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Machine learning, a collection of data-analytical techniques aimed at building predictive models from multi-dimensional datasets, is becoming integral to modern biological research. By enabling one to generate models that learn from large datasets and make predictions on likely outcomes, machine learning can be used to study complex cellular systems such as biological networks. Here, we provide a primer on machine learning for life scientists, including an introduction to deep learning. We discuss opportunities and challenges at the intersection of machine learning and network biology, which could impact disease biology, drug discovery, microbiome research, and synthetic biology.
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Biologia Computacional/métodos , Aprendizado de Máquina , Algoritmos , Bases de Dados Factuais , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Microbiota , Redes Neurais de ComputaçãoRESUMO
There is much excitement about the opportunity to harness the power of large language models (LLMs) when building problem-solving assistants. However, the standard methodology of evaluating LLMs relies on static pairs of inputs and outputs; this is insufficient for making an informed decision about which LLMs are best to use in an interactive setting, and how that varies by setting. Static assessment therefore limits how we understand language model capabilities. We introduce CheckMate, an adaptable prototype platform for humans to interact with and evaluate LLMs. We conduct a study with CheckMate to evaluate three language models (InstructGPT, ChatGPT, and GPT-4) as assistants in proving undergraduate-level mathematics, with a mixed cohort of participants from undergraduate students to professors of mathematics. We release the resulting interaction and rating dataset, MathConverse. By analyzing MathConverse, we derive a taxonomy of human query behaviors and uncover that despite a generally positive correlation, there are notable instances of divergence between correctness and perceived helpfulness in LLM generations, among other findings. Further, we garner a more granular understanding of GPT-4 mathematical problem-solving through a series of case studies, contributed by experienced mathematicians. We conclude with actionable takeaways for ML practitioners and mathematicians: models that communicate uncertainty, respond well to user corrections, and can provide a concise rationale for their recommendations, may constitute better assistants. Humans should inspect LLM output carefully given their current shortcomings and potential for surprising fallibility.
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Idioma , Matemática , Resolução de Problemas , Humanos , Resolução de Problemas/fisiologia , Estudantes/psicologiaRESUMO
BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).
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Antidepressivos , Transtorno Depressivo Resistente a Tratamento , Eletroconvulsoterapia , Ketamina , Humanos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia/efeitos adversos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/uso terapêutico , Qualidade de Vida , Resultado do Tratamento , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/diagnóstico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/terapia , Administração Intravenosa , Transtornos PsicóticosRESUMO
BACKGROUND: Despite the benefits of exercise, many individuals are unable or unwilling to adopt an exercise intervention. PURPOSE: The purpose of this analysis was to identify putative genetic variants associated with dropout from exercise training interventions among individuals in the STRRIDE trials. METHODS: We used a genome-wide association study approach to identify genetic variants in 603 participants initiating a supervised exercise intervention. Exercise intervention dropout occurred when a subject withdrew from further participation in the study or was otherwise lost to follow-up. RESULTS: Exercise intervention dropout was associated with a cluster of single-nucleotide polymorphisms with the top candidate being rs722069 (T/C, risk allele = C) (unadjusted p = 2.2 × 10-7, odds ratio = 2.23) contained within a linkage disequilibrium block on chromosome 16. In Genotype-Tissue Expression, rs722069 is an expression quantitative trait locus of the EARS2, COG7, and DCTN5 genes in skeletal muscle tissue. In subsets of the STRRIDE genetic cohort with available muscle gene expression (n = 37) and metabolic data (n = 82), at baseline the C allele was associated with lesser muscle expression of EARS2 (p < .002) and COG7 (p = .074) as well as lesser muscle concentrations of C2- and C3-acylcarnitines (p = .026). CONCLUSIONS: Our observations imply that exercise intervention dropout is genetically moderated through alterations in gene expression and metabolic pathways in skeletal muscle. Individual genetic traits may allow the development of a biomarker-based approach for identifying individuals who may benefit from more intensive counseling and other interventions to optimize exercise intervention adoption. CLINICAL TRIAL INFORMATION: STRRIDE I = NCT00200993; STRRIDE AT/RT = NCT00275145; STRRIDE-PD = NCT00962962.
