MSTPublications: March 2022
Introduction to the BioChemical Library (BCL): An Application-Based Open-Source Toolkit for Integrated Cheminformatics and Machine Learning in Computer-Aided Drug Discovery.
Brown BP, Vu O, Geanes AR, Kothiwale S, Butkiewicz M, Lowe EW Jr, Mueller R, Pape R, Mendenhall J, Meiler J.
Front Pharmacol. 2022 Feb 21;13:833099. doi: 10.3389/fphar.2022.833099. eCollection 2022.
The BioChemical Library (BCL) cheminformatics toolkit is an application-based academic open-source software package designed to integrate traditional small molecule cheminformatics tools with machine learning-based quantitative structure-activity/property relationship (QSAR/QSPR) modeling. In this pedagogical article we provide a detailed introduction to core BCL cheminformatics functionality, showing how traditional tasks (e.g., computing chemical properties, estimating druglikeness) can be readily combined with machine learning. In addition, we have included multiple examples covering areas of advanced use, such as reaction-based library design. We anticipate that this manuscript will be a valuable resource for researchers in computer-aided drug discovery looking to integrate modular cheminformatics and machine learning tools into their pipelines.
Rare Diseases That Impersonate One Another: X-Linked Hypophosphatemia and Tumor-Induced Osteomalacia, a Retrospective Analysis of Discriminating Features.
DeCorte J, Randazzo E, Black M, Hendrickson C, Dahir K.
JBMR Plus. 2022 Jan 7;6(2):e10580. doi: 10.1002/jbm4.10580. eCollection 2022 Feb.
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate-wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients’ emotional and economic burden. Current diagnostics for TIO rely on decades-old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (n = 9) and X-linked hypophosphatemia (XLH; n = 43), a frequent misdiagnosis for patients with TIO. The TIO cohort had significantly elevated FGF23 (365 versus 95 RU/mL, p < 0.001) and alkaline phosphatase (282.8 versus 118.5 IU/L, p < 0.01) but significantly reduced phosphorus (1.4 versus 2.2 mg/dL, p < 0.05) and 1,25(OH)2 D (16.6 versus 59.8 pg/mL, p < 0.01). By contrast, total vitamin D was similar between the two groups. Dual-energy X-ray absorptiometry (DXA) scans reveal lower Z-scores in the hip (-1.6 versus 0.050, p < 0.01) and spine (0.80 versus 2.35, p < 0.05). TIO patients were more likely to have prior clinical diagnosis of osteoporosis (67% versus 0%), use assistive devices in daily living (100% versus 14%), and have received a knee arthroplasty (33% versus 7%). TIO patients lost an average of 1.5 cm over their disease course and had sustained an average of 8 fractures each, whereas fractures were rare in XLH. The XLH cohort had higher incidence of osteotomy (19% versus 0%), spinal stenosis (12% versus 0%), secondary dental abnormalities (95% versus 44%, p < 0.001), and depression and anxiety (46.5% versus 11%). These results deepen our understanding of the subtle differences present between diseases of phosphate wasting. They suggest several biochemical, clinical, and historical features that effectively distinguish TIO from XLH.
Dominant negative effects of SCN5A missense variants.
O’Neill MJ, Muhammad A, Li B, Wada Y, Hall L, Solus JF, Short L, Roden DM, Glazer AM.
Genet Med. 2022 Mar 16:S1098-3600(22)00656-6. doi: 10.1016/j.gim.2022.02.010. Online ahead of print.
Purpose: Up to 30% of patients with Brugada syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel gene SCN5A encoding for the protein NaV1.5. Recent studies suggested that NaV1.5 can dimerize, and some variants exert dominant negative effects. In this study, we sought to explore the generality of missense variant NaV1.5 dominant negative effects and their clinical severity.
Methods: We identified 35 LoF variants (<10% of wild type [WT] peak current) and 15 partial LoF variants (10%-50% of WT peak current) that we assessed for dominant negative effects. SCN5A variants were studied in HEK293T cells, alone or in heterozygous coexpression with WT SCN5A using automated patch clamp. To assess the clinical risk, we compared the prevalence of dominant negative vs putative haploinsufficient (frameshift, splice, or nonsense) variants in a BrS consortium and the Genome Aggregation Database population database.
Results: In heterozygous expression with WT, 32 of 35 LoF and 6 of 15 partial LoF variants showed reduction to <75% of WT-alone peak current, showing a dominant negative effect. Individuals with dominant negative LoF variants had an elevated disease burden compared with the individuals with putative haploinsufficient variants (2.7-fold enrichment in BrS cases, P = .019).
Conclusion: Most SCN5A missense LoF variants exert a dominant negative effect. This class of variant confers an especially high burden of BrS.
A tRNA modifying enzyme as a tunable regulatory nexus for bacterial stress responses and virulence.
Fleming BA, Blango MG, Rousek AA, Kincannon WM, Tran A, Lewis AJ, Russell CW, Zhou Q, Baird LM, Barber AE, Brannon JR, Beebout CJ, Bandarian V, Hadjifrangiskou M, Howard MT, Mulvey MA.
Nucleic Acids Res. 2022 Feb 25:gkac116. doi: 10.1093/nar/gkac116. Online ahead of print.
Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice.
Holden JM, Al Hussein Al Awamlh S, Croteau LP, Boal AM, Rex TS, Risner ML, Calkins DJ, Wareham LK.
Int J Mol Sci. 2022 Mar 12;23(6):3066. doi: 10.3390/ijms23063066.
Coinfections in Patients With Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Study.
Satyanarayana G, Enriquez KT, Sun T, Klein EJ, Abidi M, Advani SM, Awosika J, Bakouny Z, Bashir B, Berg S, Bernardes M, Egan PC, Elkrief A, Feldman LE, Friese CR, Goel S, Gomez CG, Grant KL, Griffiths EA, Gulati S, Gupta S, Hwang C, Jain J, Jani C, Kaltsas A, Kasi A, Khan H, Knox N, Koshkin VS, Kwon DH, Labaki C, Lyman GH, McKay RR, McNair C, Nagaraj G, Nakasone ES, Nguyen R, Nonato TK, Olszewski AJ, Panagiotou OA, Puc M, Razavi P, Robilotti EV, Santos-Dutra M, Schmidt AL, Shah DP, Shah SA, Vieira K, Weissmann LB, Wise-Draper TM, Wu U, Wu JT, Choueiri TK, Mishra S, Warner JL, French B, Farmakiotis D.
Open Forum Infect Dis. 2022 Feb 14;9(3):ofac037. doi: 10.1093/ofid/ofac037. eCollection 2022 Mar.
SEEG Functional Connectivity Measures to Identify Epileptogenic Zones: Stability, Medication Influence, and Recording Condition.
Paulo DL, Wills KE, Johnson GW, Gonzalez HFJ, Rolston JD, Naftel RP, Reddy SB, Morgan VL, Kang H, Roberson SW, Narasimhan S, Englot DJ.
Neurology. 2022 Mar 25:10.1212/WNL.0000000000200386. doi: 10.1212/WNL.0000000000200386. Online ahead of print.
Concurrent brain-responsive and vagus nerve stimulation for treatment of drug-resistant focal epilepsy.
Brown MG, Sillau S, McDermott D, Ernst LD, Spencer DC, Englot DJ, González HFJ, Datta P, Karakis I, Becker D, Rolston JD, Arain A, Rao VR, Doherty M, Urban A, Drees C.
Epilepsy Behav. 2022 Mar 16;129:108653. doi: 10.1016/j.yebeh.2022.108653. Online ahead of print.
Massively parallel enrichment of low-frequency alleles enables duplex sequencing at low depth.
Gydush G, Nguyen E, Bae JH, Blewett T, Rhoades J, Reed SC, Shea D, Xiong K, Liu R, Yu F, Leong KW, Choudhury AD, Stover DG, Tolaney SM, Krop IE, Christopher Love J, Parsons HA, Mike Makrigiorgos G, Golub TR, Adalsteinsson VA.
Nat Biomed Eng. 2022 Mar 17. doi: 10.1038/s41551-022-00855-9. Online ahead of print.
High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster.
Jasra S, Giricz O, Zeig-Owens R, Pradhan K, Goldfarb DG, Barreto-Galvez A, Silver AJ, Chen J, Sahu S, Gordon-Mitchell S, Choudhary GS, Aluri S, Bhagat TD, Shastri A, Bejan CA, Stockton SS, Spaulding TP, Thiruthuvanathan V, Goto H, Gerhardt J, Haider SH, Veerappan A, Bartenstein M, Nwankwo G, Landgren O, Weiden MD, Lekostaj J, Bender R, Fletcher F, Greenberger L, Ebert BL, Steidl U, Will B, Nolan A, Madireddy A, Savona MR, Prezant DJ, Verma A.
Nat Med. 2022 Mar 7. doi: 10.1038/s41591-022-01708-3. Online ahead of print.
Neuroticism Drives Associations Between Repetitive Behaviors and Depression in Autistic Adults.
Schwartzman JM, Williams ZJ, Richards JK, Mattheiss SR, Gotham KO.
Front Psychiatry. 2022 Mar 2;13:803361. doi: 10.3389/fpsyt.2022.803361. eCollection 2022.