The germline mutational landscape of BRCA1 and BRCA2 in Brazil

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.This work was supported in part by grants from Barretos Cancer Hospital (FINEP - CT-INFRA, 02/2010), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2013/24633-2 and 2103/23277-8), Fundação de Apoio à Pesquisa do Rio Grande do Norte (FAPERN), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Ministério da Saúde, the Breast Cancer Research Foundation (Avon grant #02-2013-044) and National Institute of Health/National Cancer Institute (grant #RC4 CA153828-01) for the Clinical Cancer Genomics Community Research Network. Support in part was provided by grants from Fundo de Incentivo a Pesquisa e Eventos (FIPE) from Hospital de Clínicas de Porto Alegre, by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, BioComputacional 3381/2013, Rede de Pesquisa em Genômica Populacional Humana), Secretaria da Saúde do Estado da Bahia (SESAB), Laboratório de Imunologia e Biologia Molecular (UFBA), INCT pra Controle do Câncer and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). RMR and PAP are recipients of CNPq Productivity Grants, and Bárbara Alemar received a grant from the same agencyinfo:eu-repo/semantics/publishedVersio

H2S biosynthesis and catabolism: new insights from molecular studies

Hydrogen sulfide (H2S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H2S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H2S within tissues. Studies utilising these systems are revealing new insights into the biology of H2S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H2S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H2S gas within tissue

Twenty-three unsolved problems in hydrology (UPH) – a community perspective

This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through on-line media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focussed on process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Susceptibility of Duponchelia fovealis Zeller (Lepidoptera: Crambidae) to Soil-Borne Entomopathogenic Fungi

Duponchelia fovealis (Lepidoptera: Crambidae) is an invasive species that has had a large impact on strawberry crops in Brazil. Pesticides have had limited effectiveness and the use of biological control agents to improve its management is the most appropriate approach. The aim of this study was to evaluate the pathogenicity and virulence of entomopathogenic fungi—isolated from soil—against Duponchelia fovealis larvae under laboratory and greenhouse conditions. Pathogenicity screenings were performed for twenty isolates from Beauveria bassiana, Beauveria caledonica, Isaria javanica, Metarhizium anisopliae, and Lecanicillium sp. against third instar larvae of D. fovealis at the concentration of 109 conidia·mL−1. Lethal concentration (LC50) and lethal time (LT50) were determined for the most pathogenic isolates and for one commercial mycoinsecticide. Mortality rates varied from 10 to 89%. The isolates B. bassiana Bea1, Bea110, Bea111 and I. javanica Isa340 were the most pathogenic. The most virulent isolates were B. bassiana Bea111 and I. javanica Isa340 with LC50 values of 2.33 × 106 and 9.69 × 105 conidia·mL−1, respectively. Under greenhouse conditions, the efficacy of LC50 of the isolates I. javanica Isa340 and B. bassiana Bea111 were 45% and 52%, respectively. Our results indicate that these isolates are strong candidates for application in the control of D. fovealis. This study is the first evaluation of soil-borne entomopathogenic fungi against D. fovealis

Infection of Beauveria bassiana and Cordyceps javanica on different immature stages of Duponchelia fovealis Zeller (Lepidoptera: Crambidae)

31 Pags.- 2 Tabl.- 6 Figs. The definitive version is available at: https://www.sciencedirect.com/science/journal/02612194Entomopathogenic fungi (EPF) can be viable options for biological control of agricultural pests. The selection of fungal strains is crucial for a successful pest control. The current study aimed to determine in the laboratory the susceptibility of different immature stages of Duponchelia fovealis Zeller (Lepidoptera: Crambidae) to EPF strains (Beauveria bassiana Bea111 and Cordyceps javanica Isa340). Immature stages of D. fovealis were sprayed with EPF concentrations from 2 × 103 to 2 × 109 conidia mL−1 and their viability and mortality were evaluated. Lethal time and concentration were estimated for pupae and each larval instar. Virulence depended on strain, dose, and insect life stage. The eggs were resistant to Bea111 and Isa340 strains. Mortality of larvae depended on the EPF strain and the larval instar, with the first instar being the most sensitive. Lethal concentrations for D. fovealis 1st instar larvae were 3.4 × 105 and 1.7 × 107 conidia mL−1 with Bea111 and Isa340, respectively. Isa340 performed better than Bea111 for controlling pupae. Scanning electron microscopy revealed the adhesion and penetration structures of both fungi in the 2nd instar infected larvae 6 h after inoculation, while fungal extrusion occurred between 54 and 94 h after spraying with Bea111 and Isa340, respectively.This work was supported by Coordination for the Improvement of Higher Education Personnel (CAPES) [grant numbers 1726812 and 1771724], and National Council for Scientific and Technological Development (CNPq) [grant number 403266/2013–0].Peer reviewe