Structure of a mammalian sperm cation channel complex.

The cation channel of sperm (CatSper) is essential for sperm motility and fertility1,2. CatSper comprises the pore-forming proteins CATSPER1-4 and multiple auxiliary subunits, including CATSPERß, γ, δ, ε, ζ, and EFCAB91,3-9. Here we report the cryo-electron microscopy (cryo-EM) structure of the CatSper complex isolated from mouse sperm. In the extracellular view, CATSPER1-4 conform to the conventional domain-swapped voltage-gated ion channel fold10, following a counterclockwise arrangement. The auxiliary subunits CATSPERß, γ, δ and ε-each of which contains a single transmembrane segment and a large extracellular domain-constitute a pavilion-like structure that stabilizes the entire complex through interactions with CATSPER4, 1, 3 and 2, respectively. Our EM map reveals several previously uncharacterized components, exemplified by the organic anion transporter SLCO6C1. We name this channel-transporter ultracomplex the CatSpermasome. The assembly and organization details of the CatSpermasome presented here lay the foundation for the development of CatSpermasome-related treatments for male infertility and non-hormonal contraceptives.

CatLearning: highly accurate gene expression prediction from histone mark.

Histone modifications, known as histone marks, are pivotal in regulating gene expression within cells. The vast array of potential combinations of histone marks presents a considerable challenge in decoding the regulatory mechanisms solely through biological experimental approaches. To overcome this challenge, we have developed a method called CatLearning. It utilizes a modified convolutional neural network architecture with a specialized adaptation Residual Network to quantitatively interpret histone marks and predict gene expression. This architecture integrates long-range histone information up to 500Kb and learns chromatin interaction features without 3D information. By using only one histone mark, CatLearning achieves a high level of accuracy. Furthermore, CatLearning predicts gene expression by simulating changes in histone modifications at enhancers and throughout the genome. These findings help comprehend the architecture of histone marks and develop diagnostic and therapeutic targets for diseases with epigenetic changes.

Magnetically Enhanced Oxygen Evolution Reaction in Mild Alkaline Electrolytes by Building Catalysts on Magnetic Frame.

Under large current densities, the excessive hydroxide ion (OH) consumption hampers alkaline water splitting involving the oxygen evolution reaction (OER). High OH concentration (≈30 wt.%) is often used to enhance the catalytic activity of OER, but it also leads to higher corrosion in practical systems. To achieve higher catalytic activity in low OH concentration, catalysts on magnetic frame (CMF) are built to utilize the local magnetic convection induced from the host frame's magnetic field distributions. This way, a higher reaction rate can be achieved in relatively lower OH concentrations. A CMF model system with catalytically active CoFeOx nanograins grown on the magnetic Ni foam is demonstrated. The OER current of CoFeOx@NF receives ≈90% enhancement under 400 mT (900 mA cm-2 at 1.65 V) compared to that in zero field, and exhibits remarkable durability over 120 h. As a demonstration, the water-splitting performance sees a maximum 45% magnetic enhancement under 400 mT in 1 m KOH (700 mA cm-2 at 2.4 V), equivalent to the concentration enhancement of the same electrode in a more corrosive 2 m KOH electrolyte. Therefore, the catalyst-on-magnetic-frame strategy can make efficient use of the catalysts and achieve higher catalytic activity in low OH concentration by harvesting local magnetic convection.

Protective Effects of Statins on Limb and Cardiovascular Outcomes in Patients with Peripheral Artery Disease and End-Stage Renal Disease.

