Chromosome Segregation Is Biased by Kinetochore Size

Chromosome missegregation during mitosis or meiosis is a hallmark of cancer and the main cause of prenatal death in humans. The gain or loss of specific chromosomes is thought to be random, with cell viability being essentially determined by selection. Several established pathways including centrosome amplification, sister-chromatid cohesion defects, or a compromised spindle assembly checkpoint can lead to chromosome missegregation. However, how specific intrinsic features of the kinetochore—the critical chromosomal interface with spindle microtubules—impact chromosome segregation remains poorly understood. Here we used the unique cytological attributes of female Indian muntjac, the mammal with the lowest known chromosome number (2n = 6), to characterize and track individual chromosomes with distinct kinetochore size throughout mitosis. We show that centromere and kinetochore functional layers scale proportionally with centromere size. Measurement of intra-kinetochore distances, serial-section electron microscopy, and RNAi against key kinetochore proteins confirmed a standard structural and functional organization of the Indian muntjac kinetochores and revealed that microtubule binding capacity scales with kinetochore size. Surprisingly, we found that chromosome segregation in this species is not random. Chromosomes with larger kinetochores bi-oriented more efficiently and showed a 2-fold bias to congress to the equator in a motor-independent manner. Despite robust correction mechanisms during unperturbed mitosis, chromosomes with larger kinetochores were also strongly biased to establish erroneous merotelic attachments and missegregate during anaphase. This bias was impervious to the experimental attenuation of polar ejection forces on chromosome arms by RNAi against the chromokinesin Kif4a. Thus, kinetochore size is an important determinant of chromosome segregation fidelity

Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease

Abstract Background Valvular heart disease (VHD) and atrial fibrillation (AF) often coexist. Phase III trials comparing non–vitamin K antagonist oral anticoagulants (NOACs) with warfarin excluded patients with moderate/severe mitral stenosis or mechanical heart valves, but variably included patients with other VHD and valve surgeries. Objectives This study aimed to determine relative safety and efficacy of NOACs in patients with VHD. Methods We performed a meta-analysis of the 4 phase III AF trials of the currently available NOACs versus warfarin in patients with coexisting VHD to assess pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for stroke/systemic embolic events (SSEE), major bleeding, intracranial hemorrhage (ICH), and all-cause death. Results Compared with warfarin, the rate of SSEE in patients treated with higher-dose NOACs was lower and consistent among 13,585 patients with (RR: 0.70; 95% CI: 0.58 to 0.86) or 58,098 without VHD (RR: 0.84; 95% CI: 0.75 to 0.95; interaction p = 0.13). Major bleeding in patients on higher-dose NOACs versus warfarin was similar and consistent among patients with (RR: 0.93; 95% CI: 0.68 to 1.27) or without VHD (RR: 0.85; 95% CI: 0.70 to 1.02; interaction p = 0.63 for VHD/no-VHD difference). Intracranial hemorrhage was lower with higher-dose NOACs than with warfarin irrespective of VHD (RR: 0.47; 95% CI: 0.24 to 0.93, and 0.49; 95% CI: 0.41 to 059, respectively; interaction p = 0.91). No protective effect of higher-dose NOACs in preventing all-cause death seemed to be present in patients with VHD versus without VHD (RR:1.01; 95% CI: 0.90 to 1.14 vs. RR: 0.88; 95% CI: 0.82 to 0.94, respectively; interaction p = 0.03). Conclusions High-dose NOACs provide overall efficacy and safety similar in AF patients with or without VHD

Nonsense-mediated decay mechanism is a possible modifying factor of clinical outcome in nonsense cd39 beta thalassemia genotype

Nonsense-mediated mRNA decay (NMD) is a surveillance system to prevent the synthesis of non-functional proteins. In β-thalassemia, NMD may have a role in clinical outcome. An example of premature translation stop codons appearing for the first time is the β-globin cd39 mutation; when homozygous, this results in a severe phenotype. The aim of this study was to determine whether the homozygous nonsense cd39 may have a milder phenotype in comparison with IVS1,nt110/cd39 genotype. Genotypes have been identified from a cohort of 568 patients affected by β-thalassemia. These genotypes were compared with those found in 577 affected fetuses detected among 2292 prenatal diagnoses. The nine most common genotypes, each with an incidence rate of 1.5% or over, and together accounting for 80% of genotype frequencies, underwent statistical analysis. Genotype prevalence was calculated within the overall group. Results are expressed as proportions with 95% confidence intervals; P≤0.05 was considered statistically significant. A binomial distribution was assumed for each group; z-tests were used to compare genotype frequencies observed in the patient group with frequencies in the affected fetus group. In the absence of selecting factors, prevalence of these two genotypes was compared between a cohort of 568 β-thalassemia patients (PTS) and 577 affected fetuses (FOET) detected during the same period. IVS1,nt110/cd39 was significantly more prevalent in FOET than PTS (P<0.0001), while there was no significant difference in prevalence of cd39/cd39 in FOET compared with PTS (P=0.524). These results suggest a cd39 genotype NMD mechanism may be associated with improved clinical outcomes in thalassemia major

Mediterranean spreading of the bicolor purse oyster, Isognomon bicolor, and the chicken trigger, Malleus sp., vs. the Lessepsian prejudice

The introduction rate of alien species in the Mediterranean Sea is rapidly growing, and their taxonomical identification is increasingly challenging. This uncertain identification often leads to an incorrect estimation of the number of alien species, their route of introduction, and their potential negative effects. This is particularly true for some bivalves, which are characterized by high variation in their shells, resulting in uncertain morphological identification. This is the case for two alien bivalves, i.e., an Isognomonidae and a Malleidae species, both characterized by confused historical colonization records in the Mediterranean Sea, misidentifications, and controversial and changing nomenclatures that have insofar negatively affected our knowledge on their geographical distributions. In this respect, molecular approaches provide a strategy that is especially useful when traditional taxonomy fails, and DNA barcoding is a powerful and well-known tool to obtain reliable identifications through efficient molecular markers. In this work, we used the 16S rRNA marker to assess the preliminary identification of Isognomon sp. and Malleus sp. specimens from different localities in the Southern Mediterranean Sea. Bayesian inference (BI) and maximum likelihood (ML) methods were applied to test the monophyly of the phylogenetic linages and to clarify their taxonomic positions, allowing a complete overview of the colonization and spreading of these two alien bivalves in the Mediterranean Sea. In particular, the Isognomon sp. specimens were identified as the Atlantic I. bicolor, highlighting that previously suggested invasive migration patterns, (i.e., the Lessepsian migration), must be reconsidered with stronger critical attention in light of currently occurring global changes

Wide-Field Survey of Globular Clusters in M31. II. Kinematics of the Globular Cluster System

We present a kinematic analysis of the globular cluster(GC) system in M31. Using the photometric and spectroscopic database of 504 GCs, we have investigated the kinematics of the M31 GC system. We find that the all GC system shows strong rotation, with rotation amplitude of v_rot~190km/s, and that a weak rotation persists even for the outermost samples at |Y|>5kpc. The rotation-corrected velocity dispersion for the GC system is estimated to be sigma_{p,r}~130km/s, and it increases from sigma_{p,r}~120km/s at |Y|<1kpc to sigma_{p,r}~150km/s at |Y|>5kpc. These results are very similar to those for the metal-poor GCs. This shows that there is a dynamically hot halo in M31 that is rotating but primarily pressure-supported. We have identified 50 "friendless" GCs, and they appear to rotate around the major axis of M31. For the subsamples of metal-poor and metal-rich GCs, we have found that the metal-rich GCs are more centrally concentrated than the metal-poor GCs, and both subsamples show strong rotation. For the subsamples of bright and faint GCs, it is found that the rotation for the faint GCs is stronger than that for the bright GCs. We have identified 56 GCs and GC candidates with X-ray detection. It is found that the majority of X-ray emitting GCs follow the disk rotation, and that the redder, more metal-rich, and brighter GCs are more likely to be detected as X-ray emitting GCs. We have derived a rotation curve of M31 using the GCs at |Y|<0.6kpc. We have estimated the dynamical mass of M31 using `Projected Mass Estimator(PME)' and `Tracer Mass Estimator(TME)'. We finally discuss the implication of these results and compare the kinematics of GCs with that of planetary nebulae in M31.Comment: 62 pages, 26 figues, Accepted by Ap

Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named "correctors". So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors

The finding of vascular and urinary anomalies in the harvested kidney for transplantation.

INTRODUCTION: In kidney transplantation, anatomical vascular and excretory anomalies may represent causes of failure. Today's surgical techniques have made the most of the organs with anatomic anomalies and iatrogenic injury successfully used for transplantation. MATERIALS AND METHODS: From January 2000 to June 2006, we harvested 230 kidneys, of including 88 kidneys (20%) with vascular, urinary, or vascular-urinary anomalies; 64 kidneys were implanted and 15 were sent to other transplantation centers. Only 9 kidneys were not appropriate for transplantation. RESULTS: All patients who received kidneys with the above-mentioned anomalies were carefully examined after the transplantation and short-term and long-term complications were evaluated with respect to controls without anomalies. DISCUSSION: Renal anatomic anomalies are frequently observed during kidney transplantation and may produce postsurgical complications. However, the presence of these anomalies does not necessarily imply the impossibility of using the kidney for a transplant, especially because of improved surgical techniques. Our experience in transplantation procedures showed that even if kidneys present the above-mentioned anomalies they can still be considered appropriate for transplantation when we perform a correct harvesting/back-table transplant surgery. So vascular and urinary anomalies have to be considered always an incentive to research new surgical solutions and to perform a careful surgical technique

Significance of borderline hemoglobin A2 values in an Italian population with a high prevalence of -thalassemia

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Omalizumab decreases exacerbation frequency, oral intake of corticosteroids and peripheral blood eosinophils in atopic patients with uncontrolled asthma.

Omalizumab is a humanized monoclonal anti-IgE antibody approved in 2005 by the European Medicine Agency (EMA) for the treatment of severe persistent allergic asthma, which remains inadequately controlled despite optimal therapy with high doses of inhaled corticosteroids and long-acting β2-adrenergic agonists. Within this context, the present observational study refers to 16 patients currently treated with omalizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy, whose anti- IgE therapy was started in the period included between March 2007 and February 2010, thus lasting at least 10 months. After 40 weeks of add-on treatment with omalizumab, very relevant decreases were detected, in comparison with pre-treatment mean (± standard deviation) values, in monthly exacerbation numbers (from 1.1 ± 0.6 to 0.2 ± 0.4; p < 0.01) and oral corticosteroid consumption (from 22.6 ± 5.0 to 1.2 ± 2.9 mg/day of prednisone; p < 0.01). These changes were associated with stable improvements in lung function, expressed as increases of both FEV1 (from 53.6 ± 14.6% to 77.0 ± 14.9% of predicted values; p < 0.01) and FEV1/FVC ratio (from 56.3 ± 9.5% to 65.8 ± 9.2%; p < 0.01). Moreover, in 5 patients who persistently had increased numbers of eosinophils (mean ± SD: 15.9 ± 8.0% of total WBC count; absolute number: 1,588.0 ± 956.9/μl) despite a long-lasting therapy with inhaled and systemic corticosteroids, the peripheral counts of these cells decreased down to near normal levels (mean ± SD: 6.3 ± 2.3% of total WBC count; absolute number: 462.0 ± 262.3/μl) after 16 weeks of treatment with omalizumab. Therefore, this descriptive evaluation confirms the efficacy of add-on omalizumab therapy in selected patients with exacerbation-prone, chronic allergic uncontrolled asthma, requiring a continuous intake of oral corticosteroids