Imaging lifespan brain structural growth: From region, to connectome, to gradient.

Throughout human life, the brain undergoes intricate structural changes that support cognition. A study in PLOS Biology introduces new avenues for depicting the trajectory of the brain morphometric connectome and its underlying genetic and molecular mechanisms.

Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Role of HCN channels in the functions of basal ganglia and Parkinson's disease.

Parkinson's disease (PD) is a motor disorder resulting from dopaminergic neuron degeneration in the substantia nigra caused by age, genetics, and environment. The disease severely impacts a patient's quality of life and can even be life-threatening. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a member of the HCN1-4 gene family and is widely expressed in basal ganglia nuclei. The hyperpolarization-activated current mediated by the HCN channel has a distinct impact on neuronal excitability and rhythmic activity associated with PD pathogenesis, as it affects the firing activity, including both firing rate and firing pattern, of neurons in the basal ganglia nuclei. This review aims to comprehensively understand the characteristics of HCN channels by summarizing their regulatory role in neuronal firing activity of the basal ganglia nuclei. Furthermore, the distribution and characteristics of HCN channels in each nucleus of the basal ganglia group and their effect on PD symptoms through modulating neuronal electrical activity are discussed. Since the roles of the substantia nigra pars compacta and reticulata, as well as globus pallidus externus and internus, are distinct in the basal ganglia circuit, they are individually described. Lastly, this investigation briefly highlights that the HCN channel expressed on microglia plays a role in the pathological process of PD by affecting the neuroinflammatory response.

Self-Catalyzed Synthesis of Length-Controlled One-Dimensional Nickel Oxide@N-Doped Porous Carbon Nanostructures from Metal Ion Modified Nitrogen Heterocycles for Efficient Lithium Storage.

Transition metal oxides with the merits of high theoretical capacities, natural abundance, low cost, and environmental benignity have been regarded as a promising anodic material for lithium ion batteries (LIBs). However, the severe volume expansion upon cycling and poor conductivity limit their cycling stability and rate capability. To address this issue, NiO embedded and N-doped porous carbon nanorods (NiO@NCNR) and nanotubes (NiO@NCNT) are synthesized by the metal-catalyzed graphitization and nitridization of monocrystalline Ni(II)-triazole coordinated framework and Ni(II)/melamine mixture, respectively, and the following oxidation in air. When applied as an anodic material for LIBs, the NiO@NCNR and NiO@NCNT hybrids exhibit a decent capacity of 895/832 mA h g-1 at 100 mA g-1, high rate capability of 484/467 mA h g-1 at 5.0 A g-1, and good long-term cycling stability of 663/634 mA h g-1 at 600th cycle at 1 A g-1, which are much better than those of NiO@carbon black (CB) control sample (701, 214, and 223 mA h g-1). The remarkable electrochemical properties benefit from the advanced nanoarchitecture of NiO@NCNR and NiO@NCNT, which offers a length-controlled one-dimensional porous carbon nanoarchitecture for effective e-/Li+ transport, affords a flexible carbon skeleton for spatial confinement, and forms abundant nanocavities for stress buffering and structure reinforcement during discharge/charging processes. The rational structural design and synthesis may pave a way for exploring advanced metal oxide based anodic materials for next-generation LIBs.

Pyrazolone compounds could inhibit CES1 and ameliorates fat accumulation during adipocyte differentiation.

Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.

Naturalistic viewing increases individual identifiability based on connectivity within functional brain networks.

Naturalistic viewing (NV) is currently considered a promising paradigm for studying individual differences in functional brain organization. While whole brain functional connectivity (FC) under NV has been relatively well characterized, so far little work has been done on a network level. Here, we extend current knowledge by characterizing the influence of NV on FC in fourteen meta-analytically derived brain networks considering three different movie stimuli in comparison to resting-state (RS). We show that NV increases identifiability of individuals over RS based on functional connectivity in certain, but not all networks. Furthermore, movie stimuli including a narrative appear more distinct from RS. In addition, we assess individual variability in network FC by comparing within- and between-subject similarity during NV and RS. We show that NV can evoke individually distinct NFC patterns by increasing inter-subject variability while retaining within-subject similarity. Crucially, our results highlight that this effect is not observable across all networks, but rather dependent on the network-stimulus combination. Our results confirm that NV can improve the detection of individual differences over RS and underline the importance of selecting the appropriate combination of movie and cognitive network for the research question at hand.

Homotopic local-global parcellation of the human cerebral cortex from resting-state functional connectivity.

Resting-state fMRI is commonly used to derive brain parcellations, which are widely used for dimensionality reduction and interpreting human neuroscience studies. We previously developed a model that integrates local and global approaches for estimating areal-level cortical parcellations. The resulting local-global parcellations are often referred to as the Schaefer parcellations. However, the lack of homotopic correspondence between left and right Schaefer parcels has limited their use for brain lateralization studies. Here, we extend our previous model to derive homotopic areal-level parcellations. Using resting-fMRI and task-fMRI across diverse scanners, acquisition protocols, preprocessing and demographics, we show that the resulting homotopic parcellations are as homogeneous as the Schaefer parcellations, while being more homogeneous than five publicly available parcellations. Furthermore, weaker correlations between homotopic parcels are associated with greater lateralization in resting network organization, as well as lateralization in language and motor task activation. Finally, the homotopic parcellations agree with the boundaries of a number of cortical areas estimated from histology and visuotopic fMRI, while capturing sub-areal (e.g., somatotopic and visuotopic) features. Overall, these results suggest that the homotopic local-global parcellations represent neurobiologically meaningful subdivisions of the human cerebral cortex and will be a useful resource for future studies. Multi-resolution parcellations estimated from 1479 participants are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Yan2023_homotopic).

Mapping and candidate gene analysis of clustered bud on the main inflorescence in Brassica napus L.

Breeding rapeseed varieties with more main inflorescence siliques is an idea for developing rapeseed varieties that are suitable for light and simplified cultivation. The Brassica napus exhibited cluster bud of the main inflorescence (Bnclib) gene. At the fruiting stage, the main inflorescence had more siliques, higher density, and more main inflorescences. Moreover, the top of the main inflorescence bifurcated. Genetic analysis showed that the separation ratio between Bnclib and the wild type in the F2 generation was 3:1, which indicated that the trait was a single-gene-dominant inheritance. Among the 24 candidate genes, only one gene, BnaA03g53930D, showed differential expression between the groups (False discovery rate, FDR ≤ 0.05, |log2FC|≤ 1). qPCR verification of the BnaA03g53930D gene between Huyou 17 and its Bnclib near-isogenic line showed that BnaA03g53930D was significantly differentially expressed in the stem tissue of Huyou 17 and its Bnclib near-isogenic line (Bnclib NIL). The determination of gibberellin (GA), brassinolide (BR), cytokinin (CTK), jasmonic acid (JA), growth hormone (IAA), and strigolactone (SL) content in the shoot apex of Huyou 17 by Bnclib NIL and wild type showed that all six hormones significantly differed between the Bnclib NIL and Huyou 17. It is necessary to conduct further research on the interactions between JA and the other five hormones and the main inflorescence bud clustering in B. napus.

Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors.

Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

Brain white matter extracellular free-water increases are related to reduced neurocognitive function in systemic lupus erythematosus.