Background: Previous studies have reported that statins have inconsistent and marginal cardiovascular (CV) benefits in patients with end-stage renal disease (ESRD). However, whether statins play a secondary preventive role in patients with peripheral artery disease (PAD) and ESRD remains unclear. Objectives: This study aimed to compare the long-term clinical outcomes between statin users and nonusers with PAD and ESRD. Methods: This retrospective cohort study assessed the long-term protective effects of statins using data from the National Health Insurance Research Database in Taiwan. Propensity score matching was performed according to sex, age, index year, related comorbidities, and medications. The main outcomes were limb events and major adverse CV events (MACEs). Results: The statin user group (n = 4,460) was compared with the propensity score-matched statin nonuser group (n = 4,460). The mean age of the matched patients was 64 years, and 40% of the patients were men. The baseline characteristics of the groups were well-balanced. The overall limb event and MACE rates were not different between the two groups. However, the statin user group had lower rates of limb amputation [adjusted hazard ratio (aHR): 0.85, 95% confidence interval (CI): 0.73-0.99], stroke (aHR: 0.71, 95% CI: 0.62-0.83), CV death (aHR: 0.46, 95% CI: 0.32-0.66), and all-cause death (aHR: 0.45, 95% CI: 0.42-0.48) despite having a higher rate of percutaneous transluminal angioplasty for PAD. Conclusions: This population-based retrospective cohort study demonstrated that statin therapy was associated with a lower risk of limb amputation, nonfatal stroke, CV death, and all-cause death in patients with PAD and ESRD.

Electronic Regulation of ZnCo Dual-Atomic Active Sites Entrapped in 1D@2D Hierarchical N-Doped Carbon for Efficient Synergistic Catalysis of Oxygen Reduction in Zn-Air Battery.

Transition metal-based nitrogen-doped carbon (M-Nx -C) is considered as a promising catalyst for the oxygen reduction reaction (ORR) in clean energy storage and conversion devices. Herein, ZnCo dual-atomic sites are incorporated in hierarchical N-doped carbon (HNC), with 1D nanotubes wrapped in 2D nanosheets structure (termed as 1D@2D ZnCo-HNC), via a one-step bio-inspired pyrolysis. The feeding ratio of Zn to Co precursor and pyrolytic temperature are critically modulated to achieve well-defined morphologies of the products, endowing them with the integrated merits of nanotubes and nanosheets as efficient ORR catalysts. Benefiting from the particular structure and electronic regulation of Zn on Co, the ZnCo-Nx dual-atomic system exhibits excellent ORR catalytic characteristics with an onset potential of 1.05 V and a half-wave potential of 0.82 V. Density functional theory calculations further explain the regulating role of Zn, such that the adjusted Co in ZnCo-Nx sites significantly reduces the energy cost to ultimately facilitate the ORR. Moreover, the Zn-air battery assembled with ZnCo-HNC is capable of delivering the maximum power density of 123.7 mW cm-2 and robust stability for 110 h (330 cycles). This method provides a promising strategy for fabricating efficient transition metal-based carbon catalysts for green energy devices.

A novel missense mutation of LRP6 identified by whole-exome sequencing in a Chinese family with non-syndromic tooth agenesis.

OBJECTIVE: The aim of this study was to explore the genetic basis of non-syndromic tooth agenesis (TA) in a Chinese family of five individuals using whole-exome sequencing (WES) analysis. SETTINGS AND SAMPLE POPULATION: Five participants/Family-based study of a non-syndromic TA proband. METHODS: The proband, proband's mother and grandmother displayed congenital tooth deficiency. Genomic DNA was extracted from the peripheral blood or saliva samples of the proband, her parents and her grandmother, and WES was utilized to identify the causal genetic mutation. The identified mutation was further verified by Sanger sequencing and analysed using bioinformatics tools. RESULTS: A novel missense mutation, c.G711T (p.L237F), was identified in the low-density lipoprotein receptor-related protein 6 (LRP6) gene in all affected individuals. Bioinformatics analysis predicted the mutation to be deleterious, with the mutant LRP6 protein displaying a tertiary structural change that might disturb the Wnt/ß-catenin signalling pathway. CONCLUSIONS: The identification of the mutation in the LRP6 gene and autosomal dominant inheritance with TA in the generations is consistent with the mutation being responsible for TA in the family, and furthers the association of LRP6 with nonsyndromic TA.

Constituents from the Seeds of Sophora Alopecuroides L.

Three new isoflavone glucosides, kudonol A-C (1-3), two new ester derivatives of phenylpropanoid, kudolignan A and B (4-5) and five known compounds, (-)-maackiain (6), neoliquiritin (7), methyl 4-coumarate (8), methyl ferulate (9) and (+)-wikstromol (10), were isolated from an extract of dried seeds of the traditional Chinese medicinal plant Sophora alopecuroides L. Their structures were established by NMR and HRESIMS data analyses. The monosaccharide part's configuration of isoflavone glucosides was confirmed by acid hydrolysis and analyzed by a JAsco OR-4090 chiral detector, comparing it to standard substance D-glucose. The cytotoxicity effects against HeLa, Hep3B, MCF-7 and H1299 cells were tested by CCK-8 assay.

