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The surging demand for high-purity individual lanthanides necessitates the development of novel and exceptionally selective separation strategies. At the heart of these separation systems is an organic compound that, based on its structural features, selectively recognizes the lighter or heavier lanthanides in the trivalent lanthanide (Ln) series. This work emphasizes the significant implications resulting from modifying the donor group configuration within an N,O-based tetradentate ligand and the changes in the solvation environment of Ln ions in the process of separating Lns, with the unique ability to achieve peak selectivity in the light, medium, and heavy Ln regions. The structural rigidity of the bis-lactam-1,10-phenanthroline ligand enforces size-based selectivity, displaying an exceptional affinity for Lns having larger ionic radii such as La. Modifying the ligand by eliminating one preorganization element (phenanthroline â bipyridine) results in the fast formation of complexes with light Lns, but, in the span of hours, the peak selectivity shifts toward middle Ln (Sm), resulting in time-resolved separation. As expected, at low nitric acid concentrations, the neutral tetradentate ligand complexes with Ln3+ ions. However, the change in extraction mechanism is observed at high nitric acid concentrations, leading to the formation and preferential extraction of anionic heavy Ln species, [Ln(NO3)x+3]x-, that self-assemble with two ligands that have undergone protonation, forming intricate supramolecular architectures. The tetradentate ligand that is structurally balanced with restrictive and unrestrictive motifs demonstrates unique, controllable selectivity for light, middle, and heavy Lns, underscoring the pivotal role of solvation and ion interactions within the first and second coordination spheres.
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We investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n=15). All patients received remdesivir and some also received nirmatrelvir-ritonavir or monoclonal antibodies. Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient treated with remdesivir and nirmatrelvir-ritonavir. In vitro characterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibility in vivo.
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Adrenal pathologies have variable clinical presentations and primary care providers should be aware of common and serious adrenal disorders. All adrenal masses require evaluation for malignancy, whether primary or metastatic, and all masses require evaluation for inappropriate hormonal secretion. In the event of adrenal insufficiency, the etiology of cortisol inadequacy must be identified and appropriately treated to prevent life-threatening complications.
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Enfermedades de las Glándulas Suprarrenales , Neoplasias de las Glándulas Suprarrenales , Humanos , Enfermedades de las Glándulas Suprarrenales/diagnóstico , Enfermedades de las Glándulas Suprarrenales/terapia , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/terapia , Atención Primaria de Salud , Insuficiencia Suprarrenal/diagnóstico , Hidrocortisona , Feocromocitoma/diagnóstico , Feocromocitoma/terapiaRESUMEN
OBJECTIVES: The objective of this study was to gain knowledge and ascertain challenges about periviability counseling among obstetricians to inform curricular development. METHODS: Focus groups were utilized. A series of open-ended questions was posed to each group of obstetricians; responses were audio recorded and transcribed. Transcriptions were analyzed by two coders using thematic analysis. RESULTS: Four focus groups were convened. Prominent themes included: (1) Obstetrician knowledge about neonatal outcomes is limited, (2) Periviability counseling is both time intensive and time-challenged, (3) Patient processing of information relies on the content, delivery and patient readiness, and (4) Obstetrician bias is toward advocating for maternal safety, which may run counter to parental instinct to "do everything." The last theme was specifically focused on the role of cesarean delivery. CONCLUSIONS: Curricula focused on improving obstetrician periviability counseling should focus on neonatal outcomes, the role of cesarean delivery, and utilization of shared decision-making.