Regular participation in exercise can provide a myriad of health benefits. Although individuals recognize these benefits, many are unable or unwilling to adopt an exercise intervention once initiated. The purpose of this analysis was to identify genetic variants associated with dropout from an exercise training intervention. We found exercise intervention dropout to be genetically moderated through changes in gene expression and metabolic pathways in muscle. Thus, individual genetic traits may allow for the development of a biomarker-based targeted approach for identifying individuals who may benefit from more intensive counseling and interventions to optimize the adoption of an exercise intervention program.
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Doenças Cardiovasculares , Sobrepeso , Adulto , Humanos , Estudo de Associação Genômica Ampla , Obesidade , Terapia por ExercícioRESUMO
Recent progress in DNA synthesis and sequencing technology has enabled systematic studies of protein function at a massive scale. We explore a deep mutational scanning study that measured the transcriptional repression function of 43,669 variants of the Escherichia coli LacI protein. We analyze structural and evolutionary aspects that relate to how the function of this protein is maintained, including an in-depth look at the C-terminal domain. We develop a deep neural network to predict transcriptional repression mediated by the lac repressor of Escherichia coli using experimental measurements of variant function. When measured across 10 separate training and validation splits using 5,009 single mutations of the lac repressor, our best-performing model achieved a median Pearson correlation of 0.79, exceeding any previous model. We demonstrate that deep representation learning approaches, first trained in an unsupervised manner across millions of diverse proteins, can be fine-tuned in a supervised fashion using lac repressor experimental datasets to more effectively predict a variant's effect on repression. These findings suggest a deep representation learning model may improve the prediction of other important properties of proteins.
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Aprendizado Profundo , Proteínas de Escherichia coli/metabolismo , Repressores Lac/metabolismo , Transcrição Gênica , Epistasia Genética , Proteínas de Escherichia coli/genética , Repressores Lac/genética , Mutação/genética , Domínios Proteicos , Reprodutibilidade dos TestesRESUMO
Study abroad programs expose scholars, including nursing faculty and students, to different settings and cultures. However, the world of global health is rooted in colonial practices that have the potential to cause harm to communities. In this reflection, we provide lessons we have learned through study abroad that guide strategies for decolonizing our practice while working toward cultural safety and humility. We utilized a qualitative case study method. Authors discussed and reviewed study abroad programs through a series of virtual discussions. Discussions showed that study abroad programs present opportunities for students and faculty to grow and learn. However, unacknowledged privileges among visiting students and faculty, and lack of understanding of the impacts of colonialism, may lead to harm in communities and inequitable relationships with local providers. Understanding the privileges that we hold is important in advancing positive and equitable experiences in study abroad programs.
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Patients with obsessive-compulsive disorder (OCD) exhibit abnormality in their subjective perception of internal sensation, a process known as interoceptive sensibility (IS), as well as altered functioning of the insula, a key neural structure for interoception. We investigated the multivariate structure of IS in 77 OCD patients and 53 controls and examined associations of IS with resting-state functional connectivity (FC) of the insula within the OCD group. For each group, principal component analysis was performed on 8 subscales of the Multidimensional Assessment of Interoceptive Awareness assessing putatively "adaptive" and "maladaptive" aspects of IS. Associations between IS components and insula FC in the OCD group were evaluated using seed regions placed in each of 3 subdivisions of the insula (posterior, anterior dorsal, and anterior ventral). Behaviorally, controls showed a 2-component solution broadly categorized into "adaptive" and "maladaptive" IS, while OCD patients exhibited a 3-component solution. The general tendency to notice or be aware of sensation loaded onto an "adaptive" IS component in controls but loaded onto both "adaptive" and "maladaptive" IS components in OCD. Within OCD, insula FC was differentially associated with distinct aspects of IS, identifying network connections that could serve as future targets for the modulation of IS in OCD.
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Interocepção , Transtorno Obsessivo-Compulsivo , Humanos , Imageamento por Ressonância Magnética/métodos , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Sensação , Mapeamento Encefálico , Vias Neurais/diagnóstico por imagemRESUMO
Quantum computers and simulators may offer significant advantages over their classical counterparts, providing insights into quantum many-body systems and possibly improving performance for solving exponentially hard problems, such as optimization and satisfiability. Here, we report the implementation of a low-depth Quantum Approximate Optimization Algorithm (QAOA) using an analog quantum simulator. We estimate the ground-state energy of the Transverse Field Ising Model with long-range interactions with tunable range, and we optimize the corresponding combinatorial classical problem by sampling the QAOA output with high-fidelity, single-shot, individual qubit measurements. We execute the algorithm with both an exhaustive search and closed-loop optimization of the variational parameters, approximating the ground-state energy with up to 40 trapped-ion qubits. We benchmark the experiment with bootstrapping heuristic methods scaling polynomially with the system size. We observe, in agreement with numerics, that the QAOA performance does not degrade significantly as we scale up the system size and that the runtime is approximately independent from the number of qubits. We finally give a comprehensive analysis of the errors occurring in our system, a crucial step in the path forward toward the application of the QAOA to more general problem instances.
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Fear is an adaptive emotion that serves to protect an organism against potential dangers. It is often studied using classical conditioning paradigms where a conditioned stimulus is paired with an aversive unconditioned stimulus to induce a threat response. Less commonly studied is a phenomenon that is related to this form of conditioning, known as latent inhibition. Latent inhibition (LI) is a paradigm in which a neutral cue is repeatedly presented in the absence of any aversive associations. Subsequent pairing of this pre-exposed cue with an aversive stimulus typically leads to reduced expression of a conditioned fear/threat response. In this article, we review some of the theoretical basis for LI and its behavioral and neural mechanisms. We compare and contrast LI and fear/threat extinction-a process in which a previously conditioned cue is repeatedly presented in the absence of aversive outcomes. We end with highlighting the potential clinical utility of LI. Particularly, we focus on how LI application could be useful for enhancing resilience, especially for individuals who are more prone to continuous exposure to trauma and stressful environments, such as healthcare workers and first responders. The knowledge to be gained from advancing our understanding of neural mechanisms in latent inhibition could be applicable across psychiatric disorders characterized by exaggerated fear responses and impaired emotion regulation.
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Condicionamento Clássico , Medo , Emoções , Extinção Psicológica , Humanos , MemóriaRESUMO
AIM: Penicillin allergy accounts for the majority of all reported adverse drug reactions in adults and children. Foregoing first-line antibiotic therapy due to penicillin allergy label is associated with an increased prevalence of infections by resistant organisms and longer hospitalisation. Clinician awareness of allergy assessment, referral indications, management of allergy and anaphylaxis is therefore vital but globally lacking. We aim to assess the knowledge of penicillin allergy, assessment and management in Western Australian health professionals. METHODS: An anonymous survey was distributed to pharmacists, nurses and physicians within Western Australian paediatric and adult Hospitals, Community and General Practice. RESULTS: In total, 487/611 were completed and included in the statistical analysis. Only 62% (301/487) of respondents routinely assessed for patient medication allergies. Of those who assessed allergy, 9% (28/301) of respondents met the Australian standards for allergy assessment. Only 22% (106/487) of participants correctly cited all indications for management with adrenaline in anaphylaxis to antibiotics and 67% (197/292) of physicians rarely or never referred to an allergy service. Paediatric clinicians had an increased understanding of allergy assessment and anaphylaxis management. Recent penicillin allergy education within a 5-year period led to significant improvements in allergy knowledge. CONCLUSION: Overall, knowledge, assessment and management of penicillin allergies among practitioners in Western Australia are currently inadequate in adults and paediatric clinicians to provide safe and effective clinical care. The implementation of a targeted education program for WA health professionals is urgently required and is expected to improve clinician knowledge and aid standardised penicillin assessment (de-labelling) practices.
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Anafilaxia , Hipersensibilidade a Drogas , Adulto , Anafilaxia/tratamento farmacológico , Antibacterianos/efeitos adversos , Austrália , Criança , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/terapia , Hospitais , Humanos , Penicilinas/efeitos adversos , Inquéritos e QuestionáriosRESUMO
Mixed-status families-whose members have multiple immigration statuses-are common in US immigrant communities. Large-scale worksite raids, an immigration enforcement tactic used throughout US history, returned during the Trump administration. Yet, little research characterizes the impacts of these raids, especially as related to mixed-status families. The current study (1) describes a working definition of a large-scale worksite raid and (2) considers impacts of these raids on mixed-status families. We conducted semistructured interviews in Spanish and English at 6 communities that experienced the largest worksite raids in 2018. Participants were 77 adults who provided material, emotional, or professional support following raids. Qualitative analysis methods were used to develop a codebook and code all interviews. The unpredictability of worksite raids resulted in chaos and confusion, often stemming from potential family separation. Financial crises followed because of the removal of primary financial providers. In response, families rearranged roles to generate income. Large-scale worksite raids result in similar harms to mixed-status families as other enforcement tactics but on a much larger scale. They also uniquely drain community resources, with long-term impacts. Advocacy and policy efforts are needed to mitigate damage and end this practice.
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Emigrantes e Imigrantes , Emigração e Imigração , Adulto , Relações Familiares , Hispânico ou Latino , Humanos , Local de TrabalhoRESUMO
Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: -6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.
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Carbamatos/farmacologia , Carbamatos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Ativação do Canal Iônico/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico , Estriado Ventral/efeitos dos fármacos , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Canais de Potássio KCNQ/agonistas , Canais de Potássio KCNQ/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recompensa , Estriado Ventral/metabolismoRESUMO
TUT4 and the closely related TUT7 are non-templated poly(U) polymerases required at different stages of development, and their mis-regulation or mutation has been linked to important cancer pathologies. While TUT4(7) interaction with its pre-miRNA targets has been characterized in detail, the molecular bases of the broader target recognition process are unclear. Here, we examine RNA binding by the ZnF domains of the protein. We show that TUT4(7) ZnF2 contains two distinct RNA binding surfaces that are used in the interaction with different RNA nucleobases in different targets, i.e that this small domain encodes diversity in TUT4(7) selectivity and molecular function. Interestingly and unlike other well-characterized CCHC ZnFs, ZnF2 is not physically coupled to the flanking ZnF3 and acts independently in miRNA recognition, while the remaining CCHC ZnF of TUT4(7), ZnF1, has lost its intrinsic RNA binding capability. Together, our data suggest that the ZnFs of TUT4(7) are independent units for RNA and, possibly, protein-protein interactions that underlay the protein's functional flexibility and are likely to play an important role in building its interaction network.
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Proteínas de Ligação a DNA/metabolismo , Epistasia Genética , Regulação da Expressão Gênica , MicroRNAs/genética , Proteínas de Ligação a RNA/metabolismo , Dedos de Zinco , Composição de Bases , Proteínas de Ligação a DNA/química , Humanos , Espectroscopia de Ressonância Magnética , MicroRNAs/química , MicroRNAs/metabolismo , Poli U , Domínios e Motivos de Interação entre Proteínas , Proteínas de Ligação a RNA/química , Relação Estrutura-AtividadeRESUMO
Obsessive-compulsive disorder (OCD) is highly heterogeneous. While obsessions often involve fear of harm, many patients report uncomfortable sensations and/or urges that drive repetitive behaviors in the absence of a specific fear. Prior work suggests that urges in OCD may be similar to everyday "urges-for-action" (UFA) such as the urge to blink, swallow, or scratch, but very little work has investigated the pathophysiology underlying urges in OCD. In the current study, we used an urge-to-blink approach to model sensory-based urges that could be experimentally elicited and compared across patients and controls using the same task stimuli. OCD patients and controls suppressed eye blinking over a period of 60 s, alternating with free blinking blocks, while brain activity was measured using functional magnetic resonance imaging. OCD patients showed significantly increased activation in several regions during the early phase of eyeblink suppression (first 30 s), including mid-cingulate, insula, striatum, parietal cortex, and occipital cortex, with lingering group differences in parietal and occipital regions during late eyeblink suppression (last 30 s). There were no differences in brain activation during free blinking blocks, and no conditions where OCD patients showed reduced activation compared to controls. In an exploratory analysis of blink counts performed in a subset of subjects, OCD patients were less successful than controls in suppressing blinks. These data indicate that OCD patients exhibit altered brain function and behavior when experiencing and suppressing the urge to blink, raising the possibility that the disorder is associated with a general abnormality in the UFA system that could ultimately be targeted by future treatments.
