Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Методология синтеза архитектуры программно-технического комплекса автоматизированной системы мониторинга обстановки

Предложен подход к проектированию архитектуры программно-технического комплекса автоматизированной системы мониторинга обстановки в реальном времени, основанный на классификации решаемых функциональных задач на основе методов кластерного анализа и выбранного множества признаков подобия. Разработанный подход позволяет из множества функций системы выделить подобные (по определенным признакам) и объединить их в архитектурные компоненты (унифицированные функциональные модули).Запропоновано підхід до проектування архітектури центру обробки інформації автоматизованої системи моніторингу середовища в реальному часі, що заснований на класифікації функціональних задач на підставі методів кластерного аналізу і обраної множини ознак схожості. Розроблений підхід дозволяє вибрати із множини функцій системи схожі (за певними ознаками) і поєднати їх в архітектурні компоненти (уніфіковані функціональні модулі).The approach to designing architecture of the information processing complex of the automated real time conditions monitoring system based on classification of functional tasks on the basis of methods of cluster analysis and the chosen set of similarity attributes is offered. The developed approach allows to allocate from a set of functions the systems similar (on certain attributes) and to unite them in architectural components (unified functional modules)

Reproductive life disorders in Italian celiac women. A case-control study

BACKGROUND: The aim of this study is to explore the association between celiac disease and menstrual cycle, gestation and puerperal disorders. METHODS: The association between celiac disease and menstrual cycle, gestation and puerperal disorders in a sample of 62 childbearing age women (15-49 age) was assessed within an age and town of residence matched case-control study conducted in 2008. Main outcome measures were the presence of one or more disorders in menstrual cycle and the presence of one or more complication during pregnancy. RESULTS: 62 celiac women (median age: 31.5, range: 17-49) and 186 healthy control (median age: 32.5, range: 15-49) were interviewed. A higher percentage of menstrual cycle disorders has been observed in celiac women. 19.4% frequency of amenorrhea was reported among celiac women versus 2.2% among healthy controls (OR = 33, 95% CI = 7.17-151.8;, p = 0.000). An association has been observed between celiac disease and oligomenorrhea, hypomenorrhea, dysmenorrhea and metrorrhagia (p < 0.05). The likelihood of having at least one complication during pregnancy has been estimated to be at least four times higher in celiac women than in healthy women (OR = 4.1, 95% CI = 2-8.6, p = 0.000). A significant correlation has emerged for celiac disease and threatened abortion, gestational hypertension, placenta abruption, severe anaemia, uterine hyperkinesia, intrauterine growth restriction (p < 0.001). A shorter gestation has on average been observed in celiac women together with a lower birth weight of celiac women babies (p < 0.001). CONCLUSIONS: The occurrence of a significant correlation between celiac disease and reproductive disorders could suggest to consider celiac disease diagnostic procedures (serological screening) in women affected by these disorders

Inhibition of p38 MAPK Suppresses Inflammatory Cytokine Induction by Etoposide, 5-Fluorouracil, and Doxorubicin without Affecting Tumoricidal Activity

Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often experience debilitating fatigue similar to sickness behavior, a normal response to infection or tissue damage caused by the production of the inflammatory cytokines IL-1β, TNF-α, and IL-6. The p38 mitogen activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the development of sickness behavior. Targeted inhibitors of p38 MAPK can reduce systemic inflammatory cytokine production and the development of sickness behavior. Several systemic cancer chemotherapy drugs have been shown to stimulate inflammatory cytokine production, yet whether this response is related to a common ability to activate p38 MAPK is not known and is the focus of this study. This understanding may present the possibility of using p38 MAPK inhibitors to reduce chemotherapy-induced inflammatory cytokine production and consequently treatment-related fatigue. One caveat of this approach is a potential reduction in chemotherapeutic efficacy as some believe that p38 MAPK activity is required for chemotherapy-induced cytotoxicity of tumor cells. The purpose of this study was to demonstrate proof of principal that p38 MAPK inhibition can block chemotherapy- induced inflammatory cytokine production without inhibiting drug-induced cytotoxicity using murine peritoneal macrophages and Lewis Lung Carcinoma (LLC1) cells as model cell systems. Using these cells we assessed the requirement of etoposide, doxorubicin, 5-flourouracil, and docetaxel for p38 MAPK in inflammatory cytokine production and cytotoxicity. Study findings demonstrate that clinically relevant doses of etoposide, doxorubicin, and 5-FU activated p38 MAPK in both macrophages and LLC1 cells. In contrast, docetaxel failed to activate p38 MAPK in either cell type. Activation of p38 MAPK mediated the drug's effects on inflammatory cytokine production in macrophages but not LLC1 cytotoxicity and this was confirmed with inhibitor studies

Structural mechanism of JH delivery in hemolymph by JHBP of silkworm, Bombyx mori

Juvenile hormone (JH) plays crucial roles in many aspects of the insect life. All the JH actions are initiated by transport of JH in the hemolymph as a complex with JH-binding protein (JHBP) to target tissues. Here, we report structural mechanism of JH delivery by JHBP based upon the crystal and solution structures of apo and JH-bound JHBP. In solution, apo-JHBP exists in equilibrium of multiple conformations with different orientations of the gate helix for the hormone-binding pocket ranging from closed to open forms. JH-binding to the gate-open form results in the fully closed JHBP-JH complex structure where the bound JH is completely buried inside the protein. JH-bound JHBP opens the gate helix to release the bound hormone likely by sensing the less polar environment at the membrane surface of target cells. This is the first report that provides structural insight into JH signaling

The Schizosaccharomyces pombe Hsp104 Disaggregase Is Unable to Propagate the [PSI+] Prion

The molecular chaperone Hsp104 is a crucial factor in the acquisition of thermotolerance in yeast. Under stress conditions, the disaggregase activity of Hsp104 facilitates the reactivation of misfolded proteins. Hsp104 is also involved in the propagation of fungal prions. For instance, the well-characterized [PSI+] prion of Saccharomyces cerevisiae does not propagate in Δhsp104 cells or in cells overexpressing Hsp104. In this study, we characterized the functional homolog of Hsp104 from Schizosaccharomyces pombe (Sp_Hsp104). As its S. cerevisiae counterpart, Sp_hsp104+ is heat-inducible and required for thermotolerance in S. pombe. Sp_Hsp104 displays low disaggregase activity and cannot propagate the [PSI+] prion in S. cerevisiae. When overexpressed in S. cerevisiae, Sp_Hsp104 confers thermotolerance to Δhsp104 cells and reactivates heat-aggregated proteins. However, overexpression of Sp_Hsp104 does not propagate nor eliminate [PSI+]. Strikingly, [PSI+] was cured by overexpression of a chimeric chaperone bearing the C-terminal domain (CTD) of the S. cerevisiae Hsp104 protein. Our study demonstrates that the ability to untangle aggregated proteins is conserved between the S. pombe and S. cerevisiae Hsp104 homologs, and points to a role of the CTD in the propagation of the S. cerevisiae [PSI+] prion

Neglected Tropical Diseases in Sub-Saharan Africa: Review of Their Prevalence, Distribution, and Disease Burden

The neglected tropical diseases (NTDs) are the most common conditions affecting the poorest 500 million people living in sub-Saharan Africa (SSA), and together produce a burden of disease that may be equivalent to up to one-half of SSA's malaria disease burden and more than double that caused by tuberculosis. Approximately 85% of the NTD disease burden results from helminth infections. Hookworm infection occurs in almost half of SSA's poorest people, including 40–50 million school-aged children and 7 million pregnant women in whom it is a leading cause of anemia. Schistosomiasis is the second most prevalent NTD after hookworm (192 million cases), accounting for 93% of the world's number of cases and possibly associated with increased horizontal transmission of HIV/AIDS. Lymphatic filariasis (46–51 million cases) and onchocerciasis (37 million cases) are also widespread in SSA, each disease representing a significant cause of disability and reduction in the region's agricultural productivity. There is a dearth of information on Africa's non-helminth NTDs. The protozoan infections, human African trypanosomiasis and visceral leishmaniasis, affect almost 100,000 people, primarily in areas of conflict in SSA where they cause high mortality, and where trachoma is the most prevalent bacterial NTD (30 million cases). However, there are little or no data on some very important protozoan infections, e.g., amebiasis and toxoplasmosis; bacterial infections, e.g., typhoid fever and non-typhoidal salmonellosis, the tick-borne bacterial zoonoses, and non-tuberculosis mycobaterial infections; and arboviral infections. Thus, the overall burden of Africa's NTDs may be severely underestimated. A full assessment is an important step for disease control priorities, particularly in Nigeria and the Democratic Republic of Congo, where the greatest number of NTDs may occur

The macrophage in HIV-1 infection: From activation to deactivation?

Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-γ display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease

Dendritic cells in cancer immunology and immunotherapy

Dendritic cells (DCs) are a diverse group of specialized antigen-presenting cells with key roles in the initiation and regulation of innate and adaptive immune responses. As such, there is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs, as well as the generation of DC-based vaccines. A better understanding of the diversity and functions of DC subsets and of how these are shaped by the tumour microenvironment could lead to improved therapies for cancer. Here we will outline how different DC subsets influence immunity and tolerance in cancer settings and discuss the implications for both established cancer treatments and novel immunotherapy strategies.S.K.W. is supported by a European Molecular Biology Organization Long- Term Fellowship (grant ALTF 438– 2016) and a CNIC–International Postdoctoral Program Fellowship (grant 17230–2016). F.J.C. is the recipient of a PhD ‘La Caixa’ fellowship. Work in the D.S. laboratory is funded by the CNIC, by the European Research Council (ERC Consolidator Grant 2016 725091), by the European Commission (635122-PROCROP H2020), by the Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-79040-R), by the Comunidad de Madrid (B2017/BMD-3733 Immunothercan- CM), by FIS- Instituto de Salud Carlos III, MCNU and FEDER (RD16/0015/0018-REEM), by Acteria Foundation, by Atresmedia (Constantes y Vitales prize) and by Fundació La Marató de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III, the MCNU and the Pro CNIC Foundation, and is a Severo Ochoa Centre of Excellence (SEV-2015-0505).S

A cross-sectional analysis of the relationship between tobacco and alcohol outlet density and neighbourhood deprivation

Background There is a strong socio-economic gradient in both tobacco-and alcohol-related harm. One possible factor contributing to this social gradient may be greater availability of tobacco and alcohol in more socially-deprived areas. A higher density of tobacco and alcohol outlets is not only likely to increase supply but also to raise awareness of tobacco/alcohol brands, create a competitive local market that reduces product costs, and influence local social norms relating to tobacco and alcohol consumption. This paper examines the association between the density of alcohol and tobacco outlets and neighbourhood-level income deprivation. Methods Using a national tobacco retailer register and alcohol licensing data this paper calculates the density of alcohol and tobacco retail outlets per 10,000 population for small neighbourhoods across the whole of Scotland. Average outlet density was calculated for neighbourhoods grouped by their level of income deprivation. Associations between outlet density and deprivation were analysed using one way analysis of variance. Results There was a positive linear relationship between neighbourhood deprivation and outlets for both tobacco (p &lt;0.001) and off-sales alcohol (p &lt;0.001); the most deprived quintile of neighbourhoods had the highest densities of both. In contrast, the least deprived quintile had the lowest density of tobacco and both off-sales and on-sales alcohol outlets. Conclusions The social gradient evident in alcohol and tobacco supply may be a contributing factor to the social gradient in alcohol- and tobacco-related disease. Policymakers should consider such gradients when creating tobacco and alcohol control policies. The potential contribution to public health, and health inequalities, of reducing the physical availability of both alcohol and tobacco products should be examined in developing broader supply-side interventions