Self-sorting of nonmuscle myosins IIA and IIB polarizes the cytoskeleton and modulates cell motility

Nonmuscle myosin II (NMII) is uniquely responsible for cell contractility and thus defines multiple aspects of cell behavior. To generate contraction, NMII molecules polymerize into bipolar minifilaments. Different NMII paralogs are often coexpressed in cells and can copolymerize, suggesting that they may cooperate to facilitate cell motility. However, whether such cooperation exists and how it may work remain unknown. We show that copolymerization of NMIIA and NMIIB followed by their differential turnover leads to self-sorting of NMIIA and NMIIB along the front–rear axis, thus producing a polarized actin–NMII cytoskeleton. Stress fibers newly formed near the leading edge are enriched in NMIIA, but over time, they become progressively enriched with NMIIB because of faster NMIIA turnover. In combination with retrograde flow, this process results in posterior accumulation of more stable NMIIB-rich stress fibers, thus strengthening cell polarity. By copolymerizing with NMIIB, NMIIA accelerates the intrinsically slow NMIIB dynamics, thus increasing cell motility and traction and enabling chemotaxis

Efficacy of long-term octreotide therapy of acromegaly as the first-line medical treatment

Acromegaly is a severe neuroendocrine disease characterized by hypersecretion of growth hormone (GH) caused in 95% of cases by pituitary adenoma, which leads to the development of pathology of various organs and systems. The severity of the condition is due not only to the direct effect of somatotropic hormone on the body and the effect of the adenoma on the surrounding structures, but also to the age of the patient and complications associated with the disease. Improvement in treatment methods allows for a personalized approach to patient management, taking into account various aspects of the clinical case. It is important for a specialist to take into account comorbidity in acromegaly, both in terms of pathological disorders and the impact on the patient’s psycho-emotional state. We present a clinical case of successful treatment with somatostatin analogues (ASS) in a patient who is afraid of surgery and has cardiovascular complications of acromegaly. Since the onset of acromegaly, confirmed by an elevated level of insulin-like growth factor-1 (IGF-1) and an endosellar pituitary macroadenoma measuring 11x9.5x8 mm, ASS therapy was initiated in the patient. The choice in favor of conservative treatment was due to a burdened cardiovascular history and the patient’s fear of surgery. Within three years from the start of drug therapy, there was a significant improvement in overall well-being, a tendency to reduce the size of the pituitary adenoma, and biochemical remission was achieved. The clinical case described by us confirms the possibility of successful primary treatment of ASS in a patient with acromegaly, taking into account all individual characteristics

Long action somatostatin analogues in patients with TSH-secreted pituitary adenomas: treatment experience

Thyrotoxicosis, which characteristics are increased excitability, emotional lability, tachycardia episodes, increasing of free fractions of tetraiodothyronine (T4) and triiodothyronine (T3) is one of the most common endocrinological syndromes. However, during the interpretation of thyroid status it is very important to take into account the possibility that a patient has TSH-secreting pituitary adenoma. Timely diagnosis of TSH-secreting adenomas plays prominent role in guiding the treatment course since it is associated with an improvement of long-term prognosis and an increase of the patient’s total life expectancy. Needed to underline that in some patients with TSH-secreting adenomas manifestations of the other pituitary hormones hypersecretion (first of all — somatotropin and prolactin) come to the fore, that lead to the development of acromegaly and hyperprolactinemia accordingly. Our work basing on two clinical cases presents main principles of diagnosis and specific clinical manifestations of TSH-secreting pituitary adenomas and demonstrates efficacy of somatostatin analogues in the treatment of this pathology

Experiense of treatment with a growth hormone receptor antagonist in patients with hereditary form of acromegaly: clinical cases

