Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Cell Biology
Total Results:
14036
Radon-222 Brain Dosimetry
ABSTRACT/UNASSIGNED:The human brain dose from radon-222 (222Rn) exposure is calculated here using 222Rn tissue solubility data. A fraction of 222Rn inhaled dissolves in blood and cellular fluids and circulates to brain and all organs. Radon-222 has a relatively high solubility in blood and body fluids based on human inhalation experiments. The brain dose uses calculated concentrations of 222Rn in blood and cellular fluids from exhaled breath measurements following human exposure in a 222Rn chamber. The annual brain dose from continuous inhalation of a concentration of 100 Bq m-3 is about 450 times less than the dose to bronchial epithelium from inhalation of the same 222Rn concentration. Based on the 222Rn dosimetry here, it is highly unlikely that brain cancer is related to even high 222Rn exposures. Any functional or neurodegenerative issues from exposure to very small doses of 222Rn alpha particles are, at present, unknown.
PMID: 35228505
ISSN: 1538-5159
CID: 5174242
Combining Breast and Ovarian Operations Increases Complications
BACKGROUND:Breast cancer resulting from a genetic mutations, such as BRCA1 or BRCA2, is seen in 5 to 10 percent of patients. More widespread genetic testing has increased the number of affected women undergoing prophylactic mastectomy and oophorectomy. Recent studies have yielded mixed results regarding complication rates after combined breast and ovarian operations. The authors compared surgical outcomes of breast operations performed in combination with salpingo-oophorectomies or as separate procedures. METHODS:The authors retrospectively analyzed surgical complications and length of hospital stay in 145 female patients, from which 87 had undergone combined breast surgery and salpingo-oophorectomy, and 58 had undergone these procedures separately. Multivariate logistic regression models were used to calculate odds ratios and 95 percent confidence intervals. RESULTS:Patients undergoing combined breast and ovarian operations experienced higher rates of overall complications (46.5 percent versus 19 percent; p < 0.001), infections (22.2 percent versus 8.6 percent; p < 0.05), and delayed wound healing (13.2 percent versus 0 percent; p < 0.05) related to the breast surgery, when compared with patients undergoing separate procedures. Multivariate logistic regression analysis confirmed a significant association between combined surgery and overall postoperative complications (OR, 5.87; 95 percent CI, 2.03 to 16.91; p = 0.02). Patients undergoing tissue expander-based breast reconstruction combined with ovarian surgery had significantly longer hospital stays compared to patients undergoing separate procedures (3.5 days versus 1.8 days; p < 0.001). CONCLUSIONS:The authors' data indicate that combining breast and ovarian operations is associated with a higher risk of postoperative complications related to the breast procedure and increases the duration of hospital stay in patients with tissue expander-based reconstructions. The authors' study provides valuable information for preoperative counseling of patients considering both breast and ovarian surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE:Therapeutic, III.
PMID: 35245249
ISSN: 1529-4242
CID: 5678172
Author Correction: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
PMID: 35474365
ISSN: 1546-1718
CID: 5205632
Primary ovarian insufficiency: a glimpse into the racial and socioeconomic disparities found within third-party reproduction
Objective/UNASSIGNED:To describe a unique case of primary ovarian insufficiency and review the systemic barriers in place that hinder reproductive autonomy for Black women who require third-party reproduction. Design/UNASSIGNED:Case report and review of the literature. Setting/UNASSIGNED:Safety-net hospital in an urban community. Patients/UNASSIGNED:A 36-year-old Black woman, gravida 0, with primary ovarian insufficiency who desires future fertility but is restricted by systemic barriers. Interventions/UNASSIGNED:Chromosome analysis. Main Outcome Measures/UNASSIGNED:Not applicable. Results/UNASSIGNED:Balanced reciprocal translocation between chromosomes 1 and 13: 46,XX,t(1;13)(q25;q14.1). Conclusions/UNASSIGNED:The field of assisted reproductive technology has evolved at an exponential rate, yet it unfortunately benefits some and not all. It is imperative that when we advocate for full spectrum infertility care, that this encompasses everyone. As we continue to further study and develop assisted reproductive technology, we must not forget to consider the factors leading to racial and socioeconomic disparities in reproductive care access, utilization, and outcomes.
PMCID:9349244
PMID: 35937445
ISSN: 2666-3341
CID: 5286532
Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function
Dysfunction and mistrafficking of organelles in autophagy- and endosomal-lysosomal pathways are implicated in neurodegenerative diseases. Here, we reveal selective vulnerability of maturing degradative organelles (late endosomes/amphisomes) to disease-relevant local calcium dysregulation. These organelles undergo exclusive retrograde transport in axons, with occasional pauses triggered by regulated calcium efflux from agonist-evoked transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) channels-an effect greatly exaggerated by exogenous agonist mucolipin synthetic agonist 1 (ML-SA1). Deacidification of degradative organelles, as seen after Presenilin 1 (PSEN1) loss of function, induced pathological constitutive "inside-out" TRPML1 hyperactivation, slowing their transport comparably to ML-SA1 and causing accumulation in dystrophic axons. The mechanism involved calcium-mediated c-Jun N-terminal kinase (JNK) activation, which hyperphosphorylated dynein intermediate chain (DIC), reducing dynein activity. Blocking TRPML1 activation, JNK activity, or DIC1B serine-80 phosphorylation reversed transport deficits in PSEN1 knockout neurons. Our results, including features demonstrated in Alzheimer-mutant PSEN1 knockin mice, define a mechanism linking dysfunction and mistrafficking in lysosomal pathways to neuritic dystrophy under neurodegenerative conditions.
