Improving population scale statistical phasing with whole-genome sequencing data.

Haplotype estimation, or phasing, has gained significant traction in large-scale projects due to its valuable contributions to population genetics, variant analysis, and the creation of reference panels for imputation and phasing of new samples. To scale with the growing number of samples, haplotype estimation methods designed for population scale rely on highly optimized statistical models to phase genotype data, and usually ignore read-level information. Statistical methods excel in resolving common variants, however, they still struggle at rare variants due to the lack of statistical information. In this study we introduce SAPPHIRE, a new method that leverages whole-genome sequencing data to enhance the precision of haplotype calls produced by statistical phasing. SAPPHIRE achieves this by refining haplotype estimates through the realignment of sequencing reads, particularly targeting low-confidence phase calls. Our findings demonstrate that SAPPHIRE significantly enhances the accuracy of haplotypes obtained from state of the art methods and also provides the subset of phase calls that are validated by sequencing reads. Finally, we show that our method scales to large data sets by its successful application to the extensive 3.6 Petabytes of sequencing data of the last UK Biobank 200,031 sample release.

Synthesis and evaluation of 3,4,5-trisubstituted triazoles as G protein-biased kappa opioid receptor agonists.

Kappa opioid receptor (KOR) agonists represent promising therapeutics for pain relief due to their analgesic properties along with lower abuse potential than opioids that act at the mu opioid receptor. However, typical KOR agonists produce sedation and dysphoria. Previous studies have shown that G protein signaling-biased KOR agonists may present a means to untangle the desired analgesic properties from undesired side effects. In this paper, we report a new series of G protein signaling-biased KOR agonists entailing -S- → -CH2- replacement in a previously reported KOR agonist, triazole 1.1. With an optimized carbon linker in hand, further development of the scaffold was undertaken to investigate the appendages of the triazole core. The structure-activity relationship study of this series is described, including several analogues that display enhanced potency while maintaining G protein-signaling bias compared to triazole 1.1.

A Chronological Overview of Using Deep Learning for Leukemia Detection: A Scoping Review.

Leukemia is a rare but fatal cancer of the blood. This cancer arises from abnormal bone marrow cells and requires prompt diagnosis for effective treatment and positive patient prognosis. Traditional diagnostic methods (e.g., microscopy, flow cytometry, and biopsy) pose challenges in both accuracy and time, demanding an inquisition on the development and use of deep learning (DL) models, such as convolutional neural networks (CNN), which could allow for a faster and more exact diagnosis. Using specific, objective criteria, DL might hold promise as a tool for physicians to diagnose leukemia. The purpose of this review was to report the relevant available published literature on using DL to diagnose leukemia. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, articles published between 2010 and 2023 were searched using Embase, Ovid MEDLINE, and Web of Science, searching the terms "leukemia" AND "deep learning" or "artificial neural network" OR "neural network" AND "diagnosis" OR "detection." After screening retrieved articles using pre-determined eligibility criteria, 20 articles were included in the final review and reported chronologically due to the nascent nature of the phenomenon. The initial studies laid the groundwork for subsequent innovations, illustrating the transition from specialized methods to more generalized approaches capitalizing on DL technologies for leukemia detection. This summary of recent DL models revealed a paradigm shift toward integrated architectures, resulting in notable enhancements in accuracy and efficiency. The continuous refinement of models and techniques, coupled with an emphasis on simplicity and efficiency, positions DL as a promising tool for leukemia detection. With the help of these neural networks, leukemia detection could be hastened, allowing for an improved long-term outlook and prognosis. Further research is warranted using real-life scenarios to confirm the suggested transformative effects DL models could have on leukemia diagnosis.

Findings from the First Year of a Federally Funded, Direct-to-Consumer HIV Self-Test Distribution Program - United States, March 2023-March 2024.

In September 2022, CDC funded a nationwide program, Together TakeMeHome (TTMH), to expand distribution of HIV self-tests (HIVSTs) directly to consumers by mail through an online ordering portal. To publicize the availability of HIVSTs to priority audiences, particularly those disproportionately affected by HIV, CDC promoted this program through established partnerships and tailored resources from its Let's Stop HIV Together social marketing campaign. The online portal launched March 14, 2023, and through March 13, 2024, distributed 443,813 tests to 219,360 persons. Among 169,623 persons who answered at least one question on a postorder questionnaire, 67.9% of respondents were from priority audiences, 24.1% had never previously received testing for HIV, and 24.8% had not received testing in the past year. Among the subset of participants who initiated a follow-up survey, 88.3% used an HIVST themselves, 27.1% gave away an HIVST, 11.7% accessed additional preventive services, and 1.9% reported a new positive HIVST result. Mailed HIVST distribution can quickly reach large numbers of persons who have never received testing for HIV or have not received testing as often as is recommended. TTMH can help to achieve the goal of diagnosing HIV as early as possible and provides a path to other HIV prevention and care services. Clinicians, community organizations, and public health officials should be aware of HIVST programs, initiate discussions about HIV testing conducted outside their clinics or offices, and initiate follow-up services for persons who report a positive or negative HIVST result.