Acromegaly is a severe neuroendocrine disease caused by chronic excessive production of somatotropic hormone (STH), characterized by specific changes in appearance, metabolic disorders. In 95% of cases, the cause of pathology is STH-producing pituitary adenomas. The priority method of treatment for acromegaly is transnasal transsphenoidal adenomectomy. If it is impossible to carry out neurosurgical intervention, in order to prevent the progression of the disease and the development of complications, patients are recommended drug therapy with long-acting somatostatin analogues, and if their effectiveness is low, additional radiation therapy may be applied to the neoplasm area. The usage of a relatively new group of drugs, antagonists of STH receptors, namely Pegvisomant for the purpose of drug treatment of acromegaly demonstrates high efficacy even in cases of aggressive forms resistant to other types of treatment. In this article we present two clinical cases of hereditary acromegaly, when the initiation of Pegvisomant therapy led to the achievement of clinical and laboratory remission of acromegaly in patients with an aggressive form of the disease, accompanied by continued growth of residual neoplasm tissue and preservation of its secreting ability even after surgical interventions, radiatiotherapy and long-term drug treatment with somatostatin analogues. The results of the above clinical cases confirm the success of mono- or combined (in cases with continued growth of the neoplasm) therapy with a growth hormone receptor antagonist, Pegvisomant, especially in the case of aggressive acromegaly

Studying the effect of combination of metotrexat and hepatoprotectors on urine indicators in experiment on white laboratory rats

The article presents the results of an experiment in which the effect of the use of methotrexate and hepatoprotectors on laboratory parameters of urine, mortality, as well as the general condition of laboratory rats on dynamic body weight indicators compared with methotrexate monotherapy and the introduction of physiological protein was tested.В статье представлены результаты эксперимента, в ходе которого проверялось влияние применения комбинации метотрексата и гепатопротекторов на лабораторные показатели мочи, летальность, а также общее состояние лабораторных крыс по динамике массы тела в сравнении с монотерапией метотрексатом и введением физиологического раствора

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients

Echocardiography in laboratory rabbits

Introduction. Rabbits are used as convenient models for studying drug cardiotoxicity. Echocardiography is one of the most informative non-invasive methods of assessing the cardiovascular system function. In literature, there is no clearly formulated protocol for heart ultrasound examination in rabbits. Purpose was the systematization of literature data on echocardiography techniques in rabbitsЦель работы — систематизация данных литературы о методиках эхокардиографии у кролико

Importance of Post-Translational Modifications for Functionality of a Chloroplast-Localized Carbonic Anhydrase (CAH1) in Arabidopsis thaliana

Background: The Arabidopsis CAH1 alpha-type carbonic anhydrase is one of the few plant proteins known to be targeted to the chloroplast through the secretory pathway. CAH1 is post-translationally modified at several residues by the attachment of N-glycans, resulting in a mature protein harbouring complex-type glycans. The reason of why trafficking through this non-canonical pathway is beneficial for certain chloroplast resident proteins is not yet known. Therefore, to elucidate the significance of glycosylation in trafficking and the effect of glycosylation on the stability and function of the protein, epitope-labelled wild type and mutated versions of CAH1 were expressed in plant cells. Methodology/Principal Findings: Transient expression of mutant CAH1 with disrupted glycosylation sites showed that the protein harbours four, or in certain cases five, N-glycans. While the wild type protein trafficked through the secretory pathway to the chloroplast, the non-glycosylated protein formed aggregates and associated with the ER chaperone BiP, indicating that glycosylation of CAH1 facilitates folding and ER-export. Using cysteine mutants we also assessed the role of disulphide bridge formation in the folding and stability of CAH1. We found that a disulphide bridge between cysteines at positions 27 and 191 in the mature protein was required for correct folding of the protein. Using a mass spectrometric approach we were able to measure the enzymatic activity of CAH1 protein. Under circumstances where protein N-glycosylation is blocked in vivo, the activity of CAH1 is completely inhibited. Conclusions/Significance: We show for the first time the importance of post-translational modifications such as N-glycosylation and intramolecular disulphide bridge formation in folding and trafficking of a protein from the secretory pathway to the chloroplast in higher plants. Requirements for these post-translational modifications for a fully functional native protein explain the need for an alternative route to the chloroplast.This work was supported by the Swedish Research Council (VR), the Kempe Foundations and Carl Tryggers Foundation to GS, and grant numbers BIO2006-08946 and BIO2009-11340 from the Spanish Ministerio de Ciencia e Innovación (MICINN) to A

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd