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Infant sensory gating and a developmental cascade to autistic traits and anxiety
No full textDisruptions to the infant sensory environment can have lasting effects on neural response properties and behavior in both humans and animals. Recent work has begun to highlight an additional factor in infant sensory experience: differences in inhibitory signaling and sensory gating. Converging work from human and animal studies has begun to implicate a developmental cascade by which impaired sensory gating during a sensitive period of neonatal neurodevelopment promotes a phenotype of sensory over-responsivity, autistic traits, anxiety, and other psychiatric challenges. In this Review, I propose a model for this developmental cascade and highlight how differences in infant sensory responsivity represent an important intermediate phenotype for research, screening, and supportive intervention
Characteristics and outcomes of patients with hematologic malignancies hospitalized with respiratory viral infections
No full textBACKGROUND: Respiratory viral infections in patients with hematologic malignancies or hematopoietic stem cell transplants (HCTs) are associated with increased morbidity and mortality. However, the hospital presentations and courses of these infections remain under-described.
METHODS: We performed a multicenter retrospective cohort study of hospitalized patients with hematologic malignancy or HCT at 2 comprehensive cancer centers between January 2019 and June 2023. We included all patients with acute viral respiratory infection (identified based on a constellation of test results and objective physiology), comparing clinical presentations, care processes, and patient outcomes across pathogens; the primary outcome was the composite of hospital death or discharge to hospice.
RESULTS: We evaluated 385 hospitalizations from 346 unique patients, 162 (42%) of which were for SARS-CoV-2 infection. The primary outcome of death or discharge to hospice occurred in 54 (14%) encounters and did not significantly differ across pathogens (
INTERPRETATION: Among hospitalized patients with hematologic malignancies or HCTs, acute viral respiratory infections display similar initial physiology and outcomes regardless of pathogen. These findings may have implications for clinical practice
β2 and β3a regulatory subunits can coassemble in the same BK channels
No full textCa2+- and voltage-activated BK-type K+ channels are influenced profoundly by associated regulatory subunits, including β subunits (Kcnmb1-4; β1-β4). Although overlap in expression of different BK β subunits occurs in native tissues, whether they can coassemble in the same channel complex is not known. We coexpress β2 and β3a subunits together with BK α and, through a combination of macroscopic and single-channel recordings, along with quantitative pull-down of tagged subunits, test whether coassembly can occur. We evaluate two models: (1) random mixing in which β2 and β3a subunits coassemble in the same channels, and (2) segregation in which β2 and β3a are found in separate complexes. Our results support the view that, for β2 and β3a, BK currents arise from the random, independent assembly of both subunits in the same channels. Single-channel recordings directly confirm coassembly of β2 and β3a subunits in the same channels. Quantitative biochemical analysis of coexpression of tagged β2, β3a, and BK α subunits also reveals that β2:β3a:α ternary complexes form
Networked behaviors associated with a large-scale secure messaging network: Cross-sectional secondary data analysis
Full text linkBACKGROUND: Communication among health care professionals is essential for effective clinical care. Asynchronous text-based clinician communication-secure messaging-is rapidly becoming the preferred mode of communication. The use of secure messaging platforms across health care institutions creates large-scale communication networks that can be used to characterize how interaction structures affect the behaviors and outcomes of network members. However, the understanding of the structure and interactions within these networks is relatively limited.
OBJECTIVE: This study investigates the characteristics of a large-scale secure messaging network and its association with health care professional messaging behaviors.
METHODS: Data on electronic health record-integrated secure messaging use from 14 inpatient and 282 outpatient practice locations within a large Midwestern health system over a 6-month period (June 1, 2023, through November 30, 2023) were collected. Social network analysis techniques were used to quantify the global (network)- and node (health care professional)-level properties of the network. Hierarchical clustering techniques were used to identify clusters of health care professionals based on network characteristics; associations between the clusters and the following messaging behaviors were assessed: message read time, message response time, total volume of messages, character length of messages sent, and character length of messages received.
RESULTS: The dataset included 31,800 health care professionals and 7,672,832 messages; the resultant messaging network consisted of 31,800 nodes and 1,228,041 edges. Network characteristics differed based on practice location and professional roles (P\u3c .001). Specifically, pharmacists and advanced practice providers, as well as those working in inpatient settings, had the highest values for all network metrics considered. Four clusters were identified, representing differences in connectivity within the network. Statistically significant differences across clusters were identified between all considered secure messaging behaviors (P\u3c .001). One of the clusters with 1109 nodes, consisting mostly of physicians and other inpatient health care professionals, had the highest values for all node-level metrics compared to the other clusters found. This cluster also had the quickest message read and response times and handled the largest volume of messages per day.
CONCLUSIONS: Secure messaging use within a large health care system manifested as an expansive communication network where connectivity varied based on a health care professional\u27s role and their practice setting. Furthermore, our findings highlighted a relationship between health care professionals\u27 connectivity in the network and their daily secure messaging behaviors. These findings provide insights into the complexities of communication and coordination structures among health care providers and downstream secure messaging use. Understanding how secure messaging is used among health care professionals can offer insights into interventions aimed at streamlining communication, which may, in turn, potentially enhance clinician work behaviors and patient outcomes
Ablation of the evolutionarily acquired functions of the ATP1B4 gene increases metabolic capacity and reduces obesity
Full text linkIn placental mammals, the co-option of vertebrate orthologou
DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis
Full text linkLipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYVE1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of other known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 is a nutrient-sensitive regulator of LD catabolism
Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis
Full text linkAdipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis
ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders
Full text linkTelomere biology disorders (TBDs) are genetic diseases caused by defective telomere maintenance. TBD patients often develop bone marrow failure and have an increased risk of myeloid neoplasms. To better understand the factors underlying hematopoietic outcomes in TBD, we comprehensively evaluated acquired genetic alterations in hematopoietic cells from 166 pediatric and adult TBD patients. Of these patients, 47.6% (28.8% of children, 56.1% of adults) had clonal hematopoiesis. Recurrent somatic alterations involved telomere maintenance genes (7.6%), spliceosome genes (10.4%, mainly U2AF1 p.S34), and chromosomal alterations (20.2%), including 1q gain (5.9%). Somatic variants affecting the DNA damage response (DDR) were identified in 21.5% of patients, including 20 presumed loss-of-function variants in ataxia-telangiectasia mutated (ATM). Using multimodal approaches, including single-cell sequencing, assays of ATM activation, telomere dysfunction-induced foci analysis, and cell-growth assays, we demonstrate telomere dysfunction-induced activation of the ATM-dependent DDR pathway with increased senescence and apoptosis in TBD patient cells. Pharmacologic ATM inhibition, modeling the effects of somatic ATM variants, selectively improved TBD cell fitness by allowing cells to bypass DDR-mediated senescence without detectably inducing chromosomal instability. Our results indicate that ATM-dependent DDR induced by telomere dysfunction is a key contributor to TBD pathogenesis and suggest dampening hyperactive ATM-dependent DDR as a potential therapeutic intervention
Transcranial vibration stimulation at 40 Hz induced neural activity and promoted the coupling of global brain activity and cerebrospinal fluid flow
Full text linkBACKGROUND: Neuroscience advances have highlighted the potential of non-invasive brain stimulation in influencing cognitive and emotional processes. Conventional stimulation methods such as electrical, magnetic, and ultrasound have been studied intensively, but little is known about the mechanical stimulation.
OBJECTIVE: To investigate the effects of 40 Hz transcranial vibration stimulation (TVS) on human brain activity, specifically focusing on changes in the Amplitude of Low-Frequency Fluctuation (ALFF), fractional ALFF (fALFF) and Regional Homogeneity (ReHo) as measures of spontaneous brain activity. Additionally, this study investigates alterations in the global blood-oxygen-level-dependent (gBOLD) signal and cerebrospinal fluid (CSF) inflow coupling, which serve as indicators of glymphatic system function.
METHODS: A custom-built head actuator was used to apply 40 Hz TVS to human brain. Functional magnetic resonance imaging (fMRI) were performed before and after 5 mins TVS to explore the changes in ALFF and fALFF and the coupling of global brain activity with cerebrospinal fluid flow (CSF), which is related to the glymphatic clearance.
RESULTS: Significant increases were observed in both ALFF and fALFF metrics, indicating that 40 Hz TVS effectively enhanced spontaneous brain activity. Additionally, 40 Hz TVS promoted the synchronization of overall brain activity with CSF, suggesting an improvement in glymphatic clearance processes, an effect that 30 Hz or 50 Hz TVS did not replicate.
CONCLUSION: Non-invasive brain stimulation using TVS provided important implications for modulating brain physiology and showed prospective therapeutic benefits for neurological diseases
Preterm birth increases susceptibility to hyperglycemia induced glomerular alterations in male mice
Full text linkDiabetic kidney disease (DKD) is the leading cause of progressive chronic kidney disease in adults in the United States. However, the impact of preterm birth on the progression of DKD has not been studied. The goal of this project was to determine the effect of preterm birth on kidney health after exposure to hyperglycemia. CD-1 pups born preterm (19 days post conception (dpc)) and term (20 dpc) were studied, and outcomes of the male mice were reported. Preterm and term mice were treated with streptozotocin at six weeks to induce hyperglycemia. Body weight and blood sugar were monitored. Histologic, molecular, and imaging techniques were used to characterize the mice at 18 weeks. The preterm mice with diabetes had a lower podocyte density, lower proximal tubular fraction, and more atubular glomeruli compared to the term mice without diabetes. The preterm mice with diabetes also had a lower podocyte density and lower renin expression compared to term mice with diabetes. Based on single-cell RNA sequencing, the preterm mice with diabetes had increased expression of genes related to the angiogenesis migration pathway-related in endothelial cells and increased expression of genes in the actin adhesion pathway in podocytes compared to term mice with diabetes. Furthermore, the preterm mice with diabetes exhibited a weaker endothelial cell-podocyte interaction compared to term mice with diabetes. These data suggest that preterm birth increases susceptibility to glomerular and tubular damage after a brief second hit of hyperglycemia. In conclusion, preterm birth disrupts endothelial-podocyte crosstalk and increases susceptibility to kidney injury induced by hyperglycemia