OBJECTIVES: Brain white matter (WM) microstructural changes evaluated by diffusion MRI are well documented in patients with SLE. Yet, the conventional diffusion tensor imaging technique fails to differentiate WM changes that originate from tissue alterations from those due to increased extracellular free water (FW) related to neuroinflammation, microvascular disruption, atrophy, or other extracellular processes. Here, we sought to delineate changes in WM tissue microstructure and extracellular FW volume and examine their relationships with neurocognitive function in SLE patients. METHODS: Twenty SLE patients [16 females, aged 36.0 (10.6)] without clinically overt neuropsychiatric manifestation and 61 healthy controls (HCs) [29 females, aged 29.2 (9.4)] underwent diffusion MRI and computerized neuropsychological assessments cross-sectionally. The FW imaging method was applied to compare microstructural tissue changes and extracellular FW volume of the brain WM between SLE patients and HCs. Association between extracellular FW changes and neurocognitive performance was studied. RESULTS: SLE patients had higher WM extracellular FW compared with HCs (family-wise-error-corrected P < 0.05), while no group difference was found in FW-corrected tissue compartment and structural connectivity metrics. Extracellular FW increases in SLE patients were associated with poorer neurocognitive performance that probed sustained attention (P = 0.022) and higher cumulative glucocorticoid dose (P = 0.0041). Such findings remained robust after controlling for age, gender, intelligence quotient, and total WM volume. CONCLUSION: The association between WM extracellular FW increases and reduced neurocognitive performance suggest possible microvascular degradation and/or neuroinflammation in SLE patients with clinically inactive disease. The mechanistic impact of cumulative glucocorticoids on WM FW deserves further evaluation.

In situ encapsulation of iron oxide nanoparticles into nitrogen-doped carbon nanotubes as anodic electrode materials of lithium ion batteries.

Fe-based oxides are considered as promising anode materials for lithium-ion batteries (LIBs) due to their high theoretical capacities, low cost, natural abundance and environmental friendliness. However, their severe volume expansion upon cycling and poor conductivity limit their cycling stability and rate capability. To address this issue, a hybrid of Fe2O3 nanoparticles encapsulated at the endpoints of nitrogen-doped CNTs (Fe2O3@NCNTs) is designed and prepared using a metal-catalyzed graphitization-nitridization driven tip-growth process and subsequent oxidation in air. When evaluated as an anode material for LIBs, this Fe2O3@NCNT hybrid exhibits a high capacity of 1145 mA h g-1 at 100 mA g-1, excellent rate capability of 907 mA h g-1 at 5.0 A g-1 and remarkable cycling stability of 856 mA h g-1 after 800 cycles at 1 A g-1, which are much superior to those of the Fe2O3/carbon black (CB) control material. The outstanding electrochemical performance benefits from the unique nanoarchitecture of Fe2O3@NCNTs, which provides a porous conductive matrix for effective electron-ion transport, and provides space confining carbon nanocaps as well as stress buffer nanocavities for robust structural stability during the lithiation/delithiation process. The results may pave the way for the rational structural design of high-performance metal oxide-based anode materials for next-generation LIBs.

Post-hospital falls incidence and risk factors among older adults: a systematic review and meta-analysis.

BACKGROUND: Post-hospital falls constitute a significant health concern for older adults who have been recently discharged from the hospital. OBJECTIVES: To systematically summarise existing evidence on the incidence and risk factors for post-hospital falls among older adults. METHODS: A systematic review and meta-analysis was conducted. Six electronic databases were searched to identify cohort studies investigating the incidence and risk factors for post-hospital falls in older adults. The incidence and risk factors for post-hospital falls were extracted. The meta-analysis was used to calculate pooled incidences and 95% confidence intervals (CI). The meta-regression and subgroup meta-analysis were conducted to explore sources of heterogeneity in incidence proportions across the eligible studies. A qualitative synthesis was performed for the post-hospital falls risk factors. RESULTS: Eighteen studies from eight countries (n = 9,080,568) were included. The pooled incidence proportion of any and recurrent post-hospital falls was 14% (95% CI: 13%-15%) and 10% (95% CI: 5%-14%), respectively. Follow-up period, study quality, study country, setting, percentage of female subjects, percentage of subjects with previous falls and the primary data collection method for falls significantly contributed to the 64.8% of the heterogeneity in incidence proportions. Twenty-six risk factors for post-hospital falls were identified in the eligible studies, where biological factors were the most commonly identified factors. The highest risks were reported for previous falls, previous fractures, delirium and neurological diseases. CONCLUSION: The findings of this study suggested future post-hospital falls prevention should prioritise the needs of older adults with the dominant risk factors. Further investigations into the period-specific incidence and socioeconomic and environmental risk factors for post-hospital falls are also required.

Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1.

Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure-activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 µM and 0.014 µM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 µM and 0.055 µM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A.

Prognostic biomarker IL17A correlated with immune infiltrates in head and neck cancer.

BACKGROUND: The underlying functions and mechanisms of the Th17 pathway in Head and neck squamous cell carcinoma (HNSCC) progression and tumor immunology are still unclear. We investigated the correlation between IL17A expression and certain clinical parameters, tumor-infiltrating immune cells (TIICs) in TCGA HNSCC samples. METHODS: HNSCC files from the TCGA database were analyzed to obtain data on immune system infiltrates, gene expression, and related clinical information. R (Version 3.6.3) software, GEPIA, and TIMER online analysis tools were used to profile the relationship between the expression of IL17A and the prognosis, clinical stages, survival status and immune cell tumor-infiltrating levels of HNSCC patients. GEPIA and TIMER online analysis tools were used to verify the data. RESULTS: The expression of IL17A was significantly decreased in tumor tissues from HNSCC. IL17A expression was associated with M, N stage, lymphovascular invasion, and patients OS event. GSEA revealed that IL17A was closely related to humoral immune response, T cells response, and cytokine signal. TCGA database and TIMER online analysis indicated that the B cells and T cells levels were correlated with IL17A. The correlation between IL17A expression and correlated genes was analyzed. CONCLUSIONS: IL-17A plays a key role in HNSCC. The levels of IL17A are important values for the determination of the occurrence and development of the HNSCC. The IL17A and correlated genes may be potential immunotherapeutic targets for HNSCC.

Visits to the accident and emergency department in hot season of a city with subtropical climate: association with heat stress and related meteorological variables.

BACKGROUND: Literature reporting the association between heat stress defined by universal thermal climate index (UTCI) and emergency department visits is mainly conducted in Europe. This study aimed to investigate the association between heat stress, as defined by the UTCI, and visits to the accident and emergency department (AED) in Hong Kong, which represents a subtropical climate region. METHODS: A retrospective study involving 13,438,846 AED visits in the public sector from May 2000 to September 2016, excluding 2003 and 2009, was conducted in Hong Kong. Age-sex-specific ANCOVA models of daily AED rates on heat stress and prolonged heat stress, adjusting for air quality, prolonged poor air quality, typhoon, rainstorm, year, day of the week, public holiday, summer vacation, and fee charging, were used. RESULTS: On a day with strong heat stress (32.1 °C ≤ UTCI ≤ 38.0 °C), the AED visit rate (per 100,000) increased by 0.9 (95% CI: 0.5, 1.3) and 1.7 (95% CI: 1.3, 2.1) for females and males aged 19-64 and 4.1 (95% CI: 2.7, 5.4) and 4.1 (95% CI: 2.6, 5.6) for females and males aged ≥ 65, while keeping other variables constant. On a day with very strong heat stress (38.1 °C ≤ UTCI ≤ 46.0 °C), the corresponding rates increased by 0.6 (95% CI: 0.1, 1.2), 2.2 (95% CI: 1.7, 2.7), 4.9 (95% CI: 3.1, 6.7), and 4.7 (95% CI: 2.7, 6.6), respectively. The effect size of heat stress associated with AED visit rates was negligible among those aged ≤ 18. Heat stress showed the greatest effect size for males aged 19-64 among all subgroups. CONCLUSION: Biothermal condition from heat stress was associated with the health of the citizens in a city with a subtropical climate and reflected in the increase of daily AED visit. Public health recommendations have been made accordingly for the prevention of heat-related AED visits.

