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

Survey of sediment quality in Sabine Lake, Texas and vicinity

The toxicity of sediments in Sabine Lake, Texas, and adjoining Intracoastal Waterway canals was determined as part of bioeffects assessment studies managed by NOAA’s National Status and Trends Program. The objectives of the survey were to determine: (1) the incidence and degree of toxicity of sediments throughout the study area; (2) the spatial patterns (or gradients) in chemical contamination and toxicity, if any, throughout the study area; (3) the spatial extent of chemical contamination and toxicity; and (4) the statistical relationships between measures of toxicity and concentrations of chemicals in the sediments. Surficial sediment samples were collected during August, 1995 from 66 randomly-chosen locations. Laboratory toxicity tests were performed as indicators of potential ecotoxicological effects in sediments. A battery of tests was performed to generate information from different phases (components) of the sediments. Tests were selected to represent a range in toxicological endpoints from acute to chronic sublethal responses. Toxicological tests were conducted to measure: reduced survival of adult amphipods exposed to solid-phase sediments; impaired fertilization success and abnormal morphological development in gametes and embryos, respectively, of sea urchins exposed to pore waters; reduced metabolic activity of a marine bioluminescent bacteria exposed to organic solvent extracts; and induction of a cytochrome P-450 reporter gene system in exposures to solvent extracts of the sediments. Chemical analyses were performed on portions of each sample to quantify the concentrations of trace metals, polynuclear aromatic hydrocarbons, and chlorinated organic compounds. Correlation analyses were conducted to determine the relationships between measures of toxicity and concentrations of potentially toxic substances in the samples. Based upon the compilation of results from chemical analyses and toxicity tests, the quality of sediments in Sabine Lake and vicinity did not appear to be severely degraded. Chemical concentrations rarely exceeded effects-based numerical guidelines, suggesting that toxicant-induced effects would not be expected in most areas. None of the samples was highly toxic in acute amphipod survival tests and a minority (23%) of samples were highly toxic in sublethal urchin fertilization tests. Although toxic responses occurred frequently (94% of samples) in urchin embryo development tests performed with 100% pore waters, toxicity diminished markedly in tests done with diluted pore waters. Microbial bioluminescent activity was not reduced to a great degree (no EC50 <0.06 mg/ml) and cytochrome P-450 activity was not highly induced (6 samples exceeded 37.1 ug/g benzo[a]pyrene equivalents) in tests done with organic solvent extracts. Urchin embryological development was highly correlated with concentrations of ammonia and many trace metals. Cytochrome P450 induction was highly correlated with concentrations of a number of classes of organic compounds (including the polynuclear aromatic hydrocarbons and chlorinated compounds). (PDF contains 51 pages

Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis.

Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Assessing Theoretical Conclusions With Blinded Inference to Investigate a Potential Inference Crisis

Scientific advances across a range of disciplines hinge on the ability to make inferences about unobservable theoretical entities on the basis of empirical data patterns. Accurate inferences rely on both discovering valid, replicable data patterns and accurately interpreting those patterns in terms of their implications for theoretical constructs. The replication crisis in science has led to widespread efforts to improve the reliability of research findings, but comparatively little attention has been devoted to the validity of inferences based on those findings. Using an example from cognitive psychology, we demonstrate a blinded-inference paradigm for assessing the quality of theoretical inferences from data. Our results reveal substantial variability in experts’ judgments on the very same data, hinting at a possible inference crisis

To which world regions does the valence–dominance model of social perception apply?

Over the past 10 years, Oosterhof and Todorov’s valence–dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov’s methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov’s original analysis strategy, the valence–dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence–dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution.C.L. was supported by the Vienna Science and Technology Fund (WWTF VRG13-007); L.M.D. was supported by ERC 647910 (KINSHIP); D.I.B. and N.I. received funding from CONICET, Argentina; L.K., F.K. and Á. Putz were supported by the European Social Fund (EFOP-3.6.1.-16-2016-00004; ‘Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pécs’). K.U. and E. Vergauwe were supported by a grant from the Swiss National Science Foundation (PZ00P1_154911 to E. Vergauwe). T.G. is supported by the Social Sciences and Humanities Research Council of Canada (SSHRC). M.A.V. was supported by grants 2016-T1/SOC-1395 (Comunidad de Madrid) and PSI2017-85159-P (AEI/FEDER UE). K.B. was supported by a grant from the National Science Centre, Poland (number 2015/19/D/HS6/00641). J. Bonick and J.W.L. were supported by the Joep Lange Institute. G.B. was supported by the Slovak Research and Development Agency (APVV-17-0418). H.I.J. and E.S. were supported by a French National Research Agency ‘Investissements d’Avenir’ programme grant (ANR-15-IDEX-02). T.D.G. was supported by an Australian Government Research Training Program Scholarship. The Raipur Group is thankful to: (1) the University Grants Commission, New Delhi, India for the research grants received through its SAP-DRS (Phase-III) scheme sanctioned to the School of Studies in Life Science; and (2) the Center for Translational Chronobiology at the School of Studies in Life Science, PRSU, Raipur, India for providing logistical support. K. Ask was supported by a small grant from the Department of Psychology, University of Gothenburg. Y.Q. was supported by grants from the Beijing Natural Science Foundation (5184035) and CAS Key Laboratory of Behavioral Science, Institute of Psychology. N.A.C. was supported by the National Science Foundation Graduate Research Fellowship (R010138018). We acknowledge the following research assistants: J. Muriithi and J. Ngugi (United States International University Africa); E. Adamo, D. Cafaro, V. Ciambrone, F. Dolce and E. Tolomeo (Magna Græcia University of Catanzaro); E. De Stefano (University of Padova); S. A. Escobar Abadia (University of Lincoln); L. E. Grimstad (Norwegian School of Economics (NHH)); L. C. Zamora (Franklin and Marshall College); R. E. Liang and R. C. Lo (Universiti Tunku Abdul Rahman); A. Short and L. Allen (Massey University, New Zealand), A. Ateş, E. Güneş and S. Can Özdemir (Boğaziçi University); I. Pedersen and T. Roos (Åbo Akademi University); N. Paetz (Escuela de Comunicación Mónica Herrera); J. Green (University of Gothenburg); M. Krainz (University of Vienna, Austria); and B. Todorova (University of Vienna, Austria). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.https://www.nature.com/nathumbehav/am2023BiochemistryGeneticsMicrobiology and Plant Patholog

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Interstrand Cross-Link and Bioconjugate Formation in RNA from a Modified Nucleotide

RNA oligonucleotides containing a phenyl selenide derivative of 5-methyluridine were chemically synthesized by solid-phase synthesis. The phenyl selenide is rapidly converted to an electrophilic, allylic phenyl seleneate under mild oxidative conditions. The phenyl seleneate yields interstrand cross-links when part of a duplex and is useful for synthesizing oligonucleotide conjugates. Formation of the latter is illustrated by reaction of an oligonucleotide containing the phenyl selenide with amino acids in the presence of mild oxidant. The products formed are analogous to those observed in tRNA that are believed to be formed posttranslationally via a biosynthetic intermediate that is chemically homologous to the phenyl seleneate

Trimethylene Methane Dianion Equivalent for the Asymmetric Consecutive Allylation of Aldehydes: Applications to Prins-Driven Macrocyclizations for the Synthesis of Bryostatin 1 and Analogues

We report a one-step (one-flask) generation and reaction of a bifunctional allylating reagent, a trimethylene methane dianion equivalent, that provides a route for the asymmetric 2-(trimethylsilylmethyl) allylation of aldehydes. The product of the first aldehyde allylation process is then set to engage in a second separate aldehyde allylation, providing an improved Prins macrocyclization strategy both for the scalable synthesis of bryostatin 1 and for the total synthesis of a new potent bryostatin analogue