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Self-expanding (SE) and balloon-expandable (BE) transcatheter heart valves (THVs) have not been extensively studied in valve-in-valve transcatheter aortic valve replacement (ViV-TAVR). We compared outcomes of supra-annular SE and BE THVs used for ViV-TAVR via a retrospective analysis of institutional data (2013-2023) including all patients undergoing ViV-TAVR (TAVR in previous surgical AVR). Unmatched and propensity-matched (1:1) comparisons of clinical and echocardiographic outcomes were undertaken between SE and BE THV along with Kaplan-Meier survival analysis. A total of 315 patients undergoing ViV-TAVR were included of which 73% received a SE THV. Median age was 77 years and women comprised 42.5% of the population. Propensity-score matching (1:1) yielded 81 matched pairs. Implanted aortic valve size was comparable between the groups (23 mm [23-26] vs. 23mm [23-26], p=0.457). At 30 days following ViV-TAVR, the SE group had a lower mean aortic valve gradient (14 mmHg [11-18] vs. 17.5 mmHg [13-25], p=0.007). A higher number of BE patients had severe prosthesis-patient mismatch (PPM) (16% vs. 6.2%, p=0.04). At one-year follow-up, the SE group had a lower aortic valve gradient (14.0 mmHg [9.6-19] vs. 17 mmHg [13-25], p=0.04) compared to the BE group. 30-day mortality was 2.7% while one-year mortality was 7.5% and comparable between the groups. Survival and stroke incidence were similar in both groups up to 5 years. In conclusion, both SE and BE THVs had comparable survival following ViV-TAVR. The higher residual aortic valve gradients in BE THVs are likely due to valve design and warrant long-term evaluation for potential structural valve degeneration.

RESUMEN

Genetic research can help advance our knowledge of autism and positively impact the progress of care for individuals with autism. Asian American and Pacific Islander (AAPI) and Black participants remain significantly underrepresented in genetic research in autism in the United States, including nationwide, multisite, genetic consortiums like Simons Foundation Powering Autism Research for Knowledge (SPARK). Few studies have explored the unique motivators and barriers that influence participation in genetics research across underrepresented groups with autism and strategies to increase participation. Therefore, the aim of this study was to understand the perspectives of AAPI and Black parents of individuals with autism about participating in genetic research, specifically motivators (e.g., desire to know more about the relationship between autism and genetics) and/or barriers (e.g., mistrust of research staff) that may impact their decision to participate in genetic research. Using a mixed-methods approach, we collected surveys (n = 134) across the United States and conducted three focus groups with parents of individuals with autism (n = 16) who identified as AAPI and Black from two large metropolitan cities. No significant differences were observed in the survey data but findings from the focus groups elucidate shared motivators for participation (e.g., to help advance the autism field for future generations) and nuanced differences in barriers that influence Black and AAPI parents' decision to participate (e.g., different beliefs about the source of autism). Practical suggestions to improve outreach and study engagement in genetic research in autism were identified and discussed.

RESUMEN

Herein, we compare the electronic structures of the metal-free and nickel(II) derivatives of an annulated meso-tetraphenyldihydroxychlorin with those of the (metallo)chlorin analogues derived by pyrroline ß,ß'-ring cleavage of the annulated (metallo)chlorins. These (metallo)chlorin analogues incorporate 8-membered heterocycles in place of the pyrroline, carry oxo-functionalities on the former pyrroline ß-carbon atoms, and were previously shown to possess drastically ruffled (twisted) nonplanar conformations. The magnetic circular dichroism spectra of all chromophores investigated feature chlorin-like UV-vis spectra and correspondingly reversed (positive-to-negative in ascending energy) sign sequences in the Q-band region, indicative of ΔHOMO < ΔLUMO relationships. Density functional theory (DFT) calculations indicate that the HOMOs in all compounds are a1u-type molecular orbitals (in traditional for the porphyrin spectroscopy D4h point group). Time-dependent DFT calculations correlate well with the experimental spectra and indicate that Gouterman's four-orbital model can be applied to these chromophores. This work highlights to which degree synthetic chlorin analogues can deviate from the structural parameters of natural chlorins without losing their electronic chlorin characteristics.