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Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/psicologia , Adulto , Ansiedade/diagnóstico por imagem , Ansiedade/psicologia , Piscadela , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Mapeamento Encefálico , Depressão/diagnóstico por imagem , Depressão/psicologia , Feminino , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Motivação , Neuroimagem , Repressão PsicológicaRESUMO
RBM10 is an RNA-binding protein that plays an essential role in development and is frequently mutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3Î intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein. We show that a two-domain RRM1-ZnF unit recognizes a GGA-centered motif enriched in RBM10 exonic sites with high affinity and specificity and test that the interaction with these exonic sequences promotes exon skipping. Importantly, a second RRM domain (RRM2) of RBM10 recognizes a C-rich sequence, which explains its known interaction with the intronic 3Î site of NUMB exon 9 contributing to regulation of the Notch pathway in cancer. Together, these findings explain RBM10's broad RNA specificity and suggest that RBM10 functions as a splicing regulator using two RNA-binding units with different specificities to promote exon skipping.
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Proteínas de Ligação a RNA/fisiologia , Autoantígenos , Sequência de Bases , Sítios de Ligação , Éxons , Células HEK293 , Humanos , Ligação Proteica , Splicing de RNA , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Dedos de ZincoRESUMO
BACKGROUND: Overweight and obesity are significant public health concerns that are linked to numerous negative health consequences. Physical activity is an important lifestyle behavior that contributes to body weight regulation. CONTENT: Physical activity is inversely associated with weight gain and the incidence of obesity. Physical activity also contributes to additional weight loss when coupled with dietary modification, and it can result in modest weight loss when not coupled with dietary modification. Moreover, physical activity is associated with improved long-term weight loss and prevention of weight gain following initial weight loss. Current evidence supports that physical activity should be moderate to vigorous in intensity to influence body weight regulation. There is also a growing body of evidence that physical activity can be accumulated throughout the day in shorter periods of time rather than being performed during a structured and longer period, and that physical activity performed in this manner can be important for body weight regulation. SUMMARY: The literature supports the inclusion of physical activity as an important lifestyle behavior for regulating body weight. There are multiple intervention approaches that may be effective for enhancing physical activity engagement within the context of weight control.
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Exercício Físico , Obesidade/terapia , Sobrepeso/terapia , Dieta , Metabolismo Energético , Humanos , Estilo de Vida , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Obesidade/fisiopatologia , Sobrepeso/epidemiologia , Sobrepeso/fisiopatologia , Prevalência , Fatores de Risco , Aumento de Peso , Redução de PesoRESUMO
Background: Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Methods: Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Results: Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Conclusions: Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).
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Neuropeptídeo Y/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Adulto , Ansiedade/tratamento farmacológico , Estudos de Coortes , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
BACKGROUND: Rates of pre-gestational obesity and gestational diabetes mellitus (GDM) are increasing in Australia. While both are established risk factors for neonatal hypoglycaemia, the additive effect of both risks on neonatal hypoglycaemia is not well understood. AIMS: To determine the influence of obesity on neonatal hypoglycaemia among infants born to GDM mothers. The authors hypothesise the presence of a greater frequency and severity of neonatal hypoglycaemia in infants born to obese GDM women. MATERIALS AND METHODS: A cohort of 471 singleton GDM pregnancies was retrospectively studied. Women were divided into obese (body mass index (BMI) ≥ 30 kg/m2 ) and not-obese (BMI < 30 kg/m2 ) groups according to self-reported pre-pregnancy weight. Perinatal outcomes and details of hypoglycaemic episodes were obtained by reviewing medical records. RESULTS: Twenty-five percent (104/410) of the GDM mothers were obese, while 36% (146/410) exceeded pregnancy weight gain recommendations. GDM and obesity resulted in a greater frequency of neonatal hypoglycaemia as compared to women with GDM alone (obese 44%, not obese 34%, P = 0.046). Obesity increased the likelihood of having multiple hypoglycaemic episodes (P = 0.022). Excess weight gain increased the likelihood of the neonate requiring intravenous dextrose (P = 0.0012). No differences were found in the likelihood of nursery admissions or lowest plasma glucose levels. CONCLUSIONS: Pre-pregnancy obesity and weight gain during pregnancy above the recommended limits increased the likelihood of neonatal hypoglycaemia among infants of GDM mothers. Further studies with larger cohorts are warranted to confirm our findings.
