBC count and an absence of urinary glucose excretion were independent indicators for the diagnosis of NDKD, suggesting that patients with NDKD may require a different treatment regimen than those with DKD.

Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants.

To explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared them with wild type complex (RBDWT-ACE2) in terms of various structural dynamic properties by molecular dynamics (MD) simulations and binding free energy (BFE) calculations. The results of MD simulations suggest that the RBDs of all the Omicron subvariants (RBDOMIs) feature increased global structural fluctuations when compared with RBDWT. Detailed comparison of BFE components reveals that the enhanced electrostatic attractive interactions are the main determinant of the higher ACE2-binding affinity of RBDOMIs than RBDWT, while the weakened electrostatic attractive interactions determine RBD of BA.4/5 subvariant (RBDBA.4/5) lowest ACE2-binding affinity among all Omicron subvariants. The per-residue BFE decompositions and the hydrogen bond (HB) networks analyses indicate that the enhanced electrostatic attractive interactions are mainly through gain/loss of the positively/negatively charged residues, and the formation or destruction of the interfacial HBs and salt bridges can also largely affect the ACE2-binding affinity of RBD. It is worth pointing out that since Q493R plays the most important positive contribution in enhancing binding affinity, the absence of this mutation in RBDBA.4/5 results in a significantly weaker binding affinity to ACE2 than other Omicron subvariants. Our results provide insight into the role of electrostatic interactions in determining of the binding affinity of SARS-CoV-2 RBD to human ACE2.

[Mechanism of Liangfu Pills in treatment of functional dyspepsia: based on network pharmacology and experimental verification].

This study aims to explore the potential mechanism of Liangfu Pills in the treatment of functional dyspepsia(FD) based on network pharmacology and molecular docking, and verify the mechanism by animal experiment. The active components of Liangfu Pills were screened from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and the targets of Liangfu Pills were predicted by SwissTargetPrediction. The targets of FD were retrieved from GeneCards. On this basis, the common targets of the disease and the pills were yielded and the protein interaction was retrieved based on STRING. The core targets were screened out, followed by Gene Oncology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis with DAVID. Finally, molecular docking was carried out with the help of AutoDock Tools to predict the binding degree between the effective components of Liangfu Pills and core targets. A total of 19 active components of Liangfu Pills and 591 FD-related targets were screened out by network pharmacology, of which 253 were common targets of the disease and the prescription. Liangfu Pills was mainly involved in the biological processes of response to drug, negative regulation of transcription, positive regulation of apoptotic process, and cell surface receptor signaling pathway, and the KEGG pathways of hypoxia-inducible factor-1(HIF-1) signaling pathway, serotonergic synapse, tumor necrosis factor(TNF) signaling pathway, cyclic adenosine monophosphate(cAMP) signaling pathway, calcium signal pathway, and inflammatory mediator regulation of transient receptor potential(TRP) channels. The results of molecular docking showed that the key active components of Liangfu Pills had certain binding activity to the targets mitogen-activated protein kinase 1(MAPK1), protein kinase B(AKT1), transient receptor potential cation channel subfamily V member 1(TRPV1), 5-hydroxytryptamine receptor 1 A(HTR1 A), and 5-hydroxytryptamine receptor 2 A(HTR2 A). FD was induced in rats, and then Liangfu Pills was given to FD rats for 7 days. The results showed that Liangfu Pills could significantly relieve the symptoms of FD rats, significantly increase the expression of 5-hydroxytryptamine(5-HT), and down-regulate the expression of TRPV1. Through network pharmacology, molecular docking, and experimental verification, this study proved that Liangfu Pills improved FD through multiple components and multiple targets. The result lays a basis for further research on the mechanism and clinical application of Liangfu Pills in the treatment of FD.

[Mortality and cause of death of hospitalized neonates in Weifang, China: a multicenter study]. / æ½åŠå¸‚ä½é™¢æ–°ç”Ÿå„¿ç— æ­»çŽ‡åŠæ­»äº¡åŽŸå› çš„å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To study the changes in the mortality rate and cause of death of hospitalized neonates in grade A tertiary hospitals in Weifang City of Shandong Province during a 10-year period. METHODS: A retrospective analysis was performed on 461 neonates who died in three grade A tertiary hospitals in Weifang City of Shandong Province from January 1, 2012 to December 31, 2021. The related clinical data were collected to examine the changes of neonatal mortality with time, gestational age (GA) and birth weight (BW). The main causes of death of the neonates were compared between the first 5 years (2012-2016) and the last 5 years (2017-2021) in the period. RESULTS: A total of 43 037 neonates were admitted from 2012 to 2021, among whom 461 died, resulting in a mortality rate of 1.07%. The mortality rate in the last 5 years was significantly lower than that in the first 5 years [0.96% (211/22 059 vs 1.19% (250/20 978); P<0.05]. The mortality rate of neonates decreased with the increases in GA and BW (P<0.05). In the first 5 years, the top three main causes of neonatal death were respiratory distress syndrome (RDS), sepsis, and pneumorrhagia, while in the last 5 years, the top three causes were sepsis, pneumorrhagia, and RDS. The leading cause of death was severe asphyxia for the neonates with a GA of <26 weeks and a BW of <750 g in both the first and last 5 years. For the neonates with a GA of 26-<28 weeks, the leading cause of death changed from RDS in the first 5 years to pneumorrhagia in the last 5 years. For the neonates with a BW of 750-<1 000 g, the leading cause of death changed from pneumorrhagia in the first 5 years to RDS in the last 5 years. For the neonates with a GA of 28-<32 weeks and a BW of 1 000-<1 500 g, the leading cause of death was RDS in both the first and last 5 years. For the neonates with a GA of 32-<37 weeks and a BW of 1 500-<2 500 g, the leading cause of death changed from RDS in the first 5 years to sepsis in the last 5 years. The leading cause of death was sepsis for the neonates with a GA of 37-<42 weeks and a BW of 2 500-<4 000 g in both the first and last 5 years. CONCLUSIONS: The mortality rate of neonates in the grade A tertiary hospitals in Weifang City of Shandong Province has been decreasing in the past 10 years, and it decreases with the increases in GA and BW. Sepsis, RDS, and pneumorrhagia are the leading causes of neonatal death. The mortality rate caused by RDS decreases from the first 5 years to the last 5 years, while the mortality rate caused by sepsis or pneumorrhagia increases from the first 5 years to the last 5 years. Therefore, reducing the incidence rates of sepsis, RDS, and pneumorrhagia is the key to reducing neonatal mortality.

Sulfitobacter maritimus sp. nov., isolated from coastal sediment.

A facultatively anaerobic bacterium, strain S0837T, was isolated from the marine sediment of Jingzi Wharf, Weihai, China. Cells of the novel strain were Gram-stain-negative, non-flagellated, non-gliding, non-pigmented and rod-shaped. Cells were around 0.3-0.5×1.0-1.4 µm in size and often appeared singly. Optimum growth occurred at 33 °C, with 2 % (w/v) NaCl and at pH 7.0-7.5. On the basis of the results of 16S rRNA gene sequences, stain S0837T had the closest relative with Sulfitobacter delicatus KCTC 32183T (98.0 %). Genome sequencing revealed a genome size of 3 785 026 bp, a G+C content of 59.8 mol% and several genes related with sulphur oxidation. The strain shared 98.0 % 16S rRNA sequence similarities with closely related type species and shared ANI value below 95-96 %, dDDH value of showed relatedness of 27.4, 25.2 and 25.2 % respectively with the closely related type species. Strain S0837T had ubiquinone-10 as the sole respiratory quinone, and possessed summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c) as the major fatty acid. The major polar lipids were phosphatidylglycerol, phosphatidylcholine and phosphatidylethanolamine. According to the results of the phenotypic, chemotaxonomic characterization, phylogenetic properties and genome analysis, strain S0837T should represent a novel species of the genus Sulfitobacter, for which the name Sulfitobacter maritimus sp. nov. is proposed. The type strain is S0837T (=MCCC 1K04635T=KCTC 72860T).

Association between heart rate variability indices and features of spontaneous ventricular tachyarrhythmias in mice.

Direct evidence is limited for the association between heart rate variability (HRV) indices and ventricular tachyarrhythmias (VTAs). While galectin-3 (Gal-3) is regarded as a causal factor for cardiac remodelling and a biomarker for arrhythmias, its regulation on VTAs and HVR is unknown. Using aged transgenic (TG) mice with cardiac overexpression of ß2 -adrenoceptors and spontaneous VTAs, we studied whether changes in HRV indices correlated with the severity of VTAs, and whether Gal-3 gene knockout (KO) in TG mice might limit VTA. Body-surface ECG was recorded (10-minute period) in 9- to 10-month-old mice of non-transgenic (nTG), TG and TG × Gal-3 knockout (TG/KO). Time-domain, frequency-domain and nonlinear-domain HRV indices were calculated using the R-R intervals extracted from ECG signals and compared with frequency of VTAs. TG and TG/KO mice developed frequent VTAs and showed significant changes in certain time-domain and nonlinear-domain HRV indices relative to nTG mice. The severity of VTAs in TG and TG/KO mice in combination, estimated by VTA counts and arrhythmia score, was significantly correlated with certain time-domain and nonlinear-domain HRV indices. In conclusion, significant changes in HRV indices were evident and correlated with the severity of spontaneous VTAs in TG mice. The frequency of VTA and HRV indices were largely comparable between TG and TG/KO mice. Deletion of Gal-3 in TG mice altered certain HRV indices implying influence by neuronally localized Gal-3 on autonomic nervous activity.

Role of Exosomes in Cancer-Related Cognitive Impairment.

A decline in cognitive function following cancer treatment is one of the most commonly reported post-treatment symptoms among patients with cancer and those in remission, and include memory, processing speed, and executive function. A clear understanding of cognitive impairment as a result of cancer and its therapy can be obtained by delineating structural and functional changes using brain imaging studies and neurocognitive assessments. There is also a need to determine the underlying mechanisms and pathways that impact the brain and affect cognitive functioning in cancer survivors. Exosomes are small cell-derived vesicles formed by the inward budding of multivesicular bodies, and are released into the extracellular environment via an exocytic pathway. Growing evidence suggests that exosomes contribute to various physiological and pathological conditions, including neurological processes such as synaptic plasticity, neuronal stress response, cell-to-cell communication, and neurogenesis. In this review, we summarize the relationship between exosomes and cancer-related cognitive impairment. Unraveling exosomes' actions and effects on the microenvironment of the brain, which impacts cognitive functioning, is critical for the development of exosome-based therapeutics for cancer-related cognitive impairment.

Organocatalytic Asymmetric α-Sulfenylation of 2-Substituted Indolin-3-ones: A Strategy for the Synthesis of Chiral 2,2-Disubstituted Indole-3-ones with S- and N-Containing Heteroquaternary Carbon Stereocenter.

An organocatalytic asymmetric α-sulfenylation of 2-substituted indolin-3-ones with N-(alkylthio or arylthio)succinimides has been developed for the first time using Cinchona-derived squaramide as the catalyst. Various chiral 2,2-disubstituted indole-3-ones with S- and N-containing heteroquaternary carbon stereocenters were obtained with up to 98% yield and 99% ee.

Suppressing microRNA-29c promotes biliary atresia-related fibrosis by targeting DNMT3A and DNMT3B.

This study was designed to investigate the potential role of microRNA-29c (miR-29c) in biliary atresia-related fibrosis. The expression of miR-29c was determined in 15 pairs of peripheral blood samples from infants with biliary atresia (BA) and infants with non-BA neonatal cholestasis using quantitative real-time PCR. EMT was established by induction with TGF-ß1 in HIBEpiC cells. MiR-29c was inhibited by lipofectamine transfection. The expressions of proteins related to epithelial-mesenchymal transition (EMT), i.e., E-cadherin, N-cadherin and vimentin, were determined using quantitative real-time PCR and western blotting. Direct interaction between miR-29c and DNMT3A and DNMT3B was identified using a luciferase reporter assay. The expressions of DNMT3A and DNMT3B were suppressed by treatment with SGI-1027. Patients with BA showed significantly lower miR-29c levels in peripheral blood samples than the control subjects. In vitro, TGF-ß1-induced EMT significantly decreased the expression of miR-29c. Downregulation of miR-29c had a promotional effect on BA-related fibrosis in HIBEpiC cells, as confirmed by the decrease in E-cadherin and increase in N-cadherin and vimentin levels. MiR-29c was found to target the 3'UTR of DNMT3A and DNMT3B and inhibit their expression. Suppression of DNMT3A and DNMT3B reversed the effects of miR-29c downregulation on BA-related fibrosis in HIBEpiC cells. These data suggest that BA-related fibrosis is closely associated with the occurrence of EMT in HIBEpiC cells. MiR-29c might be a candidate for alleviating BA-related fibrosis by targeting DNMT3A and DNMT3B.

Resistin Regulates Fatty Acid Β Oxidation by Suppressing Expression of Peroxisome Proliferator Activator Receptor Gamma-Coactivator 1α (PGC-1α).

BACKGROUND/AIMS: Abnormal fatty acid ß oxidation has been associated with obesity and type 2 diabetes. Resistin is an adipokine that has been considered as a potential factor in obesity-mediated insulin resistance and type 2 diabetes. However, the effect of resistin on fatty acid ß oxidation needs to be elucidated. METHODS: We detected the effects of resistin on the expression of fatty acid oxidation (FAO) transcriptional regulatory genes, the fatty acid transport gene, and mitochondrial ß-oxidation genes using real-time PCR. The rate of FAO was measured using 14C-palmitate. Immunofluorescence assay and western blot analysis were used to explore the underlying molecular mechanisms. RESULTS: Resistin leads to a reduction in expression of the FAO transcriptional regulatory genes ERRα and NOR1, the fatty acid transport gene CD36, and the mitochondrial ß-oxidation genes CPT1, MCAD, and ACO. Importantly, treatment with resistin led to a reduction in the rate of cellular fatty acid oxidation. In addition, treatment with resistin reduced phosphorylation of acetyl CoA carboxylase (ACC) (inhibitory). Mechanistically, resistin inhibited the activation of CREB, resulting in suppression of PGC-1α. Importantly, overexpressing PGC-1α can rescue the inhibitory effects of resistin on fatty acid ß oxidation. CONCLUSIONS: Activating the transcriptional activity of CREB using small molecular chemicals is a potential pharmacological strategy for preventing the inhibitory effects of resistin on fatty acid ß oxidation.

FeS2 /CoS2 Interface Nanosheets as Efficient Bifunctional Electrocatalyst for Overall Water Splitting.

Electrochemical water splitting to produce hydrogen and oxygen, as an important reaction for renewable energy storage, needs highly efficient and stable catalysts. Herein, FeS2 /CoS2 interface nanosheets (NSs) as efficient bifunctional electrocatalysts for overall water splitting are reported. The thickness and interface disordered structure with rich defects of FeS2 /CoS2 NSs are confirmed by atomic force microscopy and high-resolution transmission electron microscopy. Furthermore, extended X-ray absorption fine structure spectroscopy clarifies that FeS2 /CoS2 NSs with sulfur vacancies, which can further increase electrocatalytic performance. Benefiting from the interface nanosheets' structure with abundant defects, the FeS2 /CoS2 NSs show remarkable hydrogen evolution reaction (HER) performance with a low overpotential of 78.2 mV at 10 mA cm-2 and a superior stability for 80 h in 1.0 m KOH, and an overpotential of 302 mV at 100 mA cm-2 for the oxygen evolution reaction (OER). More importantly, the FeS2 /CoS2 NSs display excellent performance for overall water splitting with a voltage of 1.47 V to achieve current density of 10 mA cm-2 and maintain the activity for at least 21 h. The present work highlights the importance of engineering interface nanosheets with rich defects based on transition metal dichalcogenides for boosting the HER and OER performance.

Lefty promotes the proliferation and invasion of trophoblast cells by inhibiting nodal expression.

Trophoblast cells play a vital role in embryo implantation. Exploring cytokines secreted by trophoblast cells will be significant in revealing the molecular mechanism of embryo implantation. In vitro-cultured trophoblast cells treated with Lefty revealed that Lefty could downregulate the expression of Nodal while promoting the expression of MMP-2 and MMP-9. Thus, Lefty may promote the proliferation and invasion of trophoblast cells, thereby reducing the amount of apoptosis of these cells. Lefty siRNA knockdown or overexpression of Nodal showed opposite effects to treatment with Lefty. When trophoblast cells overexpressing Nodal were treated with Lefty, Nodal expression increased, and MMP-2 and MMP-9 expression was still promoted. Additionally, the proliferation and invasion of trophoblast cells were upregulated, and trophoblast apoptosis was reduced. Together, these data reveal that Lefty can promote the proliferation and invasion of trophoblast cells and inhibit their apoptosis by downregulating Nodal expression while promoting the expression of MMP-2 and MMP-9. This finding provides new proof for the mechanism of trophoblast cell invasion in decidua.

Proteome profiling of exosomes derived from plasma of heifers with divergent genetic merit for fertility.

The current study evaluated exosomes isolated from plasma of heifers bred to have high or low fertility through developing extreme diversity in fertility breeding values, however, key animal traits (e.g., body weight, milk production, and percentage of North American genetics) remained similar between the 2 groups. The exosomes were isolated by a combined ultracentrifugation and size exclusion chromatography approach and characterized by their size distribution (nanoparticle tracking analysis), morphology (transmission electron microscopy), and presence of exosomal markers (immunoblotting). In addition, a targeted mass spectrometry approach was used to confirm the presence of 2 exosomal markers, tumor susceptibility gene 101 and flotillin 1. The number of exosomes from plasma of high fertility heifers was greater compared with low fertility heifers. Interestingly, the exosomal proteomic profile, evaluated using mass spectrometry, identified 89 and 116 proteins in the high and low fertility heifers respectively, of which 4 and 31 were unique, respectively. These include proteins associated with specific biological processes and molecular functions of fertility. Most notably, the tetratricopeptide repeat protein 41-related, glycodelin, and kelch-like protein 8 were identified in plasma exosomes unique to the low fertility heifers. These proteins are suggested to play a role in reproduction; however, the role of these proteins in dairy cow reproduction remains to be elucidated. Their identification underscores the potential for proteins within exosomes to provide information on the fertility status and physiological condition of the cow. This may potentially lead to the development of prognostic tools and interventions to improving dairy cow fertility.