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BACKGROUND: There is a lack of uniformity across hospitals in applying inpatient versus observation status for short-stay (<48 h) pediatric hospitalizations, with negative financial implications associated with observation. Children with medical complexity (CMC) represent a growing population and incur high costs of care. The financial implications of inpatient and observation status for CMC have not been studied. OBJECTIVES: To compare costs and reimbursement for short-stay hospitalizations for CMC by inpatient and observation status, overall and stratified by payor. METHODS: We performed a cohort study of short-stay hospitalizations for CMC from 2016 to 2021 at 10 children's hospitals reporting reimbursement in the Pediatric Health Information System and Revenue Management Program. The primary outcome was the cost coverage ratio (CCR), defined as an encounter's reimbursement divided by the estimated cost. RESULTS: There were 89,282 encounters included. The median costs per encounter were similar across observation ($5206, IQR $3604-$7484) and inpatient ($6547, IQR $4725-$9349) encounters. For government payors, the median CCR was 0.6 (IQR 0.2-0.9) for observation encounters and 1.2 (IQR 0.8-1.9) for inpatient. For nongovernment payors, the median CCR was 1.6 (IQR 1.3-1.9) for observation and 1.6 (IQR 1.4-2) for inpatient. Government reimbursement was associated with increased risk for financial loss (OR 13.91, 95% CI 7.23, 26.77) and with a median net loss of $985,952 (IQR $389,871-$1,700,041) per hospital annually for observation encounters. CONCLUSIONS: Government-paid observation encounters for CMC are associated with significant financial loss at children's hospitals. This reimbursement model may pose a threat to children's hospitals' ability to care for CMC.
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Obesity is well established as a risk factor for many noncommunicable diseases; however, its consequences for infectious disease are poorly understood. Here, we investigated the impact of host obesity on influenza A virus (IAV) genetic variation using a diet-induced obesity ferret model and the A/Hong Kong/1073/1999 (H9N2) strain. Using a co-caging study design, we investigated the maintenance, generation, and transmission of intrahost IAV genetic variation by sequencing viral genomic RNA obtained from nasal wash samples over multiple days of infection. We found evidence for an enhanced role of positive selection acting on de novo mutations in obese hosts that led to nonsynonymous changes that rose to high frequency. In addition, we identified numerous cases of mutations throughout the genome that were specific to obese hosts and that were preserved during transmission between hosts. Despite detection of obese-specific variants, the overall viral genetic diversity did not differ significantly between obese and lean hosts. This is likely due to the high supply rate of de novo variation and common evolutionary adaptations to the ferret host regardless of obesity status, which we show are mediated by variation in the hemagglutinin and polymerase genes (PB2 and PB1). We also identified defective viral genomes (DVGs) that were found uniquely in either obese or lean hosts, but the overall DVG diversity and dynamics did not differ between the two groups. Our study suggests that obesity may result in a unique selective environment impacting intrahost IAV evolution, highlighting the need for additional genetic and functional studies to confirm these effects.IMPORTANCEObesity is a chronic health condition characterized by excess adiposity leading to a systemic increase in inflammation and dysregulation of metabolic hormones and immune cell populations. Influenza A virus (IAV) is a highly infectious pathogen responsible for seasonal and pandemic influenza. Host risk factors, including compromised immunity and pre-existing health conditions, can contribute to increased infection susceptibility and disease severity. During viral replication in a host, the negative-sense single-stranded RNA genome of IAV accumulates genetic diversity that may have important consequences for viral evolution and transmission. Our study provides the first insight into the consequences of host obesity on viral genetic diversity and adaptation, suggesting that host factors associated with obesity alter the selective environment experienced by a viral population, thereby impacting the spectrum of genetic variation.
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Hurones , Variación Genética , Genoma Viral , Virus de la Influenza A , Obesidad , Infecciones por Orthomyxoviridae , Animales , Humanos , Masculino , Modelos Animales de Enfermedad , Evolución Molecular , Hurones/virología , Variación Genética/genética , Genoma Viral/genética , Interacciones Microbiota-Huesped , Virus de la Influenza A/genética , Mutación , Obesidad/virología , Infecciones por Orthomyxoviridae/virología , ARN Viral/genética , Delgadez/virologíaRESUMEN
OBJECTIVE: The primary objective was to determine if vaginal progesterone following cerclage for cervical length <10 mm or cervical dilation in patients without a history of spontaneous preterm birth (sPTB) decreased the risk of preterm birth at <34 weeks' gestation compared with cerclage alone. Secondary objectives were to determine if vaginal progesterone following cerclage (1) decreased the risk of preterm birth at <24, <28, and <37 weeks' gestation and (2) increased the latency period from cerclage placement to delivery compared with treatment with cerclage alone. STUDY DESIGN: Multicenter retrospective cohort study from 2015 to 2020 of singleton pregnancies, without prior sPTB, who had cerclage placement <24 weeks' gestation for cervical length <10 mm or cervical dilation. Exposure defined as cerclage plus vaginal progesterone postoperatively (dual therapy) and unexposed as cerclage alone (monotherapy), based on surgeon preference. RESULTS: We included 122 patients, 78 (64%) treated with dual therapy and 44 (36%) treated with monotherapy. In the crude analysis, dual therapy was associated with a lower risk of delivery at <28 weeks' gestation (13%) compared with monotherapy (34%; crude risk ratio: 0.38 [95% confidence interval (CI): 0.19-0.75]). When adjusted for preoperative vaginal progesterone, results were attenuated (adjusted risk ratio: 0.45 [95% CI: 0.20-1.01]). In both the crude and adjusted analyses, the risk of sPTB was not statistically different at <24, <34 or <37 weeks' gestation. Dual therapy was associated with a greater pregnancy latency from cerclage to delivery (16.3 vs. 14.4 weeks; p = 0.04), and greater gestational age at delivery (37.3 vs. 35.8 weeks' gestation; p = 0.02) compared with monotherapy. CONCLUSION: While not statistically significant, the risk of sPTB was lower at all gestational ages studied in patients treated with dual therapy compared with monotherapy. Dual therapy was associated with longer pregnancy latency and greater gestational age at delivery compared with monotherapy. KEY POINTS: · Dual therapy did not decrease preterm birth risk compared with monotherapy.. · Dual therapy prolonged pregnancy compared with monotherapy.. · Dual therapy can be considered but further studies are needed..
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Cerclaje Cervical , Nacimiento Prematuro , Progesterona , Progestinas , Humanos , Femenino , Embarazo , Nacimiento Prematuro/prevención & control , Estudios Retrospectivos , Progesterona/administración & dosificación , Administración Intravaginal , Adulto , Progestinas/administración & dosificación , Progestinas/uso terapéutico , Cuello del Útero , Edad Gestacional , Medición de Longitud CervicalRESUMEN
Atypical sustained attention is a symptom in a number of neurological and psychological conditions. Investigations into its neural underpinnings are required for improved management and treatment. Rodents are useful in investigating the neurobiology underlying atypical sustained attention and several rodent tasks have been developed for use in touchscreen testing platforms that mimic methodology used in human clinical attention assessment. This systematic review was conducted to assess how translatable these rodent tasks are to equivalent clinical human tasks. Studies using the rodent Continuous Performance Task (rCPT), Sustained Attention Task (SAT), and 5-choice CPT (5C-CPT) were sought and screened. Included in the review were 138 studies, using the rCPT (n = 21), SAT (n = 90), and 5C-CPT (n = 27). Translatability between rodent and human studies was assessed based on (1) methodological similarity, (2) performance similarity, and (3) replication of results. The 5C-CPT was found to be the most translatable cross-species paradigm with good utility, while the rCPT and SAT require adaptation and further development to meet these translatability benchmarks. With greater replication and more consistent results, greater confidence in the translation of sustained attention results between species will be engendered.
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The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.
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Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.
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Neoplasias Encefálicas , Proteínas que Contienen Bromodominio , Proliferación Celular , Resistencia a Antineoplásicos , Glioblastoma , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Proteómica/métodos , Proteínas/metabolismo , Proteínas/antagonistas & inhibidoresRESUMEN
Research is equivocal on whether attention orienting is atypical in autism. This study investigated two types of attention orienting in autistic people and accounted for the potential confounders of alerting level, co-occurring symptoms of attention-deficit/hyperactivity disorder (ADHD) and anxiety, age, and sex. Twenty-seven autistic participants (14 males; 9-43 years) and 22 age- and sex-matched non-autistic participants (13 males; 9-42 years) completed the exogenous and endogenous Posner tasks. Response time and pupillometric data were recorded. Autistic participants were faster at orienting attention to valid cues in the exogenous task and slower at disengaging from invalid cues in the endogenous task compared to non-autistic participants. With increasing age, autistic participants showed faster exogenous and endogenous orienting, whereas non-autistic participants showed faster exogenous orienting but stable speed of endogenous orienting. Higher ADHD symptoms were associated with slower exogenous orienting in both groups, whereas higher anxiety symptoms were associated with faster exogenous orienting only in autistic participants. No group differences were noted for alerting levels, sex, or pupillary responses. This study provides new evidence of superior exogenous orienting and inefficient endogenous orienting in autistic people and suggests that age and co-occurring symptoms are important to consider when assessing attention orienting in autism.
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Gomphonema parvulum is a cosmopolitan freshwater diatom that is used as an indicator in water quality biomonitoring. In this study, we report the culturing of two geographically separated isolates from southeastern North America, their morphology, and the sequencing and assembly of their mitochondrial and chloroplast genomes. Morphologically, both strains fit G. parvulum sensu lato, but the frustules from a protected habitat in South Carolina were smaller than those cited in the historic data of this species from the same location as well as a second culture from Virginia. Phylogenetic analyses using the rbcL gene placed both within a clade with G. parvulum. Genetic markers, including full chloroplast and mitochondrial genomes and the nuclear small subunit rRNA gene region were assembled from each isolate. The organellar genomes of the two strains varied slightly in size due to small differences in intergenic regions with chloroplast genomes of 121,035 bp and 121,482 bp and mitochondrial genomes of 34,639 bp and 34,654 bp. The intraspecific pairwise identities of the chloroplast and mitochondrial genomes of these two isolates were 97.9% and 95.4%, respectively. Multigene phylogenetic analysis demonstrated a close relationship between G. parvulum, Gomphoneis minuta, and Didymosphenia geminata.
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Diatomeas , Genoma del Cloroplasto , Genoma Mitocondrial , Filogenia , Diatomeas/genética , South Carolina , Virginia , Cloroplastos/genéticaRESUMEN
OBJECTIVE: In this report, we discuss the case of a patient with minimally conscious state (MCS) whose clinical condition significantly improved after Zolpidem therapy. We aim to provide supportive evidence for inclusion of zolpidem trials in patients with MCS. METHODS: Our team used electronic medical records, direct patient care experiences, and literature review to obtain information for this case report. RESULTS: Twice daily zolpidem therapy led to significant clinical improvement in our patient with MCS. In addition, this improvement was maintained throughout an increasingly arduous medical course. CONCLUSIONS: Minimally conscious state is a disorder with limited proven therapeutic options. Zolpidem administration has demonstrated immense benefit in a select population of patients, including ours. Given the potential for great improvement with limited downside, zolpidem trial presents an intriguing treatment option. Further clarification of prognostic features to stratify responders and nonresponders to therapy is needed.
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Piridinas , Accidente Cerebrovascular , Humanos , Zolpidem/uso terapéutico , Piridinas/uso terapéutico , Estado Vegetativo Persistente/tratamiento farmacológico , Estado Vegetativo Persistente/etiología , Accidente Cerebrovascular/complicacionesRESUMEN
A recent national survey of bereaved partners found high levels of complicated grief and psychological distress, with evidence that loneliness and isolation may contribute to these outcomes. However, the mechanisms of action for this have not been explored. To advance grief theory this paper reports analysis of the survey free-text data to examine the relationship between social support and emotional responses to bereavement. Individuals bereaved of a civil partner or spouse 6-10 months previously were identified through death registration data. 569/1945 (29 %) completed surveys were received. Of those, 311 participants (55 %) provided responses to two free-text questions which asked about their 'feelings since the death of their partner or spouse', and 'about the support around' them. Data were analysed using corpus-assisted discourse analysis and the discourse dynamics approach for figurative language. Participants described diverse emotional responses to the bereavement (e.g. sadness, anger, denial, acceptance), and the value of formal and informal bereavement support. Although many of the experiences described are accounted for in existing grief theory, some participants described a liminal experience not recognised within these theories. They felt trapped, unable to engage with loss or restoration, and unable to move forward as their planned future no longer existed. They sought out 'communitas' (solidarity in experiences), but often found support from their social networks had diminished. Metaphors were used to describe this liminality, with partner grief expressed as a dark agentic force, a monster, an abyss, and as water. The findings of this study offer original insights into experiences and trajectories of bereavement, and our understandings of prolonged or complicated grief. A novel model 'Between Loss and Restoration' is presented to include these experiences. Recognition of the place for liminality within the spectrum of grief experiences could enhance grief literacy and improve formal and informal bereavement support provision.
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Aflicción , Humanos , Pesar , Ira , Soledad , LenguajeRESUMEN
SARS-CoV-2 is the causative agent of COVID-19 and continues to pose a significant public health threat throughout the world. Following SARS-CoV-2 infection, virus-specific CD4+ and CD8+ T cells are rapidly generated to form effector and memory cells and persist in the blood for several months. However, the contribution of T cells in controlling SARS-CoV-2 infection within the respiratory tract are not well understood. Using C57BL/6 mice infected with a naturally occurring SARS-CoV-2 variant (B.1.351), we evaluated the role of T cells in the upper and lower respiratory tract. Following infection, SARS-CoV-2-specific CD4+ and CD8+ T cells are recruited to the respiratory tract and a vast proportion secrete the cytotoxic molecule Granzyme B. Using antibodies to deplete T cells prior to infection, we found that CD4+ and CD8+ T cells play distinct roles in the upper and lower respiratory tract. In the lungs, T cells play a minimal role in viral control with viral clearance occurring in the absence of both CD4+ and CD8+ T cells through 28 days post-infection. In the nasal compartment, depletion of both CD4+ and CD8+ T cells, but not individually, results in persistent and culturable virus replicating in the nasal compartment through 28 days post-infection. Using in situ hybridization, we found that SARS-CoV-2 infection persisted in the nasal epithelial layer of tandem CD4+ and CD8+ T cell-depleted mice. Sequence analysis of virus isolates from persistently infected mice revealed mutations spanning across the genome, including a deletion in ORF6. Overall, our findings highlight the importance of T cells in controlling virus replication within the respiratory tract during SARS-CoV-2 infection.
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THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology.
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Discapacidad Intelectual , ARN , Estilbenos , Ácidos Sulfónicos , Humanos , Animales , Ratones , ARN/metabolismo , Discapacidad Intelectual/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Procesamiento Postranscripcional del ARN , Transporte de ARN , Mamíferos/genética , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Despite overwhelming international evidence of elevated rates of poor mental health in LGBTQ+ youth compared to their cis-heterosexual peers, we know relatively little about effective mental health services for this population group. This study aims to produce the first early intervention model of "what works" to support LGBTQ+ youth with emerging mental health problems. Utilizing a mixed method case study, we collected data across 12 UK mental health service case study sites that involved: (a) interviews with young people, parents, and mental health practitioners (n = 93); (b) documentary analysis; (c) nonparticipant observation. The data analysis strategy was theoretical using the "explanation-building" analytical technique. Our analysis suggests an intersectional youth rights approach with 13 principles that must be enacted to provide good mental health services as advocated by the United Nations Convention on the Rights of the Child and World Health Organization. This approach should address the multiple forms of marginalization and stigmatization that LGBTQ+ youth may experience, enable informed independent decision-making, and uphold the right to freedom of safe self-expression. A rights-based approach to mental health services for LGBTQ+ young people is not prominent. This needs to change if we are to tackle this mental health inequality and improve the mental well-being of LGBTQ+ youth worldwide.
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Salud Mental , Minorías Sexuales y de Género , Niño , Humanos , Adolescente , Disparidades en el Estado de Salud , Proyectos de InvestigaciónRESUMEN
Sexual violence is common on US college campuses and can result in negative health and academic outcomes. Credit-bearing courses are a possible innovative intervention, but few have been studied, and little is known about enrolled students' experiences. Our institution, located in the Southern United States, developed a semester-long class as a curricular intervention after our institutional climate survey results showed high rates of sexual violence among undergraduate students. Students enrolled in the course wrote a final reflection paper on what they found meaningful about the class (N = 62). Qualitative conventional content analysis was used to examine what students found most salient. Three overarching categories emerged: course content, course delivery and course impact, each with multiple themes. For course content, students wrote about 22 different topics from the class. For course delivery, students discussed the open forum to discuss sexuality, the importance of taking the course in their first year of college and the course structure. For course impact, students discussed gaining new knowledge, questioning prior assumptions, experiencing personal transformation and feeling empowered to act. Results indicated that students had a powerful class experience and that this kind of educational intervention has the potential to positively impact enrolled students.
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Delitos Sexuales , Estudiantes , Humanos , Universidades , Delitos Sexuales/prevención & control , Femenino , Estudiantes/psicología , Masculino , Adulto Joven , Curriculum , Adolescente , Investigación Cualitativa , AdultoRESUMEN
RATIONALE: Atypical attention orienting has been associated with some autistic symptoms, but the neural mechanisms remain unclear. The human Posner task, a classic attention orienting paradigm, was recently adapted for use with mice, supporting the investigation of the neurobiological underpinnings of atypical attention orienting in preclinical mouse models. OBJECTIVE: The current study tested mice expressing the autism-associated R451C gene mutation in neuroligin-3 (NL3) on the mouse-Posner (mPosner) task. METHODS: NL3R451C and wild-type (WT) mice were trained to respond to a validly or invalidly cued target on a touchscreen. The cue was a peripheral non-predictive flash in the exogenous task and a central spatially predictive image in the endogenous task. The effects of dopaminergic- and noradrenergic-modulating drugs, methylphenidate and atomoxetine, on task performance were assessed. RESULTS: In both tasks, mice were quicker and more accurate in the validly versus invalidly cued trials, consistent with results in the human Posner task. NL3R451C and WT mice showed similar response times and accuracy but responded differently when treated with methylphenidate and atomoxetine. Methylphenidate impaired exogenous attention disengagement in NL3R451C mice but did not significantly affect WT mice. Atomoxetine impaired endogenous orienting in WT mice but did not significantly affect NL3R451C mice. CONCLUSIONS: NL3R451C mice demonstrated intact attention orienting but altered responses to the pharmacological manipulation of the dopaminergic and noradrenergic networks. These findings expand our understanding of the NL3R451C mutation by suggesting that this mutation may lead to selective alterations in attentional processes.
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Trastorno Autístico , Ratones , Humanos , Animales , Clorhidrato de Atomoxetina/farmacología , Neuroliginas , Mutación/genética , AtenciónRESUMEN
Sepsis is a systemic response to infection with life-threatening consequences. Our understanding of the molecular and cellular impact of sepsis across organs remains rudimentary. Here, we characterize the pathogenesis of sepsis by measuring dynamic changes in gene expression across organs. To pinpoint molecules controlling organ states in sepsis, we compare the effects of sepsis on organ gene expression to those of 6 singles and 15 pairs of recombinant cytokines. Strikingly, we find that the pairwise effects of tumor necrosis factor plus interleukin (IL)-18, interferon-gamma or IL-1ß suffice to mirror the impact of sepsis across tissues. Mechanistically, we map the cellular effects of sepsis and cytokines by computing changes in the abundance of 195 cell types across 9 organs, which we validate by whole-mouse spatial profiling. Our work decodes the cytokine cacophony in sepsis into a pairwise cytokine message capturing the gene, cell and tissue responses of the host to the disease.