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Phase variation of Clostridioides difficile colony morphology occurs via modulation of cell division.
Get PDFPhase variation of C. difficile colony morphology occurs via modulation of transcription of cmrRST, which encodes a three-protein signal transduction system. Response regulators CmrR and CmrT promote rough colony development, cell elongation and chaining, surface motility, and disease in the hamster model of infection, while impairing swimming motility and biofilm formation. Using RNA-Seq, we identified the CmrR and CmrT-dependent transcriptional differences in rough and smooth colonies. Further analysis showed that CmrT, but not CmrR, is required for differential expression of most of the genes. Two CmrT-regulated genes, herein named mrpA and mrpB, were together sufficient for restoring all CmrT-dependent in vitro phenotypes in a cmrT mutant and alleviating selection of cmr phase ON cells during growth on an agar surface. MrpA and MrpB are uncharacterized proteins with no known function but are highly conserved in C. difficile. Using immunoprecipitation and mass spectrometry to identify interacting partners, we found that MrpA interacts with the septum-site determining protein MinD and several other proteins involved in cell division and cell shape determination. Ectopic expression of mrpAB resulted in atypical cell division, consistent with MrpAB interference with MinD function. Our findings reveal a potential mechanism by which phase variation of CmrRST modulates colony morphology and motility: in cmr phase ON cells, CmrT-mediated expression of mrpAB interferes with normal cell division resulting elongated cells that enable expansion of the population across a surface while limiting swimming motility
Functional organization of the allostatic interoceptive network in adolescence: Links to peer victimization and prospective depressive symptoms.
Get PDFThe present study examines the role of brain network organization in the prospective prediction of adolescent depressive symptoms and links to the social and psychological context. Using a path model with data from a larger longitudinal study of adolescents beginning in 6th-8th grade (N = 117, 55 % female, Mage at scan= 12.99), we first established that organizational properties of brain networks theoretically linked to depression predicted greater depressive symptoms two years later. Specifically, when controlling for gender and initial depression, greater global efficiency of the allostatic interoceptive network (AIN) and greater segregation of the frontoparietal network (FPN) from the salience network (SN) predicted depressive symptoms an average of two years later. Linking these neural findings to psychological individual differences, we found that self-reported rumination mediated the effect of AIN global efficiency on prospective depressive symptoms. We further linked these neural findings to the social context by demonstrating that greater self-reported relational peer victimization prospectively predicted AIN global efficiency. Collectively, these findings situate the emergence of adolescent depressive symptoms as a confluence of brain organization properties, perceived social rejection, and individual differences in rumination
Sex differences in BNST signaling and BNST CRF in fear processing
Get PDFFear responses to perceived danger are critical for survival, as they prompt the individual to respond to threats and avoid harm. However, excessive fear can impede normal biological processes and become harmful. This study investigates the neural mechanisms underlying two distinct forms of fear—phasic and sustained—in male and female mice, with a focus on the bed nucleus of the stria terminalis (BNST) and corticotropin-releasing factor (CRF) signaling. Phasic fear is characterized by immediate responses to clear threats, while sustained fear is driven by ambiguous or uncertain cues and persists longer. Using rodent models, we found that sustained fear, modeled by partial fear conditioning, induced greater arousal and BNST activity in males, especially during ambiguous threat cues. In contrast, females exhibited reduced BNST and BNSTCRF activity, highlighting significant sex differences in fear learning and expression. Additionally, CRF is crucial for appropriate fear response in females, as CRF knockdown led to increased fear responses, but had no effect in males. These sex-specific differences could help inform the development of targeted treatments for anxiety and trauma-related disorders, which disproportionately affect women
Child Health Service Nurses' Experiences of Providing Support to Parents With Overweight During Clinical Encounters About Their Child's Overweight—a Qualitative Study
