Digital Commons Network^™

Novel Variants In Kat6b Spectrum Of Disorders Expand Our Knowledge Of Clinical Manifestations And Molecular Mechanisms, Megan Yabumoto, Catherine Gooch, Et Al

Open Access Publications

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families …

X-Treme Loss Of Sequence Diversity Linked To Neo-X Chromosomes In Filarial Nematodes, John Mattick, Ramakrishna Rao, Et Al

Open Access Publications

The sequence diversity of natural and laboratory populations of Brugia pahangi and Brugia malayi was assessed with Illumina resequencing followed by mapping in order to identify single nucleotide variants and insertions/deletions. In natural and laboratory Brugia populations, there is a lack of sequence diversity on chromosome X relative to the autosomes (πX/πA = 0.2), which is lower than the expected (πX/πA = 0.75). A reduction in diversity is also observed in other filarial nematodes with neo-X chromosome fusions in the genera Onchocerca and Wuchereria, but not those without neo-X chromosome fusions in the genera Loa and Dirofilaria. In the species …

Cortical Feedback And Gating In Odor Discrimination And Generalization, Gaia Tavoni, David E. Chen Kersen, Vijay Balasubramanian

Open Access Publications

A central question in neuroscience is how context changes perception. In the olfactory system, for example, experiments show that task demands can drive divergence and convergence of cortical odor responses, likely underpinning olfactory discrimination and generalization. Here, we propose a simple statistical mechanism for this effect based on unstructured feedback from the central brain to the olfactory bulb, which represents the context associated with an odor, and sufficiently selective cortical gating of sensory inputs. Strikingly, the model predicts that both convergence and divergence of cortical odor patterns should increase when odors are initially more similar, an effect reported in recent …

Investigation Of Effect Of Modulation Frequency On High-Density Diffuse Optical Tomography Image Quality, Weihao Fan, Hamid Dehghani, Adam Eggebrecht

Open Access Publications

No abstract provided.

Cd177 Modulates The Function And Homeostasis Of Tumor-Infiltrating Regulatory T Cells, Myung-Chul Kim, Nicholas Borcherding, Kawther K. Ahmed, Andrew P. Voigt, Gaurav Pandey, Et Al

Open Access Publications

No abstract provided.

Upstaging And Survival Outcomes For Non-Muscle Invasive Bladder Cancer After Radical Cystectomy: Results From The International Robotic Cystectomy Consortium, Umar Iqbal, Eric Kim, Et Al

Open Access Publications

No abstract provided.

Friends And Foes: Extracellular Vesicles In Aging And Rejuvenation, Brian V Lananna, Shin-Ichiro Imai

2020-Current year OA Pubs

Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies. Nonetheless, emerging evidence suggests that EVs regulate systemic aging as well as the pathophysiology of age-related diseases. Here, we review …

Clinical Trial And Postmarketing Safety Of Onasemnogene Abeparvovec Therapy, John W Day, Jerry R Mendell, Eugenio Mercuri, Richard S Finkel, Kevin A Strauss, Aaron Kleyn, Sitra Tauscher-Wisniewski, Francis Fonyuy Tukov, Sandra P Reyna, Deepa H Chand

2020-Current year OA Pubs

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.

OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.

METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign …

Estimating The Effects Of Race And Social Vulnerability On Hospital Admission And Mortality From Covid-19, Joshua M Landman, Karen Steger-May, Karen E Joynt Maddox, Gmerice Hammond, Aditi Gupta, Adriana M Rauseo, Min Zhao, Randi E Foraker

2020-Current year OA Pubs

OBJECTIVE: To estimate the risk of hospital admission and mortality from COVID-19 to patients and measure the association of race and area-level social vulnerability with those outcomes.

MATERIALS AND METHODS: Using patient records collected at a multisite hospital system from April 2020 to October 2020, the risk of hospital admission and the risk of mortality were estimated for patients who tested positive for COVID-19 and were admitted to the hospital for COVID-19, respectively, using generalized estimating equations while controlling for patient race, patient area-level social vulnerability, and time course of the pandemic.

RESULTS: Black individuals were 3.57 as likely (95% …

Combined Thoracic Endovascular Aortic Repair And Endovascular Aneurysm Repair And The Long-Term Consequences Of Altered Cardiovascular Haemodynamics On Morbidity And Mortality: Case Series And Literature Review, Sherif Sultan, Yogesh Acharya, Mohiey Hazima, Hiba Salahat, Juan Carlos Parodi, Niamh Hynes

2020-Current year OA Pubs

BACKGROUND: Thoracic and abdominal aortic stent grafts are firmer and more rigid than the native aorta. Aortic implanted devices have been implicated in the development of acute systolic hypertension, elevated pulse pressure, and reduced coronary perfusion.

CASE SUMMARY: We report four cases of staged thoracic endovascular aortic repair (TEVAR) and then endovascular aneurysm repair (EVAR). All patients had TEVAR first for thoracic aortic aneurysm and later on developed infra-renal abdominal aortic aneurysm (AAA) that required EVAR. There were three males and one female with a median age of 74.5 years (range 67.5-78.5). None of the patients developed aortic-related major clinical …

Gut Microbiota-Derived Short-Chain Fatty Acids Protect Against The Progression Of Endometriosis, Sangappa B Chadchan, Pooja Popli, Chandrasekhar R Ambati, Eric Tycksen, Sang Jun Han, Serdar E Bulun, Nagireddy Putluri, Scott W Biest, Ramakrishna Kommagani

2020-Current year OA Pubs

Worldwide, ∼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces. Theories on the origin of endometriosis remained inconclusive. Whereas up to 90% of women experience retrograde menstruation, only 10% develop endometriosis, suggesting that factors that alter peritoneal environment might contribute to endometriosis. Herein, we report that whereas some gut bacteria promote endometriosis, others protect against endometriosis by fermenting fiber to produce short-chain fatty acids. Specifically, we found that altered gut microbiota drives endometriotic lesion growth and feces from mice with endometriosis contained less of short-chain fatty acid and n-butyrate …

Thrombolytic Enzymes Of Microbial Origin: A Review, Deepti Diwan, Zeba Usmani, Minaxi Sharma, James W Nelson, Vijay Kumar Thakur, Graham Christie, Gustavo Molina, Vijai Kumar Gupta

2020-Current year OA Pubs

Enzyme therapies are attracting significant attention as thrombolytic drugs during the current scenario owing to their great affinity, specificity, catalytic activity, and stability. Among various sources, the application of microbial-derived thrombolytic and fibrinolytic enzymes to prevent and treat vascular occlusion is promising due to their advantageous cost-benefit ratio and large-scale production. Thrombotic complications such as stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, and peripheral occlusive diseases resulting from blood vessel blockage are the major cause of poor prognosis and mortality. Given the ability of microbial thrombolytic enzymes to dissolve blood clots and prevent any adverse effects, their use as …

Genetic Characterization, Current Model Systems And Prognostic Stratification In Pax Fusion-Negative Vs. Pax Fusion-Positive Rhabdomyosarcoma, Carina A Dehner, Amy E Armstrong, Marielle Yohe, Jack F Shern, Angela C Hirbe

Open Access Publications

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents and accounts for approximately 2% of soft tissue sarcomas in adults. It is subcategorized into distinct subtypes based on histological features and fusion status (

Inhibition Of Chylomicron Assembly Leads To Dissociation Of Hepatic Steatosis From Inflammation And Fibrosis, Yan Xie, Elizabeth P Newberry, Elizabeth M Brunt, Samuel J Ballentine, Saeed Soleymanjahi, Elizabeth A Molitor, Nicholas O Davidson

Open Access Publications

Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline deficient (MCD) diet exhibited reduced hepatic triglycerides (TG), inflammation and fibrosis, associated with reduced oxidative stress and downstream activation of JNK and NFκB signaling pathways. However, when Mttp

A Novel Mitragynine Analog With Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception With Attenuated Adverse Effects, Soumen Chakraborty, Abdelfattah Faouzi, Sarah M Bernhard, Nitin Nuthikattu, Rahul Jilakara, Satyanarayana M Chintala, Tao Che, Susruta Majumdar, Et Al

2020-Current year OA Pubs

Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH

Metformin Selectively Dampens The Acute Inflammatory Response Through An Ampk-Dependent Mechanism, Thomas S Postler, Vincent Peng, Dev M Bhatt, Sankar Ghosh

2020-Current year OA Pubs

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the …

Increased Blood Pressure Variability And The Risk Of Probable Dementia Or Mild Cognitive Impairment: A Post Hoc Analysis Of The Sprint Mind Trial, Adam De Havenon, Mohammad Anadani, Shyam Prabhakaran, Ka-Ho Wong, Shadi Yaghi, Natalia Rost

Open Access Publications

Background Increased systolic blood pressure variability (BPV) is associated with stroke, cardiovascular disease, and dementia and mild cognitive impairment. However, prior studies assessing the relationship between BPV and dementia or mild cognitive impairment had infrequent measurement of blood pressure or suboptimal blood pressure control. Methods and Results We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial) MIND (Memory and Cognition in Decreased Hypertension) trial. The primary outcome was probable dementia during follow-up. We defined our exposure period, during which blood pressures were collected, as the first 600 days of the trial, and outcomes were ascertained …

Metformin Selectively Dampens The Acute Inflammatory Response Through An Ampk-Dependent Mechanism, Thomas S Postler, Vincent Peng, Dev M Bhatt, Sankar Ghosh

Open Access Publications

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the …

Structural Variants Are A Major Source Of Gene Expression Differences In Humans And Often Affect Multiple Nearby Genes, Alexandra J Scott, Colby Chiang, Ira M Hall

2020-Current year OA Pubs

Structural variants (SVs) are an important source of human genome diversity, but their functional effects are poorly understood. We mapped 61,668 SVs in 613 individuals from the GTEx project and measured their effects on gene expression. We estimate that common SVs are causal at 2.66% of eQTLs, a 10.5-fold enrichment relative to their abundance in the genome. Duplications and deletions were the most impactful variant types, whereas the contribution of mobile element insertions was small (0.12% of eQTLs, 1.9-fold enriched). Multitissue analysis of eQTLs revealed that gene-altering SVs show more constitutive effects than other variant types, with 62.09% of coding …

Autologous And Allogeneic Hematopoietic Cell Transplantation For Diffuse Large B-Cell Lymphoma–Type Richter Syndrome, Alex F. Herrera, Shalini Shenoy, Et Al

Open Access Publications

No abstract provided.

Genetic Counseling As Preventive Intervention: Toward Individual Specification Of Transgenerational Autism Risk, Natasha Marrus, Tychele N Turner, Elizabeth Forsen, Drew Bolster, Alison Marvin, Andrew Whitehouse, Laura Klinger, Christina A Gurnett, J N Constantino

2020-Current year OA Pubs

BACKGROUND: Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3-5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling.

METHODS: We assembled what is to our knowledge the largest collection of data on the …

Intestinal Antiviral Signaling Is Controlled By Autophagy Gene Epg5 Independent Of The Microbiota, Sanghyun Lee, Gowri Kalugotla, Harshad Ingle, Rachel Rodgers, Yating Wang, Yuhao Li, Nicolette R Borella, Hongju Deng, Lindsay Droit, Ryan Hill, Stefan T Peterson, Chandni Desai, Dylan Lawrence, Megan T Baldridge, Et Al

Open Access Publications

Mutations in the macroautophagy/autophagy gene

Improved Gal4 And Tet Off Drivers For C. Elegans Bipartite Expression, Michael Nonet

2020-Current year OA Pubs

The first generation of

Is Comprehensiveness Critical? Comparing Short And Long Format Cognitive Assessments In Preclinical Alzheimer Disease, Jason Hassenstab, Jessica Nicosia, Megan Larose, Andrew J Aschenbrenner, Brian A Gordon, Tammie L S Benzinger, Chengjie Xiong, John C Morris

2020-Current year OA Pubs

BACKGROUND: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a "sampling" of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers.

METHODS: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal …

Neuropathic Pain: Biomolecular Intervention And Imaging Via Targeting Microglia Activation, Aijun Ji, Jinbin Xu

Open Access Publications

Many diseases, including cancer, can lead to neuropathic pain (NP). NP is one of the accompanying symptoms of suffering in many conditions and the life quality of NP patient is seriously affected. Due to complex causes, the effects of clinical treatments have been very unsatisfactory. Many experts have found that neuron-microglia interaction plays an essential role in NP occurrence and development. Therefore, the activation of microglia, related inflammatory mediators and molecular and cellular signaling pathways have become the focus of NP research. With the help of modern functional imaging technology, advanced pre-and clinical studies have been carried out and NP …

Signaling Through Retinoic Acid Receptors Is Essential For Mammalian Uterine Receptivity And Decidualization, Yan Yin, Meade E. Haller, Sangappa B. Chadchan, Ramakrishna Kommagani, Liang Ma

Open Access Publications

Retinoic acid (RA) signaling has long been speculated to regulate embryo implantation, because many enzymes and proteins responsible for maintaining RA homeostasis and transducing RA signals are tightly regulated in the endometrium during this critical period. However, due to a lack of genetic data, it was unclear whether RA signaling is truly required for implantation and which specific RA signaling cascades are at play. Herein we utilize a genetic murine model that expresses a dominant-negative form of RA receptor (RAR) specifically in female reproductive organs to show that functional RA signaling is fundamental to female fertility, particularly implantation and decidualization. …

Brain White Matter Structure And Amyloid Deposition In Black And White Older Adults: The Aric-Pet Study, Keenan A Walker, Noah Silverstein, Yun Zhou, Timothy M Hughes, Clifford R Jack, David S Knopman, A Richey Sharrett, Dean F Wong, Thomas H Mosley, Rebecca F Gottesman

Open Access Publications

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross-sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion …

Quality Of Life Analyses In Patients With Multiple Myeloma: Results From The Selinexor (Kpt-330) Treatment Of Refractory Myeloma (Storm) Phase 2b Study, Gabriel Tremblay, Ravi Vij, Et Al.

2020-Current year OA Pubs

BACKGROUND: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM.

METHODS: FACT-MM data …

Hsp90 Inhibitors Reduce Cholesterol Storage In Niemann-Pick Type C1 Mutant Fibroblasts, Nina H Pipalia, Syed Z Saad, Kanagaraj Subramanian, Abigail Cross, Aisha Al-Motawa, Kunal Garg, Brian S J Blagg, Len Neckers, Paul Helquist, Olaf Wiest, Daniel S Ory, Frederick R Maxfield

Open Access Publications

Niemann Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work …

Protection Levels Of N95-Level Respirator Substitutes Proposed During The Covid-19 Pandemic: Safety Concerns And Quantitative Evaluation Procedures, David Ballard, Alex Scott, Broc Burke, Jason Morris, Connie Gan, Jesse Hu, Udayabhanu Jammalamadaka, Sena Sayood, Stephen Liang, Bruno Maranhao, J. Tyler Bertroche, Nirah Shomer, Pamela Woodard, Kathleen Meacham, Et Al

Open Access Publications

OBJECTIVE: The COVID-19 pandemic has precipitated widespread shortages of filtering facepiece respirators (FFRs) and the creation and sharing of proposed substitutes (novel designs, repurposed materials) with limited testing against regulatory standards. We aimed to categorically test the efficacy and fit of potential N95 respirator substitutes using protocols that can be replicated in university laboratories.

SETTING: Academic medical centre with occupational health-supervised fit testing along with laboratory studies.

PARTICIPANTS: Seven adult volunteers who passed quantitative fit testing for small-sized (n=2) and regular-sized (n=5) commercial N95 respirators.

METHODS: Five open-source potential N95 respirator substitutes were evaluated and compared with commercial National Institute …