Altered Ultrasonic Vocalization and Impaired Learning and Memory in Angelman Syndrome Mouse Model with a Large Maternal Deletion from Ube3a to Gabrb3

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11–q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11–q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m−/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m−/p+), but not paternal (m+/p−), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone

The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension

Aims Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. Conclusion May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk

Buildout and integration of an automated high-throughput CLIA laboratory for SARS-CoV-2 testing on a large urban campus

In 2019, the first cases of SARS-CoV-2 were detected in Wuhan, China, and by early 2020 the first cases were identified in the United States. SARS-CoV-2 infections increased in the US causing many states to implement stay-at-home orders and additional safety precautions to mitigate potential outbreaks. As policies changed throughout the pandemic and restrictions lifted, there was an increase in demand for COVID-19 testing which was costly, difficult to obtain, or had long turn-around times. Some academic institutions, including Boston University (BU), created an on-campus COVID-19 screening protocol as part of a plan for the safe return of students, faculty, and staff to campus with the option for in-person classes. At BU, we put together an automated high-throughput clinical testing laboratory with the capacity to run 45,000 individual tests weekly by Fall of 2020, with a purpose-built clinical testing laboratory, a multiplexed reverse transcription PCR (RT-qPCR) test, robotic instrumentation, and trained staff. There were many challenges including supply chain issues for personal protective equipment and testing materials in addition to equipment that were in high demand. The BU Clinical Testing Laboratory (CTL) was operational at the start of Fall 2020 and performed over 1 million SARS-CoV-2 PCR tests during the 2020-2021 academic year.Boston UniversityPublished versio

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Estudios de marcado y recaptura de especies marinas

Los resultados obtenidos del marcado y posterior recaptura de los ejemplares son una herramienta muy valiosa para contribuir a mejorar el conocimiento de la biología y ecología de una especie, examinando ciertos aspectos como son: el crecimiento, los movimientos o migraciones, la mortalidad o supervivencia, la abundancia y distribución de la especie, el hábitat y diferenciación de poblaciones o stocks. Actualmente la técnica de marcado se aplica a muchas especies, tanto terrestres como marinas, pertenecientes a diversos grupos zoológicos: peces, crustáceos, reptiles, moluscos y mamíferos. Este libro repasa algunos ejemplos de marcado de especies marinas de interés comercial. No todas las especies pueden ser marcadas, porque es necesario cumplir una serie de requisitos para poder llevar a cabo con éxito un experimento de marcado. En uno de los apartados de esta guía, se describen los distintos aspectos a tener en cuenta para obtener buenos resultados. Se describen los principales proyectos de marcado actualmente en ejecución o en marcha llevados a cabo por el Instituto Español de Oceanografía (IEO). En primer lugar, se describe brevemente la especie, su distribución, crecimiento, reproducción, alimentación, etc. A continuación, se presenta la información del marcado, es decir, campañas realizadas, número de ejemplares marcados y algunos de los resultados obtenidos hasta la fecha a partir de las recapturas disponibles. En algunas especies, los programas de marcado se llevan realizando desde hace más de 20 años, como es el caso del atún rojo, por lo que la información disponible es bastante amplia. En otros casos por el contrario como la merluza, los proyectos son relativamente recientes, no obstante los resultados son bastante interesantes y prometedores.Nowadays many different marine animals are being tagged. This book summarizes recent tagging programs carried out by the Spanish Institute of Oceanography (IEO). Although the objectives of these various studies mainly depend on the species and each project in particular, the general aim is to better understand the biology and ecology of these animals the structure and dynamics of their populations and their capacity to respond to human activities. This book provides an overview of different aspects of this technique such as a brief history of tagging, the types of tags currently used, including both conventional and electronic tags, where and how to put them on the marine animals, some recommendations regarding how to perform a tagging survey and where to go or what to do if anyone recovers a tagged fish or marine animal. The book then summarizes the main species tagged by the IEO, making a short description of their biology followed by some of the results obtained from tagging studies undertaken until now. Other applications are to know the spatial distribution (spawning or feeding areas), estimate growth parameters, mortality and survival rates, longevity, the size of the population or identifying stocks. Nowadays the advances in electronics have also open new fields such us the possibility of tracking an animal and knowing its habitat preferences and behaviour. Besides some of these tags have the capacity of recording this information during long periods and sending the data from long distances even without the need to recover the animal. Tagging activities constitute a very useful tool to improve the knowledge of many species and contribute to their management and conservation. For that reason this methodology is included in many IEO projects in which other activities like the monitoring of the fishery (landings, fishing effort, fleet characteristics, fishing areas, biological sampling, etc.) are carried out. Some projects are related with coastal pelagic fisheries including anchovy, sardine and mackerel or oceanic pelagic fisheries like tuna and billfish species and pelagic sharks. Others are focused on benthic and demersal species such as hake, black spot seabream, anglerfish, flatfish, etc. Nevertheless not all species can be tagged, as they have to survive being caught and handled before being release. For this reason, tagging techniques may not easily be applied to some species.Versión del edito

Differences in n-type doping efficiency between Al- and Ga-ZnO films

A careful and wide comparison between Al and Ga as substitutional dopants in the ZnO wurtzite structure is presented. Both cations behave as n-type dopants and their inclusion improves the optical and electrical properties of the ZnO matrix, making it more transparent in the visible range and rising up its electrical conductivity. However, the same dopant/Zn ratio leads to a very different doping efficiency when comparing Al and Ga, being the Ga cation a more effective dopant of the ZnO film. The measured differences between Al- and Ga-doped films are explained with the hypothesis that different quantities of these dopant cations are able to enter substitutionally in the ZnO matrix. Ga cations seem to behave as perfect substitutional dopants, while Al cation might occupy either substitutional or interstitial sites. Moreover, the subsequent charge balance after doping appear to be related with the formation of different intrinsic defects that depends on the dopant cation. The knowledge of the doped-ZnO films microstructure is a crucial step to optimize the deposition of transparent conducting electrodes for solar cells, displays, and other photoelectronic devices. © 2013 AIP Publishing LLC.Peer Reviewe