Microwave-assisted synthesis of a MK2 inhibitor by Suzuki-Miyaura coupling for study in Werner syndrome cells

Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells

Sexual Wellness and Rare Disease Considerations: A Behavioral Case Conceptualization and Approach to Counseling Treatment

Sexual wellness is infrequently addressed with individuals with a rare disease. Counselors must be competent in working with sexual wellness issues, especially those related to medical conditions, since clients may not share those concerns with healthcare providers. This article presents a case scenario involving a client living with a rare disease called Hereditary Angioedema, the symptoms of which present challenges to her intimate and sexual relationship with her partner due to unpredictable and painful swelling. A behavioral theoretical lens is used to conceptualize the case scenario and inform treatment. Implications for counselor competency, interdisciplinary collaboration, and client empowerment toward advocacy are discussed

The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells

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Early childhood lung function is a stronger predictor of adolescent lung function in cystic fibrosis than early Pseudomonas aeruginosa infection

Pseudomonas aeruginosa has been suggested as a major determinant of poor pulmonary outcomes in cystic fibrosis (CF), although other factors play a role. Our objective was to investigate the association of early childhood Pseudomonas infection on differences in lung function in adolescence with CF

Cognitive and psychomotor responses to high-altitude exposure in sea level and high-altitude residents of Ecuador

Background High-altitude inhabitants have cardiovascular and respiratory adaptations that are advantageous for high-altitude living, but they may have impaired cognitive function. This study evaluated the influence of altitude of residence on cognitive and psychomotor function upon acute exposure to very high altitude. Findings Ecuadorians (31 residing at 0–1,500 m [LOW], 78 from 1,501–3,000 m [MOD], and 23 living \u3e3,000 m [HIGH]) were tested upon their arrival to a hut at 4,860 m on Mount Chimborazo. Cognitive/psychomotor measurements included a go-no-go test (responding to a non-visual stimulus), a verbal fluency test (verbalizing a series of words specific to a particular category), and a hand movement test (rapidly repeating a series of hand positions). Mean differences between the three altitude groups on these cognitive/psychomotor tests were evaluated with one-way ANOVA. There were no significant differences (p = 0.168) between LOW, MOD, and HIGH for the verbal fluency test. However, the go-no-go test was significantly lower (p \u3c 0.001) in the HIGH group (8.8 ± 1.40 correct responses) than the LOW (9.8 ± 0.61) or MOD (9.8 ± 0.55) groups, and both MOD (97.9 ± 31.2) and HIGH (83.5 ± 26.7) groups completed fewer correct hand movements than the LOW (136.6 ± 37.9) subjects (p \u3c 0.001). Conclusions Based on this field study, high-altitude residents appear to have some impaired cognitive function suggesting the possibility of maladaptation to long-term exposure to hypobaric hypoxia

Nonsuicidal Self-injury as a Risk Factor for Purging Onset: Negatively Reinforced Behaviours that Reduce Emotional Distress

Both nonsuicidal self-injury (NSSI) and purging behaviour are thought to involve harm to the self. The acquired capability for self-harm model holds that engaging in one self-harming behaviour increases the capability to tolerate harm to the self, thus increasing risk for engaging on other such behaviours. In addition, both behaviours are thought to serve the similar function of relief from distress. We thus tested whether engagement in one of these behaviours predicts the subsequent onset of the other. In a longitudinal design, 1158 first-year college women were assessed for purging and NSSI at two time points. Engagement in NSSI at time 1 predicted the college onset of purging behaviour 9 months later (OR = 2.20, p \u3c .04, CI = 1.07-4.19) beyond prediction from time 1 binge behaviour, and purging behaviour at time 1 predicted the subsequent onset of NSSI (OR = 6.54, p \u3c .01, CI = 1.71-25.04). These findings are consistent with the acquired capability for harm model and with the possibility that the two behaviours serve a similar function

An Event-Level Evaluation of Women’s Self-Medicated Drinking: The Role of Sexual Assault Severity, Affect, and Drinking Motives

Objective.—Women with sexual assault (SA) histories report heavier and more frequent drinking. Consistent with the motivational model of alcohol use, women with SA histories may consume alcohol to both down-regulate negative emotions and up-regulate positive ones. The present event-level study used a Bayesian multilevel moderated mediation approach to examine the extent to which women’s alcohol use and intoxication was influenced by coping and enhancement drinking motives to down-regulate or up-regulate affect, respectively. Method.—Women ages 21–30 were recruited from the community to participate in a larger study that included a 32-day daily diary assessment of affect, drinking motives, and alcohol use. Results.—We found consistent support for women’s tendencies to be motivated to drink to cope or enhance negative or positive affect, respectively, and those drinking motives were associated with indicators of increased drinking. Becoming intoxicated to down-regulate negative emotion was common and this pathway was particularly strong for women who reported more severe SA histories. Although women with more severe SA histories were generally more likely to drink more, they were not likely to do so as a way to enhance positive experiences. Conclusions.—Alcohol interventions that provide adaptive regulatory strategies are needed for women who experience increased negative or positive affect, with a particular focus on self-medication for young women with more severe SA histories

Home-based tuberculosis contact investigation in Uganda: a household randomised trial.

IntroductionThe World Health Organization (WHO) recommends household tuberculosis (TB) contact investigation in low-income countries, but most contacts do not complete a full clinical and laboratory evaluation.MethodsWe performed a randomised trial of home-based, SMS-facilitated, household TB contact investigation in Kampala, Uganda. Community health workers (CHWs) visited homes of index patients with pulmonary TB to screen household contacts for TB. Entire households were randomly allocated to clinic (standard-of-care) or home (intervention) evaluation. In the intervention arm, CHWs offered HIV testing to adults; collected sputum from symptomatic contacts and persons living with HIV (PLWHs) if ≥5 years; and transported sputum for microbiologic testing. CHWs referred PLWHs, children <5 years, and anyone unable to complete sputum testing to clinic. Sputum testing results and/or follow-up instructions were returned by automated SMS texts. The primary outcome was completion of a full TB evaluation within 14 days; secondary outcomes were TB and HIV diagnoses and treatments among screened contacts.ResultsThere were 471 contacts of 190 index patients allocated to the intervention and 448 contacts of 182 index patients allocated to the standard-of-care. CHWs identified 190/471 (40%) intervention and 213/448 (48%) standard-of-care contacts requiring TB evaluation. In the intervention arm, CHWs obtained sputum from 35/91 (39%) of sputum-eligible contacts and SMSs were sent to 95/190 (50%). Completion of TB evaluation in the intervention and standard-of-care arms at 14 days (14% versus 15%; difference -1%, 95% CI -9% to 7%, p=0.81) and yields of confirmed TB (1.5% versus 1.1%, p=0.62) and new HIV (2.0% versus 1.8%, p=0.90) diagnoses were similar.ConclusionsHome-based, SMS-facilitated evaluation did not improve completion or yield of household TB contact investigation, likely due to challenges delivering the intervention components

Whole-Genome Sequencing and Concordance Between Antimicrobial Susceptibility Genotypes and Phenotypes of Bacterial Isolates Associated with Bovine Respiratory Disease.

Extended laboratory culture and antimicrobial susceptibility testing timelines hinder rapid species identification and susceptibility profiling of bacterial pathogens associated with bovine respiratory disease, the most prevalent cause of cattle mortality in the United States. Whole-genome sequencing offers a culture-independent alternative to current bacterial identification methods, but requires a library of bacterial reference genomes for comparison. To contribute new bacterial genome assemblies and evaluate genetic diversity and variation in antimicrobial resistance genotypes, whole-genome sequencing was performed on bovine respiratory disease-associated bacterial isolates (Histophilus somni, Mycoplasma bovis, Mannheimia haemolytica, and Pasteurella multocida) from dairy and beef cattle. One hundred genomically distinct assemblies were added to the NCBI database, doubling the available genomic sequences for these four species. Computer-based methods identified 11 predicted antimicrobial resistance genes in three species, with none being detected in M. bovis While computer-based analysis can identify antibiotic resistance genes within whole-genome sequences (genotype), it may not predict the actual antimicrobial resistance observed in a living organism (phenotype). Antimicrobial susceptibility testing on 64 H. somni, M. haemolytica, and P. multocida isolates had an overall concordance rate between genotype and phenotypic resistance to the associated class of antimicrobials of 72.7% (P < 0.001), showing substantial discordance. Concordance rates varied greatly among different antimicrobial, antibiotic resistance gene, and bacterial species combinations. This suggests that antimicrobial susceptibility phenotypes are needed to complement genomically predicted antibiotic resistance gene genotypes to better understand how the presence of antibiotic resistance genes within a given bacterial species could potentially impact optimal bovine respiratory disease treatment and morbidity/mortality outcomes