Viral population genomics reveals host and infectivity impact on SARS-CoV-2 adaptive landscape

Public health surveillance, drug treatment development, and optimization of immunological interventions all depend on understanding pathogen adaptation, which differ for specific pathogens. SARS-CoV-2 is an exceptionally successful human pathogen, yet complete understanding of the forces driving its evolution is lacking. Here, we leveraged almost four million SARS-CoV-2 sequences originating mostly from non-vaccinated naive patients to investigate the impact of functional constraints and natural immune pressures on the sequence diversity of the SARS-CoV-2 genome. Overall, we showed that the SARS-CoV-2 genome is under strong and intensifying levels of purifying selection with a minority of sites under diversifying pressure. With a particular focus on the spike protein, we showed that sites under selection were critical for protein stability and virus fitness related to increased infectivity and/or reduced neutralization by convalescent sera. We investigated the genetic diversity of SARS-CoV-2 B and T cell epitopes and determined that the currently known T cell epitope sequences were highly conserved. Outside of the spike protein, we observed that mutations under selection in variants of concern can be associated to beneficial outcomes for the virus. Altogether, the results yielded a comprehensive map of all sites under selection across the entirety of SARS-CoV-2 genome, highlighting targets for future studies to better understand the virus spread, evolution and success.

Applying Synthetic Biology with Rational Design to Nature’s Greatest Challenges: Bioengineering Immunotherapeutics for the Treatment of Glioblastoma

Improvements in bioengineering methodology and tools have allowed for significant progress in the development of therapeutics and diagnostics in medicine, as well as progress in many other diverse industries, such as materials manufacturing, food and agriculture, and consumer goods. Glioblastomas present significant challenges to adequate treatment, in part due to their immune-evasive and manipulative nature. Rational-design bioengineering using novel scaffolds, biomaterials, and inspiration across disciplines can push the boundaries in treatment development to create effective therapeutics for glioblastomas. In this review, we will discuss bioengineering strategies currently applied across diseases and disciplines to inspire creative development for GBM immunotherapies.

Surgical creation of multiple drainage holes versus local injection of corticosteroids for treatment of aural hematomas in dogs: 51 dogs with 71 aural hematomas (2000–2017)

OBJECTIVE To investigate the outcome of surgical creation of multiple drainage holes (MDHs) versus local corticosteroid injection (LCI) for treatment of aural hematomas (AHs) in dogs and identify risk factors for recurrence and development of new AHs. ANIMALS 51 dogs with 71 AHs. PROCEDURES Medical records were reviewed, and information on signalment, clinical findings, and outcome was recorded. Recurrence was defined as development of an AH at the primary site after the first month of treatment. Development of a new AH was defined as an AH occurring at a site different from the treated site. RESULTS The recurrence rate after the first month of treatment was significantly higher following the LCI procedure (17/48 AHs [33%]) than after the MDH procedure (1/24 AHs [4%]). The odds of recurrence increased as the numbers of LCI in the first month increased (OR, 2.414). Recurrent AHs after LCI resolved with additional LCIs; only 1 AH (2%) required a change to MDHs. No recurrence was observed after the eighth month, and the cosmetic results were good. Sixteen of 51 (31%) dogs had multiple or new AHs. The risk of new AHs was higher in Golden Retrievers and Labrador Retrievers and in dogs with allergic dermatitis. CONCLUSIONS AND CLINICAL RELEVANCE Long-term outcomes suggested that both creation of MDHs and LCI can be therapeutic options for dogs with AHs. However, the risk of new AH development should be considered, especially in retriever breeds and dogs with allergic dermatitis.

4-phenylbutyrate restored GABA uptake and reduced seizures in SLC6A1 variants-mediated disorders

We have previously studied the molecular mechanisms of solute carrier family 6 member 1 (SLC6A1) associated with a continuum of neurodevelopmental disorders, including various epilepsy syndromes, autism, and intellectual disability. Based on functional assays of variants in a large cohort with heterogenous clinical phenotypes, we conclude that partial or complete loss of GABA uptake function in the mutant GAT-1 is the primary etiology as identified in GABAA receptor mutation-mediated epilepsy and in cystic fibrosis. Importantly, we identified that there are common patterns of the mutant protein trafficking from biogenesis, oligomerization, glycosylation, and translocation to the cell membrane across variants with the conservation of this process across cell types. Conversely any approach to facilitate membrane trafficking would increase presence of the functional protein in the targeted destination in all involved cells. PBA is an FDA-approved drug for pediatric use and is orally bioavailable so it can be quickly translated to patient use. It has been demonstrated that PBA can correct protein misfolding, reduce ER stress, and attenuate unfolded protein response in neurodegenerative diseases, it has also showed promise in treatment of cystic fibrosis. The common cellular mechanisms shared by the mutant GAT-1 and the mutant cystic fibrosis transmembrane conductance regulator led us to test if PBA and other pharmaco-chaperones could be a potential treatment option for SLC6A1 mutations. We examined the impact of PBA and other small molecules in a library of variants and in cell and knockin mouse models. Because of the critical role of astrocytic GAT-1 deficit in seizures, we focused on astrocytes, and demonstrated that the existence of the mutant GAT-1 retained the wildtype GAT-1, suggesting aberrant protein oligomerization and trafficking caused by the mutant GAT-1. PBA increased GABA uptake in both mouse and human astrocytes bearing the mutations. Importantly, PBA increased GAT-1 expression and suppressed spike wave discharges (SWDS) in the heterozygous knockin mice. Although the detailed mechanisms of action for PBA are ambiguous, it is likely that PBA can facilitate the forward trafficking of the wildtype GAT-1 favoring over the mutant GAT-1, thus increasing GABA uptake. Since all patients with SLC6A1 mutations are heterozygous and carry one wildtype functional allele, this suggests a great opportunity for treatment development by leveraging the endogenous protein trafficking pathway to promote forward trafficking of the wildtype in combination with enhancing the disposal of the mutant allele as treatment mode. The study opens a novel avenue of treatment development for genetic epilepsy via drug repurposing.

A MODEL OF ENGAGEMENT FOR CORRECTIONAL PRACTICE

<p>Despite recent advances in correctional rehabilitation, rates of treatment attrition remain high and low efficacy rates suggest improvements in treatment development and delivery are needed. Treatment engagement is an important concept which remains poorly understood. In order to enhance understanding and facilitate higher levels of engagement in treatment, robust theoretical models need to be developed. In light of this, two key questions need to be answered; (1) what is engagement? And (2) what are the underlying causal mechanisms which facilitate or hinder engagement? I explore the contributions of current conceptualisations and models of correctional treatment engagement. I explain how evolutionary psychology, agency, norms and the therapeutic alliance can contribute to our theoretical understanding. These concepts are then integrated to form the Model of Engagement for Correctional Practice. Engagement is conceptualised as a set of adaptive, goal-directed behaviours occurring as a result of the dynamic interactions between contextual, psychological and social processes. I argue that these factors influence the nature of the therapeutic alliance and subsequently participant engagement. The model is then evaluated in terms of critical features required for a robust theory of engagement. I then suggest some practice principles and guidelines to demonstrate how this model can be applied to enhance treatment engagement.</p>

A MODEL OF ENGAGEMENT FOR CORRECTIONAL PRACTICE

<p>Despite recent advances in correctional rehabilitation, rates of treatment attrition remain high and low efficacy rates suggest improvements in treatment development and delivery are needed. Treatment engagement is an important concept which remains poorly understood. In order to enhance understanding and facilitate higher levels of engagement in treatment, robust theoretical models need to be developed. In light of this, two key questions need to be answered; (1) what is engagement? And (2) what are the underlying causal mechanisms which facilitate or hinder engagement? I explore the contributions of current conceptualisations and models of correctional treatment engagement. I explain how evolutionary psychology, agency, norms and the therapeutic alliance can contribute to our theoretical understanding. These concepts are then integrated to form the Model of Engagement for Correctional Practice. Engagement is conceptualised as a set of adaptive, goal-directed behaviours occurring as a result of the dynamic interactions between contextual, psychological and social processes. I argue that these factors influence the nature of the therapeutic alliance and subsequently participant engagement. The model is then evaluated in terms of critical features required for a robust theory of engagement. I then suggest some practice principles and guidelines to demonstrate how this model can be applied to enhance treatment engagement.</p>

A paradoxical role for sestrin 2 protein in tumor suppression and tumorigenesis

Sestrin 2, a highly conserved stress-induced protein, participates in the pathological processes of metabolic and age-related diseases. This p53-inducible protein also regulates cell growth and metabolism, which is closely related to malignant tumorigenesis. Sestrin 2 was reported to regulate various cellular processes, such as tumor cell proliferation, invasion and metastasis, apoptosis, anoikis resistance, and drug resistance. Although sestrin 2 is associated with colorectal, lung, liver, and other cancers, sestrin 2 expression varies among different types of cancer, and the effects and mechanisms of action of this protein are also different. Sestrin 2 was considered a tumor suppressor gene in most studies, whereas conflicting reports considered sestrin 2 an oncogene. Thus, this review aims to examine the literature regarding sestrin 2 in various cancers, summarize its roles in suppression and tumorigenesis, discuss potential mechanisms in the regulation of cancer, and provide a basis for follow-up research and potential cancer treatment development.