Rigorous modelling of second harmonic generation imaging through stratified media focused by radially polarized beams.

For second harmonic generation (SHG) imaging, the specimen is often observed through an immersion medium and a cover glass whose refractive indices are usually different from that of the specimen. However, the currently used theoretical models are based on the assumption that the specimen is situated in a homogeneous medium. The limitation of these models is that they ignore the effects of the refractive index mismatches and the imaging depth. In this paper, we have demonstrated, for the first time to our knowledge, a rigorous model of SHG imaging through stratified media focused by radially polarized beams. Based on the proposed model, the detected SHG intensity patterns excited in a refractive index perfectly matched, aberration-free medium and in mismatched stratified media are compared. The effects of the imaging depth and effective numerical aperture (NA) on the performance of SHG imaging with oil immersion objectives are investigated by the stratified media model. It is found that the full width at half maximum (FWHM) in the axial direction at imaging depth of 80 µm is ~3.1 times as large as that of 10 µm imaging depth. While for the transverse FWHM, the increment is only about 23%. The quality of the SHG intensity distribution can be increased by reducing the NA appropriately at the expense of the detected signal strength. The proposed model is helpful to provide guidelines for the adaptive aberration correction in SHG imaging and can be used to optimize the experimental configuration.

Levodopa alone compared with levodopa-sparing therapy as initial treatment for Parkinson's disease: a meta-analysis.

To assess the long-term use of L-dopa alone vs L-dopa-sparing therapy, as initial treatment, provides the most efficient long-term control of symptoms and best quality of life for people with early Parkinson's disease (PD). PubMed; Google scholar; Cochrane Central Register of Controlled Trials and the Web of Science were searched for randomised, placebo-controlled trials (RCTs) on L-dopa alone and L-dopa sparing as initial treatment in early PD patients. We used a random effects model rather than a fixed effects model because of this takes into account heterogeneity between multi-studies. Eleven RCTs were included. The results showed that L-dopa alone could evidently improve the UPDRS part I (p = 0.005), part II (p < 0.0001), part III (p < 0.0001) and UPDRS total score (p = 0.004) compared with L-dopa-sparing therapy in PD patients. Meanwhile, a reduced risk of dyskinesia (p < 0.0001, RR = 1.88, 95 % CI 1. 37-2.59) and wearing-off phenomenon (p < 0.00001, RR = 1.36, 95 % CI 1. 20-1.55) in patients treated initially with L-dopa-sparing therapy compared to L-dopa has been consistently reported. What is more, we found more patients on aL-dopa-sparing therapy were more than triple as likely to discontinue treatment prematurely due to adverse events than L-dopa treatment patients (43.7 vs 15.8 %). L-Dopa alone is the most effective medication available for treating the motor symptoms of PD patients, despite the greater incidence of involuntary movements. Meanwhile, more patients on dopamine agonists or MAOBI were more likely to discontinue treatment prematurely than L-dopa alone treatment patients within the long follow-up period.

Repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression in Parkinson disease: a meta-analysis of randomized controlled clinical trials.

The objective of this meta-analysis was to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression in patients with Parkinson disease in order to arrive at qualitative and quantitative conclusions about the efficacy of rTMS. We included randomized controlled trials examining the effects of rTMS compared with sham-rTMS or selective serotonin re-uptake inhibitors (SSRIs). The quality of included studies was strictly evaluated. Data analyses were performed using the RevMan5.1 software. Eight studies including 312 patients met all inclusion criteria. The results showed that rTMS could evidently improve the HRSD score compared with sham-rTMS (p < 0.00001). However, we found similar antidepressant efficacy between rTMS and SSRIs groups in terms of HRSD and BDI score (p = 0.65; p = 0.75, respectively). Furthermore, patients who received rTMS could evidently show improvement on the unified Parkinson's disease rating scale (UPDRS), ADL score, and UPDRS motor score compared with sham-rTMS or SSRIs (p < 0.05, p = 0.05, respectively). The subgroup analysis by frequency of rTMS evidenced that the efficacy of low-frequency rTMS was superior to sham-rTMS (p < 0.0001) in terms of the outcome measure according to HAMD scale. Meanwhile, the high-frequency rTMS has the same antidepressant efficacy as SSRIs (p = 0.94). The current meta-analysis provided evidence that rTMS was superior to sham-rTMS and had similar antidepressant efficacy as SSRIs, and may have the additional advantage of some improvement in motor function.

