Evaluating Poloxamers as Agents for Acceleration of Skeletal Muscle Membrane Repair

Sarcolemmal membrane fragility is a major contributor to the pathology of various muscular dystrophies, including Duchenne Muscular Dystrophy (DMD). DMD is a fatal X- linked genetic disorder resulting from a loss of the dystrophin protein. This causes muscle degeneration and weakness, in both skeletal and cardiac tissue. Muscle fibers with more fragile membranes experience a higher degree of damage and are more prone to necrotic cell death. Increasing the membrane repair capacity of these fibers can serve as a potential therapeutic by effectively restoring the barrier function of the damaged membrane and prevent muscle fiber death and muscle loss. One strategy to increase the membrane repair capacity is to expose the muscle fibers to Poloxamer 188 (P188), a polymer with affinity to exposed hydrophobic lipid chains that can reseal membrane wounds. P188 is part of a family of poloxamers, all of which contain a hydrophobic region of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene. These regions vary in length between different poloxamers. Although P188 has shown promising results in membrane repair, other poloxamers in this family have not been tested for their membrane sealing capacity. It is hypothesized that other poloxamers in the P188 family such as F38, P84, and P407 will reseal membrane wounds as or more effectively than P188. To investigate this hypothesis, we used both a rotation damage assay and a laser injury assay to examine the repair efficiency of poloxamers on in vitro human embryonic kidney (HEK293) cells and ex vivo muscle fibers isolated from mdx mice. Studying the effect of these compounds on muscle fibers with compromised membrane integrity allowed for the evaluation of these poloxamers as potential therapeutic agents for muscular dystrophy. The conclusion of these assays indicates that there are poloxamers other than P188 that can improve the repair capacity in both HEK293 cells and dystrophic mdx muscle fibers.Mayers Summer Research ScholarshipNo embargoAcademic Major: Molecular Genetic

Inheritance and fitness costs Of field-derived resistance To Cry3Bb1 corn by western corn rootworm

The western corn rootworm (Diabrotica virgifera virgifera LeConte) is serious pest of corn, particularly in the Midwestern United States. One strategy used to manage western corn rootworm is the planting of transgenic corn that produces one or more Cry toxins derived from Bacillus thuringiensis (Bt). Refuges of non-Bt corn function to delay the development of resistance to these toxins. The greatest delay in resistance development is expected when the inheritance of resistance is recessive and there are associated fitness costs. We characterized the inheritance of resistance of two strains of western corn rootworm with field-derived resistance to the Bt toxin Cry3Bb1 (Elma and Monona) and tested for fitness costs of resistance. The inheritance of resistance to Cry3Bb1 was investigated by crossing resistant and susceptible western corn rootworm and evaluating the survival of their progeny on Bt using diet-based assays and experiments with whole plants and seedling mats. For both strains, resistance was found to be non-recessive. In a greenhouse experiment in which larvae were reared on whole corn plants in field soil, no fitness costs of resistance were detected for Monona. In a laboratory experiment with Elma, in which larvae experienced intraspecific and interspecific competition for food, a fitness cost of delayed larval development was identified, however, no other fitness costs were found. These findings underscore the need for rootworm resistance management beyond the refuge strategy. Multiple tactics such as crop rotation, the planting of non-Bt corn with soil-applied insecticide, and planting pyramids of multiple Bt toxins that target western corn rootworm must be used to maintain the effectiveness of available Bt toxins

Developmental Regression Analysis and Investigation of Genotype Correlations in Individuals With Classic Rett Syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder impacting 1 in 10,000 females worldwide, making it one of the most common causes of complex disability in girls. RTT is caused by pathogenic variants in the MECP2 gene and is characterized by developmental regression, stereotypical hand movements, and an abnormal gait. Despite consistency in the presence of these core features, a wide range of features and varying severity can be observed in girls with RTT. Similarly, the particular type of MECP2 variant present also differs between patients. Previous studies have assessed correlations between genotype and phenotype in patients with RTT. While past research revealed some correlations, they were limited by small sample size and inconsistencies in data collection methods. This study uses data from the Rett Syndrome Natural History Study (RSNHS), a nationwide study that has been enrolling patients for the past 15 years. The analysis focuses on further characterizing developmental regression and features present in patients with RTT. The study also elucidates genotype-phenotype correlations in RTT, including patients with less common variants in MECP2. Analysis of these correlations focuses not only on overall severity but also on details of development and the presence of particular features. Results are consistent with previous studies of genotype-phenotype correlations in RTT and suggest that multiple features of RTT, including overall severity, regression onset, motor skills, and head circumference, differ significantly based on the type of MECP2 variant present. These correlations could provide important prognostic information for families with a new diagnosis of RTT

Inadequate Protection: Examining the Due Process Rights of Individuals in Child Abuse and Neglect Registries

This Article seeks to advance due process protections for people included in state child abuse and neglect registries. Between states, there are differences in the types of cases included in the state registry and the process required to be placed on or removed from the registry. To obtain judicial due process review, a plaintiff must demonstrate that a protected liberty or property interest is at stake. When federal courts have evaluated the individual liberty interest(s) implicated by placement on state child abuse and neglect registries, they have so far only found such an interest when the plaintiff’s employment opportunities were clearly affected. We identify a more principled method by which courts should evaluate challenges to state child abuse and neglect registries. Our proposed method would root the analysis in the core constitutional right of family integrity. We then go on to identify ways in which states could structure their child abuse and neglect registries to better comport with due process requirements

RSK tableaux and box-ball systems

A box-ball system is a discrete dynamical system whose dynamics come from the balls jumping according to certain rules. A permutation on n objects gives a box-ball system state by assigning its one-line notation to n consecutive boxes. After a finite number of steps, a box-ball system will reach a steady state. From any steady state, we can construct a tableau called the soliton decomposition of the box-ball system. We prove that if the soliton decomposition of a permutation w is a standard tableau or if its shape coincides with the Robinson-Schensted (RS) partition of w, then the soliton decomposition of w and the RS insertion tableau of w are equal. We also use row reading words, Knuth moves, RS recording tableaux, and a localized version of Greene's theorem (proven recently by Lewis, Lyu, Pylyavskyy, and Sen) to study various properties of a box-ball system.Comment: 32 pages, 5 figures. Comments are welcom

The distribution of burden of dental caries in schoolchildren: a critique of the high-risk caries prevention strategy for populations

BACKGROUND: The 'high-risk approach' is a commonly adopted strategy recommended for the prevention of dental caries in populations. The scientific basis for the strategy has been questioned. The objective of this study is to assess the contribution that children identified at 'high-risk' made towards the total of new caries lesions over a 4-year period, by analysing the distribution of new lesions per 100 children. METHODS: Data are from the National Preventive Dentistry Demonstration Programme (NPDDP) in the United States. The analyses identified the distribution of new carious lesions over a 4-year period in four groups of 7 year-old children who received differing preventive regimes. RESULTS: The majority of new lesions occurred in those children classified at lowest caries risk at baseline. Irrespective of the preventive regime adopted and the initial caries levels, children classified as 'highest risk' contributed less than 6% of the total number of new lesions developing over 4 years. CONCLUSION: These findings challenge the basis for the adoption of a high-risk strategy

Genetic Risk Factors for Alzheimer’s Disease in Racial/Ethnic Minority Populations in the U.S.: A Scoping Review

As the United States (U.S.) population rapidly ages, the incidence of Alzheimer\u27s Disease and Related Dementias (ADRDs) is rising, with racial/ethnic minorities affected at disproportionate rates. Much research has been undertaken to test, sequence, and analyze genetic risk factors for ADRDs in Caucasian populations, but comparatively little has been done with racial/ethnic minority populations. We conducted a scoping review to examine the nature and extent of the research that has been published about the genetic factors of ADRDs among racial/ethnic minorities in the U.S. Using an established scoping review methodological framework, we searched electronic databases for articles describing peer-reviewed empirical studies or Genome-Wide Association Studies that had been published 2005-2018 and focused on ADRD-related genes or genetic factors among underrepresented racial/ethnic minority population in the U.S. Sixty-six articles met the inclusion criteria for full text review. Well-established ADRD genetic risk factors for Caucasian populations including , and have not been studied to the same degree in minority U.S. populations. Compared to the amount of research that has been conducted with Caucasian populations in the U.S., racial/ethnic minority communities are underrepresented. Given the projected growth of the aging population and incidence of ADRDs, particularly among racial/ethnic minorities, increased focus on this important segment of the population is warranted. Our review can aid researchers in developing fundamental research questions to determine the role that ADRD risk genes play in the heavier burden of ADRDs in racial/ethnic minority populations

Practical Pharmacist-Led Interventions to Improve Antimicrobial Stewardship in Ghana, Tanzania, Uganda and Zambia.

The World Health Organisation (WHO) and others have identified, as a priority, the need to improve antimicrobial stewardship (AMS) interventions as part of the effort to tackle antimicrobial resistance (AMR). An international health partnership model, the Commonwealth Partnerships for Antimicrobial Stewardship (CwPAMS) programme, was established between selected countries in Africa (Ghana, Tanzania, Zambia and Uganda) and the UK to support AMS. This was funded by UK aid under the Fleming Fund and managed by the Commonwealth Pharmacists Association (CPA) and Tropical Health and Education Trust (THET). The primary aims were to develop local AMS teams and generate antimicrobial consumption surveillance data, quality improvement initiatives, infection prevention and control (IPC) and education/training to reduce AMR. Education and training were key components in achieving this, with pharmacists taking a lead role in developing and leading AMS interventions. Pharmacist-led interventions in Ghana improved access to national antimicrobial prescribing guidelines via the CwPAMS mobile app and improved compliance with policy from 18% to 70% initially for patients with pneumonia in one outpatient clinic. Capacity development on AMS and IPC were achieved in both Tanzania and Zambia, and a train-the-trainer model on the local production of alcohol hand rub in Uganda and Zambia. The model of pharmacy health partnerships has been identified as a model with great potential to be used in other low and middle income countries (LMICs) to support tackling AMR

Allometry and Ecology of the Bilaterian Gut Microbiome.

Classical ecology provides principles for construction and function of biological communities, but to what extent these apply to the animal-associated microbiota is just beginning to be assessed. Here, we investigated the influence of several well-known ecological principles on animal-associated microbiota by characterizing gut microbial specimens from bilaterally symmetrical animals (Bilateria) ranging from flies to whales. A rigorously vetted sample set containing 265 specimens from 64 species was assembled. Bacterial lineages were characterized by 16S rRNA gene sequencing. Previously published samples were also compared, allowing analysis of over 1,098 samples in total. A restricted number of bacterial phyla was found to account for the great majority of gut colonists. Gut microbial composition was associated with host phylogeny and diet. We identified numerous gut bacterial 16S rRNA gene sequences that diverged deeply from previously studied taxa, identifying opportunities to discover new bacterial types. The number of bacterial lineages per gut sample was positively associated with animal mass, paralleling known species-area relationships from island biogeography and implicating body size as a determinant of community stability and niche complexity. Samples from larger animals harbored greater numbers of anaerobic communities, specifying a mechanism for generating more-complex microbial environments. Predictions for species/abundance relationships from models of neutral colonization did not match the data set, pointing to alternative mechanisms such as selection of specific colonists by environmental niche. Taken together, the data suggest that niche complexity increases with gut size and that niche selection forces dominate gut community construction.IMPORTANCEThe intestinal microbiome of animals is essential for health, contributing to digestion of foods, proper immune development, inhibition of pathogen colonization, and catabolism of xenobiotic compounds. How these communities assemble and persist is just beginning to be investigated. Here we interrogated a set of gut samples from a wide range of animals to investigate the roles of selection and random processes in microbial community construction. We show that the numbers of bacterial species increased with the weight of host organisms, paralleling findings from studies of island biogeography. Communities in larger organisms tended to be more anaerobic, suggesting one mechanism for niche diversification. Nonselective processes enable specific predictions for community structure, but our samples did not match the predictions of the neutral model. Thus, these findings highlight the importance of niche selection in community construction and suggest mechanisms of niche diversification

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes