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RATIONALE: Premenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD. AIMS: The goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers. METHODS: Participants were females age 18-50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50â¯mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1ß were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity. RESULTS: The sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1ß, nor TNF-α (p's>0.05). CONCLUSION: Serum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD.
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BACKGROUND: A recent meta-analysis revealed that vagally mediated heart rate variability (vmHRV; a biomarker of emotion regulation capacity) significantly decreases in the luteal phase of the menstrual cycle. As two follow-up studies suggest, these vmHRV decreases are driven primarily by increased luteal progesterone (P4). However, analyses also revealed significant interindividual differences in vmHRV reactivity to the cycle, which is in line with longstanding evidence for interindividual differences in mood sensitivity to the cycle. The present study begins to investigate whether these interindividual differences in vmHRV cyclicity can explain who is at higher risk of showing premenstrual emotional changes. We expected a greater degree of midluteal vmHRV decrease to be predictive of a greater premenstrual increase in negative affect. METHODS: We conducted an observational study with a naturally cycling community sample (N = 31, M = 26.03 years). Over a span of six weeks, participants completed (a) daily ratings of negative affect and (b) counterbalanced lab visits in their ovulatory, midluteal, and perimenstrual phases. Lab visits were scheduled based on positive ovulation tests and included assessments of baseline vmHRV and salivary ovarian steroid levels. RESULTS: In line with previous research, multilevel models suggest that most of the sample shows ovulatory-to-midluteal vmHRV decreases which, however, were not associated with premenstrual emotional changes. Interestingly, it was only the subgroup with luteal increases in vmHRV whose negative affect markedly worsened premenstrually and improved postmenstrually. CONCLUSION: The present study begins to investigate cyclical changes in vmHRV as a potential biomarker of mood sensitivity to the menstrual cycle. The results demonstrate a higher level of complexity in these associations than initially expected, given that only atypical midluteal increases in vmHRV are associated with greater premenstrual negative affect. Potential underlying mechanisms are discussed, among those the possibility that luteal vmHRV increases index compensatory efforts to regulate emotion in those with greater premenstrual negative affect. However, future studies with larger and clinical samples and more granular vmHRV assessments should build on these findings and further explore associations between vmHRV cyclicity and menstrually related mood changes.
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Frecuencia Cardíaca , Fase Luteínica , Progesterona , Humanos , Femenino , Fase Luteínica/fisiología , Fase Luteínica/psicología , Frecuencia Cardíaca/fisiología , Adulto , Progesterona/sangre , Emociones/fisiología , Afecto/fisiología , Nervio Vago/fisiología , Adulto Joven , Síndrome Premenstrual/fisiopatología , Síndrome Premenstrual/psicologíaRESUMEN
Objective: The northeastern state of Rhode Island (RI) has a Vaccinate Before You Graduate (VBYG) program that supplements the traditional primary care infrastructure by providing vaccines to adolescents while they are in school, with no out-of-pocket expenses. We analyzed data from RI's immunization registry to evaluate whether VBYG also reduces disparities in adolescent immunization rates. Methods: We identified adolescent and catch-up vaccines administered in RI to people who were aged 11-18 at any point during the 5-year study period of 2019-2023, and conducted bivariate and multivariate analyses of vaccine administration data by setting (VBYG clinics, community health centers [CHCs], all other primary care practices [oPCPs], other school-based clinics, and other sites) and adolescent demographics (racial and ethnic identity, insurance status, sex, and age at time of vaccine). Results: Of over 387,000 routine vaccines administered during the study period, 3.3 % were administered by a VBYG clinic despite significant declines during school closures associated with the early COVID-19 pandemic. VBYG-administered doses went to slightly older youth, and a higher proportion were catch-up doses (25.7 % versus 14.1 % for CHC doses and 6.5 % for oPCP). Youths received an average of 2.71 vaccines in VBYG clinics compared to 1.77 from oPCPs and 2.08 from CHCs. A higher proportion of vaccines administered by VBYG went to adolescents of color and those without private insurance than those administered by oPCPs. Conclusions: VBYG provides a model to other jurisdictions of a vaccine safety net for adolescents who may not otherwise receive recommended vaccines before exiting the school system.
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Minimum spanning trees and forests are powerful sparsification techniques that remove cycles from weighted graphs to minimize total edge weight while preserving node reachability, with applications in computer science, network science, and graph theory. Despite their utility and ubiquity, they have several limitations, including that they are only defined for undirected networks, they significantly alter dynamics on networks, and they do not generally preserve important network features such as shortest distances, shortest path distribution, and community structure. In contrast, distance backbones, which are subgraphs formed by all edges that obey a generalized triangle inequality, are well defined in directed and undirected graphs and preserve those and other important network features. The backbone of a graph is defined with respect to a specified path-length operator that aggregates weights along a path to define its length, thereby associating a cost to indirect connections. The backbone is the union of all shortest paths between each pair of nodes according to the specified operator. One such operator, the max function, computes the length of a path as the largest weight of the edges that compose it (a weakest link criterion). It is the only operator that yields an algebraic structure for computing shortest paths that is consistent with De Morgan's laws. Applying this operator yields the ultrametric backbone of a graph in that (semi-triangular) edges whose weights are larger than the length of an indirect path connecting the same nodes (i.e. those that break the generalized triangle inequality based on max as a path-length operator) are removed. We show that the ultrametric backbone is the union of minimum spanning forests in undirected graphs and provides a new generalization of minimum spanning trees to directed graphs that, unlike minimum equivalent graphs and minimum spanning arborescences, preserves all max - min shortest paths and De Morgan's law consistency.
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Domestic dogs (Canis lupus familiaris) live with humans, frequently contact other animals and may serve as intermediary hosts for the transmission of viruses. Free-roaming dogs, which account for over 70% of the world's domestic dog population, may pose a particularly high risk in this regard. We conducted an epidemiological study of dog viromes in three locations in Uganda, representing low, medium and high rates of contact with wildlife, ranging from dogs owned specifically for traditional hunting in a biodiversity and disease 'hotspot' to pets in an affluent suburb. We quantified rates of contact between dogs and wildlife through owner interviews and conducted canine veterinary health assessments. We then applied broad-spectrum viral metagenomics to blood plasma samples, from which we identified 46 viruses, 44 of which were previously undescribed, in three viral families, Sedoreoviridae, Parvoviridae and Anelloviridae. All 46 viruses (100â%) occurred in the high-contact population of dogs compared to 63â% and 39â% in the medium- and low-contact populations, respectively. Viral prevalence ranged from 2.1â% to 92.0â% among viruses and was highest, on average, in the high-contact population (22.3â%), followed by the medium-contact (12.3â%) and low-contact (4.8â%) populations. Viral richness (number of viruses per dog) ranged from 0 to 27 and was markedly higher, on average, in the high-contact population (10.2) than in the medium-contact (5.7) or low-contact (2.3) populations. Viral richness was strongly positively correlated with the number of times per year that a dog was fed wildlife and negatively correlated with the body condition score, body temperature and packed cell volume. Viral abundance (cumulative normalized metagenomic read density) varied 124-fold among dogs and was, on average, 4.1-fold higher and 2.4-fold higher in the high-contact population of dogs than in the low-contact or medium-contact populations, respectively. Viral abundance was also strongly positively correlated with the number of times per year that a dog was fed wildlife, negatively correlated with packed cell volume and positively correlated with white blood cell count. These trends were driven by nine viruses in the family Anelloviridae, genus Thetatorquevirus, and by one novel virus in the family Sedoreoviridae, genus Orbivirus. The genus Orbivirus contains zoonotic viruses and viruses that dogs can acquire through ingestion of infected meat. Overall, our findings show that viral prevalence, richness and abundance increased across a gradient of contact between dogs and wildlife and that the health status of the dog modified viral infection. Other ecological, geographic and social factors may also have contributed to these trends. Our finding of a novel orbivirus in dogs with high wildlife contact supports the idea that free-roaming dogs may serve as intermediary hosts for viruses of medical importance to humans and other animals.
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Animales Salvajes , Enfermedades de los Perros , Animales , Perros , Uganda/epidemiología , Enfermedades de los Perros/virología , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/transmisión , Prevalencia , Animales Salvajes/virología , Viroma , Virus/clasificación , Virus/aislamiento & purificación , Virus/genética , Metagenómica , Anelloviridae/genética , Anelloviridae/aislamiento & purificación , Anelloviridae/clasificación , Humanos , Virosis/epidemiología , Virosis/veterinaria , Virosis/transmisión , Virosis/virologíaRESUMEN
Culture-positive (CP) and culture-negative (CN) periprosthetic joint infections (PJI) remain a crucial area of research; however, current studies comparing these infections rely on unstandardized outcome reporting tools. Our study aimed to compare the outcomes of two-stage revision of CP and CN PJI using the standardized Musculoskeletal Infection Society (MSIS) outcome reporting tool. We retrospectively reviewed 138 patients who were diagnosed with PJI and indicated for two-stage revision total knee arthroplasty (rTKA). The majority of patients in both CP and CN cohorts achieved infection control without the need for reoperation (54.1% and 62.5%, respectively). There was a significant difference in the overall distribution of MSIS outcomes (p = 0.043), with a significantly greater rate of CN patients falling into Tier 1 (infection control without the use of suppressive antibiotics) (52.5% versus 29.6%, p = 0.011). There was also a significant difference in the distribution of septic versus aseptic reoperations after 2nd stage (p = 0.013), with more CP reoperations being septic and more CN reoperations being aseptic. The duration from first to second stage was significantly shorter in the CN cohort (p = 0.002). While overall infection control was similar between cohorts, these data suggest that the outcomes of two-stage rTKA are favorable in cases of CN PJI.
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Among extant species, the ability to sample the extremes of body size-one of the most useful predictors of an individual's ecology-is highly unlikely. This improbability is further exaggerated when sampling the already incomplete fossil record. We quantify the likelihood of sampling the uppermost limits of body size in the fossil record using Tyrannosaurus rex Osborn, 1905 as a model, selected for its comparatively well-understood life history parameters. We computationally generate a population of 140 million T. rex (based on prior estimates), modelling variation about the growth curve both with and without sexual dimorphism (the former modelled after Alligator mississippiensis), and building in sampling limitations related to species survivorship and taphonomic bias, derived from fossil data. The 99th percentile of body mass in T. rex has likely already been sampled, but it will probably be millennia before much larger giants (99.99th percentile) are sampled at present collecting rates. Biomechanical and ecological limitations notwithstanding, we estimate that the absolute largest T. rex may have been 70% more massive than the currently largest known specimen (~15,000 vs. ~8800 kg). Body size comparisons of fossil species should be based on ontogenetically controlled statistical parameters, rather than simply comparing the largest known individuals whose recovery is highly subject to sampling intensity.
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Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here, we focused on Alcaligenes faecalis, a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes reepithelialization of diabetic keratinocytes, a process that is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.
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Alcaligenes faecalis , Queratinocitos , Metaloproteinasas de la Matriz , Cicatrización de Heridas , Alcaligenes faecalis/metabolismo , Animales , Queratinocitos/metabolismo , Queratinocitos/microbiología , Humanos , Metaloproteinasas de la Matriz/metabolismo , Metaloproteinasas de la Matriz/genética , Pie Diabético/microbiología , Pie Diabético/patología , Pie Diabético/metabolismo , Ratones , Repitelización , MasculinoRESUMEN
OBJECTIVE: To investigate the perspectives of pediatric otolaryngologists on the impact of the coronavirus disease 2019 (COVID-19) pandemic on their research. METHODS: Two surveys were sent to members of the American Society of Pediatric Otolaryngology (ASPO) in 2019 and 2021 to assess research perspectives before and during the COVID-19 pandemic. The surveys contained questions about research engagement, barriers, time allocation, and shifts in research focus. RESULTS: The COVID-19 pandemic reshaped research within pediatric otolaryngology, with a mixed impact on the amount of time allocated to research endeavors. Almost half of respondents reported a change in research focus to COVID-19-related studies. Protected time and funding were significant pre-pandemic barriers, whereas reduced staff, collaboration opportunities, and enrollment limitations emerged as key pandemic-related obstacles. A personal commitment to research was most strongly correlated with time spent on this endeavor. During the pandemic, women were less likely to report an increase in research activity when compared to men, possibly due to a disproportionate burden of caregiving on women during school closures and stay-at-home orders. CONCLUSION: Overall, the pandemic prompted both increases and decreases in research time allocation, depending on individual circumstances and priorities. Despite new challenges, pediatric otolaryngologists remain committed to research and have continued to remain productive.
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Cholesterol-dependent cytolysins (CDCs) comprise a large family of pore-forming toxins produced by Gram-positive bacteria, which are used to attack eukaryotic cells. Here, we functionally characterize a family of 2-component CDC-like (CDCL) toxins produced by the Gram-negative Bacteroidota that form pores by a mechanism only described for the mammalian complement membrane attack complex (MAC). We further show that the Bacteroides CDCLs are not eukaryotic cell toxins like the CDCs, but instead bind to and are proteolytically activated on the surface of closely related species, resulting in pore formation and cell death. The CDCL-producing Bacteroides is protected from the effects of its own CDCL by the presence of a surface lipoprotein that blocks CDCL pore formation. These studies suggest a prevalent mode of bacterial antagonism by a family of two-component CDCLs that function like mammalian MAC and that are wide-spread in the gut microbiota of diverse human populations.
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Complejo de Ataque a Membrana del Sistema Complemento , Humanos , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Bacteroides/genética , Bacteroides/metabolismo , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/genética , Citotoxinas/metabolismo , Microbioma Gastrointestinal , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas del Sistema Complemento/metabolismo , Proteínas del Sistema Complemento/inmunología , Animales , Células Eucariotas/metabolismoRESUMEN
Despite advances in clinical science, the burden of mental health problems among youth is not improving. To tackle this burden, clinical science with youth needs methods that include youth and family perspectives on context and public health. In this paper, we illustrate how community-engaged research (CEnR) methods center these perspectives. Although CEnR methods are well-established in other disciplines (e.g. social work, community psychology), they are underutilized in clinical science with youth. This is due in part to misperceptions of CEnR as resource-intensive, overly contextualized, incompatible with experimentally controlled modes of inquiry, or irrelevant to understanding youth mental health. By contrast, CEnR methods can provide real-world impact, contextualized clinical solutions, and sustainable outcomes. A key advantage of CEnR strategies is their flexibility-they fall across a continuum that centers community engagement as a core principle, and thus can be infused in a variety of research efforts, even those that center experimental control (e.g. randomized controlled trials). This paper provides a brief overview of this continuum of strategies and its application to youth-focused clinical science. We then discuss future directions of CEnR in clinical science with youth, as well as structural changes needed to advance this work. The goals of this paper are to help demystify CEnR and encourage clinical scientists to consider adopting methods that better consider context and intentionally engage the communities that our work seeks to serve.
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Investigación Participativa Basada en la Comunidad , Humanos , Adolescente , Niño , Trastornos Mentales/psicología , Trastornos Mentales/terapia , Salud MentalRESUMEN
One in three children in the United States is exposed to insecure housing conditions, including unaffordable, inconsistent, and unsafe housing. These exposures have detrimental impacts on youth mental health. Delineating the neurobehavioral pathways linking exposure to housing insecurity with children's mental health has the potential to inform interventions and policy. However, in approaching this work, carefully considering the lived experiences of youth and families is essential to translating scientific discovery to improve health outcomes in an equitable and representative way. In the current paper, we provide an introduction to the range of stressful experiences that children may face when exposed to insecure housing conditions. Next, we highlight findings from the early-life stress literature regarding the potential neurobehavioral consequences of insecure housing, focusing on how unpredictability is associated with the neural circuitry supporting cognitive and emotional development. We then delineate how community-engaged research (CEnR) approaches have been leveraged to understand the effects of housing insecurity on mental health, and we propose future research directions that integrate developmental neuroscience research and CEnR approaches to maximize the impact of this work. We conclude by outlining practice and policy recommendations that aim to improve the mental health of children exposed to insecure housing.
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Vivienda , Salud Mental , Neurociencias , Humanos , Niño , Adolescente , Estrés Psicológico/psicología , Estados UnidosRESUMEN
Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such methods must reach a high level of reliability, accuracy, and automation to be effectively deployed in practical industrial settings in a way that impacts protein design projects. Here, we present a benchmark study for the calculation of relative changes in protein-protein binding affinity for single point mutations across a variety of systems from the literature, using free energy perturbation (FEP+) calculations. We describe a method for robust treatment of alternate protonation states for titratable amino acids, which yields improved correlation with and reduced error compared to experimental binding free energies. Following careful analysis of the largest outlier cases in our dataset, we assess limitations of the default FEP+ protocols and introduce an automated script which identifies probable outlier cases that may require additional scrutiny and calculates an empirical correction for a subset of charge-related outliers. Through a series of three additional case study systems, we discuss how Protein FEP+ can be applied to real-world protein design projects, and suggest areas of further study.
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Unión Proteica , Proteínas , Termodinámica , Proteínas/metabolismo , Proteínas/química , Proteínas/genética , Mutación , Mutación Puntual , Conformación Proteica , Biología Computacional/métodos , Modelos MolecularesRESUMEN
In March 2020, the World Health Organization declared COVID-19 a pandemic, which ultimately led to many meat processors temporarily shutting down or reducing processing capacity. This backlog in processing capacity forced many feedlots to retain cattle for longer periods of time and assume the risk of major market fluctuations. The aim of this study was to understand how a dietary insult affects meat quality and muscle metabolism in market-ready steers (590 kg). Sixteen market-ready (590 kg) commercial Angus crossbred steers were subjected to a maintenance diet of either forage or grain for 60 d. Longissimus lumborum (LL) muscle samples were collected immediately postmortem and processed for characteristics reflecting the underlying muscle fiber type and energy state of the tissue. Despite cattle being subjected to a 60-d feeding period, there were no detectable differences (Pâ >â 0.05) in carcass characteristics, color of lean, or ultimate pH (pHu). Moreover, our data show that muscle plasticity is rather resilient, as reflected by lack of significance (Pâ >â 0.05) in oxidative and glycolytic enzymes, myosin heavy chain isoforms (MyHC), myoglobin, and mitochondrial DNA (mtDNA) contents. These data show that market-ready steers are capable of withstanding a low-input feeding strategy up to 60 d without dramatically impacting underlying muscle characteristics and meat quality development.
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BACKGROUND: Self-stigma of seeking psychological help is a critical factor prohibiting individuals from seeking eating disorder (ED) treatment, but has been widely unexplored in racial/ethnic and sexual minority (SM) samples. The current study examined differences in ED pathology and self-stigma of help-seeking at the intersection of race and gender within a cisgender SM sample. METHODS: Cisgender SM participants (n = 354) identifying as Black, Indigenous, or People of Color (BIPOC; 52%), Asian American and Pacific Islander (AAPI; 24%), or White (24%) were recruited through Prolific Academic. One-way analyses of variance were used to examine differences in the Self-Stigma of Seeking Help Scale (SSOSH) and Eating Pathology Symptom Inventory (EPSI) subscales among men and women in each group. Pearson's correlations explored associations between SSOSH and EPSI subscales within each subgroup. RESULTS: Findings indicated significant between-group differences on the SSOSH and the EPSI subscales of Body Dissatisfaction, Purging, and Excessive Exercise. SSOSH was significantly positively correlated with Body Dissatisfaction in the White SM cis-women group and Binge Eating in the BIPOC SM cis-men group. CONCLUSIONS: Results demonstrate unique, intersectional between-group differences in ED pathology and self-stigma among SM individuals. Further research on the impact of intersectionality on these constructs within larger samples is warranted.
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Whole-genome bisulfite sequencing (BS-Seq) measures cytosine methylation changes at single-base resolution and can be used to profile cell-free DNA (cfDNA). In plasma, ultrashort single-stranded cfDNA (uscfDNA, â¼50 nt) has been identified together with 167 bp double-stranded mononucleosomal cell-free DNA (mncfDNA). However, the methylation profile of uscfDNA has not been described. Conventional BS-Seq workflows may not be helpful because bisulfite conversion degrades larger DNA into smaller fragments, leading to erroneous categorization as uscfDNA. We describe the '5mCAdpBS-Seq' workflow in which pre-methylated 5mC (5-methylcytosine) single-stranded adapters are ligated to heat-denatured cfDNA before bisulfite conversion. This method retains only DNA fragments that are unaltered by bisulfite treatment, resulting in less biased uscfDNA methylation analysis. Using 5mCAdpBS-Seq, uscfDNA had lower levels of DNA methylation (â¼15%) compared to mncfDNA and was enriched in promoters and CpG islands. Hypomethylated uscfDNA fragments were enriched in upstream transcription start sites (TSSs), and the intensity of enrichment was correlated with expressed genes of hemopoietic cells. Using tissue-of-origin deconvolution, we inferred that uscfDNA is derived primarily from eosinophils, neutrophils, and monocytes. As proof-of-principle, we show that characteristics of the methylation profile of uscfDNA can distinguish non-small cell lung carcinoma from non-cancer samples. The 5mCAdpBS-Seq workflow is recommended for any cfDNA methylation-based investigations.
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5-Metilcitosina , Ácidos Nucleicos Libres de Células , Islas de CpG , Metilación de ADN , ADN de Cadena Simple , Humanos , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/genética , ADN de Cadena Simple/metabolismo , ADN de Cadena Simple/genética , ADN de Cadena Simple/sangre , 5-Metilcitosina/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Sulfitos/química , Regiones Promotoras Genéticas , Análisis de Secuencia de ADN/métodos , Secuenciación Completa del Genoma/métodosRESUMEN
Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such methods must reach a high level of reliability, accuracy, and automation to be effectively deployed in practical industrial settings in a way that impacts protein design projects. Here, we present a benchmark study for the calculation of relative changes in protein-protein binding affinity for single point mutations across a variety of systems from the literature, using free energy perturbation (FEP+) calculations. We describe a method for robust treatment of alternate protonation states for titratable amino acids, which yields improved correlation with and reduced error compared to experimental binding free energies. Following careful analysis of the largest outlier cases in our dataset, we assess limitations of the default FEP+ protocols and introduce an automated script which identifies probable outlier cases that may require additional scrutiny and calculates an empirical correction for a subset of charge-related outliers. Through a series of three additional case study systems, we discuss how protein FEP+ can be applied to real-world protein design projects, and suggest areas of further study.
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The onset of the COVID-19 pandemic saw a significant surge in the utilization of telemental health (TMH) services. This narrative review aimed to investigate the efficacy of TMH for serious mood disorders prior to the COVID-19 pandemic. A search across databases was conducted for randomized controlled trials focusing on TMH interventions for mood disorders, encompassing major depressive disorder (MDD) and bipolar disorder (BD). Study and patient characteristics, interventions, and outcomes were extracted. From a pool of 2611 papers initially identified, 17 met the inclusion criteria: 14 focused on MDD, while 4 addressed BD. Among these, 6 papers directly compared TMH interventions to in-person of same treatment, revealing improved access to care and higher rates of appointment follow-up with TMH. Additionally, 6 papers comparing TMH to treatment as usual demonstrated improvements in mood outcomes. Conversely, 3 papers comparing different TMH interventions found no discernible differences in outcomes. Notably, 3 studies evaluated TMH as an adjunct to usual care, all reporting enhancements in depression outcomes. Overall, preliminary evidence suggests that prior to COVID-19, TMH interventions for serious mood disorders facilitated improved access to care and follow-up, with comparable clinical outcomes to traditional in-person interventions. The discussion addresses limitations and provides recommendations for future research in this domain.
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COVID-19 , Trastornos del Humor , Telemedicina , Humanos , COVID-19/psicología , Trastornos del Humor/terapia , Trastornos del Humor/psicología , Trastorno Depresivo Mayor/terapia , Trastorno Depresivo Mayor/psicología , Pandemias , Trastorno Bipolar/terapia , Trastorno Bipolar/psicología , Servicios de Salud Mental , SARS-CoV-2 , Resultado del Tratamiento , Teleterapia de Salud MentalRESUMEN
Giant colonic diverticulum (GCD) is a well-recognized but infrequently encountered disease in clinical practice. GCD is its own unique entity and differs from commonly seen diverticular disease in both size and management. Initial clinical presentation is typically associated with diverticulitis and symptoms such as abdominal pain, fever, nausea, vomiting, rectal bleeding, or even a palpable abdominal mass. Surgery is the recommended treatment option largely due to the risk of associated complications including colonic perforation. We describe the case of a 56-year-old female diagnosed with a sigmoid GCD that was successfully stabilized medically and definitively treated surgically.