A Functional Role for 4qA/B in the Structural Rearrangement of the 4q35 Region and in the Regulation of FRG1 and ANT1 in Facioscapulohumeral Dystrophy

The number of D4Z4 repeats in the subtelomeric region of chromosome 4q is strongly reduced in patients with Facio-Scapulo-Humeral Dystrophy (FSHD). We performed chromosome conformation capture (3C) analysis to document the interactions taking place among different 4q35 markers. We found that the reduced number of D4Z4 repeats in FSHD myoblasts was associated with a global alteration of the three-dimensional structure of the 4q35 region. Indeed, differently from normal myoblasts, the 4qA/B marker interacted directly with the promoters of the FRG1 and ANT1 genes in FSHD cells. Along with the presence of a newly identified transcriptional enhancer within the 4qA allele, our demonstration of an interaction occurring between chromosomal segments located megabases away on the same chromosome 4q allows to revisit the possible mechanisms leading to FSHD

Опыт применения фокусированного ультразвукового исследования сердца у пациентов с COVID-19 в Prone-позиции

Aim of the study. To study the experience of using focused transthoracic echocardiography in patients with COVID-19 in prone position (fEchoPr) in intensive care units (ICU).Materials and methods. The retrospective observational study included 53 patients (period from 15 April to 31 December 2020). Inclusion criteria: confirmed diagnosis of COVID-19, availability of fEchoPr data, outcome certainty (discharge/death). We analyzed electronic medical records. The fEchoPr was performed in patients in the prone position with a bolster under the left side of the chest and left arm raised (‘swimmer’s position’). We assessed the systolic function of the right ventricle (RV) (tricuspid annular plane systolic excursion (TAPSE)), RV size, RV/LV ratio, systolic function of the left ventricle (LV) (left ventricular outflow tract velocity time integral. (LVOT VTI)), and pulmonary hypertension (PH) (tricuspid regurgitation peak gradient (PGTR). Depending on the results, the patients were divided into 2 groups: informative (+fEchoPr) and non-informative (–fEchoPr) examinations.Results. There was no statistically significant difference in the groups (+fEcho n = 35 vs –fEcho n = 18) by age (65.6 ± 15.3 vs 60.2 ± 15.8, p > 0.05), by gender (male: 23 (65.7%) vs 14 (77.8%), p > 0.05), by body mass index (31.3 ± 5.3 kg/m 2 vs 29.5 ± 5.4 kg/m2 , p > 0.05), by mechanical ventilation support (24 (68.6%) vs 17 (94.4%), p = 0.074), by NEWS scale indicators (6.9 ± 3.7 vs 8.5 ± 3.5 points), by mortality (82.8% vs 94.4%, p > 0.05). Correlation analysis revealed a moderate inverse relationship between being on mechanical ventilation and the informative value of the study (Spearman's r = −0.30 at p = 0.033). In the +fEchoPr group, the correct measurement of TAPSE and RV/LV was carried out in 100%: a decrease in RV systolic function was recorded in 5 patients (14%), expansion of the RV in 13 patients (37%). Signs of PH were detected in 11 patients (31%), PGTR could not be measured in 10 patients (28%). LV systolic dysfunction was detected in 7 patients (20%). No pathology was detected in 16 patients (46%). One patient was diagnosed with infective endocarditis of native mitral valve, which was later confirmed by autopsy.Conclusion. In 66% of cases, fEchoPr examinations were informative, especially in terms of assessing the state of the right heart. fEchoPr examination is an affordable, valid and reproducible method to assess and monitor the state of the heart in ICU patients.Цель исследования: изучение опыта применения фокусированного трансторакального эхокардиографического исследования в Prone-позиции (фЭхоPr) в отделениях реанимации и интенсивной терапии (ОРИТ) у пациентов с COVID-19.Материал и методы. В ретроспективное наблюдательное исследование включено 53 пациента (период 15.04–31.12.20). Критерии включения: подтвержденный диагноз COVID-19, наличие данных фЭхоPr, определенность исхода (выписка/смерть). Анализировались электронные истории болезни. фЭхоPr выполнялось в положении пациента на животе с валиком под левой частью грудной клетки и поднятой левой рукой (“поза пловца”). Проводилась оценка систолической функции правого желудочка (ПЖ) (измерение экскурсии фиброзного кольца трикуспидального клапана (TAPSE)), размера ПЖ, систолической функции левого желудочка (ЛЖ) (измерение интеграла линейной скорости кровотока в выходном тракте ЛЖ (VTIвтлж)), параметра ПЖ/ЛЖ, легочной гипертензии (ЛГ) (измерение пикового градиента трикуспидальной регургитации (PGTR)). В зависимости от результатов пациенты были разделены на 2 группы: информативные (+фЭхоPr) и неинформативные (−фЭхоPr) исследования.Результаты. Не выявлено статистически значимой разницы в группах (+фЭхоPr n = 35 vs -фЭхоPr n = 18) по возрасту (65,6 ± 15,3 года vs 60,2 ± 15,8 года, р > 0,05), полу (муж.: 23 (65,7%) vs 14 (77,8%), р > 0,05), индексу массы тела (31,3 ± 5,3 кг/м 2 vs 29,5 ± 5,4 кг/м2 , р > 0,05), нахождению на искусственной вентиляции легких (ИВЛ) (24 (68,6%) vs 17 (94,4%), р = 0,074), показателям шкалы NEWS (6,9 ± 3,7 vs 8,5 ± 3,5 балла), летальности (82,8% vs 94,4%, р > 0,05). Корреляционный анализ выявил умеренную обратную связь между нахождением на ИВЛ и информативностью исследования (r-Спирмена = −0,30 при р = 0,033). В группе +фЭхоPr корректное измерение TAPSE и ПЖ/ЛЖ проведено в 100%: снижение систолической функции ПЖ зафиксировано у 5 (14%), расширение ПЖ у 13 (37%) пациентов. Признаки ЛГ выявлены у 11 (31%), измерить PGTR не удалось у 10 (28%) человек. Систолическая дисфункция ЛЖ выявлена у 7 (20%). Не было выявлено патологии у 16 (46%) пациентов. У одного пациента диагностирован инфекционный эндокардит нативного митрального клапана, подтвердившийся при проведении аутопсии.Заключение. В 66% случаев проведение фЭхоPr было информативным, особенно в части оценки состояния правых отделов сердца. фЭхоPr – доступный, валидный и воспроизводимый метод оценки и мониторинга состояния сердца у пациентов в ОРИТ

DUX4c Is Up-Regulated in FSHD. It Induces the MYF5 Protein and Human Myoblast Proliferation

Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contractions of the D4Z4 repeat array in 4q35. We have previously identified a double homeobox gene (DUX4) within each D4Z4 unit that encodes a transcription factor expressed in FSHD but not control myoblasts. DUX4 and its target genes contribute to the global dysregulation of gene expression observed in FSHD. We have now characterized the homologous DUX4c gene mapped 42 kb centromeric of the D4Z4 repeat array. It encodes a 47-kDa protein with a double homeodomain identical to DUX4 but divergent in the carboxyl-terminal region. DUX4c was detected in primary myoblast extracts by Western blot with a specific antiserum, and was induced upon differentiation. The protein was increased about 2-fold in FSHD versus control myotubes but reached 2-10-fold induction in FSHD muscle biopsies. We have shown by Western blot and by a DNA-binding assay that DUX4c over-expression induced the MYF5 myogenic regulator and its DNA-binding activity. DUX4c might stabilize the MYF5 protein as we detected their interaction by co-immunoprecipitation. In keeping with the known role of Myf5 in myoblast accumulation during mouse muscle regeneration DUX4c over-expression activated proliferation of human primary myoblasts and inhibited their differentiation. Altogether, these results suggested that DUX4c could be involved in muscle regeneration and that changes in its expression could contribute to the FSHD pathology

About the role of sulfur and nitrogen in forming of mechanical characteristics in cast steel

The role of the nitrogen-containing sulfides and nitrides in forming of mechanical characteristics of cast- steel is shown