PMCID:9054012
PMID: 35486730
ISSN: 2375-2548
CID: 5217702
Reduced chromatin accessibility correlates with resistance to Notch activation
The Notch signalling pathway is a master regulator of cell fate transitions in development and disease. In the brain, Notch promotes neural stem cell (NSC) proliferation, regulates neuronal migration and maturation and can act as an oncogene or tumour suppressor. How NOTCH and its transcription factor RBPJ activate distinct gene regulatory networks in closely related cell types in vivo remains to be determined. Here we use Targeted DamID (TaDa), requiring only thousands of cells, to identify NOTCH and RBPJ binding in NSCs and their progeny in the mouse embryonic cerebral cortex in vivo. We find that NOTCH and RBPJ associate with a broad network of NSC genes. Repression of NSC-specific Notch target genes in intermediate progenitors and neurons correlates with decreased chromatin accessibility, suggesting that chromatin compaction may contribute to restricting NOTCH-mediated transactivation.
PMID: 35468895
ISSN: 2041-1723
CID: 5193592
Escargot controls somatic stem cell maintenance through the attenuation of the insulin receptor pathway in Drosophila
Adult stem cells coordinate intrinsic and extrinsic, local and systemic, cues to maintain the proper balance between self-renewal and differentiation. However, the precise mechanisms stem cells use to integrate these signals remain elusive. Here, we show that Escargot (Esg), a member of the Snail family of transcription factors, regulates the maintenance of somatic cyst stem cells (CySCs) in the Drosophila testis by attenuating the activity of the pro-differentiation insulin receptor (InR) pathway. Esg positively regulates the expression of an antagonist of insulin signaling, ImpL2, while also attenuating the expression of InR. Furthermore, Esg-mediated repression of the InR pathway is required to suppress CySC loss in response to starvation. Given the conservation of Snail-family transcription factors, characterizing the mechanisms by which Esg regulates cell-fate decisions during homeostasis and a decline in nutrient availability is likely to provide insight into the metabolic regulation of stem cell behavior in other tissues and organisms.
PMID: 35443165
ISSN: 2211-1247
CID: 5193582
Intrahepatic microbes govern liver immunity by programming NKT cells
The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced hepatic immune cells by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial - glycosphingolipid - NKT - CCL5 axis that underlies hepatic immunity.
PMID: 35175938
ISSN: 1558-8238
CID: 5163572
A novel Vascular Leak Index identifies sepsis patients with a higher risk for in-hospital death and fluid accumulation
PURPOSE/OBJECTIVE:Sepsis is a leading cause of morbidity and mortality worldwide and is characterized by vascular leak. Treatment for sepsis, specifically intravenous fluids, may worsen deterioration in the context of vascular leak. We therefore sought to quantify vascular leak in sepsis patients to guide fluid resuscitation. METHODS:We performed a retrospective cohort study of sepsis patients in four ICU databases in North America, Europe, and Asia. We developed an intuitive vascular leak index (VLI) and explored the relationship between VLI and in-hospital death and fluid balance using generalized additive models (GAM). RESULTS:Using a GAM, we found that increased VLI is associated with an increased risk of in-hospital death. Patients with a VLI in the highest quartile (Q4), across the four datasets, had a 1.61-2.31 times increased odds of dying in the hospital compared to patients with a VLI in the lowest quartile (Q1). VLI Q2 and Q3 were also associated with increased odds of dying. The relationship between VLI, treated as a continuous variable, and in-hospital death and fluid balance was statistically significant in the three datasets with large sample sizes. Specifically, we observed that as VLI increased, there was increase in the risk for in-hospital death and 36-84Â h fluid balance. CONCLUSIONS:Our VLI identifies groups of patients who may be at higher risk for in-hospital death or for fluid accumulation. This relationship persisted in models developed to control for severity of illness and chronic comorbidities.
PMCID:9003991
PMID: 35410278
ISSN: 1466-609x
CID: 5201862
Preserved cardiac performance and adrenergic response in a rabbit model with decreased ryanodine receptor 2 expression
Ryanodine receptor 2 (RyR2) is an ion channel in the heart responsible for releasing into the cytosol most of the Ca2+ required for contraction. Proper regulation of RyR2 is critical, as highlighted by the association between channel dysfunction and cardiac arrhythmia. Lower RyR2 expression is also observed in some forms of heart disease; however, there is limited information on the impact of this change on excitation-contraction (e-c) coupling, Ca2+-dependent arrhythmias, and cardiac performance. We used a constitutive knock-out of RyR2 in rabbits (RyR2-KO) to assess the extent to which a stable decrease in RyR2 expression modulates Ca2+ handling in the heart. We found that homozygous knock-out of RyR2 in rabbits is embryonic lethal. Remarkably, heterozygotes (KO+/-) show ~50% loss of RyR2 protein without developing an overt phenotype at the intact animal and whole heart levels. Instead, we found that KO+/- myocytes show (1) remodeling of RyR2 clusters, favoring smaller groups in which channels are more densely arranged; (2) lower Ca2+ spark frequency and amplitude; (3) slower rate of Ca2+ release and mild but significant desynchronization of the Ca2+ transient; and (4) a significant decrease in the basal phosphorylation of S2031, likely due to increased association between RyR2 and PP2A. Our data show that RyR2 deficiency, although remarkable at the molecular and subcellular level, has only a modest impact on global Ca2+ release and is fully compensated at the whole-heart level. This highlights the redundancy of RyR2 protein expression and the plasticity of the e-c coupling apparatus.
PMID: 35413295
ISSN: 1095-8584
CID: 5201912
