Brain penetrant LRRK2 inhibitor

This is the author accepted manuscript. The final version is available from ACS via the DOI in this record. Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5- chloropyrimidine, HG-10-102-01 (4), is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 μM in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg. © 2012 American Chemical Society.NIHMedical Research CouncilMichael J Fox foundation for Parkinson’s disease researchPharmaceutical companies supporting the DSTT (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer

Experimental and theoretical investigation of ligand effects on the synthesis of ZnO nanoparticles

ZnO nanoparticles with highly controllable particle sizes(less than 10 nm) were synthesized using organic capping ligands in Zn(Ac)2 ethanolic solution. The molecular structure of the ligands was found to have significant influence on the particle size. The multi-functional molecule tris(hydroxymethyl)-aminomethane (THMA) favoured smaller particle distributions compared with ligands possessing long hydrocarbon chains that are more frequently employed. The adsorption of capping ligands on ZnnOn crystal nuclei (where n = 4 or 18 molecular clusters of(0001) ZnO surfaces) was modelled by ab initio methods at the density functional theory (DFT) level. For the molecules examined, chemisorption proceeded via the formation of Zn...O, Zn...N, or Zn...S chemical bonds between the ligands and active Zn2+ sites on ZnO surfaces. The DFT results indicated that THMA binds more strongly to the ZnO surface than other ligands, suggesting that this molecule is very effective at stabilizing ZnO nanoparticle surfaces. This study, therefore, provides new insight into the correlation between the molecular structure of capping ligands and the morphology of metal oxide nanostructures formed in their presence

Defective Fluid Secretion from Submucosal Glands of Nasal Turbinates from CFTR-/- and CFTRΔF508/ΔF508 Pigs

Cystic fibrosis (CF), caused by reduced CFTR function, includes severe sinonasal disease which may predispose to lung disease. Newly developed CF pigs provide models to study the onset of CF pathophysiology. We asked if glands from pig nasal turbinates have secretory responses similar to those of tracheal glands and if CF nasal glands show reduced fluid secretion.Unexpectedly, we found that nasal glands differed from tracheal glands in five ways, being smaller, more numerous (density per airway surface area), more sensitive to carbachol, more sensitive to forskolin, and nonresponsive to Substance P (a potent agonist for pig tracheal glands). Nasal gland fluid secretion from newborn piglets (12 CF and 12 controls) in response to agonists was measured using digital imaging of mucus bubbles formed under oil. Secretion rates were significantly reduced in all conditions tested. Fluid secretory rates (Controls vs. CF, in pl/min/gland) were as follows: 3 µM forskolin: 9.2±2.2 vs. 0.6±0.3; 1 µM carbachol: 143.5±35.5 vs. 52.2±10.3; 3 µM forskolin + 0.1 µM carbachol: 25.8±5.8 vs. CF 4.5±0.9. We also compared CF(ΔF508/ΔF508) with CFTR(-/-) piglets and found significantly greater forskolin-stimulated secretion rates in the ΔF508 vs. the null piglets (1.4±0.8, n = 4 vs. 0.2±0.1, n = 7). An unexpected age effect was also discovered: the ratio of secretion to 3 µM forskolin vs. 1 µM carbachol was ∼4 times greater in adult than in neonatal nasal glands.These findings reveal differences between nasal and tracheal glands, show defective fluid secretion in nasal glands of CF pigs, reveal some spared function in the ΔF508 vs. null piglets, and show unexpected age-dependent differences. Reduced nasal gland fluid secretion may predispose to sinonasal and lung infections

Sphalerons and the Electroweak Phase Transition in Models with Higher Scalar Representations

In this work we investigate the sphaleron solution in a $SU(2)\times U(1)_X$ gauge theory, which also encompasses the Standard Model, with higher scalar representation(s) ($J^{(i)},X^{(i)}$). We show that the field profiles describing the sphaleron in higher scalar multiplet, have similar trends like the doublet case with respect to the radial distance. We compute the sphaleron energy and find that it scales linearly with the vacuum expectation value of the scalar field and its slope depends on the representation. We also investigate the effect of $U(1)$ gauge field and find that it is small for the physical value of the mixing angle, $\theta_{W}$ and resembles the case for the doublet. For higher representations, we show that the criterion for strong first order phase transition, $v_{c}/T_{c}>\eta$, is relaxed with respect to the doublet case, i.e. $\eta<1$.Comment: 20 pages, 5 figures & 1 table, published versio

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

Funding: This work was funded by a Career Development Fellowship (1028634) and a project grant (GRNT1028641) awarded to AHa by the Australian National Health & Medical Research Council (NHMRC). IS was supported by The University of Queensland Centennial and IPRS Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Genotyping of single nucleotide polymorphisms related to attention-deficit hyperactivity disorder

Pharmacological treatment of several diseases, such as attention-deficit hyperactivity disorder (ADHD), presents marked variability in efficiency and its adverse effects. The genotyping of specific single nucleotide polymorphisms (SNPs) can support the prediction of responses to drugs and the genetic risk of presenting comorbidities associated with ADHD. This study presents two rapid and affordable microarray-based strategies to discriminate three clinically important SNPs in genes ADRA2A, SL6CA2, and OPRM1 (rs1800544, rs5569, and rs1799971, respectively). These approaches are allele-specific oligonucleotide hybridization (ASO) and a combination of allele-specific amplification (ASA) and solid-phase hybridization. Buccal swab and blood samples taken from ADHD patients and controls were analyzed by ASO, ASA, and a gold-reference method. The results indicated that ASA is superior in genotyping capability and analytical performance.This research has been funded through projects FEDER MINECO INNPACTO IPT-2011-1132-010000, CTQ/2013/45875R, and PrometeoII/2014/040 (GVA).Tortajada-Genaro, LA.; Mena-Mollá, S.; Niñoles Rodenes, R.; Puigmule, M.; Viladevall, L.; Maquieira Catala, Á. (2016). Genotyping of single nucleotide polymorphisms related to attention-deficit hyperactivity disorder. Analytical and Bioanalytical Chemistry. 408(9):2339-2345. https://doi.org/10.1007/s00216-016-9332-3S233923454089Cortese S. The neurobiology and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): what every clinician should know. Eur J Paediatr Neurol. 2012;16:422–33.Contini V, Rovaris DL, Victor MM, Grevet EH, Rohde LA, Bau CH. Pharmacogenetics of response to methylphenidate in adult patients with attention-deficit/hyperactivity disorder (ADHD): a systematic review. Eur Neuropsychopharmacol. 2013;23:555–60.Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev. 2006;58(3):521–90.Abul-Husn NS, Obeng AO, Sanderson SC, Gottesman O, Scott SA. Implementation and utilization of genetic testing in personalized medicine. Pharmacogenomics Pers Med. 2014;7:227.Altman RB, Flockhart D, Goldstein DB, editors. Principles of pharmacogenetics and pharmacogenomics. Cambridge: Cambridge University Press; 2012.Hawi Z, Cummins TDR, Tong J, Johnson B, Lau R, Samarrai W, et al. The molecular genetic architecture of attention deficit hyperactivity disorder. Mol Psychiatry. 2015;20:289–97.Limaye N. Pharmacogenomics, Theranostics and Personalized Medicine-the complexities of clinical trials: challenges in the developing world. Appl Transl Genomics. 2013;2:17–21.Manolio TA, Chisholm RL, Ozenberger B, Roden DM, Williams MS, Wilson R, et al. Implementing genomic medicine in the clinic: the future is here. Genet Med. 2013;15:258–67.Kim S, Misra A. PharmGKB: the Pharmacogenomics Knowledge Base. Annu Rev Biomed Eng. 2007;9:289–320.Lucarelli F, Tombelli S, Minunni M, Marrazza G, Mascini M. Electrochemical and piezoelectric DNA biosensors for hybridisation detection. Anal Chim Acta. 2008;609:139–59.Knez K, Spasic D, Janssen KP, Lammertyn J. Emerging technologies for hybridization based single nucleotide polymorphism detection. Analyst. 2014;139:353–70.Choi JY, Kim YT, Byun JY, Ahn J, Chung S, Gweon DG, et al. Integrated allele-specific polymerase chain reaction–capillary electrophoresis microdevice for single nucleotide polymorphism genotyping. Lab Chip. 2012;12:5146–54.Ragoussis J. Genotyping Technologies for Genetic Research. Annu Rev Genomics Hum Genet. 2009;10:117–33.Sethi D, Gandhi RP, Kuma P, Gupta KC. Chemical strategies for immobilization of oligonucleotides. Biotechnol J. 2009;4:1513–29.Bañuls MJ, Morais SB, Tortajada-Genaro LA, Maquieira A. Microarray Developed on Plastic Substrates. Microarray Technology: Methods and Applications, 2016; 37-51.Tortajada-Genaro LA, Rodrigo A, Hevia E, Mena S, Niñoles R, Maquieira A. Microarray on digital versatile disc for identification and genotyping of Salmonella and Campylobacter in meat products. Anal Bioanal Chem. 2015;407:7285–94.Kieling C, Genro JP, Hutz MH, Rohde LA. A current update on ADHD pharmacogenomics. Pharmacogenomics. 2010;11:407–19.Kim BN, Kim JW, Cummins TD, Bellgrove MA, Hawi Z, Hong SB, et al. Norepinephrine genes predict response time variability and methylphenidate-induced changes in neuropsychological function in attention deficit hyperactivity disorder. J Clin Psychopharmacol. 2013;33:356–62.Carpentier PJ, Arias Vasquez A, Hoogman M, Onnink M, Kan CC, Kooij JJS, et al. Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders: A pilot study of six candidate genes. Eur Neuropsychopharmacol. 2013;23:448–57.Zhang Y, Haraksingh R, Grubert F, Abyzov A, Gerstein M, Weissman S, et al. Child development and structural variation in the human genome. Child Dev. 2013;84:34–48.Asari M, Watanabe S, Matsubara K, Shiono H, Shimizu K. Single nucleotide polymorphism genotyping by mini-primer allele-specific amplification with universal reporter primers for identification of degraded DNA. Anal Biochem. 2009;386:85–90.Choi JY, Kim YT, Ahn J, Kim KS, Gweon DG, Seo TS. Integrated allele-specific polymerase chain reaction–capillary electrophoresis microdevice for single nucleotide polymorphism genotyping. Biosens Bioelectron. 2012;35:327–34.Konstantou JK, Ioannou PC, Christopoulos TK. Dual-allele dipstick assay for genotyping single nucleotide polymorphisms by primer extension reaction. Eur J Hum Genet. 2009;17:105–11.Sebastian T, Cooney CG, Parker J, Qu P, Perov A, Golova JB, et al. Integrated amplification microarray system in a lateral flow cell for warfarin genotyping from saliva. Clin Chim Acta. 2014;429:198–205

Risk Model-Based Lung Cancer Screening and Racial and Ethnic Disparities in the US

Importance The revised 2021 US Preventive Services Task Force (USPSTF) guidelines for lung cancer screening have been shown to reduce disparities in screening eligibility and performance between African American and White individuals vs the 2013 guidelines. However, potential disparities across other racial and ethnic groups in the US remain unknown. Risk model–based screening may reduce racial and ethnic disparities and improve screening performance, but neither validation of key risk prediction models nor their screening performance has been examined by race and ethnicity.Objective To validate and recalibrate the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012) model—a well-established risk prediction model based on a predominantly White population—across races and ethnicities in the US and evaluate racial and ethnic disparities and screening performance through risk-based screening using PLCOm2012 vs the USPSTF 2021 criteria.Design, Setting, and Participants In a population-based cohort design, the Multiethnic Cohort Study enrolled participants in 1993-1996, followed up through December 31, 2018. Data analysis was conducted from April 1, 2022, to May 19. 2023. A total of 105 261 adults with a smoking history were included.Exposures The 6-year lung cancer risk was calculated through recalibrated PLCOm2012 (ie, PLCOm2012-Update) and screening eligibility based on a 6-year risk threshold greater than or equal to 1.3%, yielding similar eligibility as the USPSTF 2021 guidelines.Outcomes Predictive accuracy, screening eligibility-incidence (E-I) ratio (ie, ratio of the number of eligible to incident cases), and screening performance (sensitivity, specificity, and number needed to screen to detect 1 lung cancer).Results Of 105 261 participants (60 011 [57.0%] men; mean [SD] age, 59.8 [8.7] years), consisting of 19 258 (18.3%) African American, 27 227 (25.9%) Japanese American, 21 383 (20.3%) Latino, 8368 (7.9%) Native Hawaiian/Other Pacific Islander, and 29 025 (27.6%) White individuals, 1464 (1.4%) developed lung cancer within 6 years from enrollment. The PLCOm2012-Update showed good predictive accuracy across races and ethnicities (area under the curve, 0.72-0.82). The USPSTF 2021 criteria yielded a large disparity among African American individuals, whose E-I ratio was 53% lower vs White individuals (E-I ratio: 9.5 vs 20.3; P &lt; .001). Under the risk-based screening (PLCOm2012-Update 6-year risk ≥1.3%), the disparity between African American and White individuals was substantially reduced (E-I ratio: 15.9 vs 18.4; P &lt; .001), with minimal disparities observed in persons of other minoritized groups, including Japanese American, Latino, and Native Hawaiian/Other Pacific Islander. Risk-based screening yielded superior overall and race and ethnicity–specific performance to the USPSTF 2021 criteria, with higher overall sensitivity (67.2% vs 57.7%) and lower number needed to screen (26 vs 30) at similar specificity (76.6%).Conclusions The findings of this cohort study suggest that risk-based lung cancer screening can reduce racial and ethnic disparities and improve screening performance across races and ethnicities vs the USPSTF 2021 criteria

Multiparticle azimuthal correlations for extracting event-by-event elliptic and triangular flow in Au + Au collisions at sNN =200 GeV

We present measurements of elliptic and triangular azimuthal anisotropy of charged particles detected at forward rapidity 1&lt;|η|&lt;3 in Au + Au collisions at sNN=200 GeV, as a function of centrality. The multiparticle cumulant technique is used to obtain the elliptic flow coefficients v2{2},v2{4},v2{6}, and v2{8}, and triangular flow coefficients v3{2} and v3{4}. Using the small-variance limit, we estimate the mean and variance of the event-by-event v2 distribution from v2{2} and v2{4}. In a complementary analysis, we also use a folding procedure to study the distributions of v2 and v3 directly, extracting both the mean and variance. Implications for initial geometrical fluctuations and their translation into the final-state momentum distributions are discussed