RESUMEN

Diabetic wound healing is uniquely challenging to manage due to chronic inflammation and heightened microbial growth from elevated interstitial glucose. Carbon monoxide (CO), widely acknowledged as a toxic gas, is also known to provide unique therapeutic immune modulating effects. To facilitate delivery of CO, we have designed hyaluronic acid-based CO-gas-entrapping materials (CO-GEMs) for topical and prolonged gas delivery to the wound bed. We demonstrate that CO-GEMs promote the healing response in murine diabetic wound models (full-thickness wounds and pressure ulcers) compared to N2-GEMs and untreated controls.

RESUMEN

OBJECTIVE: Research provides support for the associated risk of inadequate sleep duration, limited physical activity, and excessive media use in attention-deficit/hyperactivity disorder (ADHD) and obesity. The present study aims to (1) examine the association between ADHD and overweight or obese status (OW/OB); (2) comprehensively examine sleep duration, physical activity, and media use as potential moderators of OW/OB; and (3) examine the moderating effects of these health behaviors cross-sectionally by comparing medicated youth with ADHD, unmedicated youth with ADHD, and youth without ADHD. METHODS: Data were acquired from the 2018 and 2019 National Survey of Children's Health, a nationally representative survey of caregivers conducted across the United States. The current study used data for youth 11-17 years old with a final sample size of 26,644. Hours of sleep, physical activity, and media use per day were dichotomized based on national recommendation guidelines for each health behavior (i.e., either meeting or not meeting guidelines). RESULTS: The OW/OB prevalence rate was 7% greater among unmedicated youth with ADHD than among medicated youth with ADHD. Medicated youth with ADHD and peers without ADHD had similar OW/OB rates. Among medicated youth with ADHD, physical activity, sleep duration, and media use did not contribute to OW/OB risk after controlling for family poverty level. However, among unmedicated youth with ADHD, meeting sleep duration guidelines was linked to a lower OW/OB risk. CONCLUSION: Overall, findings suggest that clinical providers and parents may wish to prioritize improved sleep duration in the management of OW/OB risk in youth with ADHD.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Ejercicio Físico , Conductas Relacionadas con la Salud , Obesidad Infantil , Humanos , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Masculino , Femenino , Adolescente , Niño , Estados Unidos , Obesidad Infantil/epidemiología , Estudios Transversales , Sueño , Prevalencia

RESUMEN

OBJECTIVES: This study aimed to identify differences in length of stay and readmission in patients admitted with bronchiolitis based on preferred written language. A secondary aim was to assess adherence to providing written discharge instructions in patients' preferred language. METHODS: In this cross-sectional study, we included 384 patients aged 0 to 2 years discharged from 2 children's hospitals with bronchiolitis from May 1, 2021, through April 30, 2022; patients were excluded for history of prematurity, complex chronic condition, or ICU stay during the study period. A manual chart review was performed to determine preferred written language and language of written discharge instructions. RESULTS: Patients preferring a written language other than English had a longer length of stay compared with English-preferring patients (37.9 vs 34.3 hours, P < .05), but there was no significant difference in unplanned 7-day readmissions. All patients who preferred English and Spanish received written discharge instructions in their preferred written language; no patients with other preferred languages did. CONCLUSIONS: Patients who preferred a written language other than English had a longer length of stay than those preferring English but there was no difference in 7-day readmissions, though power for readmissions was limited. The study also identified significant disparities in the provision of written discharge instructions in languages other than English and Spanish.

Asunto(s)

Bronquiolitis , Alta del Paciente , Humanos , Bronquiolitis/terapia , Estudios Transversales , Hospitalización , Hospitales Pediátricos , Recién Nacido , Lactante , Preescolar

RESUMEN

BACKGROUND: There continues to be debate regarding the superiority of transcatheter (TAVR) over surgical aortic valve replacement (SAVR) in patients with bicuspid aortic valves (BAV). We aimed to compare outcomes during readmissions in elderly patients with BAV who underwent SAVR or TAVR. METHODS: Patients 65 years or older with BAV who underwent TAVR or isolated SAVR were identified using the National Readmission Database from 2012 through 2018. We compared outcomes during readmissions within 90 days after discharge from the index surgery. Propensity score matching was performed to adjust the baseline differences. RESULTS: During the study period, 8555 and 1081 elderly patients with BAV underwent SAVR and TAVR, respectively. The number of patients who underwent TAVR went up by 179 % from 2012 to 2018. Propensity score matching yielded 573 patients in each group. A total of 111 (19.4 %) in the SAVR group and 125 (21.8 %) in the TAVR group were readmitted within 90 days after the index surgery (p = .31). The mortality during the readmissions within 90 days was equivalent between the two groups (0.9 % in the SAVR group vs. 3.2 % in the TAVR group, p = .22). However, the median hospital cost was approximately doubled in the TAVR group during the readmission (18,250 dollars vs. 9310 dollars in the SAVR group, p < .001). CONCLUSIONS: Readmission within 90 days was common in both groups. While the mortality during the readmissions after the surgery was equivalent between the two groups, hospital cost was significantly more expensive in the TAVR group.

Asunto(s)

Válvula Aórtica , Enfermedad de la Válvula Aórtica Bicúspide , Bases de Datos Factuales , Enfermedades de las Válvulas Cardíacas , Implantación de Prótesis de Válvulas Cardíacas , Readmisión del Paciente , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Reemplazo de la Válvula Aórtica Transcatéter/economía , Masculino , Femenino , Anciano , Resultado del Tratamiento , Factores de Tiempo , Enfermedad de la Válvula Aórtica Bicúspide/cirugía , Enfermedad de la Válvula Aórtica Bicúspide/diagnóstico por imagen , Enfermedad de la Válvula Aórtica Bicúspide/mortalidad , Enfermedad de la Válvula Aórtica Bicúspide/fisiopatología , Anciano de 80 o más Años , Válvula Aórtica/cirugía , Válvula Aórtica/anomalías , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/fisiopatología , Factores de Riesgo , Estados Unidos , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/mortalidad , Implantación de Prótesis de Válvulas Cardíacas/economía , Estudios Retrospectivos , Factores de Edad , Medición de Riesgo , Enfermedades de las Válvulas Cardíacas/cirugía , Enfermedades de las Válvulas Cardíacas/mortalidad , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Enfermedades de las Válvulas Cardíacas/fisiopatología , Complicaciones Posoperatorias/etiología , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/mortalidad , Estenosis de la Válvula Aórtica/fisiopatología

RESUMEN

The King Rail (Rallus elegans) is a wetland dependent species of conservation concern. Our objective was to gain a better understanding of the breeding habitat associations of King Rails in the Midwestern United States and the relationship of this species to other obligate marsh birds using occupancy and MaxEnt models. To collect data pertaining to occupancy, we placed trail cameras at 50 random points in coastal wetlands in the western Lake Erie basin where calls of King Rails were continuously broadcast at night. Data pertaining to other marsh bird species were collected via call-broadcast surveys and camera surveys at each sample point. For MaxEnt modeling, we obtained presence data for King Rails and other obligate marsh birds from eBird and habitat data from GIS databases. Trail cameras and call-broadcast surveys captured 10 detections of King Rails at nine sites, an 18% naive occupancy rate. King Rail occupancy was positively related to amount of interspersion, average water depth, and percent cover of emergent vegetation at local scales within a 5-m radius. Our MaxEnt models indicated that, at a broader scale, the presence of other rail species such as the Sora (Porzana carolina) may be more important for predicting King Rail presence than other marsh birds or coarse wetland categories such as "emergent vegetation." Our results could help wetland managers to predict where King Rails occur and to adapt management plans to incorporate King Rail conservation.