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Diabetes Gestacional/epidemiologia , Ganho de Peso na Gestação , Hipoglicemia/epidemiologia , Doenças do Recém-Nascido/epidemiologia , Obesidade , Adulto , Diabetes Gestacional/sangue , Feminino , Humanos , Hipoglicemia/sangue , Recém-Nascido , Doenças do Recém-Nascido/sangue , Gravidez , Cuidado Pré-Natal , Estudos Retrospectivos , Fatores de Risco , Austrália Ocidental/epidemiologiaRESUMO
Defining the RNA target selectivity of the proteins regulating mRNA metabolism is a key issue in RNA biology. Here we present a novel use of principal component analysis (PCA) to extract the RNA sequence preference of RNA binding proteins. We show that PCA can be used to compare the changes in the nuclear magnetic resonance (NMR) spectrum of a protein upon binding a set of quasi-degenerate RNAs and define the nucleobase specificity. We couple this application of PCA to an automated NMR spectra recording and processing protocol and obtain an unbiased and high-throughput NMR method for the analysis of nucleobase preference in protein-RNA interactions. We test the method on the RNA binding domains of three important regulators of RNA metabolism.
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Ensaios de Triagem em Larga Escala/métodos , Ressonância Magnética Nuclear Biomolecular/métodos , Proteínas de Ligação a RNA/metabolismo , RNA/genética , RNA/metabolismo , Sequência de Bases , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Ensaios de Triagem em Larga Escala/estatística & dados numéricos , Humanos , Modelos Moleculares , Análise de Componente Principal , Domínios e Motivos de Interação entre Proteínas , Proteínas de Ligação a RNA/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/química , Fatores de Poliadenilação e Clivagem de mRNA/metabolismoRESUMO
BACKGROUND: Major depressive disorder is a disabling neuropsychiatric condition that is associated with disrupted functional connectivity across brain networks. The precise nature of altered connectivity, however, remains incompletely understood. The current study was designed to examine the coherence of large-scale connectivity in depression using a recently developed technique termed global brain connectivity. METHODS: A total of 82 subjects, including medication-free patients with major depression (n = 57) and healthy volunteers (n = 25) underwent functional magnetic resonance imaging with resting data acquisition for functional connectivity analysis. Global brain connectivity was computed as the mean of each voxel's time series correlation with every other voxel and compared between study groups. Relationships between global connectivity and depressive symptom severity measured using the Montgomery-Åsberg Depression Rating Scale were examined by means of linear correlation. RESULTS: Relative to the healthy group, patients with depression evidenced reduced global connectivity bilaterally within multiple regions of medial and lateral prefrontal cortex. The largest between-group difference was observed within the right subgenual anterior cingulate cortex, extending into ventromedial prefrontal cortex bilaterally (Hedges' g = -1.48, P < 0.000001). Within the depressed group, patients with the lowest connectivity evidenced the highest symptom severity within ventromedial prefrontal cortex (r = -0.47, P = 0.0005). CONCLUSIONS: Patients with major depressive evidenced abnormal large-scale functional coherence in the brain that was centered within the subgenual cingulate cortex, and medial prefrontal cortex more broadly. These data extend prior studies of connectivity in depression and demonstrate that functional disconnection of the medial prefrontal cortex is a key pathological feature of the disorder. Hum Brain Mapp 37:3214-3223, 2016. © 2016 Wiley Periodicals, Inc.