КЛИНИЧЕСКИЙ СЛУЧАЙ ВЕДЕНИЯ ПАЦИЕНТА С ЭКСТРЕМАЛЬНОЙ ГИПЕРТРОФИЧЕСКОЙ КАРДИОМИОПАТИЕЙ И РЕЦИДИВИРУЮЩИМ ИДИОПАТИЧЕСКИМ ГИДРОПЕРИКАРДОМ

HighlightsWe report a case of a patient with extreme hypertrophic cardiomyopathy and complex cardiac pathology undergoing heart transplantation. The article will be useful for cardiologists, therapists and cardiovascular surgeons. AbstractWe present a case of a patient with extreme hypertrophic cardiomyopathy, Wolff–Parkinson–White syndrome and nonspecific chronic exudative pericardial effusion with recurrent idiopathic transudative pericardial effusion. This case involves several approaches to treatment – medication and surgery for treating a patient with combined cardiomyopathy and pericardial effusion, which served as a “bridge” for a later change inro radical treatment - orthotopic heart transplantation.Основные положенияОписан редкий случай экстремальной гипертрофической кардиомиопатии у пациента с комплексной кардиологической патологией, особенности ведения которого позволили дождаться этапа радикального хирургического лечения в виде трансплантации сердца. Статья будет полезна кардиологам, терапевтам и сердечно-сосудистым хирургам. РезюмеВ рамках клинического случая представлен портрет пациента с экстремальной гипертрофической кардиомиопатией, синдромом Вольфа – Паркинсона – Уайта и неспецифическим хроническим экссудативным перикардитом с рецидивирующим гидроперикардом идиопатического генеза. Данный случай актуален комплексным подходом – выбором как медикаментозного, так и интервенционного, хирургического способов лечения пациента с сочетанной кардиологической патологией, которые явились «мостом» для радикального лечения в виде ортотопической трансплантации сердца.

«Портрет» пациентов c легочной гипертензией на фоне приобретенного порока митрального Клапана сердца до хирургической коррекции

Aim. To study “the portrait” of patients with acquired mitral valve (MV) heart disease of various origins and pulmonary hypertension hospitalized for surgical correction of the defect.Methods. The study included 97 patients with acquired diseases of mitral valve and pulmonary hypertension. The assessment of demographic, clinical and anamnestic data, indicators of transthoracic echocardiography, quality of life before the correction of MV defect was carried out.Results. The studied cohort is mostly represented by female patients (n = 70; 72.2%). The most common cause of mitral valve disease was rheumatic heart disease (n = 40; 41.2%). Overweight, hypertension (n = 76; 78.4%) and atrial fibrillation (n = 62; 63.9%) were the most common comorbidities. The mean pressure level in the pulmonary artery according to echocardiography was 35.5 (29.0; 40.0) mm Hg, with no significant difference among the patients, regardless the mitral defect etiology. Less pronounced remodeling of the left ventricle was noted in patients with rheumatic heart disease, which is caused by a lesion of the MV by the type of stenosis in contrast to patients with connective tissue dysplasia syndrome or against the background of detachment of MV chords with MV damage in the form of its insufficiency. There were no significant differences in the systolic function of the right ventricle depending on the etiology of MV defect.Conclusion. The “portrait” of a patient with pulmonary hypertension associated with an acquired mitral valve defect before its correction is the predominance of female, overweight, with II or III functional class of chronic heart failure, more frequent rheumatic genesis of MV defect, the presence of concomitant pathology in the form of hypertension and persistent atrial fibrillation, and increased size of the left atrium and left ventricle, reduced systolic function of the right ventricle according to the data of Echocardiography. Цель. Изучить «портрет» больных приобретенным пороком митрального клапана (МК) различного генеза и легочной гипертензией, госпитализированных для хирургической коррекции патологии.Материалы и методы В исследование включены 97 пациентов с приобретенными пороками МК и легочной гипертензией. Оценены демографические, клинико-анамнестические данные, показатели трансторакальной эхокардиографии, качества жизни до коррекции порока МК. Результаты Исследуемая когорта представлена в большей степени больными женского пола (n = 70; 72,2%). Чаще всего причиной порока МК была ревматическая болезнь сердца (n = 40; 41,2%). Избыточная масса тела, гипертоническая болезнь (n = 76; 78,4%) и фибрилляция предсердий (n = 62; 63,9%) – наиболее частые сопутствующие патологии. Уровень среднего давления в легочной артерии по данным эхокардиографии составил 35,5 (29,0; 40,0) мм рт. ст., значимо не различаясь у пациентов независимо от этиологии митрального порока. Менее выраженное ремоделирование левого желудочка отмечено у лиц с ревматической болезнью сердца, что обусловлено поражением МК по типу стеноза, по сравнению с пациентами с синдромом соединительно-тканной дисплазии или на фоне отрыва хорд МК, имеющих поражение МК в виде его недостаточности. Значимых различий в систолической функции правого желудочка в зависимости от этиологии порока МК не выявлено.Заключение. «Портрет» пациента с легочной гипертензией, ассоциированной с приобретенным пороком МК до его коррекции, включает: преобладание женского пола, избыточную массу тела, II–III функциональный класс хронической сердечной недостаточности, более частый ревматический генез порока МК, наличие сопутствующей патологии в виде гипертонической болезни и персистирующей формы фибрилляции предсердий, увеличенные размеры левого предсердия и левого желудочка, сниженную систолическую функцию правого желудочка по данным эхокардиографии.

Identifying Determinants of Cullin Binding Specificity Among the Three Functionally Different Drosophila melanogaster Roc Proteins via Domain Swapping

BACKGROUND: Cullin-dependent E3 ubiquitin ligases (CDL) are key regulators of protein destruction that participate in a wide range of cell biological processes. The Roc subunit of CDL contains an evolutionarily conserved RING domain that binds ubiquitin charged E2 and is essential for ubiquitylation. Drosophila melanogaster contains three highly related Roc proteins: Roc1a and Roc2, which are conserved in vertebrates, and Roc1b, which is specific to Drosophila. Our previous genetic data analyzing Roc1a and Roc1b mutants suggested that Roc proteins are functionally distinct, but the molecular basis for this distinction is not known. METHODOLOGY/PRINCIPAL FINDINGS: Using co-immunoprecipitation studies we show that Drosophila Roc proteins bind specific Cullins: Roc1a binds Cul1-4, Roc1b binds Cul3, and Roc2 binds Cul5. Through domain swapping experiments, we demonstrate that Cullin binding specificity is strongly influenced by the Roc NH(2)-terminal domain, which forms an inter-molecular beta sheet with the Cullin. Substitution of the Roc1a RING domain with that of Roc1b results in a protein with similar Cullin binding properties to Roc1a that is active as an E3 ligase but cannot complement Roc1a mutant lethality, indicating that the identity of the RING domain can be an important determinant of CDL function. In contrast, the converse chimeric protein with a substitution of the Roc1b RING domain with that of Roc1a can rescue the male sterility of Roc1b mutants, but only when expressed from the endogenous Roc1b promoter. We also identified mutations of Roc2 and Cul5 and show that they cause no overt developmental phenotype, consistent with our finding that Roc2 and Cul5 proteins are exclusive binding partners, which others have observed in human cells as well. CONCLUSIONS: The Drosophila Roc proteins are highly similar, but have diverged during evolution to bind a distinct set of Cullins and to utilize RING domains that have overlapping, but not identical, function in vivo

CSN-mediated deneddylation differentially modulates Ci155 proteolysis to promote Hedgehog signalling responses

The Hedgehog (Hh) morphogen directs distinct cell responses according to its distinct signalling levels. Hh signalling stabilizes transcription factor cubitus interruptus (Ci) by prohibiting SCFSlimb-dependent ubiquitylation and proteolysis of Ci. How graded Hh signalling confers differential SCFSlimb-mediated Ci proteolysis in responding cells remains unclear. Here, we show that in COP9 signalosome (CSN) mutants, in which deneddylation of SCFSlimb is inactivated, Ci is destabilized in low-to-intermediate Hh signalling cells. As a consequence, expression of the low-threshold Hh target gene dpp is disrupted, highlighting the critical role of CSN deneddylation on low-to-intermediate Hh signalling response. The status of Ci phosphorylation and the level of E1 ubiquitin-activating enzyme are tightly coupled to this CSN regulation. We propose that the affinity of substrate–E3 interaction, ligase activity and E1 activity are three major determinants for substrate ubiquitylation and thereby substrate degradation in vivo

Neurospora COP9 Signalosome Integrity Plays Major Roles for Hyphal Growth, Conidial Development, and Circadian Function

The COP9 signalosome (CSN) is a highly conserved multifunctional complex that has two major biochemical roles: cleaving NEDD8 from cullin proteins and maintaining the stability of CRL components. We used mutation analysis to confirm that the JAMM domain of the CSN-5 subunit is responsible for NEDD8 cleavage from cullin proteins in Neurospora crassa. Point mutations of key residues in the metal-binding motif (EXnHXHX10D) of the CSN-5 JAMM domain disrupted CSN deneddylation activity without interfering with assembly of the CSN complex or interactions between CSN and cullin proteins. Surprisingly, CSN-5 with a mutated JAMM domain partially rescued the phenotypic defects observed in a csn-5 mutant. We found that, even without its deneddylation activity, the CSN can partially maintain the stability of the SCFFWD-1 complex and partially restore the degradation of the circadian clock protein FREQUENCY (FRQ) in vivo. Furthermore, we showed that CSN containing mutant CSN-5 efficiently prevents degradation of the substrate receptors of CRLs. Finally, we found that deletion of the CAND1 ortholog in N. crassa had little effect on the conidiation circadian rhythm. Our results suggest that CSN integrity plays major roles in hyphal growth, conidial development, and circadian function in N. crassa

Uncovering Ubiquitin and Ubiquitin-like Signaling Networks

Microscopic imaging and technolog

Personality profiles and the "russian soul": Literary and scholarly views evaluated

Many domestic and foreign observers have claimed that Russians have a unique constellation of personality traits that mirrors their distinctive historical and cultural experience. To examine the hypothesized uniqueness of Russian personality, members of the Russian Character and Personality Survey collected data from 39 samples in 33 administrative areas of the Russian Federation. Respondents (N = 7,065) identified an ethnically Russian adult or college-aged man or woman whom they knew well and rated the target using the Russian observer-rating version of the Revised NEO Personality Inventory. The mean personality profile of Russians was very similar to the international average based on 50 different countries, debunking the myth of a unique Russian soul.The small variations from world norms did not converge with depictions of Russian national character in fiction and the scholarly literature. New items intended to capture distinctive, emic aspects of Russian personality provided no new information beyond the familiar Big Five dimensions. Religion, ethnicity, and beliefs about the uniqueness of the Russian character and the malleability of personality traits had little effect on personality ratings. Perceptions of the Russian soul do not seem to be based on the personality traits of Russians

Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case fora causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding