Chromosome Segregation: Organizing Overlap at the Midzone

SummarySets of overlapping microtubules support the segregation of chromosomes by linking the poles of mitotic spindles. Recent work examines the effect of putting these linkages under pressure by the activation of dicentric chromosomes and sheds new light on the structural role of several well-known spindle midzone proteins

Microtubule rescue at midzone edges promotes overlap stability and prevents spindle collapse during anaphase B

During anaphase B, molecular motors slide interpolar microtubules to elongate the mitotic spindle, contributing to the separation of chromosomes. However, sliding of antiparallel microtubules reduces their overlap, which may lead to spindle breakage, unless microtubules grow to compensate sliding. How sliding and growth are coordinated is still poorly understood. In this study, we have used the fission yeastS. pombeto measure microtubule dynamics during anaphase B. We report that the coordination of microtubule growth and sliding relies on promoting rescues at the midzone edges. This makes microtubules stable from pole to midzone, while their distal parts including the plus ends alternate between assembly and disassembly. Consequently, the midzone keeps a constant length throughout anaphase, enabling sustained sliding without the need for a precise regulation of microtubule growth speed. Additionally, we found that inS. pombe, which undergoes closed mitosis, microtubule growth speed decreases when the nuclear membrane wraps around the spindle midzone

Microtubule rescue at midzone edges promotes overlap stability and prevents spindle collapse during anaphase B

During anaphase B, molecular motors slide interpolar microtubules to elongate the mitotic spindle, contributing to the separation of chromosomes. However, sliding of antiparallel microtubules reduces their overlap, which may lead to spindle breakage, unless microtubules grow to compensate sliding. How sliding and growth are coordinated is still poorly understood. In this study, we have used the 1ssion yeast S. pombe to measure microtubule dynamics during anaphase B. We report that the coordination of microtubule growth and sliding relies on promoting rescues at the midzone edges. This makes microtubules stable from pole to midzone, while their distal parts including the plus ends alternate between assembly and disassembly. Consequently, the midzone keeps a constant length throughout anaphase, enabling sustained sliding without the need for a precise regulation of microtubule growth speed. Additionally, we found that in S. pombe, which undergoes closed mitosis, microtubule growth speed decreases when the nuclear 22 membrane wraps around the spindle midzone

Simple Transferability Estimation for Regression Tasks

We consider transferability estimation, the problem of estimating how well deep learning models transfer from a source to a target task. We focus on regression tasks, which received little previous attention, and propose two simple and computationally efficient approaches that estimate transferability based on the negative regularized mean squared error of a linear regression model. We prove novel theoretical results connecting our approaches to the actual transferability of the optimal target models obtained from the transfer learning process. Despite their simplicity, our approaches significantly outperform existing state-of-the-art regression transferability estimators in both accuracy and efficiency. On two large-scale keypoint regression benchmarks, our approaches yield 12% to 36% better results on average while being at least 27% faster than previous state-of-the-art methods.Comment: Paper published at The 39th Conference on Uncertainty in Artificial Intelligence (UAI) 202

Validation of Mesocyclops (Copepoda) and community participation as an effective combination for Dengue control in Northern Vietnam

The “Programme Meso-Vietnam” was implemented in Vietnam from October 2007 to December 2010 to reduce dengue and dengue hemorrhagic fever incidence and to improve the quality of life in the four project communes. This dengue control project was based on biological control using Mesocyclops, a larvivorous micro-crustacean, as well as on the establishment of a strong community involvement to educate the population on dengue transmission and to reduce Aedes breeding by removal of containers. During three years, a network of collaborators was responsible for introducing Mesocyclops in all the containers defined as key breeding-sites, and regular activities such as community training workshops, school programmes, clean-up campaigns and health promotion through IEC programmess were performed. To make this programme sustainable, local leadership has been strengthened as well. The use of these larvivorous micro-crustaceans as a biological control strategy against dengue over the medium and long term, when combined with community participation and effective health promotion, demonstrated a significant reduction in dengue vector populations and dengue cases.  In Vietnam, this study reconfirms that there is an ecological alternative to systematic use of insecticides to control dengue vector population. (Abstract word count: 186)Le " Programme Meso-Vietnam " a été mis en œuvre au Vietnam entre octobre 2007 et décembre 2010. Ce programme vise à réduire l'incidence de la dengue et de la fièvre hémorragique de la dengue et à améliorer la qualité de vie dans les quatre communes sélectionnées pour le projet. Ce projet de lutte contre la dengue était basé sur un contrôle biologique assuré par des Mésocyclopes, micro-crustacés larvivores, et sur l'établissement d'une forte implication de la communauté pour éduquer la population sur la transmission de la dengue et pour réduire la reproduction des moustiques Aedes par élimination des conteneurs leur servant de site de ponte. Pendant trois ans, un réseau de collaborateurs a été chargé d'introduire des Mésocyclopes dans tous les conteneurs définis comme des sites de reproduction clés, et des activités régulières telles que des ateliers de formation communautaires, des programmes scolaires, des campagnes de nettoyage et des activités de promotion de la santé via les programmes IEC ont été mises en place. En outre, pour assurer la pérennité de ce programme, le leadership local a été renforcé. L'utilisation de ces micro-crustacés larvivores comme stratégie de contrôle biologique de la dengue à moyen et long terme, associée à une participation communautaire et à une promotion efficace de la santé, a permis d'aboutir à une réduction significative des populations vecteurs de la dengue et des cas de dengue. Au Vietnam, cette étude confirme une fois de plus qu'il existe une alternative écologique à l'utilisation systématique d'insecticides pour lutter contre les vecteurs de la dengue.El “Programa Meso-Vietnam” se implementó en Vietnam desde octubre de 2007 hasta diciembre de 2010 para reducir la incidencia del dengue y la fiebre hemorrágica del dengue y para mejorar la calidad de vida en los cuatro municipios del proyecto. Este proyecto de control del dengue se basaba en el control biológico usando Mesocyclops, un microcrustáceo larvívoro, así como en el establecimiento de una fuerte implicación comunitaria para educar a la población sobre la transmisión del dengue y para reducir la cría de Aedes mediante la eliminación de recipientes. Durante tres años, una red de colaboradores fue responsable de la introducción de Mesocyclops en todos los recipientes definidos como sitios clave para la cría, y se realizaron actividades regulares tales como talleres de formación comunitaria, programas escolares, campañas de limpieza y promoción de la salud a través de programas de IEC. Para hacer sostenible este programa, también se reforzó el liderazgo local. El uso de estos microcrustáceos larvívoros como estrategia de control biológico contra el dengue a medio y largo plazo demostró una reducción significativa de las poblaciones de vectores del dengue y los casos de dengue cuando se combinaba con la participación comunitaria y la promoción eficaz de la salud. En Vietnam, este estudio vuelve a confirmar que existe una alternativa ecológica al uso sistemático de insecticidas para controlar la población de vectores del dengue

Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis

BACKGROUND Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients. METHODS We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization. RESULTS A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08). CONCLUSIONS Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.)

Combination Antifungal Therapy for Cryptococcal Meningitis

Background Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. Methods We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. Results A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P=0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P=0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P=0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. Conclusions Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found

Quantifying the Emergence of Dengue in Hanoi, Vietnam: 1998–2009

Dengue is the most common vector-borne viral disease of humans, causing an estimated 50 million cases per year. The number of countries affected by dengue has increased dramatically in the last 50 years and dengue is now a major public health problem in large parts of the tropical and subtropical world. It is of considerable importance to understand the factors that determine how dengue becomes newly established in areas where the risk of dengue was previously small. Hanoi in North Vietnam is a large city where dengue appears to be emerging. We analyzed 12 years of dengue surveillance data in order to characterize the temporal and spatial epidemiology of dengue in Hanoi and to establish if dengue incidence has been increasing. After excluding the two major outbreak years of 1998 and 2009 and correcting for changes in population age structure over time, we found there was a significant annual increase in the incidence of notified dengue cases over the period 1999–2008. Dengue cases were concentrated in young adults in the highly urban central areas of Hanoi. This study indicates that dengue transmission is increasing in Hanoi and provides a platform for further studies of the underlying drivers of this emergence