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Established in 1807, The School of Medicine is the first public and the fifth oldest medical school in the United States. Current programs include MD, MD/PhD, graduate, physical therapy & rehabilitation science, and medical research technology.
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What's the Buzz? 2023University of Maryland, Baltimore. School of Medicine, 2023
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SOMnews 2023University of Maryland, Baltimore. School of Medicine, 2023
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IGS Insider Newsletter 2023University of Maryland, Baltimore. School of Medicine., 2023
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The nephrocyte actin and tubulin cytoskeleton networks model slit diaphragm structural defects pertaining to podocyte pathogenesis (b)The nephrocyte is the structural and functional equivalent of a human podocyte in Drosophila melanogaster, particularly the slit diaphragm. The nephrocyte was used to determine the relationship between nephrotic function, the actin and tubulin cytoskeletons, and their shared binding proteins. Of 18 shared binding proteins between the actin and tubulin cytoskeletons, the knockdown of Pigs results in the most dramatic phenotype. Immunofluorescent staining was used to see morphological differences in actin, tubulin, dual actin and tubulin binding protein, and insulin signaling genes. This information can be used to aid further research into causes and solutions to renal diseases such as Nephrotic Syndrome and Diabetic Nephropathy
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The nephrocyte actin and tubulin cytoskeleton networks model slit diaphragm structural defects pertaining to podocyte pathogenesis (a)The nephrocyte is the Drosophila melanogaster equivalent of a human podocyte. Use the nephrocyte to determine the relationship between nephrotic function, the actin and tubulin cytoskeletons, and their shared binding proteins. RNA-seq, functional readouts, and immunofluorescent stains were conducted to understand the roles of each gene. 14 shared binding proteins between the actin and tubulin cytoskeletons, with Pigs causing the most dramatic phenotype. This information can be used to aid further research into causes and solutions to renal diseases such as Nephrotic Syndrome.
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Using the Photo-crosslinkable non-canonical amino acid BZF to capture U.V.-driven, state-dependent disruption of kinetics and voltage dependence of activation in hERG potassium channelsHuman ether-á-go-go related gene (hERG) voltage-activated potassium channels are critical for cardiac excitability. Characteristic slow closing (deactivation) in hERG is regulated by direct interaction between the Nterminal Per-Arnt-Sim (PAS) domain and the C-terminal cyclic nucleotide binding homology domain (CNBHD). Now, we aim to understand the how the conformational dynamics and accessible landscape of the hERG PAS domain contributes to channel kinetics and voltage dependence. To achieve this, we utilized the non-canonical amino acid 4-Benzoyl-L-phenylalanine (BZF) which is a photo-activatable cross-linkable probe, that when irradiated with ultraviolet (U.V.) light forms a covalent cross-link with C-H bond-containing groups, enabling selective and potent U.V.-driven state-dependent photoinactivation modification of ion channel dynamics. This is because BZF can form bonds to nearby atoms via cross-linkable reactivity reducing degrees of freedom within a domain of the channel. Here we incorporate BZF directly into the hERG potassium channel using TAG codon suppression that, upon U.V exposure, shows a large change in the biophysical properties of the channel when irradiated at -100mV when the channels are closed. When compared to wild-type hERG1a, hERG1a-E50BZF shows a U.V. dose-dependent change (speeding up) of channel deactivation. Additionally, hERG1a-E50BZF exhibits a marked change (right-shift) in the voltage-dependence of activation when irradiated at -100 mV when the channels are closed. These effects are not observed when the hERG1a-BZF channel is irradiated in at 0mV when the channels are open. This approach demonstrates that direct photo-crosslinking of hERG channels causes a measurable change in biophysical parameters and this effect is state-dependent (occurring here in the closed state but not the open state). We propose that altered channel gating is as a direct result of reduced dynamic motions in the hERG channel due to photo-chemical crosslinking.
