The Inner Centromere Protein (INCENP) Coil Is a Single α-Helix (SAH) Domain That Binds Directly to Microtubules and Is Important for Chromosome Passenger Complex (CPC) Localization and Function in Mitosis

The chromosome passenger complex (CPC) is a master regulator of mitosis. INCENP acts as a scaffold regulating CPC localisation and activity. During early mitosis the N-terminal region of INCENP forms a three-helix bundle with Survivin and Borealin, directing the CPC to the inner centromere where it plays essential roles in chromosome alignment and the spindle assembly checkpoint. The C-terminal IN-box region of INCENP is responsible for binding and activating Aurora B kinase. The central region of INCENP has been proposed to comprise a coiled-coil domain acting as a spacer between the N and C terminal domains that is involved in microtubule binding and regulation of the spindle checkpoint. Here we show that the central region (213 residues) of chicken INCENP is not a coiled coil but a ~32 nm long single alpha helical (SAH) domain. The N-terminal half of this domain directly binds to microtubules in vitro. By analogy with previous studies of myosin 10, our data suggest that the INCENP SAH might stretch up to ~80 nm under physiological forces. Thus, the INCENP SAH could act as a flexible dog-leash allowing Aurora B to phosphorylate dynamic substrates localized in the outer kinetochore while at the same time being stably anchored to the stable chromatin of the inner centromere. Furthermore, by achieving this flexibility via a SAH domain, the CPC avoids a need for dimerization (required for coiled-coil formation), which would greatly complicate regulation of the proximity-induced trans-phosphorylation that is critical for Aurora B activation

Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation

α-Actinin-2 (ACTN2) is the only muscle isoform of α-actinin expressed in cardiac muscle. Mutations in this protein have been implicated in mild to moderate forms of hypertrophic cardiomyopathy (HCM). We have investigated the effects of two mutations identified from HCM patients, A119T and G111V, on the secondary and tertiary structure of a purified actin binding domain (ABD) of ACTN2 by circular dichroism and X-ray crystallography, and show small but distinct changes for both mutations. We also find that both mutants have reduced F-actin binding affinity, although the differences are not significant. The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localization and dynamic behaviour. Overall, these two mutations have small effects on structure, function and behaviour, which may contribute to a mild phenotype for this disease

k-Selection Protocols from Energetic Complexity Perspective

International audienceIn this paper we discuss energetic complexity aspects of k-Selection protocols for the single-hop radio network (that is equivalent to Multiple Access Channel model). The aim is to grant each of k activated stations exclusive access to communication channel. We consider both deterministic as well as randomized algorithms. Our main goal is to investigate relations between minimal time of execution (time complexity) and energy consumption (energetic complexity). We present lower bound for energetic complexity for some classes of algorithms for k-Selection. We also present randomized algorithm efficient in terms of both time and energetic complexity

Lidocaine bolus may facilitate computed tomographic coronary angiography in patients with frequent premature ventricular contractions

INTRODUCTION: Heart rate irregularities are the major limitations of computed tomographic coronary angiography (CTCA) due to severe motion artifacts. AIM: To evaluate the safety and efficacy of a lidocaine intravenous bolus in preserving good image quality by the transient suppression of premature ventricular contractions (PVC) during the CTCA scan. MATERIAL AND METHODS: The study group comprised 67 consecutive patients with sinus rhythm and numerous PVC scheduled for CTCA. Intravenous boluses of 25–50 mg lidocaine were given after calcium score assessment and immediately before CTCA. The control group comprised 67 patients with sinus rhythm without PVC matched according to the body mass index (BMI), age, sex, and calcium score. All coronary vessel segments were assessed for image quality and presence of significant stenosis. RESULTS: As compared with calcium score assessment, after administration of lidocaine and during the CTCA scan PVC were completely suppressed in 22 (40%), reduced in 10 (18%), unchanged in 18 (32%), and intensified in 5 (10%) patients. Overall, there were 32 (58%) patients with sinus rhythm during CTCA as compared with only 11 (20%) patients free from PVC during calcium score assessment (p < 0.001). Image quality in 871 coronary segments including both the study group and control patients was worse in patients with PVC (p < 0.0001). However, there was no statistically significant difference in the number of patients with at least one segment of non-diagnostic quality (6% vs. 12%, p = 0.36; respectively). CONCLUSIONS: Single lidocaine bolus given prior to CTCA is safe, may temporarily eliminate or reduce the intensity of arrhythmia, and hence results in improved quality of CTCA in patients with numerous PVC