Polysaccharides from Tetrastigma hemsleyanum Diels et Gilg: optimum extraction, monosaccharide compositions, and antioxidant activity.

The optimization of extraction of Tetrastigma hemsleyanum Diels et Gilg polysaccharides (THP) using ultrasonic with enzyme method and its monosaccharide compositions and antioxidant activity were investigated in this work. Single-factor experiments and response surface methodology (RSM) were performed to optimize conditions for extraction, and the independent variables were (XA) dosage of cellulase, (XB) extraction time, (XC) ultrasonic power, and (XD) ratio of water to the material. The extraction rate of THP was increased effectively under the optimum conditions, and the maximum (4.692 ± 0.059%) was well-matched the predicted value from RSM. THP was consisted of mannose, glucuronic acid, rhamnose, galacturonic acid, glucose, galactose, and arabinose, while glucose was the dominant (26.749 ± 0.634%). According to the total antioxidant capacity assay with the FRAP method, DPPH, and hydroxyl radical scavenging assay, THP showed strong antioxidant activity with a dose-dependent behavior. The results indicated that THP has the potential to be a novel antioxidant and could expand its application in food and medicine.

Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells.

Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R1), 4-methylbenzyl (R2) and cyclohexyl (R3) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H- pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC50 value (0.13 µM). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.

The effect of antibiotic resistance on Helicobacter pylori eradication efficacy: A systematic review and meta-analysis.

BACKGROUND: The occurrence of antibiotic-resistant strains has been rapidly increasing due to the wide use of antibiotics. To evaluate the current effects of antibiotic resistance on Helicobacter pylori eradication efficacy, we conducted this systematic review and meta-analysis. METHODS: Literature searches were conducted in the following databases: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Statistical analysis was performed using STATA version 12.0 (StataCorp LP, College Station, TX, USA). RESULTS: A total of 120 studies, including 28 707 patients, were assessed. Only first-line therapy was considered. The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to clarithromycin was 0.682 (95% CI: 0.636-0.731). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to metronidazole was 0.843 (95% CI: 0.810-0.877). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to levofloxacin was 0.794 (95% CI: 0.669-0.941). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to dual clarithromycin and metronidazole was 0.674 (95% CI: 0.590-0.770). CONCLUSION: Antibiotic resistance causes a decrease in the eradication rate of H pylori today. Quadruple concomitant therapy may overcome the declining H pylori eradication rate caused by metronidazole-only resistance.

Discovery of natural alkaloids as potent and selective inhibitors against human carboxylesterase 2.

Human Carboxylesterase 2A (hCES2A), one of the most important serine hydrolases, plays crucial roles in the hydrolysis and the metabolic activation of a wide range of esters and amides. Increasing evidence has indicated that potent inhibition on intestinal hCES2A may reduce the excessive accumulation of SN-38 (the hydrolytic metabolite of irinotecan with potent cytotoxicity) in the intestinal tract and thereby alleviate the intestinal toxicity triggered by irinotecan. In this study, more than sixty natural alkaloids have been collected and their inhibitory effects against hCES2A are assayed using a fluorescence-based biochemical assay. Following preliminary screening, seventeen alkaloids are found with strong to moderate hCES2A inhibition activity. Primary structure-activity relationships (SAR) analysis of natural isoquinoline alkaloids reveal that the benzo-1,3-dioxole group and the aromatic pyridine structure are beneficial for hCES2A inhibition. Further investigations demonstrate that a steroidal alkaloid reserpine exhibits strong hCES2A inhibition activity (IC50 = 0.94 µM) and high selectivity over other human serine hydrolases including hCES1A, dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE) and thrombin. Inhibition kinetic analyses demonstrated that reserpine acts as a non-competitive inhibitor against hCES2A-mediated FD hydrolysis. Molecular docking simulations demonstrated that the potent inhibition of hCES2A by reserpine could partially be attributed to its strong σ-π and S-π interactions between reserpine and hCES2A. Collectively, our findings suggest that reserpine is a potent and highly selective inhibitor of hCES2A, which can be served as a promising lead compound for the development of more efficacious and selective alkaloids-type hCES2A inhibitors for biomedical applications.

A novel copy number variation in CATSPER2 causes idiopathic male infertility with normal semen parameters.

STUDY QUESTION: Are genetic abnormalities in CATSPER (cation channel of sperm) genes associated with idiopathic male infertility with normal semen parameters and, if so, how do they affect male fertility? SUMMARY ANSWER: A novel copy number variation (CNV) in CATSPER2 causes idiopathic male infertility with normal semen parameters by disrupting the ability of sperm to penetrate viscous media, undergo hyperactivation and respond to progesterone. WHAT IS KNOWN ALREADY: CATSPER is the principle Ca2+ channel mediating extracellular Ca2+ influx into spermatozoa. Although several case reports have suggested a causal relationship between CATSPER disruption and human male infertility, whether genetic abnormalities in CATSPER genes are associated with idiopathic male infertility with normal semen parameters remains unclear. STUDY DESIGN, SIZE, DURATION: Spermatozoa were obtained from men attending the reproductive medical center at Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi, China between January 2014 and June 2016. In total, 120 men from infertile couples and 20 healthy male donors were selected to take part in the study, based on their normal semen parameters. PARTICIPANTS/MATERIALS, SETTING, METHODS: CATSPER and KSPER currents were assessed using the whole-cell patch-clamp technique. Whole-genome sequencing and TaqMan® CNV assays were performed to identify genetic variations. The expression levels of genes encoding the CATSPER complex were measured by quantitative real-time PCR and Western blot. Sperm motion characteristics and hyperactivation were examined with a computer-aided sperm analysis (CASA) system. Sperm responses to progesterone, assessed as increases in CATSPER current and intercellular Ca2+ concentrations ([Ca2+]i), as well as inducement of penetration ability and acrosome reaction, were examined by means of whole-cell patch-clamp technique, single-sperm [Ca2+]i imaging, penetration into methylcellulose assay and chlortetracycline staining, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: An infertile man with complete disruption of CATSPER current was identified. This individual has a novel CNV which disrupts one gene copy in the region 43894500-43950000 in chromosome 15 (GRCh37.p13 Primary Assembly, nsv3067119), containing the whole DNA sequence of CATSPER2. This CNV affected the expression of CATSPER2, resulting in dramatically reduced levels of CATSPER2 proteins in the individual's spermatozoa. Although this individual exhibited normal semen parameters, his spermatozoa showed impaired penetration ability, deficient hyperactivation, and did not respond to progesterone, in terms of monovalent current potentiation, [Ca2+]i increase, penetration ability enhancement and acrosome reaction inducement, which may explain the individual's idiopathic infertility. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Our novel findings require more cases to support the CATSPER2 CNV identified in this study as a common cause of idiopathic male infertility in patients with normal semen parameters. Therefore, caution must be taken when extrapolating the use of this CNV as a potential biomarker for idiopathic male infertility. WIDER IMPLICATIONS OF THE FINDINGS: The findings from the unique human CATSPER 'knockout' model in this study not only confirm the essential roles of CATSPER in mediating progesterone response and regulating hyperactivation in human spermatozoa but also reveal that disruption of CATSPER current is a significant factor causing idiopathic male infertility. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by National Natural Science Foundation of China (81771644 and 31400996 to T.L.; 31230034 to X.Z.); National Basic Research Program of China (973 Program, 2015CB943003 to X.Z.); National Key Research and Development Program of China (2016YFC1000905 to T.L.); Natural Science Foundation of Jiangxi, China (20121BBG70021 and GJJ12015 to X.Z.; 20161BAB204167 and 20171ACB21006 to T.L.) and the open project of National Population and Family Planning Key Laboratory of Contraceptives and Devices Research (No. 2016KF07 to T.L.). The authors have no conflicts of interest to declare.