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Dysfunction of the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes a wide spectrum of disease, including cystic fibrosis (CF) and CFTR‐related diseases (CFTR‐RDs). Here, we investigate genotype–phenotype–CFTR function relationships using human nasal epithelial (hNE) cells from a small cohort of non‐CF subjects and individuals with CF and CFTR‐RDs and genotypes associated with either residual or minimal CFTR function using electrophysiological techniques. Collected hNE cells were either studied directly with the whole‐cell patch‐clamp technique or grown as primary cultures at an air–liquid interface after conditional reprogramming. The properties of cAMP‐activated whole‐cell Cl− currents in freshly isolated hNE cells identified them as CFTR‐mediated. Their magnitude varied between hNE cells from individuals within the same genotype and decreased in the rank order: non‐CF > CFTR residual function > CFTR minimal function. CFTR‐mediated whole‐cell Cl− currents in hNE cells isolated from fully differentiated primary cultures were identical to those in freshly isolated hNE cells in both magnitude and behaviour, demonstrating that conditional reprogramming culture is without effect on CFTR expression and function. For the cohort of subjects studied, CFTR‐mediated whole‐cell Cl− currents in hNE cells correlated well with CFTR‐mediated transepithelial Cl− currents measured in vitro with the Ussing chamber technique, but not with those determined in vivo with the nasal potential difference assay. Nevertheless, they did correlate with the sweat Cl− concentration of study subjects. Thus, this study highlights the complexity of genotype–phenotype–CFTR function relationships, but emphasises the value of conditionally reprogrammed hNE cells in CFTR research and therapeutic testing. Key points: The genetic disease cystic fibrosis is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel, which controls anion flow across epithelia lining ducts and tubes in the body.This study investigated CFTR function in nasal epithelial cells from people with cystic fibrosis and CFTR variants with a range of disease severity.CFTR function varied widely in nasal epithelial cells depending on the identity of CFTR variants, but was unaffected by conditional reprogramming culture, a cell culture technique used to grow large numbers of patient‐derived cells.Assessment of CFTR function in vitro in nasal epithelial cells and epithelia, and in vivo in the nasal epithelium and sweat gland highlights the complexity of genotype–phenotype–CFTR function relationships. [ABSTRACT FROM AUTHOR]

Objective: Memory symptoms and objective impairment are common in HIV disease and are associated with disability. A paradoxical issue is that objective episodic memory failures can interfere with accurate recall of memory symptoms. The present study assessed whether responses on a self-report scale of memory symptoms demonstrate measurement invariance in persons with and without objective HIV-associated memory impairment. Method: In total, 505 persons with HIV completed the Prospective and Retrospective Memory Questionnaire (PRMQ). Objective memory impairment (n = 141) was determined using a 1-SD cutoff on clinical tests of episodic memory. PRMQ measurement invariance was assessed by confirmatory factor analyses examining a one-factor model with increasing cross-group equality constraints imposed on factor loadings and item thresholds (i.e., configural, weak, and strong invariance). Results: Configural model fit indicated that identical items measured a one-factor model for both groups. Comparison to the weak model indicated that factor loadings were equivalent across groups. However, there was evidence of partial strong invariance, with two PRMQ item thresholds differing across memory impairment groups. Post hoc analyses using a 1.5-SD memory impairment cutoff (n = 77) revealed both partial weak and partial strong invariance, such that PRMQ item loadings differed across memory groups for three items. Conclusions: The PRMQ demonstrated a robust factor structure among persons with and without objective HIV-associated memory impairment. However, on select PRMQ items, individuals with memory impairment reported observed scores that were relatively higher than their latent score, while items were more strongly associated with the memory factor in a group with greater memory impairment. [ABSTRACT FROM AUTHOR]

Effective community involvement programs and programs for the conservation of protected areas should be combined for the simultaneous benefit of people living near a protected area and the area itself. Management of parks by non-governmental organizations or by the private sector will increase tourist revenue, but exploitation of the parks to create tourist attractions should not distract them from protecting the area. Revenue from tourism will benefit local communities and improve their standards of living.

A modular, UNIX/X-Windows/Sun SPARC-based data acquisition and analysis system provides NASA X-Ray Timing Explorer (XTE) Proportional Counter Array (PCA) scientists with near real-time access to space flight instrument ground test data. This system processes data directly from five large-area, xenon-filled low-background collimated proportional counters at rates up to 2 MB/s in a networked, real-time environment. Science events are sent serially from the proportional counter flight electronics and multiplexed on a custom-designed data acquisition board. Each event is tagged with a time stamp of 1 [[micro]second] resolution and a detector identifier. A commercial Direct Memory Access (DMA) board interfaces directly to the data acquisition board allowing asynchronous transfer of buffered data to software residing on a high performance workstation. A windows-based interface provides an operator with acquisition command and control functions to capture data through the DMA board. Data is collected, buffered, and archived to magnetic disk. Histogramming and statistical functions are provided by the software enabling real-time pulse height spectroscopy, rate analysis, and spectral analysis.

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chlorine channel expressed in apical and basolateral membranes in infected Fischer rat thyroid (FRT) epithelial cells. The chlorine channel is regulated by adenosine 3',5'-cyclic monophosphate (cAMP) phosphorylation even at low CFTR expressions. FRT epethelial dysfunction caused by three mutants reduces the level of apical chlorine current.

Mutant D836X that encodes the amino-terminal region of the cystic fibrosis transmembrane conductance regulator (CFTR) with a membrane-spanning domain and a nucleotide binding domain NBD. The R Domain constitutes a controlled chloride channel with characteristics that are similar to that of the wild-type channel. Activity increased with phosphorylation but conductance did not require phosphorylation.

EutR, a regulatory protein, regulates the expression of the ethanolamine utilization (eut) operon, in the presence of ethanolamine and adenosyl-cobalamin (Ado-B12). EutR is present within eut operon, and this provides a balance in the struggle for small quantities of Ado-B12 between lyase and eutR. Simultaneous stimulation of lyase and Ado-B12 leads to sustained eut operon induction and lyase activity.

Missense mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) are associated with milder cystic fibrosis. Replacements of arginine with histidine at residue 117, tryptophan at residue 334 or proline at residue 347 affect basic amino acids located at the external end of the second and the sixth putative membrane-spanning sequences. It is reported that all three mutants are correctly processed and generate cyclic AMP-regulated Cl- currents when expressed in heterologous epithelial cells.

Zora Neale Hurston's 'Their Eyes Were Watching God' deals with protagonist Janie's restless pursuit of a godhead to give meaning and order to her life. As Janie moves forward she experiences god-constructs that bring her steadily closer to her true godhead. This Modernist theme reveals Sigmund Freud's powerful influence on Hurston. Janie at last finds her optimum god-construct, reflecting Hurston's belief that God will be different for each person.

Adenosine triphosphate (ATP) dependent-potassium channel inhibitors and activators were examined to evaluate their effect on cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel regulated by ATP. Of the inhibitors tested, glibenclamide was determined to be the most effective blocker of CFTR. Potassium channel activators, on the other hand, proved to be inhibitory on CFTR. The order of inhibitory effect is diazoxide < tolbutamide < minoxidil sulfate = BRL 38227 < glibenclamide.

Many law enforcement agencies and child protective service (CPS) units of public child welfare agencies across the nation are conducting joint investigations of reported child abuse. The impetus for this [...]

The gasotransmitter carbon monoxide (CO) regulates fluid and electrolyte movements across epithelial tissues. However, its action on anion channels is incompletely understood. Here, we investigate the direct action of CO on the cystic fibrosis transmembrane conductance regulator (CFTR) by applying CO-releasing molecules (CO-RMs) to the intracellular side of excised inside-out membrane patches from cells heterologously expressing wild-type human CFTR. Addition of increasing concentrations of tricarbonyldichlororuthenium(II) dimer (CORM-2) (1–300 μM) inhibited CFTR channel activity, whereas the control RuCl3 (100 μM) was without effect. CORM-2 predominantly inhibited CFTR by decreasing the frequency of channel openings and, hence, open probability (Po). But, it also reduced current flow through open channels with very fast kinetics, particularly at elevated concentrations. By contrast, the chemically distinct CO-releasing molecule CORM-3 inhibited CFTR by decreasing Po without altering current flow through open channels. Neither depolarizing the membrane voltage nor raising the ATP concentration on the intracellular side of the membrane affected CFTR inhibition by CORM-2. Interestingly, CFTR inhibition by CORM-2, but not by CFTRinh-172, was prevented by prior enhancement of channel activity by the clinically approved CFTR potentiator ivacaftor. Similarly, when added after CORM-2, ivacaftor completely relieved CFTR inhibition. In conclusion, CORM-2 has complex effects on wild-type human CFTR consistent with allosteric inhibition and open-channel blockade. Inhibition of CFTR by CO-releasing molecules suggests that CO regulates CFTR activity and that the gasotransmitter has tissue-specific effects on epithelial ion transport. The action of ivacaftor on CFTR Cl− channels inhibited by CO potentially expands the drug’s clinical utility. [ABSTRACT FROM AUTHOR]

Objective: Older adults commonly experience declines in everyday functioning, the reasons for which are multifactorial. Prospective memory (PM), or remembering to carry out intended actions, can be an executively demanding cognitive process that declines with older age and is independently associated with a variety of everyday functions (e.g. taking medication). This study examined the hypothesis that PM mediates the relationship between older age and poorer everyday functioning. Method: A total of 468 community-dwelling adults (ages 18–75) with a range of medical comorbidities (e.g. viral infection) were classified as dependent on four well-validated measures of manifest everyday functioning: activities of daily living, employment status, the Karnofsky Scale of Performance Status, and self-reported cognitive symptoms. Participants completed the Memory for Intentions Test (MIsT) to measure PM, alongside clinical tests of executive functions and retrospective memory. Results: Controlling for education and comorbidities, bootstrap analysis revealed a significant direct effect of age on everyday functioning and a significant mediated effect of age on everyday functioning through the indirect effect of time-based b =.006 [.003,.010] and event-based PM (b =.005, [.002,.009]), as well as slightly smaller effects for executive functions (b =.003, [.001,.005]) and retrospective memory (b =.002, [.001,.005]). Conclusions: These cross-sectional data suggest that executively demanding aspects of declarative memory play an important partial mediating role between an individual factor (i.e. age) and daily life activities, and highlight the possible benefit of targeting PM for improving everyday functioning in older adults. [ABSTRACT FROM AUTHOR]

Objective: We investigated the construct and criterion validity of the source memory (SM) indices within the California Verbal Learning Test-II (CVLT-II). Method: Participants included 77 individuals with HIV-associated neurocognitive disorders (HAND+), 287 HIV + neurocognitively normal individuals (HAND−) and 203 seronegative HIV comparisons (HIV−). CVLT-II SM impairment status (normative scores ≤1 standard deviation) was determined using Total Across-List Intrusions and Source Recognition Discriminability (d′). Participants also completed a comprehensive neuropsychological battery, assessments of everyday functioning and experimental measures of SM. Results: CVLT-II SM impairment was significantly associated with increased errors on experimental SM measures and lower scores on measures of passage recall and executive functions, but not visuospatial skills. In a logistic regression controlling for clinicodemographic factors, CVLT-II SM impairment was a significant independent predictor of HAND, with the HAND + group showing higher rates of SM impairment than both the HAND − and HIV − groups. Finally, CVLT-II SM impairment was significantly related to a composite measure of everyday functioning, but this effect disappeared after adjusting for covariates. Note that, the overall pattern of findings across this study also held when CVLT-3 normative standards were applied to the SM indices. Conclusions: Results provide initial support for the construct and criterion validity of a CVLT-II SM index in the setting of HIV disease. Future studies should examine the validity of CVLT-II SM variables in other neuropsychological populations. [ABSTRACT FROM AUTHOR]