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Identifying transglutaminase 2 (TG2) downstream mediators that are required to maintain an aggressive epidermal squamous cell carcinoma cancer phenotypeEpidermal squamous cell carcinoma is among the most common cancers in humans. It is typically treated by surgical resection and chemotherapy. However, 5 – 10% of resected cases relapse as aggressive cancer. We attribute the reason as the existence of epidermal cancer stem-like cells (ECS cells). Transglutaminase 2 (TG2) is a key ECS cell survival protein. However, how TG2 maintains the aggressive ECS cell cancer phenotype is not well understood. Thus, our goal is to identify TG2-stimulated downstream mediators that are important to maintain the ECS cell cancer phenotype. In the present studies, we show that inhibition of TG2 reduces MET tyrosine kinase receptor expression and activity, and that this is associated with attenuated cancer phenotype. Inhibition of TG2 or HGF/MET function reduces downstream MEK1/2-ERK1/2 activity, and this is associated with reduced cancer cell spheroid formation, invasion, migration, and reduced EMT and stem cell marker expression. HGF partially restores the aggressive cancer phenotype, confirming that MET signaling is downstream of TG2. MET knockdown reduces ERK1/2 signaling, doubles the time to initial tumor appearance and reduces overall tumor growth. In addition, we show that TG2 knockdown or inactivation results in a reduction in mTOR level and activity in ECS cells which are associated with reduced spheroid formation, invasion, migration, and reduced stem cell and EMT marker expression. mTOR knockdown or treatment with the mTOR inhibitor rapamycin phenocopies the reductions in cancer phenotype and stem cell and EMT marker expression. Moreover, forced expression of constitutively active mTOR in TG2 knockdown cells partially restores the aggressive cancer phenotype and stem cell and EMT marker levels, suggesting that mTOR is a necessary mediator of TG2 action. Together, the present studies suggest that TG2 maintains HGF/MET/ERK1/2 signaling and mTOR signaling to maintain the aggressive ECS cell cancer phenotype and drive aggressive tumor formation, and that TG2-dependent MET or mTOR signaling may be useful anti-cancer targets.
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Relationship between kidney function and cognitive decline and moderating effects of race and SESThere is limited research as to whether pre-clinical chronic kidney disease (CKD) measured by a combination of kidney function markers such as the estimated glomerular filtration rate (eGFR), albuminuria, and Cystatin-C have an impact on cognition. Understanding kidney function decline as a potential early marker for cognitive decline has important public health implications given the high societal burden of clinically diagnosed kidney disease and cognitive disorders. The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study wave 1 and 3 datasets were used for this analysis. HANDLS Wave 1 data were collected from year 2004 to 2009, and wave 3 from year 2009 to 2013. In Aim 1, mixed effects models with interaction terms were constructed to examine the effects of time-varying eGFR on several cognitive outcomes. A backward elimination method was used to trim the models of non-significant four-way interactions of eGFR*Age*Race*Poverty and all lower-order interactions. In Aim 2, mixed effects models with interaction terms similar to those used in Aim 1 were constructed to examine the effects of baseline eGFR, urine albumin and Cystatin-C on the same set of cognitive outcomes. All significant interactions were examined by interaction plots for racial and SES subgroups. The analytical cohorts included 1,206 participants for aim 1 and 638 participants for aim 2 at baseline. The main hypothesis that African Americans living below poverty would have the worst impact of lower kidney function on cognition was not supported. Over about 5 years, eGFR over time was associated with decline in verbal learning and memory among Whites below poverty. In addition, the associations between baseline kidney function markers and cognitive decline were highly equivocal. Higher baseline Cystatin-C were found to be associated with cognitive decline in attention, and this association was no longer significant after adjusting for cardiovascular factors and inflammation. It is possible that kidney function is broadly related to performance in the domains of attention, working memory and executive function. These findings suggest that functional changes in the kidney precedes cognitive decline among Whites, especially those living below poverty.
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Designing and Implementing an Orthopedic Residency Program with a 4-month Inpatient Rotation: Benefits and ChallengesABPTRFE accreditation standards for orthopedic physical therapy residencies and the current ABPTRFE Description of Residency Practice for Orthopaedics [Jun 2017] are written with an exclusive focus on the outpatient setting. Physical therapists in the outpatient setting often care for postsurgical patients who have recently spent time in the inpatient setting. Significant exposure to the inpatient setting may be useful to support outpatient physical therapist practice. There are few orthopedic PT residency programs that include a full-time inpatient rotation, but none contains an inpatient rotation of this length. The University of Maryland is a graduate healthcare university that offers the possibility of many partnerships.
