Cleavage of endogenous gamma ENaC and elevated abundance of alpha ENaC are associated with increased Na+ transport in response to apical fluid volume expansion in human H441 airway epithelial cells

Using human H441 airway epithelial cells cultured at air–liquid interface (ALI), we have uniquely correlated the functional response to apical fluid volume expansion with the abundance and cleavage of endogenous α- and γENaC proteins in the apical membrane. Monolayers cultured at ALI rapidly elevated I(sc) when inserted into fluid-filled Ussing chambers. The increase in I(sc) was not significantly augmented by the apical addition of trypsin, and elevation was abolished by the protease inhibitor aprotinin and an inhibitor of the proprotein convertase, furin. These treatments also increased the IC(50) amiloride indicating that the effect was via inhibition of highly Na(+)-selective ENaC channels. Apical fluid, 5–500 μl for 1 h in culture, increased the spontaneous starting I(sc) in a dose-dependent manner, whilst maximal fluid-induced I(sc) in the Ussing chamber was unchanged. Apical fluid expansion increased the abundance of 63–65-kDa αENaC proteins in the apical membrane. However, this could not be attributed to increased cleavage as protease inhibitors had no effect on the ratio of cleaved to non-cleaved (90 kDa) αENaC proteins. Instead, fluid expansion increased αENaC abundance in the membrane. In contrast, function correlated well with γENaC cleavage at known sites by furin and extracellular proteases. Interestingly, cleavage of γENaC was associated with increased retrieval from the membrane via the proteosomal pathway. Thus, the response to apical fluid volume expansion in H441 airway epithelial cells involves cleavage of γENaC, and changes in α- and γENaC protein abundance at the apical membrane. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00424-011-0982-x) contains supplementary material, which is available to authorized users

Dynamic double directional propagation channel analysis with dual circular arrays

Dynamic double directional propagation channel analysis with dual circular arrays. (pp. 6 p). Peer reviewed versio

On the relationships among cloud cover, mixed-phase partitioning, and planetary albedo in GCMs

In this study, it is shown that CMIP5 global climate models (GCMs) that convert supercooled water to ice at relatively warm temperatures tend to have a greater mean-state cloud fraction and more negative cloud feedback in the middle and high latitude Southern Hemisphere. We investigate possible reasons for these relationships by analyzing the mixed-phase parameterizations in 26 GCMs. The atmospheric temperature where ice and liquid are equally prevalent (T5050) is used to characterize the mixed-phase parameterization in each GCM. Liquid clouds have a higher albedo than ice clouds, so, all else being equal, models with more supercooled liquid water would also have a higher planetary albedo. The lower cloud fraction in these models compensates the higher cloud reflectivity and results in clouds that reflect shortwave radiation (SW) in reasonable agreement with observations, but gives clouds that are too bright and too few. The temperature at which supercooled liquid can remain unfrozen is strongly anti-correlated with cloud fraction in the climate mean state across the model ensemble, but we know of no robust physical mechanism to explain this behavior, especially because this anti-correlation extends through the subtropics. A set of perturbed physics simulations with the Community Atmospheric Model Version 4 (CAM4) shows that, if its temperature-dependent phase partitioning is varied and the critical relative humidity for cloud formation in each model run is also tuned to bring reflected SW into agreement with observations, then cloud fraction increases and liquid water path (LWP) decreases with T5050, as in the CMIP5 ensemble

A Randomized Clinical Trial Comparing Individual Cognitive Behavioral Therapy and Child-Centered Therapy for Child Anxiety Disorders

This study compared individual cognitive behavioral therapy (CBT) and a supportive child-centered therapy (CCT) for child anxiety disorders on rates of treatment response and recovery at posttreatment and 1-year follow-up, as well as on real-world measures of emotional functioning. Youth (N = 133; ages 9–14) with anxiety disorders (generalized, separation, and/or social anxiety) were randomized using a 2:1 ratio to CBT (n = 90) or CCT (n = 43), which served as an active comparison. Treatment response and recovery at posttreatment and 1-year follow-up were assessed by Independent Evaluators, and youth completed ecological momentary assessment of daily emotions throughout treatment. The majority of youth in both CBT and CCT were classified as treatment responders (71.1% for CBT, 55.8% for CCT), but youth treated with CBT were significantly more likely to fully recover, no longer meeting diagnostic criteria for any of the targeted anxiety disorders and no longer showing residual symptoms (66.7% for CBT vs. 46.5% for CCT). Youth treated with CBT also reported significantly lower negative emotions associated with recent negative events experienced in daily life during the latter stages of treatment relative to youth treated with CCT. Furthermore, a significantly higher percentage of youth treated with CBT compared to CCT were in recovery at 1-year follow-up (82.2% for CBT vs. 65.1% for CCT). These findings indicate potential benefits of CBT above and beyond supportive therapy on the breadth, generalizability, and durability of treatment-related gains

Comprehensive analysis of type 1 fimbriae regulation in fimB -null strains from the multidrug resistant Escherichia coli ST131 clone

Summary\ud \ud Uropathogenic Escherichia coli (UPEC) of sequence type 131 (ST131) are a pandemic multidrug resistant clone associated with urinary tract and bloodstream infections. Type 1 fimbriae, a major UPEC virulence factor, are essential for ST131 bladder colonization. The globally dominant sub-lineage of ST131 strains, clade C/H30-R, possess an ISEc55 insertion in the fimB gene that controls phase-variable type 1 fimbriae expression via the invertible fimS promoter. We report that inactivation of fimB in these strains causes altered regulation of type 1 fimbriae expression. Using a novel read-mapping approach based on Illumina sequencing, we demonstrate that ‘off’ to ‘on’ fimS inversion is reduced in these strains and controlled by recombinases encoded by the fimE and fimX genes. Unlike typical UPEC strains, the nucleoid-associated H-NS protein does not strongly repress fimE transcription in clade C ST131 strains. Using a genetic screen to identify novel regulators of fimE and fimX in the clade C ST131 strain EC958, we defined a new role for the guaB gene in the regulation of type 1 fimbriae and in colonisation of the mouse bladder. Our results provide a comprehensive analysis of type 1 fimbriae regulation in ST131, and highlight important differences in its control compared to non-ST131 UPEC

The impact of hyperhidrosis on patients' daily life and quality of life : A qualitative investigation

Background: An understanding of the daily life impacts of hyperhidrosis and how patients deal with them, based on qualitative research, is lacking. This study investigated the impact of hyperhidrosis on the daily life of patients using a mix of qualitative research methods. Methods: Participants were recruited through hyperhidrosis patient support groups such as the Hyperhidrosis Support Group UK. Data were collected using focus groups, interviews and online surveys. A grounded theory approach was used in the analysis of data transcripts. Data were collected from 71 participants, out of an initial 100 individuals recruited. Results: Seventeen major themes capturing the impacts of hyperhidrosis were identified; these covered all areas of life including daily life, psychological well-being, social life, professional /school life, dealing with hyperhidrosis, unmet health care needs and physical impact. Conclusions: Psychosocial impacts are central to the overall impacts of hyperhidrosis, cutting across and underlying the limitations experienced in other areas of life.Peer reviewe

Bridging the data gaps in the epidemiology of hepatitis C virus infection in Malaysia using multi-parameter evidence synthesis

BACKGROUND: Collecting adequate information on key epidemiological indicators is a prerequisite to informing a public health response to reduce the impact of hepatitis C virus (HCV) infection in Malaysia. Our goal was to overcome the acute data shortage typical of low/middle income countries using statistical modelling to estimate the national HCV prevalence and the distribution over transmission pathways as of the end of 2009. METHODS: Multi-parameter evidence synthesis methods were applied to combine all available relevant data sources - both direct and indirect - that inform the epidemiological parameters of interest. RESULTS: An estimated 454,000 (95% credible interval [CrI]: 392,000 to 535,000) HCV antibody-positive individuals were living in Malaysia in 2009; this represents 2.5% (95% CrI: 2.2-3.0%) of the population aged 15-64 years. Among males of Malay ethnicity, for 77% (95% CrI: 69-85%) the route of probable transmission was active or a previous history of injecting drugs. The corresponding proportions were smaller for male Chinese and Indian/other ethnic groups (40% and 71%, respectively). The estimated prevalence in females of all ethnicities was 1% (95% CrI: 0.6 to 1.4%); 92% (95% CrI: 88 to 95%) of infections were attributable to non-drug injecting routes of transmission. CONCLUSIONS: The prevalent number of persons living with HCV infection in Malaysia is estimated to be very high. Low/middle income countries often lack a comprehensive evidence base; however, evidence synthesis methods can assist in filling the data gaps required for the development of effective policy to address the future public health and economic burden due to HCV. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0564-6) contains supplementary material, which is available to authorized users

A New Weighted k-Nearest Neighbor Algorithm Based on Newton¿s Gravitational Force

[EN] The kNN algorithm has three main advantages that make it appealing to the community: it is easy to understand, it regularly offers competitive performance and its structure can be easily tuning to adapting to the needs of researchers to achieve better results. One of the variations is weighting the instances based on their distance. In this paper we propose a weighting based on the Newton's gravitational force, so that a mass (or relevance) has to be assigned to each instance. We evaluated this idea in the kNN context over 13 benchmark data sets used for binary and multi-class classification experiments. Results in F1 score, statistically validated, suggest that our proposal outperforms the original version of kNN and is statistically competitive with the distance weighted kNN version as well.This research was partially supported by CONACYT-Mexico (project FC-2410). The work of Paolo Rosso has been partially funded by the SomEMBED TIN2015-71147-C2-1-P MINECO research project.Aguilera, J.; González, LC.; Montes-Y-Gómez, M.; Rosso, P. (2019). A New Weighted k-Nearest Neighbor Algorithm Based on Newton¿s Gravitational Force. Lecture Notes in Computer Science. 11401:305-313. https://doi.org/10.1007/978-3-030-13469-3_36S3053131140

In-Vitro Activity of Polymyxin B, Rifampicin, Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii in Singapore

OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CR-AB) is an emerging cause of nosocomial infections worldwide. Combination therapy may be the only viable option until new antibiotics become available. The objective of this study is to identify potential antimicrobial combinations against CR-AB isolated from our local hospitals. METHODS: AB isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All CR-AB isolates were genotyped using a PCR-based method. Clonal relationship was elucidated. Time-kill studies (TKS) were conducted with polymyxin B, rifampicin and tigecycline alone and in combination using clinically relevant (achievable) unbound concentrations. RESULTS: 31 CR AB isolates were identified. They are multidrug-resistant, but are susceptible to polymyxin B. From clonal typing, 8 clonal groups were identified and 11 isolates exhibited clonal diversity. In single TKS, polymyxin B, rifampicin and tigecycline alone did not exhibit bactericidal activity at 24 hours. In combination TKS, polymyxin plus rifampicin, polymyxin B plus tigecycline and tigecycline plus rifampicin exhibited bactericidal killing in 13/31, 9/31 and 7/31 isolates respectively at 24 hours. Within a clonal group, there may be no consensus with the types of antibiotics combinations that could still kill effectively. CONCLUSION: Monotherapy with polymyxin B may not be adequate against polymyxin B susceptible AB isolates. These findings demonstrate that in-vitro synergy of antibiotic combinations in CR AB may be strain dependant. It may guide us in choosing a pre-emptive therapy for CR AB infections and warrants further investigations