The rockefeller university

A global international initiative, such as the Earth BioGenome Project (EBP), requires both agreement and coordination on standards to ensure that the collective effort generates rapid progress toward its goals. To this end, the EBP initiated five technical standards committees comprising volunteer members from the global genomics scientific community: Sample Collection and Processing, Sequencing and Assembly, Annotation, Analysis, and IT and Informatics. The current versions of the resulting standards documents are available on the EBP website, with the recognition that opportunities, technologies, and challenges may improve or change in the future, requiring flexibility for the EBP to meet its goals. Here, we describe some highlights from the proposed standards, and areas where additional challenges will need to be met.

Background: Telemedicine has the potential to increase healthcare access especially for vulnerable populations. Telemedicine for Evaluation, Adherence, and Medication for Hepatitis C (TEAM-C) is comparing telemedicine access to specialty medical care to usual care for management of hepatitis C virus (HCV) infection among persons with opioid use disorder (PWOUD). PWOUD have the highest hepatitis C virus (HCV) prevalence and incidence, yet they infrequently receive HCV care. The study objectives are to compare access to specialty care via telemedicine to offsite specialty referral (usual care) on 1) treatment initiation, completion, and sustained virological response, 2) patient satisfaction with health care delivery, and 3) HCV reinfection after successful HCV cure. Methods: TEAM-C is a multi-site, non-blinded, randomized pragmatic clinical trial conducted at 12 opioid treatment programs (OTP) throughout New York State that utilizes the stepped-wedge design. The unit of randomization is the OTP with a total sample size of 624 participants. HCV-infected PWOUD were treated via telemedicine or referral. Telemedicine encounters are conducted onsite in the OTP with co-administration of direct acting antivirals for HCV with medications for opioid use disorder. The primary outcome is undetectable HCV RNA obtained 12 weeks post-treatment cessation. We also follow participants for two years to assess for reinfection. Conclusions: The study utilizes a rigorous study design to evaluate the effectiveness and implementation of virtual treatment for HCV integrated into behavioral treatment. We demonstrate the feasibility, engagement principles and lessons learned from the initial prospective randomized trial of telemedicine targeted to a vulnerable population.

Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections(1,2). The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin(3). Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1-mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae, which, owing to a lack of effective treatment options, are considered among the highest level threat pathogens(4). In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensively drug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens.

Objective: To describe the widespread use of compounded bioidentical hormone therapies (cBHT). To define the term clinical utility and present why there is insufficient evidence to support the overall clinical utility of cBHT products. To recommend actions that pharmacists and regulators can take to promote safer cBHT use. Summary: Nationwide, millions of men and women use cBHT products. Use of these products appears to be increasing year-to-year, according to the limited data reported by the 503 A and 503 B pharmacies that formulate and dispense these products. Although use appears to be widespread, the safety, efficacy, and clinical utility of these products remains unproven. This commentary provides examples of what draws consumers to these products, comparative costs, and formulation challenges. Actions to promote the safe use of cBHT and approaches to begin the study of these products are provided. Conclusion: While significant progress was made via the Drug Supply Chain Security Act in 2013 to improve the safety of compounding practice in general, efforts to further improve the safety and transparency of cBHT dispensing and use must continue, at both the local and national level. (C) 2022 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

Genomics encompasses the entire tree of life, both extinct and extant, and the evolutionary processes that shape this diversity. To date, genomic research has focused on humans, a small number of agricultural species, and established laboratory models. Fewer than 18,000 of similar to 2,000,000 eukaryotic species (<1%) have a representative genome sequence in GenBank, and only a fraction of these have ancillary information on genome structure, genetic variation, gene expression, epigenetic modifications, and population diversity. This imbalance reflects a perception that human studies are paramount in disease research. Yet understanding how genomes work, and how genetic variation shapes phenotypes, requires a broad view that embraces the vast diversity of life. We have the technology to collect massive and exquisitely detailed datasets about the world, but expertise is siloed into distinct fields. A new approach, integrating comparative genomics with cell and evolutionary biology, ecology, archaeology, anthropology, and conservation biology, is essential for understanding and protecting ourselves and our world. Here, we describe potential for scientific discovery when comparative genomics works in close collaboration with a broad range of fields as well as the technical, scientific, and social constraints that must be addressed.

The protein kinase DYRK1A is involved in Alzheimer's disease, Down syndrome, diabetes, viral infections, and leukemia. Leucettines, a family of 2-aminoimidazolin-4-ones derived from the marine sponge alkaloid Leucettamine B, have been developed as pharmacological inhibitors of DYRKs ( dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). We report here on the synthesis and structure-activity relationship (SAR) of 68 Leucettines. Leucettines were tested on 11 purified kinases and in 5 cellular assays: (1) CLK1 pre-mRNA splicing, (2) Threonine-212-Tau phosphorylation, (3) glutamate-induced cell death, (4) autophagy and (5) antagonism of ligand-activated cannabinoid receptor CB1. The Leucettine SAR observed for DYRK1A is essentially identical for CLK1, CLK4, DYRK1B, and DYRK2. DYRK3 and CLK3 are less sensitive to Leucettines. In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.

Over the past two decades, opioid abuse has risen especially among women. In both sexes hippocampal neural circuits involved in associative memory formation and encoding of motivational incentives are critically important in the transition from initial drug use to drug abuse/dependence. Opioid circuits, particularly the mossy fiber pathway, are crucial for associative memory processes important for addiction. Our anatomical studies, especially those utilizing electron microscopic immunocytochemistry, have provided unique insight into sex differences in the distribution of opioid peptides and receptors in specific hippocampal circuits and how these distributions are altered following stress and oxycodone-associative learning processes. Here we review the hippocampal opioid system in rodents with respect to ovarian hormones effects and baseline sex differences then sex differences following acute and chronic stress. Next, we review sex differences in the hippocampal opioid system in unstressed and chronically stressed rats following oxycodone conditioned place preference. We show that opioid peptides and receptors are distributed within hippocampal circuits in females with elevated estrogen states in a manner that would enhance sensitivity to endogenous and exogenous opioids. Moreover, chronic stress primes the opioid system in females in a manner that would promote opioid-associative learning processes. In contrast, chronic stress has limited effects on the opioid system in males and reduces its capacity to support opioid-mediated learning processes. Interestingly, acute stress appears to prime males for opioid associative learning. On a broader scale the findings highlighted in this review have important implications in understanding sex differences in opioid drug use and abuse.

Rationale: The dynorphin/kappa-opioid receptor (KOR) system (encoded by PDYN and OPRK1 genes respectively) is highly regulated by repeated exposure to drugs of abuse, including mu-opioid agonists and cocaine. These changes in the dynorphin/KOR system can then influence the rewarding effects of these drugs of abuse. Activation of the dynorphin/KOR system is also thought to have a role in the pro-addictive effects of stress. Recent in vitro assays showed that the OPRK1 intron 2 may function as a genomic enhancer in the regulation KOR expression, and contains a glucocorticiod-responsive sequence site. We hypothesize that SNPs in intron 2 of OPRK1 are associated with categorical opioid or cocaine dependence diagnoses, as well as with dimensional aspects of drug use (i.e., magnitude of drug exposure). Methods: This study includes 577 subjects >= 18 years old, with African ancestry (AA) from the USA. They were divided into three groups: 152 control subjects, 142 persons with lifetime opioid dependence diagnosis (OD), and 283 subjects with lifetime cocaine dependence diagnosis (CD). Five SNPs (rs16918909, rs7016778, rs997917, rs6473797, rs10111937) that span 10 Kb nucleotides in intron 2 of OPRK1 were used for the association analyses. Genotyping was performed with the Smokescreen (R) array or sequencing of PCR-amplified DNA fragments. Association analyses for OD and CD diagnoses and the OPRK1 intron 2 alleles were carried out with Fisher's exact test. The Kreek-McHugh-Schluger-Kellogg (KMSK) scales were used for dimensional measure of maximum exposure to specific drugs, using Mann-Whitney tests. Results: Two SNPs, rs997917 and rs10111937 showed point-wise significant allelic association (p < 0.05) with CD diagnosis, and rs10111937 showed a point-wise significance in association with OD. None of these single SNP associations with categorical diagnoses were significant after correction for multiple testing (p(corr) > 0.05). However, significant associations of several genotype patterns (diplotypes) were found with cocaine dependence, but none for opioid dependence. The most significant genotype pattern with cocaine dependence diagnosis occurred for rs6473797 and rs10111937 (p(corr) = 0.036, odds ratio = 1.92, FDR < 0.05), and survived correction for multiple testing. Dimensional analyses with KMSK scores show that persons with either rs997917 or rs10111937 variants had greater exposure to cocaine, compared to those with prototype allele (Mann-Whitney tests, point-wise). Conclusions: This study provides additional support of potential importance of regulatory regions of intron 2 of the OPRK1 gene in development of cocaine and opioid dependence diagnoses, in a population with African-American ancestry.

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioim-munotherapy (PRIT) can cure colorectal peritoneal carcinoma-tosis. Nude mice were implanted intraperitoneally with lucifer-ase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 + 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intrave-nous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radio-labeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single-versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approx-imately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detect-able during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days (P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.