Anti-pPKCθ (T538) Delivery via Cell Penetrating Peptide Mimics as a Novel Treatment of Aplastic Anemia

The objective of this study is to deliver anti-pPKCθ (T538) into T cells (hPBMCs) by using cell penetrating peptide mimics (CPPMs) to neutralize PKCθ activity both in vitro and in vivo, with the eventual goal of treating aplastic anemia (AA). AA is an immune-mediated bone marrow failure disease caused by T helper type 1 (Th1) autoimmune responses, which destroy blood cell progenitors. It was previously reported that protein kinase C theta (PKCθ), expressed specifically in T cells, plays an important role in T cell signaling by mediating Th1 differentiation. Mice treated with Rottlerin, a pharmacological inhibitor of PKCθ, are rescued from the disease when PKCθ phosphorylation was inhibited. Furthermore, humanized antibodies are increasingly gaining attention as therapies. The delivery of antibodies could be achieved via cell penetrating peptides (CPPs), which are able to internalize cargo into cells. Here, we designed, synthesized and characterized CPPMs to increase delivery efficiency of an antibody against phosphorylated PKCθ (T538), which subsequently interfered with the function of the kinase. We designed an in vitro delivery method for the CPPM/Anti-pPKCθ complex then assessed T cell activation and AA disease marker expression. Also, we generated an in vivo humanized mouse model of AA and tested the complex for delivery and effect on survival of these mice. Altogether the results reveal that PKCθ may be an optimal target for bone marrow failure treatment and intracellular antibody delivery may represent a novel approach for AA treatment

The Belgrade PaleoBlitz: A Pilot Project to Engage Amateur Paleontologists

Paleontology is an interdisciplinary field that attracts a range of individuals, from hobbyists to professionals. A primary goal of the NSF-funded FOSSIL Project is to establish a unified community of paleontologists and promote best practices in the field of paleontology. The Belgrade PaleoBlitz was a pilot effort to meet these goals by guiding participants through the museum curation process via a rapid two-day immersion. The objectives of the PaleoBlitz event were to: 1) educate participants in best practices associated with the museum curation process, and 2) catalog specimens collected from the Belgrade Quarry into the Florida Museum of Natural History vertebrate paleontology collections. These objectives seek to find a balance between educating participants and contributing to science. A pre-event application dispersed to amateur paleontology clubs throughout the United States determined applicants’ baseline content knowledge and practices. To facilitate learning and promote networking, we selected 13 participants who varied in expertise from six different paleontology organizations. Immediate and delayed post-event surveys assessed acceptance and implementation of best practices, confidence related to specific aspects of the museum curation process, and expansion of individuals’ personal paleontology network. Responses showed that all participants made changes to their existing collections, felt more confident in specific aspects of the museum curation process, and had continued connections with other participants after this event

Polygenic risk heterogeneity among focal epilepsies

Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score "FE-PRS" that combines small effect sizes of thousands of common variants from the largest FE-GWAS (genome-wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE-PRS compared to 20 435 matched population controls and observed heterogeneous FE-PRS burden among the subgroups. The highest phenotypic variance explained by FE-PRS was identified in a cluster analysis-defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better-powered FE-PRS might have clinical utility.Peer reviewe

A Pharmacology-Based Enrichment Program for Undergraduates Promotes Interest in Science

There is a strong need to increase the number of undergraduate students who pursue careers in science to provide the “fuel” that will power a science and technology–driven U.S. economy. Prior research suggests that both evidence-based teaching methods and early undergraduate research experiences may help to increase retention rates in the sciences. In this study, we examined the effect of a program that included 1) a Summer enrichment 2-wk minicourse and 2) an authentic Fall research course, both of which were designed specifically to support students\u27 science motivation. Undergraduates who participated in the pharmacology-based enrichment program significantly improved their knowledge of basic biology and chemistry concepts; reported high levels of science motivation; and were likely to major in a biological, chemical, or biomedical field. Additionally, program participants who decided to major in biology or chemistry were significantly more likely to choose a pharmacology concentration than those majoring in biology or chemistry who did not participate in the enrichment program. Thus, by supporting students\u27 science motivation, we can increase the number of students who are interested in science and science careers

Repairing the Leaky Pipeline: A Motivationally Supportive Intervention to Enhance Persistence in Undergraduate Science Pathways

The current study reports on the efficacy of a multi-faceted motivationally designed undergraduate enrichment summer program for supporting science, technology, engineering and math (STEM) persistence. Structural equation modeling was used to compare summer program participants (n = 186), who participated in the program between their first and second years in college, to a propensity score matched comparison sample (n = 401). Participation in the summer program positively predicted science motivation (self-efficacy, task value), assessed eight months after the end of the program (second year in college). The summer enrichment program was also beneficial for science persistence variables, as evidenced by significant direct and indirect effects of the program on science course completion during students’ third year of college and students’ intentions to pursue a science research career assessed during the third year of college. In general, the program was equally beneficial for all participants, but ancillary analyses indicated added benefits with respect to task value for students with relatively lower prior science achievement during the first year of college and with respect to subsequent science course taking for males. Implications for developing effective interventions to reduce the flow of individuals out of STEM fields and for translating motivational theory into practice are discussed

Charming CP Violation and Dipole Operators from RS Flavor Anarchy

Recently the LHCb collaboration reported evidence for direct CP violation in charm decays. The value is sufficiently large that either substantially enhanced Standard Model contributions or non-Standard Model physics is required to explain it. In the latter case only a limited number of possibilities would be consistent with other existing flavor-changing constraints. We show that warped extra dimensional models that explain the quark spectrum through flavor anarchy can naturally give rise to contributions of the size required to explain the the LHCb result. The D meson asymmetry arises through a sizable CP-violating contribution to a chromomagnetic dipole operator. This happens naturally without introducing inconsistencies with existing constraints in the up quark sector. We discuss some subtleties in the loop calculation that are similar to those in Higgs to \gamma\gamma. Loop-induced dipole operators in warped scenarios and their composite analogs exhibit non-trivial dependence on the Higgs profile, with the contributions monotonically decreasing when the Higgs is pushed away from the IR brane. We show that the size of the dipole operator quickly saturates as the Higgs profile approaches the IR brane, implying small dependence on the precise details of the Higgs profile when it is quasi IR localized. We also explain why the calculation of the coefficient of the lowest dimension 5D operator is guaranteed to be finite. This is true not only in the charm sector but also with other radiative processes such as electric dipole moments, b to s\gamma, \epsilon'/\epsilon_K and \mu\ to e\gamma. We furthermore discuss the interpretation of this contribution within the framework of partial compositeness in four dimensions and highlight some qualitative differences between the generic result of composite models and that obtained for dynamics that reproduces the warped scenario.Comment: 14 page

LHC Searches for Non-Chiral Weakly Charged Multiplets

Because the TeV-scale to be probed at the Large Hadron Collider should shed light on the naturalness, hierarchy, and dark matter problems, most searches to date have focused on new physics signatures motivated by possible solutions to these puzzles. In this paper, we consider some candidates for new states that although not well-motivated from this standpoint are obvious possibilities that current search strategies would miss. In particular we consider vector representations of fermions in multiplets of $SU(2)_L$ with a lightest neutral state. Standard search strategies would fail to find such particles because of the expected small one-loop-level splitting between charged and neutral states.Comment: 16 pages, 9 figure

Participant engagement in a community health worker-delivered intervention and type 2 diabetes clinical outcomes: a quasiexperimental study in MexicanAmericans

Objectives This study helps to fill the existing research gap related to participant engagement in behavioural interventions and diabetes management. We examined type 2 diabetes control over time among Mexican Americans by level of engagement in a chronic care management (CCM) program that included community health worker (CHW)-delivered multilevel interventions. The programme complemented clinical care and promoted behaviour changes to improve diabetes self-management. Design Quasiexperimental study. Setting The study was implemented in the Rio Grande Valley region in the USA. Recruitment was conducted in clinics and community events. All other visits were provided in participant homes and community locations. Participants 5649 adults (aged ≥18 years) with poorly controlled type 2 diabetes who enrolled in a community-delivered CCM programme between September 2013 and 2018. Interventions The intervention comprised two components: CHW home visits conducted every 3 months and diabetes self-management education (DSME) classes provided in community locations. Primary outcome measures The primary outcome was haemoglobin A1c (HbA1c) measured at baseline every 3 months for up to 24 months. We first examined changes in HbA1c levels over time. The number of completed CHW and DSME encounters was used to classify participants into engagement groups—high engagement defined as ≥10 encounters (n=2952); low engagement defined as 1–9 encounters (n=2697). We used univariable and multivariable longitudinal linear regression models with a generalised estimating equation method. We tested interactions between engagement groups and time. Results Participants’ mean HbA1c decreased from 10.20% at baseline to 8.93% (p Conclusions Higher engagement in the CCM programme delivered by CHWs and coordinated with clinical care was associated with beneficial improvements in type 2 diabetes control, but both engagement groups showed strong improvements

TeV Scale Singlet Dark Matter

It is well known that stable weak scale particles are viable dark matter candidates since the annihilation cross section is naturally about the right magnitude to leave the correct thermal residual abundance. Many dark matter searches have focused on relatively light dark matter consistent with weak couplings to the Standard Model. However, in a strongly coupled theory, or even if the coupling is just a few times bigger than the Standard Model couplings, dark matter can have TeV-scale mass with the correct thermal relic abundance. Here we consider neutral TeV-mass scalar dark matter, its necessary interactions, and potential signals. We consider signals both with and without higher-dimension operators generated by strong coupling at the TeV scale, as might happen for example in an RS scenario. We find some potential for detection in high energy photons that depends on the dark matter distribution. Detection in positrons at lower energies, such as those PAMELA probes, would be difficult though a higher energy positron signal could in principle be detectable over background. However, a light dark matter particle with higher-dimensional interactions consistent with a TeV cutoff can in principle match PAMELA data.Comment: 30 pages, 11 figures. Minor changes, references adde