Biology subjects

Morris, M.

Publications and source records attributed to Morris, M..

27 records · Page 2Linked to original sources

bioRxiv2020

SARS-CoV2 (COVID-19) Structural/Evolution Dynamicome: Insights into functional evolution and human genomics.

The SARS-CoV-2 pandemic, starting in 2019, has challenged the speed at which labs perform science, ranging from discoveries of the viral composition to handling health outcomes in humans. The small ~30kb single-stranded RNA genome of Coronaviruses makes them adept at cross species spread and drift, increasing their probability to cause pandemics. However, this small genome also allows for a robust understanding of all proteins coded by the virus. We employed protein modeling, molecular dynamic simulations, evolutionary mapping, and 3D printing to gain a full proteome and dynamicome understanding of SARS-CoV-2. The Viral Integrated Structural Evolution Dynamic Database (VIStEDD) has been established (prokoplab.com/vistedd), opening future discoveries and educational usage. In this paper, we highlight VIStEDD usage for nsp6, Nucleocapsid (N), and Spike (S) surface glycoprotein. For both nsp6 and N we reveal highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we have developed a quantitative dynamics cross correlation matrix insight into interaction with the ACE2/SLC6A19 dimer complex. From this quantitative matrix, we elucidated 47 potential functional missense variants from population genomic databases within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Moreover, these variants have ultralow frequency, but can exist as hemizygous in males for ACE2, which falls on the X-chromosome. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2. This powerful database of SARS-CoV-2 can aid in research progress in the ongoing pandemic.

genetics↗

bioRxiv2020

A novel drug-combination screen in zebrafish identifies epigenetic small molecule candidates for Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder and is one of the most common muscular dystrophies. There are currently few effective therapies to treat the disease, although many small-molecule approaches are being pursued. Specific histone deacetylase inhibitors (HDACi) can ameliorate DMD phenotypes in mouse and zebrafish animal models and have also shown promise for DMD in clinical trials. However, beyond these HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD. Here, we performed a novel chemical screen of a library of epigenetic compounds using the zebrafish dmd model. We identified candidate pools of epigenetic compounds that improve skeletal muscle structure in dmd zebrafish. We then identified a specific combination of two drugs, oxamflatin and salermide, that significantly rescued dmd zebrafish skeletal muscle degeneration. Furthermore, we validated the effects of oxamflatin and salermide in an independent laboratory. Our results provide novel, effective methods for performing a combination small-molecule screen in zebrafish. Our results also add to the growing evidence that epigenetic small molecules may be promising candidates for treating DMD.

pharmacology and toxicology↗

bioRxiv2019

Genomics to aid species delimitation and effective conservation of the Sharpnose Guitarfish (Glaucostegus granulatus)

The Sharpnose Guitarfish (Glaucostegus granulatus) is one of fifteen critically endangered Rhino Rays which has been exploited as incidental catch, leading to severe population depletions and localized disappearances. Like many chondrichthyan species, there are no species-specific time-series data available for the Sharpnose Guitarfish that can be used to calculate population reduction, partly due to a lack of species-specific reporting as well as limitations in accurate taxonomic identification. We here present the first complete mitochondrial genome and partial nuclear genome of the species and the first detail phylogenetic assessment of the species. We expect that data presented in the current manuscript will aid in accurate species-specific landing and population assessments of the species in the future and will enable conservation efforts to protect and recover remaining populations.

genomics↗

bioRxiv2019

Genetic signature of prostate cancer resistant to optimized hK2 targeted alpha-particle therapy

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate specific enzyme human kallikrein 2 (hK2; KLK2). In multiple rodent models, Actinium-225 labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the current study we investigated options to enhance and optimize [225Ac]hu11B6 treatment. Firstly, we evaluated the possibility of exploiting IgG3, the immunoglobulin G (IgG) subclass with superior activation of complement and ability to mediate FC-gamma-receptor binding, for immunotherapeutically enhanced hK2 targeted alpha-radioimmunotherapy. Secondly, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted alpha therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression free survival was slightly increased with a single high activity compared to fractionated activity. Tumor free animals succumbing after treatment revealed no evidence of treatment associated toxicity. In addition to upregulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS and SCHLAP1, we also noted a significant decrease in both KLK3 (PSA) and FOLH1 (PSMA) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.

cancer biology↗

bioRxiv2019

Age-related Gene Expression Signatures (AGES) in rats demonstrate early, late, and linear transcriptional changes from multiple tissues

In order to understand changes in gene expression that occur as a result of age, which might create a permissive or causal environment for age-related diseases, we produced a multi-timepoint Age-related Gene Expression Signature (AGES) from liver, kidney, skeletal muscle and hippocampus of rats, comparing 6, 9, 12, 18, 21, 24 and 27-month old animals. We focused on genes that changed in one direction throughout the lifespan of the animal, either early in life (early logistic changes); at mid-age (mid-logistic); late in life (late-logistic); or linearly, throughout the lifespan. The pathways perturbed as a result of chronological age demonstrate organ-specific and more global effects of aging, and point to mechanisms that might be counter-regulated pharmacologically in order to treat age-associated diseases. A small number of genes were regulated by aging in the same manner in every tissue, suggesting they may be more universal markers of aging.

systems biology↗

bioRxiv2019

Abnormalities in Proinsulin Processing in Islets from Individuals with Longstanding T1D

Work by our group and others has suggested that elevations in circulating proinsulin relative to C-peptide is associated with development of Type 1 diabetes (T1D). We recently described the persistence of detectable serum proinsulin in a large majority (95.9%) of individuals with longstanding T1D, including individuals with undetectable serum C-peptide. Here we describe analyses performed on human pancreatic sections from the nPOD collection (n=30) and isolated human islets (n=10) to further explore mechanistic etiologies of persistent proinsulin secretion in T1D. Compared to nondiabetic controls, immunostaining among a subset (4/9) of insulin positive T1D donor islets revealed increased numbers of cells with proinsulin-enriched, insulin-poor staining. Laser capture microdissection followed by mass spectrometry revealed reductions in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE) in T1D donors. Twenty-four hour treatment of human islets with an inflammatory cytokine cocktail reduced mRNA expression of the processing enzymes PC1/3, PC2, and CPE. Taken together, these data provide new mechanistic insight into altered proinsulin processing in long-duration T1D and suggest that reduced {beta} cell prohormone processing is associated with proinflammatory cytokine-induced reductions in proinsulin processing enzyme expression.

pathology↗

bioRxiv2018

Knowledge and attitudes of Ebola among the general public of Trinidad and Tobago during the 2014-15 West Africa outbreak

ObjectiveHealth system resilience and resilience of a country include the capacity of health personnel, institutions, and populations to prepare for and effectively respond to crises. This study investigates the knowledge and attitudes of the public concerning Ebola Virus Disease in Trinidad and Tobago.\n\nDesign and MethodsA cross sectional study whereby respondents (n = 920) were sampled from public places. Data were collected via interviewer administered questionnaires. Data were analysed using SPSS version 23.\n\nResultsThe response rate was 67.6 % (622/920). The main age category of responders was the 20 to 30 year age category (40.5%); responders were mostly female (58.0 %). Regarding knowledge, there were significant differences among occupational categories (F = 2.811, df1 = 6, df2 = 571, p-value = 0.011). Tukeys HSD post hoc test revealed that the mean knowledge scores for professional and sales occupations differed significantly (p-value = 0.003). There was a significant association between being afraid to go for treatment and age (p-value = 0.001). Significant associations were also found between occupational grouping and education attainment with opinion about the preparedness of private medical facilities, likelihood to shun family members with Ebola, being afraid to go for treatment and preference for traditional medicine (p-value <0.05).\n\nConclusionThis study highlights opportunities for community engagement to enhance health system resilience during outbreaks which would maximise national and global health security.

epidemiology↗

bioRxiv2017

TORC1 inhibition as an immunotherapy to reduce infections in the elderly

mTOR inhibition extends lifespan and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this Phase 2a clinical trial was to determine if low dose mTOR inhibitor therapy enhanced immune function and thereby decreased infection rates in elderly subjects. The results indicate that 6 weeks of treatment with a low dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor (that selectively inhibits TORC1 downstream of mTOR) was safe, significantly decreased the rate of infections reported by elderly subjects for a year following study drug initiation, upregulated antiviral gene expression, and significantly improved influenza vaccination response. Thus selective TORC1 inhibition with a combination of BEZ235 and RAD001 may be efficacious as immunotherapy to reduce infections, a leading cause of death in the elderly.\n\nOne Sentence SummaryTreatment of elderly subjects with a low dose mTOR inhibitor regimen that selectively inhibits TORC1 significantly decreased infection rates

clinical trials↗

bioRxiv2017

EpiModel: An R Package for Mathematical Modeling of Infectious Disease over Networks

EpiModel provides tools for building, simulating, and analyzing mathematical models for the population dynamics of infectious disease transmission in R. Several classes of models are included, but the unique contribution of this software package is a general stochastic framework for modeling the spread of epidemics on networks. This framework integrates recent advances in statistical methods for network analysis, temporal exponential random graph models, which allows the epidemic modeling to be firmly grounded in empirical data on the contacts and persistent partnerships that can spread infection. This article provides an overview of both the modeling tools built into EpiModel, designed to facilitate learning for students new to modeling, and the application programming interface for extending EpiModel, designed to facilitate the exploration of novel research questions for advanced modelers.

epidemiology↗