RESUMEN

Background: Hyperemesis gravidarum (HG), a severe form of nausea and vomiting in pregnancy (NVP), is a leading indication for hospitalization in the first trimester. NVP and HG are associated with Helicobacter pylori (HP) infection in non-United States cohorts. How HP exposure and NVP interact to affect metabolic disturbance and pregnancy outcomes is not known. Materials and Methods: We designed a retrospective cohort study relating HP and NVP to serum electrolyte laboratory results, preterm delivery, and infant birth weight. Single academic institution discovery and independent multi-institutional validation cohorts included pregnant subjects with an HP test result. Associations of HP, NVP, and pregnancy outcomes were assessed with odds ratio calculations, Student's t-tests, and multivariate logistic regression. Results: Among subjects with positive HP test results, the prevalence of hyperemesis gravidarum (HG) was 0.025 (66 of 2671) and NVP was 0.27 (710 of 2671). Subjects with negative HP had prevalence of HG 0.015 (165 of 10,960) and NVP 0.22 (2392 of 10,960). History of HP exposure increased risk of NVP, including HG (odds ratio 1.3, 95% CI 1.1-1.4). Patients with HP exposure had lower serum potassium (mean difference 0.1 mEq/L) and bicarbonate (mean difference 0.3 mEq/L) during pregnancy than HP-negative patients (p < 0.01). Serum potassium was lowest in subjects with both NVP and HP exposure (mean 3.5 mEq/L [3.4-3.6], p < 0.0001). HP exposure alone carried increased risk for preterm delivery (OR 1.3 [1.1-1.4]). NVP alone increased risk of preterm delivery (OR 2.8 [2.5-3.1]) including second trimester delivery (OR 2.2 [1.7-2.8]). In multivariate analysis, HP exposure in the setting of NVP further increased risk of preterm delivery (adjusted OR 1.4 [1.0-1.9], p = 0.03). Conclusions: H. pylori exposure and diagnosis of NVP are individually associated with metabolic disturbances and adverse pregnancy outcomes such as preterm labor and delivery, and their combination further increases risk in US populations.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , Hiperemesis Gravídica , Nacimiento Prematuro , Femenino , Humanos , Recién Nacido , Embarazo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/diagnóstico , Hiperemesis Gravídica/complicaciones , Hiperemesis Gravídica/epidemiología , Náusea/epidemiología , Potasio , Nacimiento Prematuro/epidemiología , Prevalencia , Estudios Retrospectivos , Estudios Multicéntricos como Asunto

RESUMEN

Given the substantial increase in pediatric obesity rates in recent decades, its long-term stability, and its pervasive negative outcomes, continuous efforts to identify factors that may place children at increased risk for overweight or obesity (OW/OB) are essential. As such, the primary aim of the present investigation was to examine the extent to which symptoms of Cognitive Disengagement Syndrome (CDS; i.e., Sluggish Cognitive Tempo) relates to child body mass index (BMI) independent of Attention-Deficit/Hyperactivity Disorder (ADHD). The study is the first to examine whether CDS subdomains of slowed thinking, hypoarousal, and daydreamy is associated with BMI. Analyses included data from 72 clinically-referred children (46 males, 26 females) aged 4-12 years old (M = 8.41, SD = 2.48). CDS and ADHD were assessed using standardized parent-report rating scales, and children's BMI was collected at the time of encounter. Bayesian hierarchical regression models revealed no evidence that overall CDS symptoms or ADHD symptoms (overall and subdomain) predicted child BMI. However, models did provide moderate evidence that hypoarousal and daydream subdomains jointly predicted BMI independent of ADHD (BF10 = 19.28-21.87). The present study suggests that CDS is a risk factor for obesity in young children and future research is needed to inform clinical interventions and to provide further understanding of the relatively nuanced association between CDS symptoms and obesity.

RESUMEN

The introduction of three ß-oxosubstituents to octaethylporphyrin by means of an oxidation/rearrangement reaction generates the trioxopyrrocorphin chromophore. Pyrrocorphins (hexahydroporphyrins) are generally nonaromatic, but we recently demonstrated trioxopyrrocorphins to possess considerable aromatic character. This contribution explores the photophysical characteristics of these unusual chromophores. In agreement with density functional theory modeling, the UV-vis and magnetic circular dichroism spectra of the two─out of the four possible─triketone regioisomers investigated conform to the Gouterman model of porphyrinoid optical spectra, in alignment with their aromaticity. Their excited-state dynamics shed further light on the degree to which ß-oxo substitutions tune the photophysical properties of porphyrinoids. Introduction of ß-oxo functionalities increases the rate and yield of intersystem crossing and shortens the triplet state lifetime. Unexpectedly, the singlet oxygen generation yield of both pyrrocorphins remains relatively high, with modes of distortion from planarity likely enhancing triplet energy transfer. This work thus expands our understanding of a rare class of porphyrinoids and further characterizes them as sustaining aromatic porphyrinic π-systems. Our findings suggest triple ß-oxo substitution as a viable route toward the development of novel, high-singlet oxygen yield porphyrinic photosensitizers.

RESUMEN

The anion binding features of diphenylpyrrole-strapped calix[4]pyrrole 1 have been investigated by means of 1 H NMR spectroscopy and ITC (isothermal titration calorimetry), as well as single crystal X-ray diffraction analyses. Receptor 1 bearing an auxiliary pyrrolic NH donor and solubilizing phenyl groups on the strap was found to bind F- , Cl- , and Br- as their tetrabutylammonium salts with high affinity in DMSO-d6 . In addition, receptor 1 was found to extract the fluoride anion (as both its tetraethylammonium (TEA+ ) and tetrabutylammonium (TBA+ ) salts), as well as the chloride anion into chloroform-d from an aqueous source phase. Cation metathesis using TBAI or the use of a dual host approach involving crown ethers enabled receptor 1 to extract simple alkali metal fluoride or chloride salts from water. Quantitative binding of NaF by receptor 1 was observed in 20 % D2 O-DMSO-d6 allowing for the direct determination of the NaF concentration in an unknown sample.

RESUMEN

We report a systematic investigation of a series of Ag(II) and Ag(III) complexes of porphyrins and their analogues using UV-vis magnetic circular dichroism (MCD) spectroscopies and theoretical calculations. Ag(II) and Ag(III) octaethyl- and tetraarylporphyrins show the usual sign sequence in the Q-band region (i.e., negative to positive intensities with increasing energy) of their MCD spectra, indicative of the ΔHOMO > ΔLUMO relationship (ΔHOMO is the energy difference between Michl's a and s orbitals, and ΔLUMO is the energy difference between Michl's -a and -s pair of MOs). In contrast, Ag(II) complexes of ß,ß'-pyrrole-modified porphyrins (with an effective chlorin-type π-system) and Ag(III) corroles have sign reverse features in the MCD spectra of their Q-band region (ΔHOMO < ΔLUMO relationships). The Ag(III) complex of N-confused porphyrin shows the ΔHOMO > ΔLUMO relationship in the neutral state and the ΔHOMO < ΔLUMO relationship in the protonated form.

RESUMEN

BACKGROUND: Clinical trials play a crucial role in advancing medical knowledge and improving health outcomes. However, there is a recognized need for greater representation of marginalized groups to ensure that research findings can be generalized and effectively applied to all individuals. While the Pediatric Research Participation Questionnaire (PRPQ) was developed to assist pediatric clinical trials research by identifying benefits and barriers to research participation among children with chronic medical conditions, there is still limited insight into the structure of the PRPQ when administered in diverse samples, including the general pediatric population. Therefore, the current study examined the factor structure of the PRPQ in a general pediatric population to investigate whether rural-urban differences exist in the PRPQ factor structure. METHODS: Caregivers (N = 600) of children under age 18 completed the PRPQ in a population-based survey in Mississippi. Sampling was stratified to ensure equal representation in rural (n = 300) and urban areas (n = 300). Exploratory and confirmatory factor analyses were conducted to determine the factor structure of the PRPQ. RESULTS: A five-factor structure was identified, compromising: social pressure, direct benefit, reasons for participation, mistrust in research/researchers, reasons against participation. While results were similar among urban participants, a three-factor structure emerged for rural participants. CONCLUSIONS: This study contributes to the broader understanding of research participation among underrepresented groups. The findings suggest that clinical researchers should consider tailoring recruitment strategies to increase clinical trial participation among children in rural areas. Understanding factors that influence pediatric research participation, particularly among marginalized communities, is crucial for developing effective recruitment and retention strategies.

RESUMEN

A primary function of DNA methylation in mammalian genomes is to repress transposable elements (TEs). The widespread methylation loss that is commonly observed in cancer cells results in the loss of epigenetic repression of TEs. The aging process is similarly characterized by changes to the methylome. However, the impact of these epigenomic alterations on TE silencing and the functional consequences of this have remained unclear. To assess the epigenetic regulation of TEs in aging, we profiled DNA methylation in human mammary luminal epithelial cells (LEps)-a key cell lineage implicated in age-related breast cancers-from younger and older women. We report here that several TE subfamilies function as regulatory elements in normal LEps, and a subset of these display consistent methylation changes with age. Methylation changes at these TEs occurred at lineage-specific transcription factor binding sites, consistent with loss of lineage specificity. Whereas TEs mainly showed methylation loss, CpG islands (CGIs) that are targets of the Polycomb repressive complex 2 (PRC2) show a gain of methylation in aging cells. Many TEs with methylation loss in aging LEps have evidence of regulatory activity in breast cancer samples. We furthermore show that methylation changes at TEs impact the regulation of genes associated with luminal breast cancers. These results indicate that aging leads to DNA methylation changes at TEs that undermine the maintenance of lineage specificity, potentially increasing susceptibility to breast cancer.

Asunto(s)

Neoplasias de la Mama , Epigénesis Genética , Anciano , Femenino , Humanos , Envejecimiento/genética , Neoplasias de la Mama/genética , Metilación de ADN , Elementos Transponibles de ADN , Retroelementos

RESUMEN

The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.

Asunto(s)

Glucosa , Hiperglucemia , Ratones , Humanos , Animales , Glucosa/farmacología , Epigenoma , ADN (Citosina-5-)-Metiltransferasa 1/genética , Metilación de ADN , Glicosilación

RESUMEN

The COVID-19 pandemic has significantly disrupted the lives of children and their caregivers. Recent research has examined the impact of the pandemic on child and caregiver functioning but there is a paucity of work examining the impact of the pandemic on the broader family system. The current study examined family resilience during the COVID-19 pandemic across three aims: Aim 1 tested whether meaning, control, and emotion systems form a unitary family adaption factor, Aim 2 evaluated a concurrent model of family resilience, and Aim 3 examined whether parent gender and vaccination status moderated paths in the final model. A nationally representative sample of U.S. parents (N = 796; 51.8% fathers, M age = 38.87 years, 60.3% Non-Hispanic White) completed a cross-sectional survey about themselves and one child (5-16 years old) between February-April 2021, including measures of COVID-19 family risk and protective factors, pre-existing family health vulnerabilities, race, COVID-19 stressors, and family adaptation. Confirmatory Factor Analysis demonstrated that the meaning (i.e., family making meaning of COVID-19), control (i.e., stability in routines), and emotional (i.e., family support) facets of family adaptation are unique but related. A path model revealed that there were concurrent effects from COVID-19 exposure, pre-existing vulnerabilities, and racial diversity status to the family protective, vulnerability, and adaptation variables. Additionally, parent COVID-19 vaccination status altered the association between pre-existing family health vulnerabilities and the family protective factor. Overall, results underscore the importance of examining pre-existing and concurrent risk and protective factors for family resilience during a stressful, global, and far-reaching event.

RESUMEN

Bacteroidales use type VI secretion systems (T6SS) to competitively colonize and persist in the colon. We identify a horizontally transferred T6SS with Ntox15 family nuclease effector (Tde1) that mediates interbacterial antagonism among Bacteroidales, including several derived from a single human donor. Expression of cognate (Tdi1) or orphan immunity proteins in acquired interbacterial defense systems protects against Tde1-dependent attack. We find that immunity protein interaction induces a large effector conformational change in Tde nucleases, disrupting the active site and altering the DNA-binding site. Crystallographic snapshots of isolated Tde1, the Tde1/Tdi1 complex, and homologs from Phocaeicola vulgatus (Tde2/Tdi2) illustrate a conserved mechanism of immunity inserting into the central core of Tde, splitting the nuclease fold into two subdomains. The Tde/Tdi interface and immunity mechanism are distinct from all other polymorphic toxin-immunity interactions of known structure. Bacteroidales abundance has been linked to inflammatory bowel disease activity in prior studies, and we demonstrate that Tde and T6SS structural genes are each enriched in fecal metagenomes from ulcerative colitis subjects. Genetically mobile Tde1-encoding T6SS in Bacteroidales mediate competitive growth and may be involved in inflammatory bowel disease. Broad immunity is conferred by Tdi1 homologs through a fold-disrupting mechanism unique among polymorphic effector-immunity pairs of known structure. IMPORTANCE Bacteroidales are related to inflammatory bowel disease severity and progression. We identify type VI secretion system (T6SS) nuclease effectors (Tde) which are enriched in ulcerative colitis and horizontally transferred on mobile genetic elements. Tde-encoding T6SSs mediate interbacterial competition. Orphan and cognate immunity proteins (Tdi) prevent intoxication by multiple Tde through a new mechanism among polymorphic toxin systems. Tdi inserts into the effector central core, splitting Ntox15 into two subdomains and disrupting the active site. This mechanism may allow for evolutionary diversification of the Tde/Tdi interface as observed in colicin nuclease-immunity interactions, promoting broad neutralization of Tde by orphan Tdi. Tde-dependent T6SS interbacterial antagonism may contribute to Bacteroidales diversity in the context of ulcerative colitis.

RESUMEN

The COVID-19 pandemic led to increased mental health concerns among parents. Emerging studies have shown links between COVID-19 vaccine hesitancy and psychological distress, including among parents. The primary aim of this study was to extend these emerging findings by examining the role of COVID-19 vaccine hesitancy in mental health functioning in a national sample of U.S. parents, accounting for the effects of COVID-19 vaccination status and underlying medical conditions increasing COVID-19 risk. A nationally representative sample of U.S. parents (N = 796) completed a cross-sectional survey between February-April 2021, including measures of depressive, anxiety, and COVID-19 acute stress symptoms; COVID-19 vaccination status; underlying medical conditions increasing COVID-19 risk; and COVID-19 vaccine hesitancy. The sample consisted of 51.8% fathers, Mage=38.87 years, 60.3% Non-Hispanic white, 18.1% Hispanic/Latinx, 13.2% Non-Hispanic Black/African American, 5.7% Asian, and 2.8% Other Race. Hierarchical regression models adjusted for demographic covariates revealed that greater COVID-19 vaccination hesitancy and presence of an underlying medical condition were consistently associated with higher levels of depressive, anxiety, and COVID-19 acute stress symptoms among parents. Having had at least one COVID-19 vaccination dose was associated with greater levels of COVID-19 acute stress, but was not associated with depressive or anxiety symptoms. Results add new evidence from the U.S. in support of the link between COVID-19 vaccine hesitancy and psychological distress, point to the potential utility of behavioral health care workers in helping reduce vaccine hesitancy, and provide tentative data suggesting that COVID-19 vaccination for parents alone may not have provided mental health relief.

RESUMEN

3-O-sulfogalactosylceramide (sulfatide) constitutes a class of sphingolipids that comprise about 4% of myelin lipids in the central nervous system. Previously, our group characterized a mouse with sulfatide's synthesizing enzyme, cerebroside sulfotransferase (CST), constitutively disrupted. Using these mice, we demonstrated that sulfatide is required for establishment and maintenance of myelin, axoglial junctions, and axonal domains and that sulfatide depletion results in structural pathologies commonly observed in Multiple Sclerosis (MS). Interestingly, sulfatide is reduced in regions of normal appearing white matter (NAWM) of MS patients. Sulfatide reduction in NAWM suggests depletion occurs early in disease development and consistent with functioning as a driving force of disease progression. To closely model MS, an adult-onset disease, our lab generated a "floxed" CST mouse and mated it against the PLP-creERT mouse, resulting in a double transgenic mouse that provides temporal and cell-type specific ablation of the Cst gene (Gal3st1). Using this mouse, we demonstrate adult-onset sulfatide depletion has limited effects on myelin structure but results in the loss of axonal integrity including deterioration of domain organization accompanied by axonal degeneration. Moreover, structurally preserved myelinated axons progressively lose the ability to function as myelinated axons, indicated by the loss of the N1 peak. Together, our findings indicate that sulfatide depletion, which occurs in the early stages of MS progression, is sufficient to drive the loss of axonal function independent of demyelination and that axonal pathology, which is responsible for the irreversible loss of neuronal function that is prevalent in MS, may occur earlier than previously recognized.

Asunto(s)

Vaina de Mielina , Sulfoglicoesfingolípidos , Ratones , Animales , Vaina de Mielina/patología , Ratones Noqueados , Axones/fisiología , Neuronas , Ratones Transgénicos