Bio-derived FeNi alloy confined in N-doped carbon nanosheets as efficient air electrodes for Zn-air battery.

It is imperative to design and manufacture electrocatalysts towards oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) for popularization of rechargeable Zn-air batteries. Herein, FeNi alloy confined in N-doped carbon nanosheets (FeNi@NCSs) was harvested via a facile complexation-pyrolysis strategy from the mixture of guanine and metal chlorides. After strictly exploring the pyrolysis temperature and metal types, the resulted FeNi@NCSs showed greatly improved performances on both the ORR (onset potential of 0.93 V and half-wave potential of 0.84 V) and OER (overpotential of 318 mV at 10 mA cm-2 and 379 mV at 100 mA cm-2). Further, the FeNi@NCSs based Zn-air battery exhibited a higher open circuit voltage (1.496 V), a larger power density (128.8 mW cm-2), and prominent durability (360 cycles, 120 h). This study provides an appealing approach to utilize biomass for synthesis of low-cost and high-efficiency electrocatalysts in energy associated systems.

Coordination regulated pyrolysis synthesis of ultrafine FeNi/(FeNi)9S8 nanoclusters/nitrogen, sulfur-codoped graphitic carbon nanosheets as efficient bifunctional oxygen electrocatalysts.

Design of advanced carbon nanomaterials with high-efficiency oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) activities is still imperative yet challenging for searching green and renewable energies. Herein, we synthesized ultrafine FeNi/(FeNi)9S8 nanoclusters encapsulated in nitrogen, sulfur-codoped graphitic carbon nanosheets (FeNi/(FeNi)9S8/N,S-CNS) by coordination regulated pyrolyzing the mixture of the metal precursors, dithizone and g-C3N4 at 800 °C. The as-prepared FeNi/(FeNi)9S8/N,S-CNS exhibited distinct electrocatalytic activity and stability for the ORR with positive onset (Eonset) and half-wave (E1/2) potentials (Eonset = 0.97 V; E1/2 = 0.86 V) and OER with the small overpotential (η = 283 mV) at 10 mA cm-2 in the alkaline media, outperforming commercial Pt/C and RuO2 catalysts. This research provides some constructive guidelines for preparing efficient, low-cost and stable nanocatalysts for electrochemical energy devices.

FeCo/FeCoP encapsulated in N, Mn-codoped three-dimensional fluffy porous carbon nanostructures as highly efficient bifunctional electrocatalyst with multi-components synergistic catalysis for ultra-stable rechargeable Zn-air batteries.

Currently, it is critical but a tricky point to develop economical, high-efficiency, and durable non-precious metal electrocatalysts towards oxygen reduction and oxygen evolution reaction (ORR/OER) in rechargeable Zn-air batteries. Herein, N, Mn-codoped three-dimensional (3D) fluffy porous carbon nanostructures encapsulating FeCo/FeCoP alloyed nanoparticles (FeCo/FeCoP@NMn-CNS) are prepared by one-step pyrolysis of the metal precursors and polyinosinic acid. The optimized hybrid nanocomposite (obtained at 800 °C, named as FeCo/FeCoP@NMn-CNS-800) exhibits outstanding catalytic performance in the alkaline electrolyte with a half-wave potential (E1/2) of 0.84 V for the ORR and an overpotential of 325 mV towards the OER at 10 mA cm-2. Impressively, the FeCo/FeCoP@NMn-CNS-800-assembled rechargeable Zn-air battery presents an open-circuit voltage of 1.522 V (vs. RHE), a peak power density of 135.0 mW cm-2, and long-term durability by charge-discharge cycling for 200 h, surpassing commercial Pt/C + RuO2 based counterpart. This work affords valuable guidelines for exploring advanced bifunctional ORR and OER catalysts in rational construction of high-quality Zn-air batteries.

Omentin-1: Protective impact on ischemic stroke via ameliorating atherosclerosis.

Omentin-1, a newly identified adipokine, has recently been revealed as a novel biomarker for ischemic stroke (IS). Low circulating omentin-1 levels could indicate a high risk of IS, and elevated omentin-1 levels exert a favorable impact on cerebral ischemia. Furthermore, omentin-1 has anti-atherosclerotic, anti-inflammatory, and cardiovascular protective capabilities through the intracellular Akt/AMP-activated protein kinase (AMPK)/ nuclear factor-κB (NF-κB) and certain protein kinase (ERK, JNK, and p38) signaling pathways. Omentin-1 also alleviates endothelial cell dysfunction, improves revascularization via the Akt-endothelial nitric-oxide synthase (eNOS) regulatory axis, promotes endothelium-dependent vasodilation through endothelium-derived NO in an eNOS fashion, and inhibits VSMC proliferation by means of AMPK/ERK signaling pathways, VSMC migration via inactivation of the NADPH oxidase (NOX)/ROS/p38/HSP27 pathways and artery calcification via the PI3K-Akt pathway. These findings indicate that omentin-1 may be a negative mediator of IS. Pharmacologically, several lines of clinical evidence indicate that metformin and statins could elevate omentin-1 levels, although the specific mechanism has not been precisely delineated until now. This study is the first to summarize the comprehensive mechanisms between omentin-1 and atherosclerosis and to review the shielding effect of omentin-1 on IS. We shed light on omentin-1 as a novel therapeutic target for combating IS.

CoFe alloy embedded in N-doped carbon nanotubes derived from triamterene as a highly efficient and durable electrocatalyst beyond commercial Pt/C for oxygen reduction.

For development of green and sustainable energy, it is of importance to search highly efficient and low-cost electrocatalysts of oxygen reduction reaction (ORR) in energy conversion devices. Herein, CoFe alloyed nanocrystals embedded in N-doped bamboo-like carbon nanotubes (CoFe@NCNTs) were facilely synthetized by one-step co-pyrolysis with the mixture of triamterene, metal chlorides and graphitic carbon nitride (g-C3N4). The resultant CoFe@NCNTs exhibited excellent ORR activity with the positive shifts in the onset potential (Eonset = 0.97 V) and half-wave potential (E1/2 = 0.88 V), outperforming commercial Pt/C (Eonset = 0.96 V; E1/2 = 0.84 V). Compared to metal organic frameworks (MOFs)-based strategy for synthesis of low-cost carbon-based ORR catalysts, this method is simple and convenient, coupled by avoiding the complicated synthesis of MOFs and its ligands. This work provides a promising route to fabricate advanced transition-metal-based carbon catalysts in the researches correlated with energy conversion devices.

Effects of lemon essential oil and limonene on the progress of early caries: An in vitro study.

OBJECTIVE: The purpose of this study was to investigate the effects of Lemon essential oil (LEO) and Limonene (LIM) in the progress of early caries. DESIGN: LEO and LIM were selected as experimental medicine, while sodium fluoride (NaF) and deionized water (DW) were positive and blank controls, respectively. Bovine incisors were used to establish enamel and dentin early caries models by demineralization method in vitro. Then specimens were subjected to pH cycling. Calcium and phosphate release of demineralizing solution were measured by an automatic biochemical analyzer; Surface microhardness tester and energy dispersive X-ray spectrometer were used to detect the surface microhardness recovery and calcium- phosphate ratio on tooth surface; Degraded collagen matrix by collagenase was investigated by assaying hydroxyproline. RESULTS: Calcium release of dentin demineralizing solution of LEO group was lower than DW group's and higher than NaF group's. Both of LEO and LIM groups, the surface microhardness recovery were significantly lower than those of NaF group, which were similar to DW group. Dentin surface calcium- phosphate ratio of LEO and LIM groups were lower than those of NaF group and higher than those of DW group. Hydroxyproline concentration in the remineralizing solution of LEO and LIM groups were lower than DW groups' and higher than NaF groups'. CONCLUSIONS: LEO and LIM have influence on the progress of dentin early caries, which can stabilize its structure by inhibiting collagen degradation. Meanwhile, these medicines may provide a new drug choice for the prevention and treatment of early root caries.

Structure of the human sodium leak channel NALCN in complex with FAM155A.

NALCN, a sodium leak channel expressed mainly in the central nervous system, is responsible for the resting Na+ permeability that controls neuronal excitability. Dysfunctions of the NALCN channelosome, NALCN with several auxiliary subunits, are associated with a variety of human diseases. Here, we report the cryo-EM structure of human NALCN in complex with FAM155A at an overall resolution of 3.1 angstroms. FAM155A forms extensive interactions with the extracellular loops of NALCN that may help stabilize NALCN in the membrane. A Na+ ion-binding site, reminiscent of a Ca2+ binding site in Cav channels, is identified in the unique EEKE selectivity filter. Despite its 'leaky' nature, the channel is closed and the intracellular gate is sealed by S6I, II-III linker and III-IV linker. Our study establishes the molecular basis of Na+ permeation and voltage sensitivity, and provides important clues to the mechanistic understanding of NALCN regulation and NALCN channelosome-related diseases.

Qingxin Kaiqiao Recipe Improves Cognitive Performance, Inhibits Apoptosis, and Reduces Pathological Deposits in APP/PS1 Double Transgenic Mice via the PI3K/Akt Pathway.

The traditional Chinese medicine of Qingxin Kaiqiao Recipe (QKR) is effective in the treatment of Alzheimer's disease (AD). This study aims to investigate whether QKR improves the cognitive ability and takes neuroprotective effect on APP/PS1 double transgenic mice via the PI3K/Akt pathway. APP/PS1 double transgenic mice were randomly divided into a model, donepezil-treated, or QKR-treated group (L-QKR: 4.75 mg/kg/d, M-QKR: 9.5 mg/kg/d, and H-QKR: 19 mg/kg/d, respectively). Wild-type C57/BL6J mice were used as the control group. Morris water maze (MWM) was used to test the ability of spatial navigation and memorization; terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) assay was applied to test the apoptosis; amyloid protein granule deposition was detected via Methenamine silver staining; Western blot (WB) analysis, immunohistochemistry, and RT-PCR were applied to measure the expression of Aß and corresponding indicators of the PI3K/Akt pathway. Compared with the model group, QKR significantly relieved the cognitive impairment, reduced the deposition of senile plaques, decreased the expression of GSK-3α and Aß, and increased the expression of p-PI3K, p-Akt, and IDE. In addition, the number of TUNEL-positive cells decreased after treatment using QKR. The current study proved that QKR, especially at the high dose tested, exerted a protective effect on improving learning and memory, inhibiting apoptosis, and reducing the process of pathological degeneration in the hippocampus of AD mice.

Senegenin exerts anti-depression effect in mice induced by chronic un-predictable mild stress via inhibition of NF-κB regulating NLRP3 signal pathway.

Depressive disorder is a kind of affective disturbance disease. Emerging evidence has suggested that inflammation may contribute to the pathologic process of depressive disorder. Senegenin (SEN), a major bioactive constituent in Polygala tenuifolia Willd, has much bioactivity including anti-inflammatory and neuroprotection effects. However, the mechanism of its anti-depressant effect in mice remains unknown. This study aimed to explore the anti-depressant effects of SEN on behavioral changes and inflammatory responses in mice induced by chronic un-predictable mild stress (CUMS). SEN treatment remarkably ameliorated CUMS-induced behavioral abnormalities, such as improving locomotor activity, decreasing immobility time in Tail suspension test (TST) and Forced swimming test (FST), and increasing sucrose intake in Sucrose preference test (SPT). Additionally, SEN improve protein levels of Brain-derived neurotrophic factor (BDNF) and Neurotrophin-3 (NT-3) expression. In response to stress, p65 was activated to promote production of pro-IL-1ß, and then cleaved to mature IL-1ß by NOD-like receptor protein 3 (NLRP3) inflammasome pathway in hippocampus of CUMS mice. After SEN treatment, protein activation related to NLRP3 inflammasome pathway was down-regulated, which inhibited IL-1ß secretion. These results demonstrate that SEN plays an important role in treatment CUMS-induced depression in mice, possibly via suppression of pathway activation associated with NLRP3 inflammasome.