In Situ Transfection by Controlled Release of Lipoplexes Using Acoustic Droplet Vaporization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133565/1/adhm201600008_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133565/2/adhm201600008.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133565/3/adhm201600008-sup-0001-S1.pd

The Earth BioGenome Project 2020: Starting the clock

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Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis

Close Encounters: Intimate service interactions in lap dancing work as a nexus of ‘self-others-things’

Drawing on ethnographic research on lap dancing work, this paper focuses on how the subjectivities, interactions and settings that constitute the lap dancing industry come into being through three interrelated processes of encoding, embodying and embedding. In considering how these processes combine to ‘enact’ the industry, the paper draws on Merleau Ponty’s understanding of the world as a dynamic nexus of ‘self-others-things’. Focusing on how this nexus shapes lived experiences of intimate service interactions, the analysis considers how dancers continually negotiate customers’ expectations of the service encounter given the ways in which these are: (i) encoded in depictions of lap dancing work in marketing and advertising materials on club websites; (ii) embodied by lap dancers through their interactions with customers; and (iii) embedded within the materiality of lap dancing clubs. The paper shows how intimate service encounters can be understood as the outcome of a nexus of ‘self-others-things’ through which particular organizational subjectivities and settings are brought into being through these three interrelated processes

Mammal responses to global changes in human activity vary by trophic group and landscape

Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in human–wildlife interactions along gradients of human influence.Peer reviewe

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility

Counseling With Male Clients: The Case for Relational Resilience Approach

Although there is no lack of research on masculinity and help-seeking behavior, men continue to seek counseling less often than women. It is crucial we find effective therapeutic approaches to connect and meet men where they are, acknowledging the positive aspects of their masculinity while addressing their needs in the counseling setting. In this conceptual research article, we propose a new approach for counselors to utilize with men seeking counseling, the Relational Resilience Approach, which applies tenets of Relational-Cultural Theory, Positive Psychology, and Shame Resilience Theory