Prognostic value of computed tomography derived measurements of pulmonary artery diameter for long-term outcomes after transcatheter aortic valve replacement

Background: An increase in pulmonary artery diameter (PAD) on multi-detector computed tomography (MDCT) may indicate pulmonary hypertension. We assessed the prognostic value of MDCT-derived measurements of PAD on outcomes after successful transcatheter aortic valve replacement (TAVR).Methods: Consecutive patients treated with TAVR from February 2013 to October 2017, with a 68.8% rate of new generation valves, underwent pre-interventional MDCT with measurements of PAD (in the widest short-axis within 3 cm of the bifurcation) and ascending aortic diameter (AoD; at the level of the PAD). The PAD/AoD ratio was calculated. Patients with high-density lipoprotein cholesterol levels ≤46 mg/dl and C-reactive protein levels ≥0.20 mg/dl at baseline were identified as the frail group. One-year mortality was established for all subjects.Results: Among studied 266 patients (median age, 82.0 years; 63.5% women) those who died at 1 year (n = 34; 12.8%) had larger PAD and PAD/AoD (28.9 [5.0] vs. 26.5 [4.6] mm and 0.81 [0.13] vs. 0.76 [0.13] mm vs. the rest of the studied subjects; P = 0.005 and P = 0.02, respectively) but similar AoD. The cutoff value for the PAD to predict 1-year mortality was 29.3 mm (sensitivity, 50%; specificity, 77%; area under the curve, 0.65). Patients with PAD &gt;29.3 mm (n = 72; 27%) had higher 1-year mortality (23.6% vs. 8.8%, log-rank P = 0.001). Baseline characteristics associated with PAD 29.3 mm were a bigger body mass index, more frequent diabetes mellitus, more prior stroke/transient ischemic attacks and atrial fibrillation, and lower baseline maximal aortic valve gradient with higher pulmonary artery systolic pressure (PASP). PAD &gt;29.3 mm and frailty, but not baseline PASP, remained predictive of 1-year mortality in the multivariable model (hazard ratio [HR], 2.221; 95%CI, 1.038–4.753; P = 0.04 and HR, 2.801; 95% CI, 1.328–5.910; P = 0.007, respectively).Conclusion: PAD &gt;29.3 mm on baseline MDCT is associated with higher 1-year mortality after TAVR, independently of echocardiographic measures of PH and frailty

Computed tomographic characteristics of congenital coronary artery fistulas in an adult population

Background: Coronary artery fistulas (CAFs) are usually congenital coronary artery anomalies of termination.Aims: This study aimed to assess the prevalence, anatomic characteristics, and clinical significance of CAFs detected by computed tomography (CT) in an adult population.Methods: We performed 45 817 CT examinations in 39 066 subjects between 2008 and 2020. The electronic database was manually checked using specific keywords to identify patients with CAFs. The CT characteristics of CAFs were evaluated. CAF was defined as clinically significant if it was the most plausible cause of myocardial infarction, infective endocarditis, heart failure, death during follow-up, hospitalization, or if it required either percutaneous or surgical intervention.Results: Of 39 066 patients, 56 CAFs were detected in 42 subjects (20 men, 47.6%) with a prevalence of 0.11%. Most CAFs originated from the right coronary artery (RCA) (48.2%) and drained into the pulmonary artery (PA) (58.9%). CAFs terminating in the PA were more frequently multiple (P &lt;0.001) and tortuous (P &lt;0.001) as compared to CAFs without PA drainage. Clinically significant CAFs, identified in 7 of 42 patients, were more common in younger (P = 0.03) and male (P = 0.04) subjects and had larger lumen area and diameter at the site of origin (P = 0.03, P = 0.03, respectively).Conclusions: In the unselected adult population undergoing coronary CT angiography, the RCA and the PA are the most common sites of origin and termination of CAFs, respectively. CAFs draining into the PA are more often multiple and tortuous. Clinically meaningful CAFs are larger and most frequently detected in younger and male patients

Histone Deacetylase 3 indirectly modulates tubulin acetylation

Histone Deacetylase 3 (HDAC3), a member of the Class I subfamily of histone deacetylases, is found in both the nucleus and the cytoplasm. Its roles in the nucleus have been well characterised, but its cytoplasmic roles are still not elucidated fully. We found that blocking HDAC3 activity using MI192, a compound specific for HDAC3, modulated tubulin acetylation in the human prostate cancer cell line PC3. A brief 1 hour treatment of PC3 cells with MI192 significantly increased levels of tubulin acetylation and ablated the dynamic behaviour of microtubules in live cells. siRNA mediated knockdown of HDAC3 in PC3 cells, significantly increased levels of tubulin acetylation, and overexpression reduced it. However, the active HDAC3:SMRT-DAD complex did not directly deacetylate tubulin in vitro. These data suggest that HDAC3 indirectly modulates tubulin acetylation

Key Amino Acid Residues of Ankyrin-Sensitive Phosphatidylethanolamine/Phosphatidylcholine-Lipid Binding Site of βI-Spectrin

It was shown previously that an ankyrin-sensitive, phosphatidylethanolamine/phosphatidylcholine (PE/PC) binding site maps to the N-terminal part of the ankyrin-binding domain of β-spectrin (ankBDn). Here we have identified the amino acid residues within this domain which are responsible for recognizing monolayers and bilayers composed of PE/PC mixtures. In vitro binding studies revealed that a quadruple mutant with substituted hydrophobic residues W1771, L1775, M1778 and W1779 not only failed to effectively bind PE/PC, but its residual PE/PC-binding activity was insensitive to inhibition with ankyrin. Structure prediction and analysis, supported by in vitro experiments, suggests that “opening” of the coiled-coil structure underlies the mechanism of this interaction. Experiments on red blood cells and HeLa cells supported the conclusions derived from the model and in vitro lipid-protein interaction results, and showed the potential physiological role of this binding. We postulate that direct interactions between spectrin ankBDn and PE-rich domains play an important role in stabilizing the structure of the spectrin-based membrane skeleton

Reintegration of pupils of social rehabilitation centres. Systemic remarks. Report of the Helsinki Foundation for Human Rights

The article is a summary of the report prepared by the Helsinki Foundation for Human Rights under the "Children Rights Behind Bars 2.0" project. The authors - based on the analysis of information taken on the basis of access to public information, the conclusions from the report of the Supreme Audit Office [pl. Najwyższa Izba Kontroli] and 8 interviews and focus groups with persons working in the system of juvenile social rehabilitation and foster care - indicate doubts related to the functioning of solutions supporting the reintegration of pupils of social rehabilitation institutions. Among the observed problems, they identify a multitude of entities responsible for the functioning of the system, lack of coordination of activities, lack of tools to verify the effectiveness of social rehabilitation work, as well as numerous formal criteria limiting the availability of reintegration services. </jats:p

Reintegration of pupils of social rehabilitation centres. Systemic remarks. Report of the Helsinki Foundation for Human Rights

The article is a summary of the report prepared by the Helsinki Foundation for Human Rights under the "Children Rights Behind Bars 2.0" project. The authors - based on the analysis of information taken on the basis of access to public information, the conclusions from the report of the Supreme Audit Office [pl. Najwyższa Izba Kontroli] and 8 interviews and focus groups with persons working in the system of juvenile social rehabilitation and foster care - indicate doubts related to the functioning of solutions supporting the reintegration of pupils of social rehabilitation institutions. Among the observed problems, they identify a multitude of entities responsible for the functioning of the system, lack of coordination of activities, lack of tools to verify the effectiveness of social rehabilitation work, as well as numerous formal criteria limiting the availability of reintegration services.Artykuł stanowi skrót raportu opracowanego przez Helsińską Fundację Praw Człowieka w ramach projektu „Children Rights Behind Bars 2.0”. Autorzy, opierając się na analizie informacji zaczerpniętych w trybie dostępu do informacji publicznej, wnioskach z raportu Najwyższej Izby Kontroli oraz 8 wywiadach i grupach fokusowych z osobami pracującymi w systemie resocjalizacji nieletnich oraz pieczy zastępczej, wskazują na wątpliwości związane funkcjonowaniem rozwiązań wspierających reintegrację wychowanków placówek resocjalizacyjnych. Wśród obserwowanych problemów identyfikują m.in. wielość podmiotów odpowiedzialnych za funkcjonowanie systemu, brak koordynacji działań, narzędzi do weryfikacji skuteczności pracy resocjalizacyjnej, jak również liczne kryteria formalne ograniczające dostępność świadczeń reintegracyjnych