The Fission Yeast Homeodomain Protein Yox1p Binds to MBF and Confines MBF-Dependent Cell-Cycle Transcription to G1-S via Negative Feedback

The regulation of the G1- to S-phase transition is critical for cell-cycle progression. This transition is driven by a transient transcriptional wave regulated by transcription factor complexes termed MBF/SBF in yeast and E2F-DP in mammals. Here we apply genomic, genetic, and biochemical approaches to show that the Yox1p homeodomain protein of fission yeast plays a critical role in confining MBF-dependent transcription to the G1/S transition of the cell cycle. The yox1 gene is an MBF target, and Yox1p accumulates and preferentially binds to MBF-regulated promoters, via the MBF components Res2p and Nrm1p, when they are transcriptionally repressed during the cell cycle. Deletion of yox1 results in constitutively high transcription of MBF target genes and loss of their cell cycle–regulated expression, similar to deletion of nrm1. Genome-wide location analyses of Yox1p and the MBF component Cdc10p reveal dozens of genes whose promoters are bound by both factors, including their own genes and histone genes. In addition, Cdc10p shows promiscuous binding to other sites, most notably close to replication origins. This study establishes Yox1p as a new regulatory MBF component in fission yeast, which is transcriptionally induced by MBF and in turn inhibits MBF-dependent transcription. Yox1p may function together with Nrm1p to confine MBF-dependent transcription to the G1/S transition of the cell cycle via negative feedback. Compared to the orthologous budding yeast Yox1p, which indirectly functions in a negative feedback loop for cell-cycle transcription, similarities but also notable differences in the wiring of the regulatory circuits are evident

Enhancement of Cell Membrane Invaginations, Vesiculation and Uptake of Macromolecules by Protonation of the Cell Surface

The different pathways of endocytosis share an initial step involving local inward curvature of the cell’s lipid bilayer. It has been shown that to generate membrane curvature, proteins or lipids enforce transversal asymmetry of the plasma membrane. Thus it emerges as a general phenomenon that transversal membrane asymmetry is the common required element for the formation of membrane curvature. The present study demonstrates that elevating proton concentration at the cell surface stimulates the formation of membrane invaginations and vesiculation accompanied by efficient uptake of macromolecules (Dextran-FITC, 70 kD), relative to the constitutive one. The insensitivity of proton induced uptake to inhibiting treatments and agents of the known endocytic pathways suggests the entry of macromolecules to proceeds via a yet undefined route. This is in line with the fact that neither ATP depletion, nor the lowering of temperature, abolishes the uptake process. In addition, fusion mechanism such as associated with low pH uptake of toxins and viral proteins can be disregarded by employing the polysaccharide dextran as the uptake molecule. The proton induced uptake increases linearly in the extracellular pH range of 6.5 to 4.5, and possesses a steep increase at the range of 4> pH>3, reaching a plateau at pH≤3. The kinetics of the uptake implies that the induced vesicles release their content to the cytosol and undergo rapid recycling to the plasma membrane. We suggest that protonation of the cell’s surface induces local charge asymmetries across the cell membrane bilayer, inducing inward curvature of the cell membrane and consequent vesiculation and uptake

Transtornos mentais comuns entre estudantes de medicina da Universidade Federal de Sergipe: estudo transversal

Objetivo: Estimar a prevalência de transtorno mental comum e fatores associados entre estudantes de Medicina da Universidade Federal de Sergipe. Método: Estudo transversal com 473 dos 512 matriculados em 2006, aplicando o Self Reporting Questionnaire-20 e um questionário estruturado sobre características sociodemográficas, processo ensino-aprendizagem e vivências psicoemocionais. Os calouros foram excluídos após comparação inicial com os alunos do 2° ao 12° períodos. Análise estatística por regressão logística múltipla, após estatística descritiva e cálculo das ORs simples e ajustadas. Resultados: A prevalência de transtorno mental comum geral foi de 40% (n = 473), mas com a retirada dos calouros, aumentou para 42,5% (n = 433) entre os alunos do 2° ao 12° semestre, sendo maior entre aqueles que não acreditavam ter adquirido habilidades para se tornarem bons médicos (OR = 2,82), que se sentiam pouco confortáveis com as atividades do curso (OR = 3,75), que se consideravam emocionalmente tensos (OR = 2,14), nos que não se consideravam felizes (OR = 2,85), nos que achavam que o curso era menos do que esperavam (OR = 1,64) e nos que tiveram diagnóstico prévio de transtorno mental feito por psiquiatra (OR = 3,78). Conclusão: Os resultados sugerem a necessidade de mudanças no processo ensino-aprendizagem, bem como estruturação de programas para cuidar da saúde mental dos estudantes. _________________________________________________________________________________________ ABSTRACT: Objective: Estimate the prevalence of common mental disorder and its associated factors among medical students of the Universidade Federal de Sergipe. Method: A cross-sectional study was carried out, applying Self Reporting Questionnaire-20 to 473 students from the 512 medical students enrolled in 2006 and compared with compared with a structured questionnaire by the authors containing information on the socio-demographic characteristics, the teaching–learning process and the psycho-emotional experiences of the students. Freshmen were excluded after initial comparison with the students already exposed to the medical course. Statistical analysis by multiple logistic regression after calculating simple and adjusted odds ratio (OR). Results: The general prevalence of common mental disorder was 40% (n = 473); after exclusion of the freshmen it increased to 42.5% among students from the 2nd to the 12th semester.It was higher among those who did not have faith in their acquisition of the skills needed to become a good doctor (OR = 2.82), who felt less comfortable about course activities (OR = 3.75), who considered themselves emotionally stressed (OR = 2.14), among those who did not consider themselves happy (OR = 2.85), who believed that the course did not match their expectations (OR = 1.64) and those who had a prior diagnosis of mental disorder by a psychiatrist (OR = 3.78). Conclusion: The results suggest the necessity of changes to the teaching-learning process and the establishment of a preventive mental health program for medical students

Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases

Scintillation light detection in the 6-m drift-length ProtoDUNE Dual Phase liquid argon TPC

DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6  ×  6  ×  6 m 3 liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019-2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties