A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in Candida albicans.

Eukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis, and yet specific aneuploidies can be adaptive during environmental stress. Here, we identify a chromatin-based system required for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire tolerance to antifungal drugs and for nonmeiotic ploidy reduction after mating. We discovered that the ancestor of C. albicans and 2 related pathogens evolved a variant of histone 2A (H2A) that lacks the conserved phosphorylation site for kinetochore-associated Bub1 kinase, a key regulator of chromosome segregation. Using engineered strains, we show that the relative gene dosage of this variant versus canonical H2A controls the fidelity of chromosome segregation and the rate of acquisition of tolerance to antifungal drugs via aneuploidy. Furthermore, whole-genome chromatin precipitation analysis reveals that Centromere Protein A/ Centromeric Histone H3-like Protein (CENP-A/Cse4), a centromeric histone H3 variant that forms the platform of the eukaryotic kinetochore, is depleted from tetraploid-mating products relative to diploid parents and is virtually eliminated from cells exposed to aneuploidy-promoting cues. We conclude that genetically programmed and environmentally induced changes in chromatin can confer the capacity for enhanced evolvability via chromosome missegregation

Using the COM-B model to characterize the barriers and facilitators of pre-exposure prophylaxis (PrEP) uptake in men who have sex with men.

Using the COM-B model, this study aimed to characterize barriers and facilitators to pre-exposure prophylaxis (PrEP) uptake amongst men who have sex with men (MSM). Semistructured interviews with 13 MSM who were non-PrEP users were conducted with a specific focus on barriers and facilitators to PrEP uptake. A 15-item interview schedule was created informed by the COM-B model. Transcripts were transcribed verbatim and inductively analysed using thematic analysis. To illustrate pathways for intervention design, inductive themes were then deductively mapped onto COM-B constructs. Results demonstrated that barriers to PrEP uptake were closely aligned with five (of six) COM-B components: psychological capability, physical opportunity, social opportunity, reflective motivation and automatic motivation. These COM-B subcomponents reflected seven thematized barriers: (1) limited information about PrEP, (2) restricted access to PrEP, (3) gay identity and sexual stigmatization, (4) social and cultural stigmatization, (5) capabilities in treatment adherence, (6) optimistic bias about sexual behaviours and (7) calculating risk. No facilitators or physical capability concerns were demonstrated. This study adopted a novel behaviour change-informed approach to understanding barriers and facilitators to PrEP uptake amongst MSM. Unrealistic optimism about self-protective individual behaviours, the physical accessibility of PrEP and (mis)information together interacted closely with perceptions of personal and social stigmatization to dynamically impact PrEP uptake decisions. Barriers to PrEP uptake mapped clearly to the COM-B; therefore, these results provide the foundation for Behaviour Change Wheel intervention development to improve rates of PrEP uptake and its acceptability for MSM. [Abstract copyright: © 2022 The British Psychological Society.

Prevalence of Muscle Dysmorphia and Associated Health Activities in Male Medical Students in Karachi, Pakistan

Background: Muscle Dysmorphia (MD) is a subtype of body dysmorphic disorder (BDD) and is currently classified under anxiety disorders (subheading: Obsessive-compulsive disorder) in DSM 5. MD is hypothesized to affect the self-esteem and social outlook of the younger generation. MD shows a higher rate in males and may influence their self-confidence rendering them more prone towards using steroids, supplementary proteins and other drugs to alter their physical outlooks as shown in previous studies. This problem has been on the rise lately due to revolutionary advancement in the media and film industry and the abrupt changes about the standards of physical good looks and body shapes. With the lack of studies done in our population, our study will be helpful to consider the prevalence of the disease in our setting and increase awareness in the general public and clinicians. We hope to help clinicians/ therapists find better options in managing the disease. Materials: We performed a cross-sectional study with a sample size of 246 medical school students in Karachi to collect data through self-administered questionnaires. We used the DSM 5 criteria for the diagnosis of BDD and additional questions on the presence of MD. Nutritional habits, exercise routines, use of supplements and drugs were also obtained for exploratory analysis. Results: Our study predicted the prevalence of MD to be 25%. Other main findings included statistical significant associations between MD and the thoughts and practice of steroid use for muscularity. Conclusion: MD is an underdiagnosed and often unrecognized disease that we believe has significant consequences for the young male population. Further work is needed on this in our part of the world. Our research, we believe, can be a stepping stone for further studies that would incorporate wider populations

إيقاع الصورة الشعرية الداخلي عند فاروق جويدة (The rhythm of poetic image with Farouq Juwaidah)

تناول الباحث مفهوم الصورة الشعرية وناقش بعضا من تعريفاتها وخصائصها، والمؤثرات فيها وتصنيفاتها، وأنواع الإيقاع المؤثر فيها، وكان تركيز الباحث منصبا على الإيقاع الداخلي الذي تكونه الصورة الشعرية نفسها، والإيقاع الداخلي الذي يوظفه الشاعر في صورته الشعرية، وقد استخرجنا تمثيلا أربعة أنواع من أنواع الإيقاع الداخلي الذي تكونه الصورة الشعرية، في شعر فاروق جويدة، وهي الإيقاع التقابلي المتضاد، والإيقاع التسلسلي، وإيقاع العجز صدري، والإيقاع القصصي الشعري، وقد بينا مفاهيمها، وكيف استثمرها الشاعر في التكثيف الدلالي الشعري في قصائده. Abstract The researcher studied the concept of poetic image and discussed some of its definitions, characteristics, influences, classifications, and the types of rhythm that affected it. The researcher's focus was on the internal rhythm formed by the poetic image itself, and the internal rhythm that the poet uses in his poetic image. The researcher extracted, as examples, four types of internal rhythm that the poetic image forms in Farouk Juwaida's poetry, which are the contrasting contrast rhythm, the serial rhythm, the chest-back rhythm and poetic narrative rhythm. The researcher extracted, as examples, three types of internal rhythm formed by the poetic image in Farouk Juwaida's poetry, which are the contrasting contrast rhythm, the serial rhythm, and the rhythm of the chest sacrum, and he explained its concepts, and how the poet Semitic invested them in the poetic intensification in his poems

THE USE OF HPLC AS A TOOL FOR NEONATAL CORD BLOOD SCREENING OF HAEMOGLOBINOPATHY - A VALIDATION STUDY

Background: Newborn cord blood screening identifies infants with underlying haemoglobinopathies before they develop the characteristic symptoms or sequelae.  Aims: This study was performed to validate the interpretation high-performance chromatography (HPLC) along with complete blood count (CBC) results as a tool for universal neonatal screening of hemoglobin disorders in Oman.  Methods: HPLC and CBC data on subjects who participated in the National Neonatal screening program at birth were obtained from archival records. The results recorded at birth were compared with a second study performed on the same subjects, after approval from the local medical research and ethics committee. Results: Only 290 subjects from amongst the original cohort of 3740 newborns could be recalled between April 2010 to March 2011, to repeat HPLC and CBC, as well as perform confirmatory DNA studies, wherever necessary. All these subjects had been documented to show an initial abnormal result. 31 cases who had no HbA at birth on HPLC were confirmed as either homozygous β-thalassaemia major (n=5 subjects) or homozygous sickle cell anemia (n=26 subjects) by appropriate DNA analysis. Additionally, amongst 151 subjects, 72 subjects were studied in the initial study by Hb Bart’s quantitation using aalpha thalassaemia short program at birth. In this cohort, 42 subjects with Hb Bart’s >1% at birth could be confirmed as having either deletional or non-deletional thalassaemia by GAP PCR studies. No case of HbH was detected in this cohort. Further, carrier status for structural hemoglobin variants (HbS, HbC, HbD, HbE) (n=67) and beta thalassaemia allele with low HbA at birth (n=29 out of 41) were confirmed by relevant molecular studies. Conclusions: The study validated the earlier observation by 100% concordance with results of CBC and HPLC. Presence of Hb Bart’s at birth does not always mean the presence of alpha thalassemia, as subjects with Hb Bart’s was below 1% by quantitation, were shown to be normal by molecular studies.   Key Words: Neonatal, screening, HPLC validation, haemoglobinopathy, sickle cell disease, thalassaemi

Pheromone-Dependent Destruction of the Tec1 Transcription Factor Is Required for MAP Kinase Signaling Specificity in Yeast

AbstractThe yeast MAPK pathways required for mating versus filamentous growth share multiple components yet specify distinct programs. The mating-specific MAPK, Fus3, prevents crosstalk between the two pathways by unknown mechanisms. Here we show that pheromone signaling induces Fus3-dependent degradation of Tec1, the transcription factor specific to the filamentation pathway. Degradation requires Fus3 kinase activity and a MAPK phosphorylation site in Tec1 at threonine 273. Fus3 associates with Tec1 in unstimulated cells, and active Fus3 phosphorylates Tec1 on T273 in vitro. Destruction of Tec1 requires the F box protein Dia2 (Digs-into-agar-2), and Cdc53, the Cullin of SCF (Skp1-Cdc53-F box) ubiquitin ligases. Notably, mutation of the phosphoacceptor site in Tec1, deletion of FUS3, or deletion of DIA2 results in a loss of signaling specificity such that pheromone pathway signaling erroneously activates filamentation pathway gene expression and invasive growth. Signal-induced destruction of a transcription factor for a competing pathway provides a mechanism for signaling specificity

Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI).

AIM: Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this double-blind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 μmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6-8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6-8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size -0.7% 95% CI: -2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6-8 days and at 6 months and final infarct size (FIS) measured at 6 months. CONCLUSIONS: Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size