Examining the potential of anti-A(beta) antibodies as Alzheimer's therapeutics

Alzheimer’s disease results from an accumulation of aggregated amyloid beta peptide into oligomeric forms. Soluble oligomers are neurotoxic species, which are believed to be the pathophysiological cause of Alzheimer’s neurodegeneration. Amyloid β species (Aβ) are formed via normal physiological cleavage of amyloid precursor protein by β and γ secretases. Cleaved isoforms aggregate further to form oligomeric configurations of Αβ peptide. To target toxic soluble Aβ oligomers, monoclonal antibodies have been synthesized. Experimental analysis demonstrates the ability of these antibodies to recognize synthetic and endogenous oligomers. In transgenic mice designed to overexpress oligomeric isoforms of Aβ, the antibodies were able to reduce the cerebral amyloid load with proceeding improvements in cognitive abilities. However, large-scale clinical trials corroborated results indicating diminished amyloid load, but failed to produce observable improvements in clinical outcome in patients with Alzheimer’s disease. Simply put, the removal of amyloidogenic species was insufficient in alleviating the associated neurodegeneration and elicited no improvement in cognitive ability, suggesting that Aβ might not be the responsible pathogen in Alzheimer’s. The successes of antibodies in in vitro and transgenic mice studies suggest the potential of antibodies in the treatment of Alzheimer’s, but the inability of these drugs to produce marked improvements in clinical trials questions the role of amyloid in the pathophysiology of the disease

Functional Characterization of Vesicular Trafficking Genes in the Midgut of Tetranychus Urticae via RNA Interference

The two-spotted spider mite Tetranychus urticae is a polyphagous agricultural pest of economic importance. Previous studies have established that reduced gene expression of COPB2, SNAP-α, and V-ATPase genes with RNAi and lowers both the survivorship and fecundity of T. urticae. A visible phenotype was also associated with changes to the digestive cells of the midgut after treatment. Serial sections of paraffin embedded RNAi treated mites to determine the changes caused by the transcriptional silencing of the three focal genes. COPB2 silencing leads to a significant increase in the number of juvenile digestive cells, while SNAP-α and V-ATPase silencing caused dysfunctional mature digestive cells. The formation and disruption of these digestive cells may provide a potential tool in integrated pest management

Exploring the Antecedents of Shadow Information Security Practices

Employees are both the first line of defence in organisations as well as a significant source of vulnerability. Behavioural research in information security (InfoSec) has studied compliance of employees with organisational directives. Less understood are ‘shadow security practices’–a related category of behaviour where employees invent InfoSec workarounds albeit with the intention of still complying with organisational InfoSec directives. In this research-in-progress paper, we present the theoretical development of a model, by conducting in-depth reviews of the relevant and multidisciplinary literatures, to identify the potential antecedents of the employees\u27 intention to perform shadow security

Microscopic crystallographic analysis of dislocations in molecular crystals

Organic molecular crystals encompass a vast range of materials from pharmaceuticals to organic optoelectronics and proteins to waxes in biological and industrial settings. Crystal defects from grain boundaries to dislocations are known to play key roles in mechanisms of growth and also in the functional properties of molecular crystals. In contrast to the precise analysis of individual defects in metals, ceramics, and inorganic semiconductors enabled by electron microscopy, significantly greater ambiguity remains in the experimental determination of individual dislocation character and slip systems in molecular materials. In large part, nanoscale dislocation analysis in molecular crystals has been hindered by the severely constrained electron exposures required to avoid irreversibly degrading these crystals. Here, we present a low-dose, single-exposure approach enabling nanometre-resolved analysis of individual extended dislocations in molecular crystals. We demonstrate the approach for a range of crystal types to reveal dislocation character and operative slip systems unambiguously.Comment: Manuscript (14 pages, 4 figures) and Supplementary Material (32 pages, 19 figures) in a single PDF fil

Comparative Analysis of Plastid Genomes Using Pangenome Research ToolKit (PGR-TK)

Plastid genomes (plastomes) of angiosperms are of great interest among biologists. High-throughput sequencing is making many such genomes accessible, increasing the need for tools to perform rapid comparative analysis. This exploratory analysis investigates whether the Pangenome Research Tool Kit (PGR-TK) is suitable for analyzing plastomes. After determining the optimal parameters for this tool on plastomes, we use it to compare sequences from each of the genera - Magnolia, Solanum, Fragaria and Cotoneaster, as well as a combined set from 20 rosid genera. PGR-TK recognizes large-scale plastome structures, such as the inverted repeats, among combined sequences from distant rosid families. If the plastid genomes are rotated to the same starting point, it also correctly groups different species from the same genus together in a generated cladogram. The visual approach of PGR-TK provides insights into genome evolution without requiring gene annotations.Comment: 15 pages, 4 figure

Anesthesia Services in the Time of COVID

Our hospital is a 400-bed Level-1 trauma center with 78 ICU beds serving the greater Louisville metropolitan area. The COVID-19 pandemic forced our hospital to re-evaluate our core business operations and to develop a coherent response to a fluid situation. Between March 15 and May 15, 2020, the University of Louisville Hospital admitted more than 100 COVID-19 inpatients, approximately 30 were admitted to the intensive care unit (ICU) and most required endotracheal intubation. The following review describes our Department of Anesthesiology & Perioperative Medicine foci, actions and rationale during the COVID-19 pandemic. While we hope not to experience another pandemic in the near future, this review may be a helpful starting point for preparing for future respiratory spread pandemics

Rapid model-guided design of organ-scale synthetic vasculature for biomanufacturing

Our ability to produce human-scale bio-manufactured organs is critically limited by the need for vascularization and perfusion. For tissues of variable size and shape, including arbitrarily complex geometries, designing and printing vasculature capable of adequate perfusion has posed a major hurdle. Here, we introduce a model-driven design pipeline combining accelerated optimization methods for fast synthetic vascular tree generation and computational hemodynamics models. We demonstrate rapid generation, simulation, and 3D printing of synthetic vasculature in complex geometries, from small tissue constructs to organ scale networks. We introduce key algorithmic advances that all together accelerate synthetic vascular generation by more than 230-fold compared to standard methods and enable their use in arbitrarily complex shapes through localized implicit functions. Furthermore, we provide techniques for joining vascular trees into watertight networks suitable for hemodynamic CFD and 3D fabrication. We demonstrate that organ-scale vascular network models can be generated in silico within minutes and can be used to perfuse engineered and anatomic models including a bioreactor, annulus, bi-ventricular heart, and gyrus. We further show that this flexible pipeline can be applied to two common modes of bioprinting with free-form reversible embedding of suspended hydrogels and writing into soft matter. Our synthetic vascular tree generation pipeline enables rapid, scalable vascular model generation and fluid analysis for bio-manufactured tissues necessary for future scale up and production.Comment: 58 pages (19 main and 39 supplement pages), 4 main figures, 9 supplement figure

Long-Term Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n =4) and were compared with age-matched, untreated GRMD controls (n =3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients

Poor CD4+ T Cell Immunogenicity Limits Humoral Immunity to P. falciparum Transmission-Blocking Candidate Pfs25 in Humans.

Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4+ and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4+ T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4+/Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission