The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling

SARS-CoV-2 nonstructural protein 3 (Nsp3) contains a macrodomain that is essential for coronavirus pathogenesis and is thus an attractive target for drug development. This macrodomain is thought to counteract the host interferon (IFN) response, an important antiviral signalling cascade, via the reversal of protein ADP-ribosylation, a posttranslational modification catalyzed by host poly(ADP-ribose) polymerases (PARPs). However, the main cellular targets of the coronavirus macrodomain that mediate this effect are currently unknown. Here, we use a robust immunofluorescence-based assay to show that activation of the IFN response induces ADP-ribosylation of host proteins and that ectopic expression of the SARSCoV- 2 Nsp3 macrodomain reverses this modification in human cells. We further demonstrate that this assay can be used to screen for on-target and cell-active macrodomain inhibitors. This IFN-induced ADP-ribosylation is dependent on PARP9 and its binding partner DTX3L, but surprisingly the expression of the Nsp3 macrodomain or the deletion of either PARP9 or DTX3L does not impair IFN signaling or the induction of IFNresponsive genes. Our results suggest that PARP9/DTX3Ldependent ADP-ribosylation is a downstream effector of the host IFN response and that the cellular function of the SARSCoV- 2 Nsp3 macrodomain is to hydrolyze this end product of IFN signaling, rather than to suppress the IFN response itself

Neonatal invasive candidiasis in low-and-middle-income countries: data from the NeoOBS study

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole resistant Candida spp. isolates in low-and-middle-income -countries (LMICs) compared to high-income-countries (HIC). We describe the epidemiology, Candida spp. distribution, treatment and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalised infants < 60 days postnatal age with sepsis (August 2018-February 2021). 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34) and median birth weight was 1270 g (IQR: 990-1692). Only a minority had high risk criteria, such as being born < 28 weeks, 19% (24/127), or birth weight < 1000 g, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%) and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrolment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines

Determinants of intensive insulin therapeutic regimens in patients with type 1 diabetes: data from a nationwide multicenter survey in Brazil

Background: To evaluate the determinants of intensive insulin regimens (ITs) in patients with type 1 diabetes (T1D).Methods: This multicenter study was conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 3,591 patients (56.0% female, 57.1% Caucasian). Insulin regimens were classified as follows: group 1, conventional therapy (CT) (intermediate human insulin, one to two injections daily); group 2 (three or more insulin injections of intermediate plus regular human insulin); group 3 (three or more insulin injections of intermediate human insulin plus short-acting insulin analogues); group 4, basal-bolus (one or two insulin injections of long-acting plus short-acting insulin analogues or regular insulin); and group 5, basal-bolus with continuous subcutaneous insulin infusion (CSII). Groups 2 to 5 were considered IT groups.Results: We obtained complete data from 2,961 patients. Combined intermediate plus regular human insulin was the most used therapeutic regimen. CSII was used by 37 (1.2%) patients and IT by 2,669 (90.2%) patients. More patients on IT performed self-monitoring of blood glucose and were treated at the tertiary care level compared to CT patients (p < 0.001). the majority of patients from all groups had HbA1c levels above the target. Overweight or obesity was not associated with insulin regimen. Logistic regression analysis showed that economic status, age, ethnicity, and level of care were associated with IT (p < 0.001).Conclusions: Given the prevalence of intensive treatment for T1D in Brazil, more effective therapeutic strategies are needed for long term-health benefits.Farmanguinhos/Fundacao Oswaldo Cruz/National Health MinistryBrazilian Diabetes SocietyFundacao do Amparo a Pesquisa do Estado do Rio de JaneiroConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Estado Rio de Janeiro, Unit Diabet, BR-20551030 Rio de Janeiro, BrazilBaurus Diabet Assoc, São Paulo, BrazilFed Univ São Paulo State, Diabet Unit, São Paulo, BrazilFed Univ Hosp Porto Alegre, Porto Alegre, BrazilUniv Hosp São Paulo, Diabet Unit, São Paulo, BrazilUniv Fed Rio de Janeiro, Rio de Janeiro, BrazilUniv Fed Ceara, Fortaleza, Ceara, BrazilSanta Casa Misericordia, Belo Horizonte, MG, BrazilSanta Casa Misericordia São Paulo, São Paulo, BrazilUniv Fed Amazonas, Manaus, Amazonas, BrazilHosp Geral de Bonsucesso, Rio de Janeiro, BrazilHosp Univ Clementino Fraga Filho IPPMG, Rio de Janeiro, BrazilUniv Hosp São Paulo, São Paulo, BrazilFac Ciencias Med Santa Casa São Paulo, São Paulo, BrazilUniv São Paulo, Inst Crianca, Hosp Clin, São Paulo, BrazilUniv São Paulo, Fac Med Ribeirao Preto, Hosp Clin, Ribeirao Preto, BrazilAmbulatorio Fac Estadual Med Sao Jose Rio Preto, Ribeirao Preto, BrazilEscola Paulista Med, Ctr Diabet, Ribeirao Preto, BrazilClin Endocrinol Santa Casa Belo Horizonte, Belo Horizonte, MG, BrazilUniv Estadual Londrina, Londrina, BrazilUniv Fed Parana, Hosp Clin, Porto Alegre, RS, BrazilInst Crianca Com Diabet Rio Grande Sul, Rio Grande Do Sul, RS, BrazilGrp Hosp Conceicao, Inst Crianca Com Diabet, Porto Alegre, RS, BrazilHosp Univ Santa Catarina, Florianopolis, SC, BrazilInst Diabet Endocrinol Joinville, Joinville, BrazilHosp Reg Taguatinga, Brasilia, DF, BrazilHosp Geral Goiania, Goiania, Go, BrazilCtr Diabet & Endocrinol Estado Bahia, Goiania, Go, BrazilUniv Fed Maranhao, Sao Luis, BrazilCtr Integrado Diabet & Hipertensao Ceara, Fortaleza, Ceara, BrazilUniv Fed Sergipe, Aracaju, BrazilHosp Univ Alcides Carneiro, Campina Grande, BrazilHosp Univ Joao de Barros Barreto, Belem, Para, BrazilFed Univ São Paulo State, Diabet Unit, São Paulo, BrazilUniv Hosp São Paulo, Diabet Unit, São Paulo, BrazilUniv Hosp São Paulo, São Paulo, BrazilEscola Paulista Med, Ctr Diabet, Ribeirao Preto, BrazilWeb of Scienc

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Uso de plantas com finalidade medicinal por pessoas vivendo com HIV/ AIDS em terapia antirretroviral

Este foi um estudo observacional, transversal analítico realizado em ambulatório de referência do Estado do Maranhão-Brasil, no período de maio de 2009 a fevereiro de 2010, com o objetivo de estudar o uso de plantas com finalidade medicinal entre pessoas vivendo com HIV/AIDS, em uso de antirretrovirais. Um total de 339 pessoas respondeu um questionário abordando o uso de plantas e características demográficas, socioeconômicas, comportamentais, relacionadas à soropositividade e ao uso de antirretrovirais. A prevalência de utilização de plantas foi de 34,81%. As mais utilizadas foram: Turnera ulmifolia (12,09%); Melissa officinalis (10,62%); Plectranthus barbatus (7,67%); Cymbopogan citratus (capim limão) (4,72%) e Mentha spp. (hortelã) (2,36%). A maioria das pessoas (96,61%) referiu melhora após a utilização. Um percentual de 75,42% dos usuários de plantas não informou essa prática ao médico. Entre os que informaram o uso, 55,17% afirmaram que o médico estava de acordo e somente uma pessoa foi orientada a interromper o uso (3,45%). Apenas um médico (3,45%) indicou o uso de plantas. A análise ajustada evidenciou diferença para uso de plantas em relação ao sexo feminino (RP=1,58, 95% IC 1,15-2,15 p 0,004) e à orientação sexual do tipo homossexual (RP=0,63 IC 0,44-0,90 p 0,012). Este estudo aponta para a necessidade de melhor diálogo entre médico e pacientes sobre o uso de plantas com finalidade medicinal, alertando sobre possíveis perigos quando associados aos antirretrovirais, especialmente entre usuários do sexo feminino ou com prática do tipo homossexual.It is an observational, analytic study, developed at a hospital in Maranhao-Brazil, from May-2009 to February-2010. The objective was to study the use of plants with medicinal purpose in people living with HIV/AIDS and using retroviral therapy. A total of 339 (three hundred and thirty-nine) people answered a questionnaire about the use of plants and demographic, socioeconomic, behavioral characteristics, including those related to HIV status and use of antiretroviral therapy The prevalence of the use of plants with medicinal purpose was 34,81%. The most often used were: Turnera ulmifolia (chanana) (12,09%), Melissa officinalis (erva cidreira,) (10,62%), Plectranthus barbatus (boldo) (7,67%), Cymbopogan citratus (capim limão) (4,72%) and Mentha spp. (hortelã) (2,36%). Most people interviewed (96,61%) reported improvement after use. A rate of 75,42% of the plant users had not reported their practice to a medical doctor. Among respondents who reported use, 55.17% said their doctor agreed to it, and only one person was advised to discontinue the use (3,45%); only one doctor (3,45%) indicated the use of plants. Multivariate analysis showed differences for the use of plants in relation to gender (female PR= 1,58, 95% CI 1,15 - 2,15 p 0,004) and homosexual practices (PR= 0,63, CI 0,44 - 0,90 p 0,012). This study highlights the need for a better dialogue between doctors and patients about the use of plants with medicinal purposes, and warns about possible dangers when they are combined with antirretroviral therapy, particularly between female and homossexual users

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass