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MSTPublications: January 2025

Posted by on Thursday, January 30, 2025 in New Publications .

Interpretable Deep-Learning pKa Prediction for Small Molecule Drugs via Atomic Sensitivity Analysis.
DeCorte J, Brown B, Jeffrey R, Meiler J.
J Chem Inf Model. 2025 Jan 13;65(1):101-113. doi: 10.1021/acs.jcim.4c01472. Epub 2024 Dec 30.
PMID: 39801290 Free PMC article.
Abstract: Machine learning (ML) models now play a crucial role in predicting properties essential to drug development, such as a drug’s logscale acid-dissociation constant (pKa). Despite recent architectural advances, these models often generalize poorly to novel compounds due to a scarcity of ground-truth data. Further, these models lack interpretability. To this end, with deliberate molecular embeddings, atomic-resolution information is accessible in chemical structures by observing the model response to atomic perturbations of an input molecule. Here, we present BCL-XpKa, a deep neural network (DNN)-based multitask classifier for pKa prediction that encodes local atomic environments through Mol2D descriptors. BCL-XpKa outputs a discrete distribution for each molecule, which stores the pKa prediction and the model’s uncertainty for that molecule. BCL-XpKa generalizes well to novel small molecules. BCL-XpKa performs competitively with modern ML pKa predictors, outperforms several models in generalization tasks, and accurately models the effects of common molecular modifications on a molecule’s ionizability. We then leverage BCL-XpKa’s granular descriptor set and distribution-centered output through atomic sensitivity analysis (ASA), which decomposes a molecule’s predicted pKa value into its respective atomic contributions without model retraining. ASA reveals that BCL-XpKa has implicitly learned high-resolution information about molecular substructures. We further demonstrate ASA’s utility in structure preparation for protein-ligand docking by identifying ionization sites in 93.2% and 87.8% of complex small molecule acids and bases. We then applied ASA with BCL-XpKa to identify and optimize the physicochemical liabilities of a recently published KRAS-degrading PROTAC.

 

Prevalence and sequelae of asymptomatic Clostridioides difficile colonization in children with inflammatory bowel disease.
Reasoner SA, Zhang LS, Bernard R, Edwards KM, Nicholson MR.
J Pediatr Gastroenterol Nutr. 2024 Dec 20. doi: 10.1002/jpn3.12439. Online ahead of print.
PMID: 39704253
Abstract: Colonization by Clostridioides difficile is common in children with inflammatory bowel disease (IBD) and complicates both the management of IBD and the diagnosis of C. difficile infection (CDI). There is a paucity of data on rates, risk factors, and outcomes associated with asymptomatic C. difficile colonization in children with IBD. We enrolled and prospectively followed 87 children with IBD without acute gastrointestinal symptoms. Twelve patients (13.8%) tested positive for C. difficile and were considered to have asymptomatic colonization. Elevated white blood cell count was associated with C. difficile colonization based on univariate regression. Three of the 12 (25%) C. difficile colonized patients were diagnosed with CDI in the 90 days following screening for C. difficile, versus 0 of the 75 who tested negative for C. difficile (p = 0.002). This data set the stage for further longitudinal tracking of children with IBD for C. difficile colonization and associated outcomes.
Keywords: carriage; outcomes; pediatrics.

 

Uterine fibroids show evidence of shared genetic architecture with blood pressure traits.
Akerele AT, Piekos JA, Kim J, Khankari NK, Hellwege JN, Edwards TL, Velez Edwards DR.
Pac Symp Biocomput. 2025;30:281-295.
PMID: 39670377 Free PMC article. 

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.
Jakubek YA, Ma X, Stilp AM, Yu F, Bacon J, Wong JW, Aguet F, Ardlie K, Arnett DK, Barnes K, Bis JC, Blackwell T, Becker LC, Boerwinkle E, Bowler RP, Budoff MJ, Carson AP, Chen J, Cho MH, Coresh J, Cox NJ, de Vries PS, DeMeo DL, Fardo DW, Fornage M, Guo X, Hall ME, Heard-Costa N, Hidalgo B, Irvin MR, Johnson AD, Jorgenson E, Kenny EE, Kessler MD, Levy D, Li Y, Lima JAC, Liu Y, Locke AE, Loos RJF, Machiela MJ, Mathias RA, Mitchell BD, Murabito JM, Mychaleckyj JC, North KE, Orchard P, Parker SCJ, Pershad Y, Peyser PA, Pratte KA, Psaty BM, Raffield LM, Redline S; Regeneron Genetics Center; Rich SS, Rotter JI, Shah SJ, Smith JA, Smith AP, Smith A, Taub MA, Tiwari HK, Tracy R, Tuftin B; NHLBI Trans-Omics for Precision Medicine Consortium; Bick AG, Sankaran VG, Reiner AP, Scheet P, Auer PL.
Am J Hum Genet. 2025 Jan 6:S0002-9297(24)00456-7. doi: 10.1016/j.ajhg.2024.12.014. Online ahead of print.
PMID: 39809269 Free article. 

Novel Dynamic Organ Storage System Enhances Liver Graft Function in a Porcine Donation After Circulatory Death Model.
Shishido Y, Tracy KM, Petrovic M, Adesanya T, Fortier AK, Raietparvar K, Glomp GA, Simonds E, Harris TR, Simon V, Tucker WD, Petree B, Cortelli M, Cardwell NL, Crannell C, Liang J, Murphy AC, Fields BL, McReynolds M, Demarest CT, Ukita R, Rizzari M, Montenovo M, Magliocca JF, Karp SJ, Rauf MA, Shah AS, Bacchetta M.
ASAIO J. 2024 Dec 18. doi: 10.1097/MAT.0000000000002365. Online ahead of print.
PMID: 39693205

Resident Salary Compared With Living Wages at US Training Institutions.
Liles C, Tang AR, Petrovic M, Dambrino RJ 4th, Thompson RC, Chambless LB.
Ann Surg. 2025 Jan 1;281(1):46-53. doi: 10.1097/SLA.0000000000006335. Epub 2024 May 10.
PMID: 38726667 

A blueprint for pursuing therapeutic interventions and early phase clinical trials in clonal haematopoiesis.
Haque T, Shastri A, Desai P, Xie Z, Hammond D, King Z, Kishtagari A, Madanat YF, Abaza Y, Silver AJ, Singh A, Borate UM, Heimlich JB, Slosky DA, Bolton KL, Patnaik MS, Bick AG, Verma AK, Jaiswal S, Steensma DP, Savona MR.
Br J Haematol. 2024 Dec 9. doi: 10.1111/bjh.19925. Online ahead of print.
PMID: 39653653 Review.

Sex- and endurance training-mediated cardiovascular protection through lipids during exercise.
An J, Thorson AS, Wasserman DH, Stafford JM, Zhu L.
Trends Endocrinol Metab. 2024 Dec 31:S1043-2760(24)00326-6. doi: 10.1016/j.tem.2024.12.004. Online ahead of print.
PMID: 39743402 Review.

Attitudes of autistic adults toward genetic testing for autism.
Gallion T, Williams ZJ, Niarchou M, Duncan L, Hooker G, Taylor KA.
J Genet Couns. 2025 Feb;34(1):e1918. doi: 10.1002/jgc4.1918. Epub 2024 May 25.
PMID: 38795017 Free PMC article.

How auditory processing influences the autistic profile: A review.
Poulsen R, Williams Z, Dwyer P, Pellicano E, Sowman PF, McAlpine D.
Autism Res. 2024 Dec;17(12):2452-2470. doi: 10.1002/aur.3259. Epub 2024 Nov 17.
PMID: 39552096 Free PMC article. Review.