1,028 research outputs found
Discovery, Characterization, and Structure–Activity Relationships of an Inhibitor of Inward Rectifier Potassium (Kir) Channels with Preference for Kir2.3, Kir3.X, and Kir7.1
The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure–activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure–function relationships of these Kir channels
Airflow Dynamics of Coughing in Healthy Human Volunteers by Shadowgraph Imaging: An Aid to Aerosol Infection Control
Cough airflow dynamics have been previously studied using a variety of experimental methods. In this study, real-time, non-invasive shadowgraph imaging was applied to obtain additional analyses of cough airflows produced by healthy volunteers. Twenty healthy volunteers (10 women, mean age 32.2±12.9 years; 10 men, mean age 25.3±2.5 years) were asked to cough freely, then into their sleeves (as per current US CDC recommendations) in this study to analyze cough airflow dynamics. For the 10 females (cases 1–10), their maximum detectable cough propagation distances ranged from 0.16–0.55 m, with maximum derived velocities of 2.2–5.0 m/s, and their maximum detectable 2-D projected areas ranged from 0.010–0.11 m2, with maximum derived expansion rates of 0.15–0.55 m2/s. For the 10 males (cases 11–20), their maximum detectable cough propagation distances ranged from 0.31–0.64 m, with maximum derived velocities of 3.2–14 m/s, and their maximum detectable 2-D projected areas ranged from 0.04–0.14 m2, with maximum derived expansion rates of 0.25–1.4 m2/s
Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding
DOI is broken and has been reportedThe prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address “food-abuse” disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.
Methodology/Principal Findings
We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.
Conclusions/Significance
Acquired disruption of brain insulin action may confer risk for and/or underlie “food-abuse” disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to “the fast food lifestyle” creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.National Institutes of Health (U.S.) (grant DA14684)National Institutes of Health (U.S.) (grant DK085712
Serious fungal infections in Thailand
The burden of serious fungal infection in Thailand is increasing but data regarding its incidence and prevalence are lacking. In this study we aimed to estimate the burden of serious fungal diseases in Thailand based on the size of the populations at risk and available epidemiological databases. Data derived from The Bureau of Epidemiology, Department of Disease Control, Thai Ministry of Public Health, World Health Organisation, international and local reports, and some unreported data were used. When no data existed, risk populations were used to estimate frequencies of fungal infections, using previously described methodology by LIFE. Recurrent vulvovaginal candidiasis (>4 episodes per year) is estimated to occur in 3,310 per 100,000 population. Using a previously described rate that 14/10,000 admissions are with fungaemia and 94% of those are Candida, we estimated 8,650 patients with candidaemia. The prevalence of chronic pulmonary aspergillosis is relatively high with a total of 19,044, approximately half subsequent to pulmonary tuberculosis. Invasive aspergillosis is estimated to affect 941 patients following leukaemia therapy, transplantations, and chronic obstructive pulmonary disease, approximately 1.4/100,000. In addition, allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitisation were estimated at approximately 58.4/100,000 and 77/100,000, respectively. Given approximately 8,134 new cases of AIDS annually, cryptococcal meningitis, Pneumocystis pneumonia, and Talaromyces marneffei infection are estimated at 1.9/100,000, 2.6/100,000, and 0.3/100,000, respectively. The present study indicates that about 1.93% (1,254,562) of the population is affected by serious fungal infections. Owing to the lack of data, reports, and statistics, the number of patients with mycoses in Thailand can only be estimated
Qualitative Real-Time Schlieren and Shadowgraph Imaging of Human Exhaled Airflows: An Aid to Aerosol Infection Control
Using a newly constructed airflow imaging system, airflow patterns were visualized that were associated with common, everyday respiratory activities (e.g. breathing, talking, laughing, whistling). The effectiveness of various interventions (e.g. putting hands and tissues across the mouth and nose) to reduce the potential transmission of airborne infection, whilst coughing and sneezing, were also investigated. From the digital video footage recorded, it was seen that both coughing and sneezing are relatively poorly contained by commonly used configurations of single-handed shielding maneuvers. Only some but not all of the forward momentum of the cough and sneeze puffs are curtailed with various hand techniques, and the remaining momentum is disseminated in a large puff in the immediate vicinity of the cougher, which may still act as a nearby source of infection. The use of a tissue (in this case, 4-ply, opened and ready in the hand) proved to be surprisingly effective, though the effectiveness of this depends on the tissue remaining intact and not ripping apart. Interestingly, the use of a novel ‘coughcatcher’ device appears to be relatively effective in containing coughs and sneezes. One aspect that became evident during the experimental procedures was that the effectiveness of all of these barrier interventions is very much dependent on the speed with which the user can put them into position to cover the mouth and nose effectively
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Altered precipitation regime affects the function and composition of soil microbial communities on multiple time scales
Climate change models predict that future precipitation patterns will entail lower-frequency but larger rainfall events, increasing the duration of dry soil conditions. Resulting shifts in microbial C cycling activity could affect soil C storage. Further, microbial response to rainfall events may be constrained by the physiological or nutrient limitation stress of extended drought periods; thus seasonal or multiannual precipitation regimes may influence microbial activity following soil wet-up. We quantified rainfall-driven dynamics of microbial processes that affect soil C loss and retention, and microbial community composition, in soils from a long-term (14-year) field experiment contrasting ‘‘Ambient’’ and ‘‘Altered’’ (extended intervals between rainfalls) precipitation regimes. We collected soil before, the day following, and five days following 2.5-cm rainfall events during both moist and dry periods (June and September 2011; soil water potential =- 0.01 and - 0.83 MPa, respectively), and measured microbial respiration, microbial biomass, organic matter decomposition potential (extracellular enzyme activities), and microbial community composition (phospholipid fatty acids). The equivalent rainfall events caused equivalent microbial respiration responses in both treatments. In contrast, microbial biomass was higher and increased after rainfall in the Altered treatment soils only, thus microbial C use efficiency (CUE) was higher in Altered than Ambient treatments (0.70 ± 0.03 > 0.46 ± 0.10). CUE was also higher in dry (September) soils. C-acquiring enzyme activities (b-glucosidase, cellobiohydrolase, and phenol oxidase) increased after rainfall in moist (June), but not dry (September) soils. Both microbial biomass C:N ratios and fungal : bacterial ratios were higher at lower soil water contents, suggesting a functional and/or population-level shift in the microbiota at low soil water contents, and microbial community composition also differed following wet-up and between seasons and treatments. Overall, microbial activity may directly (C respiration) and indirectly (enzyme potential) reduce soil organic matter pools less in drier soils, and soil C sequestration potential (CUE) may be higher in soils with a history of extended dry periods between rainfall events. The implications include that soil C loss may be reduced or compensated for via different mechanisms at varying time scales, and that microbial taxa with better stress tolerance or growth efficiency may be associated with these functional shifts.Keywords: precipitation timing, microbial ecology, microbial C use efficiency, soil water, microbial activity, soil C storage, soil biomass, soil respiratio
Mutation of Archaeal Isopentenyl Phosphate Kinase Highlights Mechanism and Guides Phosphorylation of Additional Isoprenoid Monophosphates
I sopentenyl diphosphate (IPP) and its isomeric part-ner dimethylallyl diphosphate (DMAPP) are precur-sors for a diverse collection of primary and second-ary isoprenoid metabolites in all organisms. Following its formation, successive units of IPP are used together either with DMAPP, formed by the action of types I or II IPP isomerases, or with the IPP extended isoprenoid diphosphate chain, to biosynthesize C10, C15, or C20 oligoprenyl diphosphates known as geranyl diphos-phate (GPP), farnesyl diphosphate (FPP), and gera-nylgeranyl diphosphate (GGPP), respectively, as well as larger isoprenoid diphosphates. In plants and some mi-croorganisms, GPP, FPP, and GGPP also serve as start-ingmaterials for the biosynthesis of a large class of spe-cialized and often cyclic terpene hydrocarbons (1). FPP is the most ubiquitous of the three isoprenoid diphos-phate building blocks, as it resides at the juncture of bi
Dysregulation of the Norepinephrine Transporter Sustains Cortical Hypodopaminergia and Schizophrenia-Like Behaviors in Neuronal Rictor Null Mice
A novel animal model highlights the link between Akt dysfunction, reduced cortical dopamine function, norepinephrine transporters, and schizophrenia-like behaviors
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