Get PDFBackground Childhood overweight poses health risks and often persists in adulthood, making early intervention essential. Swedish Child Health Service (CHS) nurses are responsible for addressing this issue, a task perceived as important yet challenging. When supporting these families, a caring approach is crucial for well‐being and adherence. Childhood overweight is often associated with parental overweight. Due to the sensitivity and stigma surrounding adult overweight, healthcare professionals may experience discomfort, potentially leading to negatively perceived interactions. Despite these challenges, little is known about how parental overweight influences CHS nurses' approach in encounters regarding children's overweight. Therefore, this study aimed to explore how CHS nurses experience providing support to parents with overweight during clinical encounters about their child's overweight. Methods Qualitative descriptive, inductive design was applied. Individual semi‐structured digital interviews were conducted with 14 CHS nurses, and transcripts were analysed using latent content analysis. Results Four categories were identified: feeling insecurity regarding professional role, focusing on concrete aspects of health, questioning the parent and trying to influence the parent. CHS nurses perceived addressing the child's overweight as their primary duty. They focused on weight‐related aspects of the child's health, emphasising lifestyle advice, while parents' emotions or socioeconomic challenges risked being overlooked. Parental overweight could trigger negative assumptions, including doubts about parents' ability to support their child. When children's weight curve remained unchanged, frustration sometimes led CHS nurses to emphasise parental responsibility or use threats, such as involving child welfare services. Conclusion This study highlights how CHS nurses perceive both challenges and responsibility in addressing childhood overweight, difficulties that intensify when parents themselves have overweight. The findings suggest that while striving to fulfil their role and balance professional responsibility with maintaining a supportive and caring approach, CHS nurses' are sometimes shaped by weight stigma. Summary CHS nurses face challenges in clinical encounters about a child's overweight when the parent also have overweight. They are driven by a strong sense of professional responsibility, which seems to be complicated by the parents' overweight.CHS nurses may adopt an approach that is influenced by societal weight stigma, which can lead to distrust of parents and strained interactions.More guidance is needed to support CHS nurses in complex conversations about a child's overweight when the parent also has overweight.Future research should explore how CHS nurses construct their professional role and how they navigate—and potentially reinforce or resist—weight stigma in clinical encounters
Adeno-associated vector corneal gene therapy reverses corneal clouding in a feline model of mucopolysaccharidosis VI
Get PDFMucopolysaccharidosis VI (MPS VI) is a rare, autosomal recessive lysosomal storage disease caused by mutations in the arylsulfatase B gene (ARSB). Ocular manifestations of MPS VI include progressive corneal clouding, leading to vision loss. Herein, an adeno-associated virus (AAV) ARSB corneal gene addition strategy was evaluated in a naturally occurring MPS VI feline model. The AAV serotype 8 capsid was packaged with a single-strand optimized human ARSB expression cassette (optARSB) and administered to MPS VI feline corneas at a dose of 1e9 vector genomes via intrastromal injection. All AAV8-optARSB injections were well tolerated, resulting in a complete reversal of pre-existing corneal clouding within 2–3 weeks, which was maintained throughout the study. Sequential dosing of the contralateral cornea 7 weeks after the first dose also cleared the storage disease with similar kinetics despite more advanced disease. Confocal microscopy, histological analyses, and electron microscopy revealed disorganization in the posterior corneal stroma in untreated animals with AAV8-optARSB-treated corneas demonstrating improved morphology and tissue organization. Human arylsulfatase B was observed throughout the corneal stroma with decreased smooth muscle actin staining following AAV8-optARSB treatment. The collective results demonstrate that reversing feline MPS VI corneal clouding using intrastromal low-dose AAV8-optARSB is safe and effective. Furthermore, as this strategy relied on the same AAV capsid, vector dose, genetic cassette context, injection type, and volume deemed safe and effective for the treatment of MPS I, the data derived herein support a standardized pipeline for AAV corneal gene therapy
GluN2A-containing NMDA Receptors Treatment
Get PDFDepression has been linked to disruptions in excitation and inhibition within the prefrontal cortex, motivating the development of novel antidepressant strategies that restore cortical balance. GluN2A-containing NMDA receptors play a critical role in synaptic signaling, with receptor gating regulated by interactions between GluN1 and GluN2A subunits. GNE-8324 is a preclinical, GluN2A-selective positive allosteric modulator that binds at the GluN1–GluN2A interface and enhances receptor gating, particularly within inhibitory interneurons. In this project, the GluN2A-containing NMDA receptor and GNE-8324 were modeled using low-fidelity prototyping and high-resolution 3D printing techniques. The resulting physical models visualize ligand binding, conformational changes, and receptor activation states. These representations clarify the mechanism of action of GNE-8324 and its stabilizing effect on the ligand-binding domain. This work demonstrates how physical modeling can enhance understanding of NMDA receptor modulation and highlights the therapeutic potential of GluN2A-selective PAMs in depression treatment.
HIV Pre-exposure Prophylaxis Does Not Increase Gonorrhea and Chlamydia Incidence in Young Black and Hispanic Men who Have Sex With Men: An Observational Cohort Study
Get PDFBackground HIV pre-exposure prophylaxis (PrEP) use has been linked with increases in sexually transmitted infection (STI) incidence. Despite efforts to expand PrEP uptake among young Black and Hispanic men who have sex with men (YBHMSM), little research has been done to understand the impact of PrEP on STI incidence within these communities. We examine the effect of PrEP use on gonorrhea and chlamydia (NG/CT) incidence, condom use, and external STI testing (ie, outside of study visits). Methods In a longitudinal cohort of HIV-negative YBHMSM (ages 16–24 years), we modeled the effect of PrEP use on study-external STI testing and number of condomless sex partners during the following 6 months using mixed-effects generalized linear models. We modeled the effect of PrEP use on NG/CT incidence using time-updated proportional hazard regression. Results While on PrEP compared with periods not on PrEP, participants reported on average 2.51 (adjusted beta; 95% CI, 1.51–3.51; P < .001) more condomless sex partners and were 2.28 (adjusted OR; 95% CI, 1.48–3.52; P < .001) times as likely to report study-external STI testing during the following 6 months. NG/CT incidence did not increase (adjusted HR, 0.75; 95% CI, 0.45–1.27; P = .286) while on PrEP compared with not on PrEP. Conclusions Condomless sex increased with PrEP use; however, its potential to elevate STI acquisition or prolonged duration of infection may be mitigated by PrEP-associated routine testing. Efforts to expand PrEP uptake among YBHMSM appear unlikely to exacerbate the STI epidemic
Structural connectome gradients and their relationship to IQ in childhood
Get PDFThe concept of connectome gradients, which represents the continuous spatial variation of brain connectivity, offers a robust framework for exploring the hierarchical organization of the cortex and its relationship with cognitive function. We hypothesize that structural gradients in frontal and parietal regions play a significant role in shaping individual cognitive abilities during early childhood. To evaluate this hypothesis, we identified macroscale structural connectome gradients in children aged 1–6 years, where the principal gradient exhibited a left-to-right axis, and the secondary gradient exhibited an anterior-to-posterior axis. Next, we employed machine learning approaches to predict the future cognitive outcomes assessed at ages 4, 6, and 8, specifically intelligence quotient (IQ), based on the structural connectome gradients measured at age 1. We achieved consistent and robust prediction results (mean Spearman's correlation > 0.25). The regional relevance maps highlighted regions in control network, and associated sensory processing networks. Our findings indicate that the structural connectome, which undergoes maturation during early childhood, plays a crucial role in the individual variability of IQ observed in early and middle childhood. Our approach underscores the utility of structural gradients as compact and interpretable representations of the brain's complex network architecture, effectively capturing individual differences that contribute to cognitive development
Reducing door-to-ECG time in the emergency department: a quality improvement report
Get PDFBACKGROUND: Patients presenting emergently with chest pain often experience delays in obtaining an ECG. Studies have found variability in care for patients with acute coronary syndrome, with many patients facing delays to receiving timely ECGs. Delays in acquisition are associated with increased morbidity and mortality. LOCAL PROBLEM: Prior to our intervention, median time to ECG in the emergency department (ED) was 16.7 min, with peak times reaching 20.7 min in January 2024, exceeding American College of Cardiology/American Heart Association guidelines recommending an ECG within 10 min of arrival. Contributing factors included workflow inefficiencies, inadequate staffing and process inconsistency. METHODS: A quality improvement initiative was implemented from February 2024 to February 2025 aimed at reducing time to ECG and time to ECG interpretation. Key interventions included nursing education, process standardisation, stamps to standardise documentation, ECG responsibility reallocation (triage ECGs done by nurses, floor ECGs done by techs) and the creation of a designated ECG space in triage. RESULTS: There were 3510 eligible ECGs conducted across the 12-month intervention period with 1522 ECGs (43.4%) meeting the <10 min goal. The initiative led to a reduction in time to ECG by 4.68 min (95% CI -7.74 to -1.62), a 10.8% reduction in median door-to-ECG time from 1 year prior to the intervention (12.9 min to 11.4 min), and a 32% reduction in median door-to-ECG time (16.7 min to 11.4 min) from 6 months prior to the intervention. There was a 74% reduction in median ECG interpretation time (101 min to 26.5 min) over 12 months. CONCLUSIONS: Process standardisation, role delegation and education effectively reduced ECG times in the ED. Changes in staff who complete ECGs and standardisation of documentation may aid in improving performance metrics in ED settings
Association between low‐frequency oscillations in blood pressure variability and brain age derived from neuroimaging
Get PDFINTRODUCTION: We examined the association between low-frequency oscillations in blood pressure variability (LF-BPV) at baseline (past) and 12 years later (concurrent) and BrainAGE gap (an indicator of brain health). METHODS: Participants were 110 adults (age range 37-83 years at baseline, 60% female) from the Midlife in the United States (MIDUS) study. LF-BPV (0.04-0.15 Hz) was spectrally decomposed from beat-to-beat BP waveforms acquired from finger photoplethysmography. BrainAGE was estimated using a Gaussian-process regression model applied to raw T1-weighted magnetic resonance imaging (MRI) scans. BrainAGE gap was calculated as brain age minus chronological age. RESULTS: After adjustment for covariates, higher past diastolic LF-BPV was associated with significantly reduced BrainAGE gap (β = -2.24; 95% CI -4.15, -0.32, p = 0.022), as was higher concurrent diastolic LF-BPV (β = -1.90; 95% CI -3.68, -0.12, p = 0.037). CONCLUSION: Our findings suggest that low-frequency oscillations in diastolic BPV are associated with slower brain aging relative to chronological age. HIGHLIGHTS: Low-frequency oscillations in diastolic blood pressure variability, a marker of vasomotion, are reduced with aging. Low-frequency oscillations in diastolic blood pressure variability are favorably associated with BrainAGE gap, a marker of overall brain health, measured from neuroimaging. Reductions in vasomotion with aging may contribute to accelerated brain aging relative to chronological age