Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy.

Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies

An inverted virtual faculty development program for remote teaching: pilot for replication

Background: Due to the COVID 19 pandemic, all the universities worldwide are experiencing a paradigm shift to online learning. Baby boomers and Generation X need to cope with the challenging transformation, so an emerging need for a faculty development program was needed towards achieving the goal of that transformation. Objectives: To describe and assess an inverted virtual faculty development program (VFDP) that was designed and implemented for the first time in the school to equip educators with the necessary technology competencies for remote online learning. Methods: An interventional prospective study held in a university setting post need analysis conduction to prioritize the required technological skills for faculty members. The program was designed to integrate five essential skills needed to by faculty members to teach remotely. The intervention comprised attending five virtual sessions after watching a pre-distributed material, then evaluated using the Kirkpatrick model.Results: Almost 81% of faculty members completed the program and 80 % of participants were satisfied with the content of the program. There was a statistically significant difference between the perceived ability of the participants to share and record video lectures before and after the VFDP (p value <0.001). The percentage of the departments that applied the program components showed that 96% of them were able to record lectures. In addition, 80% of them were able to develop online quizzes. Conclusion: The inverted virtual faculty development program (VFDP) has supported the participating faculty in developing their needed technological competencies required to bridge the gap of remote teaching/learning

O percevejo bronzeado Thaumastocoris peregrinus: uma ameaça à eucaliptocultura mundial.

Resumo

The role of tool geometry in process damped milling

The complex interaction between machining structural systems and the cutting process results in machining instability, so called chatter. In some milling scenarios, process damping is a useful phenomenon that can be exploited to mitigate chatter and hence improve productivity. In the present study, experiments are performed to evaluate the performance of process damped milling considering different tool geometries (edge radius, rake and relief angles and variable helix/pitch). The results clearly indicate that variable helix/pitch angles most significantly increase process damping performance. Additionally, increased cutting edge radius moderately improves process damping performance, while rake and relief angles have a smaller and closely coupled effect

Manejo de pragas exóticas em florestas de eucalipto.

Resumo: As pragas exóticas do eucalipto o psilideo-de-concha Glycaspis brimblecombei (Hemiptera: Psyllidae), o percevejo bronzeado Thaumastocoris peregrinus (Hemiptera: Thaumastocoridae) e a vespa-de-galha Leptocybe invasa (Hymenoptera: Eulophidae), tem comprometido o desenvolvimento de espécies e clones de eucalipto no Brasil, Sistemas de monitoramento, baseado no uso de armadilhas adesivas tem sido utilizados. As principais estratégias de manejo dessas pragas são baseadas em controle biológico clássico, com importação e liberação de inimigos naturais, e avaliação de material genético de eucalipto resistente. Summary: The exotic pests of eucalyptus redgum lerp psyllid Glycaspis brimblecombei (Hemiptera: Psyllidae), the bronze bug Thaumastocoris peregrinus (Hemiptera: Thaumastocoridae) and gall wasp Leptocybe invasiva (Hymenoptera: Eulophidae), has compromised the development of Eucalyptus species and clones in Brazil. Monitoring systems, based on the use of sticky traps have been used. The main management strategies for these pests are based on classical biological control, with import and release of natural enemies, and evaluation of resistant genetic material to the exotic pests

Three-dimensional echocardiography for left ventricular quantification: fundamental validation and clinical applications

One of the earliest applications of clinical echocardiography is evaluation of left ventricular (LV) function and size. Accurate, reproducible and quantitative evaluation of LV function and size is vital for diagnosis, treatment and prediction of prognosis of heart disease. Early three-dimensional (3D) echocardiographic techniques showed better reproducibility than two-dimensional (2D) echocardiography and narrower limits of agreement for assessment of LV function and size in comparison to reference methods, mostly cardiac magnetic resonance (CMR) imaging, but acquisition methods were cumbersome and a lack of user-friendly analysis software initially precluded widespread use. Through the advent of matrix transducers enabling real-time three-dimensional echocardiography (3DE) and improvements in analysis software featuring semi-automated volumetric analysis, 3D echocardiography evolved into a simple and fast imaging modality for everyday clinical use. 3DE provides the possibility to evaluate the entire LV in three spatial dimensions during the complete cardiac cycle, offering a more accurate and complete quantitative evaluation the LV. Improved efficiency in acquisition and analysis may provide clinicians with important diagnostic information within minutes. The current article reviews the methodology and application of 3DE for quantitative evaluation of the LV, provides the scientific evidence for its current clinical use, and discusses its current limitations and potential future directions

mTORC1 Inhibition via Rapamycin Promotes Triacylglycerol Lipolysis and Release of Free Fatty Acids in 3T3â L1 Adipocytes

Signaling by mTOR complex 1 (mTORC1) promotes anabolic cellular processes in response to growth factors, nutrients, and hormonal cues. Numerous clinical trials employing the mTORC1 inhibitor rapamycin (aka sirolimus) to immunoâ suppress patients following organ transplantation have documented the development of hypertriglyceridemia and elevated serum free fatty acids (FFA). We therefore investigated the cellular role of mTORC1 in control of triacylglycerol (TAG) metabolism using cultured murine 3T3â L1 adipocytes. We found that treatment of adipocytes with rapamycin reduced insulinâ stimulated TAG storage ~50%. To determine whether rapamycin reduces TAG storage by upregulating lipolytic rate, we treated adipocytes in the absence and presence of rapamycin and isoproterenol, a β2â adrenergic agonist that activates the cAMP/protein kinase A (PKA) pathway to promote lipolysis. We found that rapamycin augmented isoproterenolâ induced lipolysis without altering cAMP levels. Rapamycin enhanced the isoproterenolâ stimulated phosphorylation of hormone sensitive lipase (HSL) on Serâ 563 (a PKA site), but had no effect on the phosphorylation of HSL S565 (an AMPK site). Additionally, rapamycin did not affect the isoproterenolâ mediated phosphorylation of perilipin, a protein that coats the lipid droplet to initiate lipolysis upon phosphorylation by PKA. These data demonstrate that inhibition of mTORC1 signaling synergizes with the βâ adrenergicâ cAMP/PKA pathway to augment phosphorylation of HSL to promote hormoneâ induced lipolysis. Moreover, they reveal a novel metabolic function for mTORC1; mTORC1 signaling suppresses lipolysis, thus augmenting TAG storage.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141428/1/lipd1089.pd

Genome-Wide Association Studies of the PR Interval in African Americans

The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5×10−8) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta  = 5.1 msec per minor allele, 95% CI  = 4.1–6.1, p = 3×10−23). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8–3.0, p = 3×10−16) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans