Synthesis and Pharmacology of Halogenated δ-Opiod Selective [\u3csub\u3eD\u3c/sub\u3eAla\u3csup\u3e2\u3c/sup\u3e] Deltorphin II Peptide Analogs

Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala2]deltorphin II template, which is δ-selective in in vitro radioligand binding assays over the μ- and κ-opioid receptors. It is a full agonist in [35S]GTPγS functional assays and analgesic when administered supraspinally to mice. Analgesia of 3 (GATE3-8) is blocked by the selective δ receptor antagonist naltrindole, indicating that the analgesic action of 3 is mediated by the δ-opioid receptor. We have established a radioligand in which 125I is incorporated into 3 (GATE3-8). The radioligand has a KD of 0.1 nM in Chinese hamster ovary (CHO) cells expressing the δ receptor. Additionally, a series of peptides based on 3 (GATE3-8) was synthesized by incorporating various halogens in the para position on the aromatic ring of Phe3. The peptides were characterized for binding affinity at the μ-, δ-, and κ-opioid receptors, which showed a linear correlation between binding affinity and the size of the halogen substituent. These peptides may be interesting tools for probing δ-opioid receptor pharmacology

Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder

Objective: Deficits in motor inhibition may contribute to impulsivity and irritability in children with bipolar disorder (BPD). Therefore, studies of the neural circuitry engaged during failed motor inhibition in pediatric BPD may contribute to our understanding of the pathophysiology of the illness. We tested the hypothesis that children with BPD and controls would differ in ventral prefrontal cortex (vPFC), striatal, and anterior cingulate activation during unsuccessful motor inhibition. We also compared activation in medicated vs. unmedicated children with BPD, and in children with BPD and ADHD (BPD+ADHD) vs. those with BPD but without ADHD (BPD-ADHD). Method: Event-related fMRI study comparing neural activation in children with BPD and controls while they performed a motor inhibition task. The sample included 26 children with BPD (13 unmedicated, 15 with ADHD) and 17 age, gender, and IQ matched controls. Results: On failed inhibitory trials, controls showed greater bilateral striatal and right vPFC activation than did patients. While our findings were somewhat more prominent in unmedicated than medicated, patients, and in BPD+ADHD than BPD-ADHD, the findings did not differ significantly (?) among these subgroups of children with BPD. Conclusions: Compared to controls, children with BPD may have deficits in their ability to engage striatal structures and right vPFC during unsuccessful inhibition. (this reads confusingly to me—they’re deficient in their capacity to engage structures when they’re behaviorally unsuccessful? Perhaps reword?) Further research is needed to determine whether these deficits play a role in the emotional and behavioral dysregulation characteristic of BPD

SIV-specific CD8+ T cells are clonotypically distinct across lymphoid and mucosal tissues

CD8+ T cell responses are necessary for immune control of simian immunodeficiency virus (SIV). However, the key parameters that dictate antiviral potency remain elusive, conceivably because most studies to date have been restricted to analyses of circulating CD8+ T cells. We conducted a detailed clonotypic, functional, and phenotypic survey of SIV-specific CD8+ T cells across multiple anatomical sites in chronically infected rhesus macaques with high (>10,000 copies/mL plasma) or low burdens of viral RNA (<10,000 copies/mL plasma). No significant differences in response magnitude were identified across anatomical compartments. Rhesus macaques with low viral loads (VLs) harbored higher frequencies of polyfunctional CXCR5+ SIV-specific CD8+ T cells in various lymphoid tissues and higher proportions of unique Gag-specific CD8+ T cell clonotypes in the mesenteric lymph nodes relative to rhesus macaques with high VLs. In addition, public Gag-specific CD8+ T cell clonotypes were more commonly shared across distinct anatomical sites than the corresponding private clonotypes, which tended to form tissue-specific repertoires, especially in the peripheral blood and the gastrointestinal tract. Collectively, these data suggest that functionality and tissue localization are important determinants of CD8+ T cell–mediated efficacy against SIV

Investigating the global dispersal of chickens in prehistory using ancient mitochondrial dna signatures

Data from morphology, linguistics, history, and archaeology have all been used to trace the dispersal of chickens from Asian domestication centers to their current global distribution. Each provides a unique perspective which can aid in the reconstruction of prehistory. This study expands on previous investigations by adding a temporal component from ancient DNA and, in some cases, direct dating of bones of individual chickens from a variety of sites in Europe, the Pacific, and the Americas. The results from the ancient DNA analyses of forty-eight archaeologically derived chicken bones provide support for archaeological hypotheses about the prehistoric human transport of chickens. Haplogroup E mtDNA signatures have been amplified from directly dated samples originating in Europe at 1000 B.P. and in the Pacific at 3000 B.P. indicating multiple prehistoric dispersals from a single Asian centre. These two dispersal pathways converged in the Americas where chickens were introduced both by Polynesians and later by Europeans. The results of this study also highlight the inappropriate application of the small stretch of D-loop, traditionally amplified for use in phylogenetic studies, to understanding discrete episodes of chicken translocation in the past. The results of this study lead to the proposal of four hypotheses which will require further scrutiny and rigorous future testingExcavations in Fais by MI were made possible by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science. DB gratefully acknowledges support from the Marsden Fund, and the Allan Wilson Centre for Molecular Ecology and Evolution. During the course of this research AS was supported by a Postgraduate Scholarship from the University of Auckland and a Fellowship from the Allan Wilson Centre for Molecular Ecology and Evolutio

Mortality Among Adults With Cancer Undergoing Chemotherapy or Immunotherapy and Infected With COVID-19

Importance: Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. // Objective: To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. // Design, Setting, and Participants: The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. // Exposures: SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. // Main Outcomes and Measures: The primary end point was all-cause mortality within the primary hospitalization. // Results: Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19–related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). // Conclusions and Relevance: The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

CSD 1877849: Experimental Crystal Structure Determination

Related Article: Rylan Terry, Daniel Vinton, Colin D. McMillen, Joseph W. Kolis|2018|Angew.Chem.,Int.Ed.|57|2077|doi:10.1002/anie.20170879

CSD 1877845: Experimental Crystal Structure Determination

Related Article: Rylan Terry, Daniel Vinton, Colin D. McMillen, Joseph W. Kolis|2018|Angew.Chem.,Int.Ed.|57|2077|doi:10.1002/anie.20170879