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1.
Psychol Bull ; 150(5): 586-620, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38619478

RESUMO

People feel committed to other individuals, groups, organizations, or moral norms in many contexts of everyday life. Such social commitment can lead to positive outcomes, such as increased job satisfaction or relationship longevity; yet, there can also be detrimental effects to feeling committed. Recent high-profile cases of fraud or corruption in companies like Enron or Volkswagen are likely influenced by strong commitment to the organization or coworkers. Although social commitment might increase dishonest behavior, there is little systematic knowledge about when and how this may occur. In the present project, we reviewed 20,988 articles, focusing on studies that experimentally manipulated social commitment and measured dishonest behavior. We retained 445 effect sizes from 121 articles featuring a total of 91,683 participants across 33 countries. We found no evidence that social commitment increases or reduces dishonest behavior in general. Nonetheless, we did find evidence that the effect strongly depends on the target of the commitment. Feeling committed to other individuals or groups reduces honest behavior (g = -0.17 [-0.24, -0.11]), whereas feeling committed to honesty norms through honesty oaths or pledges increases honest behavior (g = 0.27 [0.19, 0.36]). The analysis identified several moderating variables and detected some degree of publication bias across effects. Our findings highlight the diverging effects of different forms of social commitment on dishonest behavior and suggest a combination of the different forms of commitment could be a possible means to combat corruption and dishonest behavior in the organizational context. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Enganação , Comportamento Social , Humanos , Princípios Morais
2.
Cell ; 187(6): 1327-1334, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38490174

RESUMO

To build a just, equitable, and diverse academy, scientists and institutions must address systemic barriers that sex and gender minorities face. This Commentary summarizes (1) critical context informing the contemporary oppression of transgender people, (2) how this shapes extant research on sex and gender, and (3) actions to build an inclusive and rigorous academy for all.


Assuntos
Minorias Sexuais e de Gênero , Pessoas Transgênero , Masculino , Feminino , Humanos , Identidade de Gênero
3.
PLoS One ; 19(3): e0287276, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38446826

RESUMO

The European Union and United Kingdom are in the process of establishing new regulation regarding the use of new genomic techniques in crop and animal breeding. As part of this process, consultations have been launched to understand the views of stakeholders towards the use of new genomic techniques in plant and animal breeding. The responsible research and innovation framework emphasises the importance of dialogue between technology developers and stakeholders, including the public, but what are the opinions of stakeholders towards the regulation of NGTs in Europe and do they view these consultations as opportunities to engage with technology governance? We conducted semi-structured interviews with experts from a range of agri-food stakeholder groups in the European Union and United Kingdom to understand current attitudes towards new biotechnology regulation, how they viewed the process of consultation in both places and what influence they felt they had in shaping regulations. We found that the discussion is similar in both EU and UK, with predictable and fixed opinions determined by attitudes towards the perceived risks associated with direct mutagenesis. Both UK and EU consultations were considered to have the same weaknesses and stakeholders discussed a desire for more dialogic forms of engagement. We highlight several options for new forms of involvement in biotechnology regulation by exploring relevant responsible research and innovation literature.


Assuntos
Biotecnologia , Genômica , Animais , Emoções , Reino Unido , Europa (Continente)
4.
Nucleic Acids Res ; 52(4): 2030-2044, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38261971

RESUMO

DNA regulation, replication and repair are processes fundamental to all known organisms and the sliding clamp proliferating cell nuclear antigen (PCNA) is central to all these processes. S-phase delaying protein 1 (Spd1) from S. pombe, an intrinsically disordered protein that causes checkpoint activation by inhibiting the enzyme ribonucleotide reductase, has one of the most divergent PCNA binding motifs known. Using NMR spectroscopy, in vivo assays, X-ray crystallography, calorimetry, and Monte Carlo simulations, an additional PCNA binding motif in Spd1, a PIP-box, is revealed. The two tandemly positioned, low affinity sites exchange rapidly on PCNA exploiting the same binding sites. Increasing or decreasing the binding affinity between Spd1 and PCNA through mutations of either motif compromised the ability of Spd1 to cause checkpoint activation in yeast. These results pinpoint a role for PCNA in Spd1-mediated checkpoint activation and suggest that its tandemly positioned short linear motifs create a neatly balanced competition-based system, involving PCNA, Spd1 and the small ribonucleotide reductase subunit, Suc22R2. Similar mechanisms may be relevant in other PCNA binding ligands where divergent binding motifs so far have gone under the PIP-box radar.


Assuntos
Proteínas de Ciclo Celular , Antígeno Nuclear de Célula em Proliferação , Proteínas de Schizosaccharomyces pombe , Sítios de Ligação , Replicação do DNA , Proteínas Intrinsicamente Desordenadas/química , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ligação Proteica , Ribonucleotídeo Redutases/genética , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/química , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo
5.
BMJ Glob Health ; 9(1)2024 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-38199778

RESUMO

INTRODUCTION: Neonatal mortality remains significant in low-income and middle-income countries (LMICs) with in-hospital mortality rates similar to those following discharge from healthcare facilities. Care continuity interventions have been suggested as a way of reducing postdischarge mortality by better linking care between facilities and communities. This scoping review aims to map and describe interventions used in LMICs to improve care continuity for newborns after discharge and examine assumptions underpinning the design and delivery of continuity. METHODS: We searched seven databases (MEDLINE, CINAHL, Scopus, Web of Science, EMBASE, Cochrane library and (Ovid) Global health). Publications with primary data on interventions focused on continuity of care for newborns in LMICs were included. Extracted data included year of publication, study location, study design and type of intervention. Drawing on relevant theoretical frameworks and classifications, we assessed the extent to which interventions adopted participatory methods and how they attempted to establish continuity. RESULTS: A total of 65 papers were included in this review; 28 core articles with rich descriptions were prioritised for more in-depth analysis. Most articles adopted quantitative designs. Interventions focused on improving continuity and flow of information via education sessions led by community health workers during home visits. Extending previous frameworks, our findings highlight the importance of interpersonal continuity in LMICs where communication and relationships between family members, healthcare workers and members of the wider community play a vital role in creating support systems for postdischarge care. Only a small proportion of studies focused on high-risk babies. Some studies used participatory methods, although often without meaningful engagement in problem definition and intervention implementation. CONCLUSION: Efforts to reduce neonatal mortality and morbidity should draw across multiple continuity logics (informational, relational, interpersonal and managerial) to strengthen care after hospital discharge in LMIC settings and further focus on high-risk neonates, as they often have the worst outcomes.


Assuntos
Assistência ao Convalescente , Países em Desenvolvimento , Recém-Nascido , Lactente , Humanos , Alta do Paciente , Comunicação , Agentes Comunitários de Saúde
6.
Nat Commun ; 14(1): 7702, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38057330

RESUMO

Loss-of-function of DDX3X is a leading cause of neurodevelopmental disorders (NDD) in females. DDX3X is also a somatically mutated cancer driver gene proposed to have tumour promoting and suppressing effects. We perform saturation genome editing of DDX3X, testing in vitro the functional impact of 12,776 nucleotide variants. We identify 3432 functionally abnormal variants, in three distinct classes. We train a machine learning classifier to identify functionally abnormal variants of NDD-relevance. This classifier has at least 97% sensitivity and 99% specificity to detect variants pathogenic for NDD, substantially out-performing in silico predictors, and resolving up to 93% of variants of uncertain significance. Moreover, functionally-abnormal variants can account for almost all of the excess nonsynonymous DDX3X somatic mutations seen in DDX3X-driven cancers. Systematic maps of variant effects generated in experimentally tractable cell types have the potential to transform clinical interpretation of both germline and somatic disease-associated variation.


Assuntos
Neoplasias , Transtornos do Neurodesenvolvimento , Feminino , Humanos , Edição de Genes , Virulência , Transtornos do Neurodesenvolvimento/genética , Neoplasias/genética , Células Germinativas , Mutação em Linhagem Germinativa , RNA Helicases DEAD-box/genética
7.
Am J Case Rep ; 24: e942265, 2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38113193

RESUMO

BACKGROUND Spontaneous abscesses are generally typical in patients with significant risk factors and have been linked to numerous muscle groups. The sternocleidomastoid muscle, however, piqued our interest as an unusual location, especially in this patient who, other than diabetes mellitus, had no associated risk factors or signs of trauma. CASE REPORT A 61-year-old man appeared with neck pain, erythema, and swelling that had been present for 9 days and for which he had previously been examined in the Emergency Department. He was discharged on oral doxycycline after initial computed tomography (CT) of the neck revealed infiltration without collection. He returned with worsening symptoms and new-onset fever and chills. Vital signs were normal on assessment, with no evidence of trauma. Swelling was observed near the right sternocleidomastoid muscle insertion. A repeat CT scan of the neck revealed an abscess 2.5 cm in diameter. He was originally treated with empiric antibiotics before being moved to targeted medications. Incision and drainage were completed without complication. The patient was given a 6-week course of oral antibiotics. CONCLUSIONS Spontaneous intramuscular abscesses are uncommon in people who have had no previous trauma or other known risk factors, but could be encountered in diabetic patients with non-optimal blood glucose levels, due to bacteremia. As a result, these cases require a high level of suspicion to be recognized and treated early. The scarcity of literature on this illness makes determining the cause challenging. However, by highlighting this case, we intend to raise awareness and facilitate early diagnosis and treatment.


Assuntos
Abscesso , Diabetes Mellitus , Masculino , Humanos , Pessoa de Meia-Idade , Abscesso/etiologia , Abscesso/terapia , Pescoço , Cervicalgia/tratamento farmacológico , Antibacterianos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico
8.
Front Neurosci ; 17: 1274607, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37869505

RESUMO

Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly.

9.
R Soc Open Sci ; 10(10): 230725, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37800151

RESUMO

Extant neosuchian crocodiles are represented by only 24 taxa that are confined to the tropics and subtropics. However, at other intervals during their 200 Myr evolutionary history the clade reached considerably higher levels of species-richness, matched by more widespread distributions. Neosuchians have occupied numerous habitats and niches, ranging from dwarf riverine forms to large marine predators. Despite numerous previous studies, several unsolved questions remain with respect to their biogeographic history, including the geographical origins of major groups, e.g. Eusuchia and Neosuchia itself. We carried out the most comprehensive biogeographic analysis of Neosuchia to date, based on a multivariate K-means clustering approach followed by the application of two ancestral area estimation methods (BioGeoBEARS and Bayesian ancestral location estimation) applied to two recently published phylogenies. Our results place the origin of Neosuchia in northwestern Pangaea, with subsequent radiations into Gondwana. Eusuchia probably emerged in the European archipelago during the Late Jurassic/Early Cretaceous, followed by dispersals to the North American and Asian landmasses. We show that putative transoceanic dispersal events are statistically significantly less likely to happen in alligatoroids. This finding is consistent with the saltwater intolerant physiology of extant alligatoroids, bolstering inferences of such intolerance in their ancestral lineages.

10.
Int J Eat Disord ; 56(11): 2022-2031, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37564014

RESUMO

OBJECTIVE: This research forum describes the use of the intervention mapping for adaptation (IMA) framework to develop and evaluate a novel intervention for athletes with mild eating disorder (ED) symptoms. METHODS: The six IMA steps were followed. In step 1 (needs assessment), we conducted a systematic review of athlete ED interventions and held interviews/focus groups with athletes and sports professionals to inform intervention format and delivery. In step 2 (intervention search), needs assessment information guided the search for an evidence-based intervention suitable for adaptation to athletes. In steps 3 and 4 (intervention development), the identified intervention was adapted and feedback sought from athletes and sport professionals. In steps 5 and 6 (implementation and evaluation), a feasibility study was conducted with athletes (n = 35; females: n = 27; Mage = 27.1). RESULTS: The review highlighted poor evidence for the acceptability and relative efficacy of existing interventions, which were all delivered face-to-face in groups. Interview/focus group data suggested a need for more accessible intervention formats (e.g., self-help). One non-athlete self-help intervention was determined suitable for adaptation to athletes, and adaptations were made. Initial feedback suggested the adapted intervention was relevant within sport settings. The feasibility study revealed that the intervention (MOPED-A: Motivational and Psycho-Educational Self-Help Programme for Athletes with Mild Eating Disorder Symptoms) can be feasibly implemented, is acceptable to athletes and shows potential for reducing ED symptoms. DISCUSSION: IMA is a useful framework for developing participant-centered and evidence-based interventions. The findings and approach taken provide a framework for other researchers and clinicians in developing similar interventions in the ED domain. PUBLIC SIGNIFICANCE: The novel self-help intervention described in this article was developed using intervention mapping and provides promise as a tool for reducing eating disorder symptoms in athletes. We describe how adopting and systematically following a health intervention development approach, such as intervention mapping, can ensure that eating disorder interventions are participant-centered, contextually relevant, and evidence-based, which in turn could help to maximize their reach and effectiveness.


Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos , Esportes , Feminino , Humanos , Adulto , Comportamentos Relacionados com a Saúde , Atletas , Transtornos da Alimentação e da Ingestão de Alimentos/diagnóstico , Transtornos da Alimentação e da Ingestão de Alimentos/terapia
11.
BMJ Glob Health ; 8(8)2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37558270

RESUMO

Regulatory and other governance arrangements influence the introduction of medical devices into health systems and are essential for ensuring their effective and safe use. Challenges with medical device safety, quality and use are documented globally, with evidence suggesting these are linked to poor governance. Yet, medical device regulation and oversight remain inadequately defined and described, particularly in low-income and middle-income settings. Through this review, we sought to examine the literature available on regulatory and oversight processes for medical devices in African countries.Following a systematic approach, we searched academic databases including PubMed, Embase (Ovid) and MEDLINE (Ovid), supplemented by search for grey literature and relevant organisational websites, for documents describing medical device regulation and oversight in African countries. We summarised the data to present key actors, areas for regulation and oversight and challenges.A total of 39 documents reporting regulation and oversight of medical devices were included for analysis. Regulatory and oversight guidelines and processes were reported as inadequate, including limited pre-market testing, reliance on international certifications and limited processes for post-market monitoring and reporting of adverse events. Challenges for regulation and oversight reported included inadequate funding, personnel and technical expertise to perform regulatory functions. The literature highlighted gaps in guidelines for donated medical devices and in information on governance processes at the national level.The current literature provides a general overview of medical device regulatory guidelines and limited evidence on the implementation of regulatory/oversight processes at national and especially subnational levels. We recommend further research to elucidate existing governance arrangements for medical devices within African countries and propose a conceptual framework to inform future studies. The framework provides entry points for careful examination of governance and oversight in policy and practice, the exploration of governance realities across the health system and the influence of wider system dynamics.


Assuntos
Legislação de Dispositivos Médicos , Humanos , África
12.
Brain ; 146(11): 4766-4783, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37437211

RESUMO

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.


Assuntos
Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Animais , Camundongos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Encéfalo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Cognição , Proteínas dos Microfilamentos/genética
13.
J Neurogastroenterol Motil ; 29(3): 335-342, 2023 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-37417260

RESUMO

Background/Aims: Extended wireless pH monitoring (WPM) is used to investigate gastroesophageal reflux disease (GERD) as subsequent or alternative investigation to 24-hour catheter-based studies. However, false negative catheter studies may occur in patients with intermittent reflux or due to catheter-induced discomfort or altered behavior. We aim to investigate the diagnostic yield of WPM after a negative 24-hour multichannel intraluminal impedance pH (MII-pH) monitoring study and to determine predictors of GERD on WPM given a negative MII-pH. Methods: Consecutive adult patients (> 18 years) who underwent WPM for further investigation of suspected GERD following a negative 24-hour MII-pH and upper endoscopy between January 2010 and December 2019 were retrospectively included. Clinical data, endoscopy, MII-pH, and WPM results were retrieved. Fisher's exact test, Wilcoxon rank sum test, or Student's t test were used to compare data. Logistic regression analysis was used to investigate predictors of positive WMP. Results: One hundred and eighty-one consecutive patients underwent WPM following a negative MII-pH study. On average and worst day analysis, 33.7% (61/181) and 34.2% (62/181) of the patients negative for GERD on MII-pH were given a diagnosis of GERD following WPM, respectively. On a stepwise multiple logistic regression analysis, the basal respiratory minimum pressure of the lower esophageal sphincter was a significant predictor of GERD with OR = 0.95 (0.90-1.00, P = 0.041). Conclusions: WPM increases GERD diagnostic yield in patients with a negative MII-pH selected for further testing based on clinical suspicion. Further studies are needed to assess the role of WPM as a first line investigation in patients with GERD symptoms.

14.
Nat Commun ; 14(1): 3449, 2023 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-37301943

RESUMO

Muscle strength is highly heritable and predictive for multiple adverse health outcomes including mortality. Here, we present a rare protein-coding variant association study in 340,319 individuals for hand grip strength, a proxy measure of muscle strength. We show that the exome-wide burden of rare protein-truncating and damaging missense variants is associated with a reduction in hand grip strength. We identify six significant hand grip strength genes, KDM5B, OBSCN, GIGYF1, TTN, RB1CC1, and EIF3J. In the example of the titin (TTN) locus we demonstrate a convergence of rare with common variant association signals and uncover genetic relationships between reduced hand grip strength and disease. Finally, we identify shared mechanisms between brain and muscle function and uncover additive effects between rare and common genetic variation on muscle strength.


Assuntos
Força da Mão , Doenças Musculares , Humanos , Força Muscular/genética , Mutação de Sentido Incorreto , Predisposição Genética para Doença , Proteínas de Transporte
15.
Colorectal Dis ; 25(7): 1479-1488, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37237447

RESUMO

AIM: People living with ulcerative colitis (UC) have two broad treatment avenues, namely medical or surgical therapy. The choice between these can depend on patient preference as well as the receipt of relevant information. The aim of this study was to define the informational needs of patients with UC. METHOD: A postal survey was designed to capture respondent demographics, treatment experienced within the previous 12 months and informational preferences by rating a long list of items. It was delivered through two hospitals that provide tertiary inflammatory bowel disease services. Descriptive analyses were performed to describe demographics and experiences. Principal component analysis was carried out using a varimax rotation to investigate informational needs. RESULTS: A total of 101 responses were returned (20.1% response rate). The median age of respondents was 45 years and the median time since diagnosis was 10 years. Control preferences skewed towards shared (42.6%) or patient-led but clinician-informed (35.6%). Decision regret was low for the population (median 12.5/100, range 0-100). Key informational needs related to medical therapy were benefits and risks of long-term therapy, burden of hospital attendance, reproductive health, need for steroid treatment and impact on personal life. For surgery, these were stoma information, effect on daily life, effect on sexual and reproductive health, risks and benefits and disruption of life due to surgery. CONCLUSION: This study has identified key areas for discussion when counselling patients about treatment decisions around medical therapy and surgery for UC.


Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Humanos , Pessoa de Meia-Idade , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/cirurgia , Preferência do Paciente , Inquéritos e Questionários , Emoções
16.
Nat Genet ; 55(6): 927-938, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37231097

RESUMO

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.


Assuntos
Variação Genética , Transtornos do Neurodesenvolvimento , Humanos , Adulto , Animais , Camundongos , Predisposição Genética para Doença , Fenótipo , Cognição , Proteínas de Transporte/genética , Proteínas Nucleares/genética
17.
J Forensic Odontostomatol ; 41(1): 2-18, 2023 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-37149750

RESUMO

Forensic odontologists are expected to deal with challenging demands which can affect their mental health while dealing with forensic activities. This study aimed to explore the psychological impacts of forensic activities on forensic odontologists and students undertaking training. Firstly, it of an integrative review (part I) on the psychological effects of forensic odontology practice. The review was performed on Scopus, Medline and Web of Science. Next, an anonymous online survey using JISC Online Surveys tool (part II) was performed to assess the inherent opinions of forensic odontologists from the the International Organization for Forensic Odonto-Stomatology (IOFOS), and Association of Forensic Odontologists for Human Rights (AFOHR), and Dentify.me. Results were quantitatively evaluated by means of descriptive statistics and qualitatively upon reflection using Microsoft Office Excel (2010). Part I, only one full-text article out of 2235 (Webb et al., 2002) was found eligible indicating a low number of eligible studies. Part II, 75 forensic odontologists and 26 students (49.9% male; 50.5% female) from over 35 countries participated. Results showed that forensic dentists are more psychologically or emotionally affected by child abuse cases and least affected by age estimation cases. Most experienced forensic odontologists reported the lowest scores of discomforts. Males were more comfortable than women in dealing with stress. 80.77% (n= 21) of the students have not experienced any behavioural changes following mortuary sessions but 19.2% (n= 5) witnessed stress. All respondents support the inclusion of a module in Psychology or stress management in training programmes in Forensic Odontology. Suggestions to maintain mental health are considered by the respondents and topics to be taught suggested by a psychologist.


Assuntos
Maus-Tratos Infantis , Odontologia Legal , Criança , Feminino , Humanos , Masculino , Atitude , Odontologia Legal/educação , Medicina Legal , Inquéritos e Questionários , Estudantes de Ciências da Saúde/psicologia , Atitude do Pessoal de Saúde
18.
Stem Cell Reports ; 18(5): 1061-1074, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-37028423

RESUMO

Perturbing expression is a powerful way to understand the role of individual genes, but can be challenging in important models. CRISPR-Cas screens in human induced pluripotent stem cells (iPSCs) are of limited efficiency due to DNA break-induced stress, while the less stressful silencing with an inactive Cas9 has been considered less effective so far. Here, we developed the dCas9-KRAB-MeCP2 fusion protein for screening in iPSCs from multiple donors. We found silencing in a 200 bp window around the transcription start site in polyclonal pools to be as effective as using wild-type Cas9 for identifying essential genes, but with much reduced cell numbers. Whole-genome screens to identify ARID1A-dependent dosage sensitivity revealed the PSMB2 gene, and enrichment of proteasome genes among the hits. This selective dependency was replicated with a proteasome inhibitor, indicating a targetable drug-gene interaction. Many more plausible targets in challenging cell models can be efficiently identified with our approach.


Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Sistemas CRISPR-Cas/genética , Genoma , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Luminescence ; 38(5): 625-636, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36929164

RESUMO

The present investigation deals with the effect of calcination temperature on the structural and thermoluminescent (TL) properties of Zn2 SiO4 materials. For this study, Zn2 SiO4 was prepared via a simple hydrothermal route and calcinated at temperatures from 700°C to 1100°C in an air atmosphere. TL data of all Zn2 SiO4 samples showed two peaks at around 240°C and 330°C due to the formation of the luminescence centre during X-ray irradiation. More interestingly, the Zn2 SiO4 sample calcinated at 900°C exhibited a shift in the TL peak (282°C and 354°C) with an optimal TL intensity attributed to its good crystallinity with a well-defined hexagonal plate-like morphology. X-ray-irradiated Zn2 SiO4 samples calcinated at 900°C exhibited a high-temperature TL glow curve peak, suggesting that the present material could be used for high-temperature dosimetry applications.


Assuntos
Luminescência , Zinco , Temperatura , Raios X , Dosimetria Termoluminescente , Difração de Raios X
20.
Epilepsy Behav Rep ; 21: 100585, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36698381

RESUMO

Creutzfeldt Jakob Disease (CJD) is a rapidly progressive and fatal neurodegenerative disease that is uncommonly accompanied with seizures. In this case report, we describe a 63-year-old male patient who presented with a 3-week history of visual disturbances and clonic movement of his left arm. Additionally, the patient was reported to have developed erratic behaviors along with insomnia during this period. An EEG showed 4 electrographic seizures of bilateral temporo-occipital onset characterized by 1.5 Hz periodic discharges, lasting 2-13 min. Levetiracetam was started and titrated to the maximal dose however seizures continued so lacosamide and clonazepam were initiated. Despite these aggressive treatments, seizures continued, and oral clobazam 5 mg BID replaced clonazepam. Continued electrographic seizures warranted an increase in clobazam to 10 mg BID after which the seizures stopped; of note, lateralized periodic discharges (LPDs) remained. The patient's symptoms were consistent with the Heidenhain variant, along with probable CJD due to positive RT-QuIC assay, positive 14-3-3 protein, MRI FLAIR hyperintensities, and EEG findings. Although the patient passed away 3 weeks following admission as a result of CJD, we propose that there may be clinical benefit in the use of clobazam in suspected CJD patients presenting with seizures, and its use merits further investigation.

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