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Important Characteristics associated with Data source Studies in Substance Effectiveness within the Postmarketing Stage: An organized Evaluate.
Tyrosine kinase receptor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) bind to hormones, such as insulin, IGF-1, and IGF-2, and transduces the signals across the cell membrane. However, the complete structure of the receptor and the signal transduction mechanism remains unclear. Here, we report the cryo-EM structure of the ligand-bound ectodomain in the full-length human IGF-1R. We reconstructed the IGF-1R/insulin complex at 4.7 Å and the IGF-1R/IGF-1 complex at 7.7 Å. Our structures reveal that only one insulin or one IGF-1 molecule binds to and activates the full-length human IGF-1R receptor. Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOTdeficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limitingenzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy. The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3-5 kDa dextran as a model cargo and the amyloid-β (Aβ) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery. The nicotinic acetylcholine receptor, a pentameric ligand-gated ion channel, converts the free energy of binding of the neurotransmitter acetylcholine into opening of its central pore. Here we present the first high-resolution structure of the receptor type found in muscle-endplate membrane and in the muscle-derived electric tissues of fish. The native receptor was purified from Torpedo electric tissue and functionally reconstituted in lipids optimal for cryo-electron microscopy. The receptor was stabilized in a closed state by the binding of α-bungarotoxin. The structure reveals the binding of a toxin molecule at each of two subunit interfaces in a manner that would block the binding of acetylcholine. It also reveals a closed gate in the ion-conducting pore, formed by hydrophobic amino acid side chains, located ∼60 Å from the toxin binding sites. The structure provides a framework for understanding gating in ligand-gated channels and how mutations in the acetylcholine receptor cause congenital myasthenic syndromes. The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus. In the human genome, most genes undergo splicing, and patterns of codon usage are splicing dependent guanine and cytosine (GC) content is the highest within single-exon genes and within first exons of multi-exon genes. However, the effects of codon usage on gene expression are typically characterized in unspliced model genes. Here, we measured the effects of splicing on expression in a panel of synonymous reporter genes that varied in nucleotide composition. We found that high GC content increased protein yield, mRNA yield, cytoplasmic mRNA localization, and translation of unspliced reporters. AZD7762 chemical structure Splicing did not affect the expression of GC-rich variants. However, splicing promoted the expression of AT-rich variants by increasing their steady-state protein and mRNA levels, in part through promoting cytoplasmic localization of mRNA. We propose that splicing promotes the nuclear export of AU-rich mRNAs and that codon- and splicing-dependent effects on expression are under evolutionary pressure in the human genome.Host-associated microbiomes are emerging as important modifiers of brain activity and behavior. Metabolic, immune, and neuronal pathways are proposed to mediate communication across the so-called microbiota-gut-brain axis. However, strong mechanistic evidence, especially for direct signaling between microbes and sensory neurons, is lacking. Here, we discuss microbial regulation of short-chain fatty acids, neurotransmitters, as-yet-uncharacterized biochemicals, and derivatives of neuromodulatory drugs as important areas for assessing microbial interactions with the nervous system. PURPOSE Rates of burnout among health care professionals are rising. Oncology nurses are at the forefront of cancer care, and maintenance of their well-being is crucial to delivering high-quality care to people with cancer. The purpose of this pilot study was to implement a novel intervention, Storytelling Through Music, and examine the effects on depression, insomnia, loneliness, self-awareness, self-compassion, burnout, secondary traumatic stress, and compassion satisfaction in oncology nurses. METHODS This two-group (intervention and control), quasi-experimental study of a 6-week intervention combined storytelling, reflective writing, songwriting, and stress management skills. RESULTS Participants (N = 43) were predominately white (98%), with 27% reporting Hispanic ethnicity, and female (95%); their average oncology experience was 8.5 years. Both groups improved significantly over time on all measures. Compared with the control group, participants in the intervention group also had significantly less loneliness (F[3, 98] = 7.46; P less then .001) and insomnia (F[3, 120] = 5.77; P less then .001) and greater self-compassion (F[3, 105] = 2.88; P less then .05) and self-awareness (F[3, 120] = 2.42; P less then .10). CONCLUSION There are few opportunities for health care professionals to reflect on the impact of caregiving. The Storytelling Through Music intervention provided a structured space for reflection by participants, individually and among their peers, which decreased loneliness and increased self-compassion. Both factors relate to the burnout that affects the oncology health care workforce.PURPOSE Burnout in the medical workforce leads to early retirement, absenteeism, career changes, financial losses for medical institutions, and adverse outcomes for patients. Recent literature has explored burnout in different specialties of medicine. This article examines burnout among medical oncology trainees and identifies factors associated with burnout and professional dissatisfaction, including socioeconomic factors. METHODS US medical oncology programs were sent a survey that included the Maslach Burnout Index-Human Services Survey as well as demographic, socioeconomic, and program-specific questions tailored to medical oncology fellowship. Primary binary end points included burnout, satisfaction with being a physician, and satisfaction with being a medical oncologist. Binomial logistic models determined associations between various characteristics and end points. RESULTS Overall, 261 US fellows completed the survey. Seventy percent of international medical graduates reported no educational debt, whereas only 36% of US graduates reported no educational debt. Eighty-two percent of survey respondents reported their mother had at least a bachelor's degree, and 87% of respondents reported their father had at least a bachelor's degree. At least 27% of respondents had symptoms of burnout. Factors inversely associated with burnout on multivariable analysis included having a mother who graduated college (odds ratio [OR], 0.27), reporting an adequate perceived balance between work and personal life (OR, 0.22), feeling that faculty care about educational success (OR, 0.16), and being in the final year of training (OR, 0.45). Having debt ≥ $150,000 (OR, 2.14) was directly associated with burnout. CONCLUSION Symptoms of burnout are common among medical oncology fellows and are associated with educational debt and socioeconomic factors.BACKGROUND Physician burnout, characterized by exhaustion of physical or emotional strength, cynicism, and lack of achievement, has become a worsening phenomenon in medicine, contributing to higher health care costs and patient/physician dissatisfaction. How burnout has affected hematologists and oncologists is not well studied. METHODS US community oncologists/hematologists were queried via a Web-based survey from September-November 2018. Physicians were asked about frequency of burnout symptoms, drivers of work-related stress, and their perceptions on management of workload. RESULTS Among the 163 physicians surveyed, 46% felt a substantial amount of stress at work. Most physicians felt emotionally (85%) and physically (87%) exhausted. A majority of physicians felt lethargic (67%), ineffective (64%), and/or detached (63%). In a typical workweek, 93% needed time beyond time allocated to clinical care to complete work responsibilities. Electronic health record (EHR) responsibilities caused moderate to excessive stress at work for 67% of physicians; 79% of physicians worked on EHRs outside of clinic hours. Other sources of excessive stress were changing reimbursement models (33%), interactions with payers (31%), and increasing patient and caregiver demands (31%). A third of physicians have considered retiring early or changing their career path to cope. To combat burnout, physicians' practices have used advanced practice providers, invested in information technology, and/or hired additional administrative staff. However, the majority of physicians stated they had optimal or good control over their workload. CONCLUSION Most oncologists experience burnout symptoms and require additional time beyond that allocated to clinical care to complete their workload. The discordance between oncologists' admission of stress and exhaustion while claiming good control over those same burdens warrants exploration in future research.
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