Developmental origin of oligodendrocytes determines their function in the adult brain.

In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function.

The occurrence and bioactivity of tetrahydronaphthoquinoline-diones (THNQ-dione).

Natural products have been important in the discovery of new drugs, but their use is limited due to issues with accessibility and synthesis. Tetrahydronaphthoquinoline-dione (THNQ-dione) is a key structural feature found in several natural and synthetic compounds that exhibit notable biological properties. The unique properties of THNQ-diones can be attributed to the fusion of tetrahydroquinoline and anthraquinone moieties. These alkaloids are synthesised through various biosynthetic pathways, leading to diverse structures and bioactivities. Despite their significance, THNQ-diones have not been extensively covered in the review literature, highlighting the importance of this article in discussing their natural occurrence and biological activities. This article explores the distribution of THNQ-dione alkaloids in different organisms and their potential as a source of novel bioactive natural products.

Asymmetric allostery in estrogen receptor-α homodimers drives responses to the ensemble of estrogens in the hormonal milieu.

The estrogen receptor-α (ER) is thought to function only as a homodimer but responds to a variety of environmental, metazoan, and therapeutic estrogens at subsaturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations-receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining the binding of the same ligand in crystal structures of ER in the agonist vs. antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist vs. antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from the ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric vs. dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing different modes for ligand-dependent regulation of ER activity.

Use of Artificial Intelligence in Triage in Hospital Emergency Departments: A Scoping Review.

The integration of artificial intelligence (AI) and machine learning (ML) in healthcare has become a major point of interest and raises the question of its impact on the emergency department (ED) triaging process. AI's capacity to emulate human cognitive processes coupled with advancements in computing has shown positive outcomes in various aspects of healthcare but little is known about the use of AI in triaging patients in ED. AI algorithms may allow for earlier diagnosis and intervention; however, overconfident answers may present dangers to patients. The purpose of this review was to explore comprehensively recently published literature regarding the effect of AI and ML in ED triage and identify research gaps. A systemized search was conducted in September 2023 using the electronic databases EMBASE, Ovid MEDLINE, and Web of Science. To meet inclusion criteria, articles had to be peer-reviewed, written in English, and based on primary data research studies published in US journals 2013-2023. Other criteria included 1) studies with patients needing to be admitted to hospital EDs, 2) AI must have been used when triaging a patient, and 3) patient outcomes must be represented. The search was conducted using controlled descriptors from the Medical Subject Headings (MeSH) that included the terms "artificial intelligence" OR "machine learning" AND "emergency ward" OR "emergency care" OR "emergency department" OR "emergency room" AND "patient triage" OR "triage" OR "triaging." The search initially identified 1,142 citations. After a rigorous, systemized screening process and critical appraisal of the evidence, 29 studies were selected for the final review. The findings indicated that 1) ML models consistently demonstrated superior discrimination abilities compared to conventional triage systems, 2) the integration of AI into the triage process yielded significant enhancements in predictive accuracy, disease identification, and risk assessment, 3) ML accurately determined the necessity of hospitalization for patients requiring urgent attention, and 4) ML improved resource allocation and quality of patient care, including predicting length of stay. The suggested superiority of ML models in prioritizing patients in the ED holds the potential to redefine triage precision.

Osteopathic Medical Students' Concerns About the Future of Abortion Education and Training Post-Roe v. Wade.

Background In the United States, new regulations on access to abortion and, in some cases, penalization of physicians who provide abortions, have been established on a state-by-state basis. The American College of Obstetricians and Gynecologists recommends that medical schools include abortion training in their curriculum. It is still unknown if the Dobbs decision will limit medical students' abortion training and/or discourage them from pursuing a career in obstetrics. The goal of this study was to investigate the attitudes of medical students toward abortion following the Dobbs decision and their beliefs about its possible effect on future medical education and practice. Methods This cross-sectional, observational study collected data from students enrolled in a Florida, United States osteopathic medical school using an anonymous online questionnaire from February to March 2023. The questionnaire contained 35 items that addressed medical students' attitudes towards a range of potential implications on medical training due to the new abortion restrictions. Hypothesis testing was performed using Spearman's rho correlation and multivariate linear regression to explore the relationship between the predictor variables (concerns about future practice regarding abortion, religiosity, and acceptability of abortion based on gestation age) and the predicted variable (attitudes about abortion). Data were analyzed using Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 28.0, Armonk, NY). Results In total, 158 participants completed the questionnaire; 91 (57.6%) were women. The mean age was 25.8 (range 21-37 years). Using a stepwise regression analysis, only the variables shown to be statistically associated (per Spearman's rho bivariate correlation) with the predicted variable (abortion attitudes) were entered into the model (i.e., concerns about abortion education and future practice, religiosity, and abortion acceptability based on gestational age). A significant regression equation was found (F(3,134) = 205.750, p < 0.001, R2 = 0.822, R2 adjusted = 0.818). The percentage of variance in the scores accounted for by the model was 82%. Higher levels of feeling that the abortion ban would negatively affect their training and future practice, greater religiosity, and acceptability of abortion at later gestation ages were statistically significant predictors of more positive attitudes toward abortion in this sample of osteopathic medical students. Conclusions The results suggest that the attitudes of medical students toward abortion are related to multiple factors, including concerns about future abortion training, religiosity, and the week of pregnancy acceptable for a woman to have an abortion. Findings also highlight the attitudes of medical students in response to more restrictive abortion legislation, emphasizing their desire for possible curricular enhancements to safeguard their training and education.

Host resources and parasite traits interact to determine the optimal combination of host parasite-mitigation strategies.

Organisms have evolved diverse strategies to manage parasite infections. Broadly, hosts may avoid infection by altering behaviour, resist infection by targeting parasites or tolerate infection by repairing associated damage. The effectiveness of a strategy depends on interactions between, for example, resource availability, parasite traits (virulence, life-history) and the host itself (nutritional status, immunopathology). To understand how these factors shape host parasite-mitigation strategies, we developed a mathematical model of within-host, parasite-immune dynamics in the context of helminth infections. The model incorporated host nutrition and resource allocation to different mechanisms of immune response: larval parasite prevention; adult parasite clearance; damage repair (tolerance). We also considered a non-immune strategy: avoidance via anorexia, reducing intake of infective stages. Resources not allocated to immune processes promoted host condition, whereas harm due to parasites and immunopathology diminished it. Maximising condition (a proxy for fitness), we determined optimal host investment for each parasite-mitigation strategy, singly and combined, across different environmental resource levels and parasite trait values. Which strategy was optimal varied with scenario. Tolerance generally performed well, especially with high resources. Success of the different resistance strategies (larval prevention or adult clearance) tracked relative virulence of larval and adult parasites: slowly maturing, highly damaging larvae favoured prevention; rapidly maturing, less harmful larvae favoured clearance. Anorexia was viable only in the short term, due to reduced host nutrition. Combined strategies always outperformed any lone strategy: these were dominated by tolerance, with some investment in resistance. Choice of parasite mitigation strategy has profound consequences for hosts, impacting their condition, survival and reproductive success. We show that the efficacy of different strategies is highly dependent on timescale, parasite traits and resource availability. Models that integrate such factors can inform the collection and interpretation of empirical data, to understand how those drivers interact to shape host immune responses in natural systems.

First-line palliative systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: A single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy. METHODS: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached). CONCLUSIONS: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

Biological activity of natural 2-quinolinones.

While natural products have undeniably played a crucial role in drug discovery, challenges such as limited availability and complex synthesis methods have hindered the identification of lead compounds. At the core of numerous natural and synthetic compounds, each displaying distinct biological behaviours, lies the foundational structure of 2-quinolinone. Compounds with this structural motif exhibit a broad range of effects in different tissues. Furthermore, specific members showcase therapeutic potential for various disorders. Despite the significance of these compounds, the current review literature has not provided a comprehensive overview, underscoring the essential contribution of this article in exploring their biological functions. This study examines the biological activity of selected 2-quinolinone alkaloids across diverse organisms, unveiling their potential as a source of innovative bioactive natural products.

Recommended measurement instruments for genitourinary symptoms associated with menopause: the COMMA (Core outcomes in menopause) consortium.

OBJECTIVE: The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects. METHODS: We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome. RESULTS: A total of 87 publications reporting on 34 PROMs were identified from 21,207 publications screened. Of these 34 PROMs, 29 were not considered to sufficiently map onto the core outcomes, and 26 of these also had insufficient measurement properties. Therefore, only five PROMs corresponding to two core outcomes were considered for recommendation. We recommend the PROMIS Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity to measure the outcome of "pain with sexual activity" and the Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire to measure "distress, bother or interference" from genitourinary symptoms. Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events in study participants, which is a requirement of Good Clinical Practice. CONCLUSIONS: Suitable PROMs and definitions were identified to measure three of eight core outcomes. Because of the lack of existing measures, which align with the core outcomes and have evidence of high-quality measurement properties, future work will focus on developing or validating PROMs for the remaining five core outcomes.

Learning Robust and Sparse Principal Components With the α-Divergence.

In this paper, novel robust principal component analysis (RPCA) methods are proposed to exploit the local structure of datasets. The proposed methods are derived by minimizing the α -divergence between the sample distribution and the Gaussian density model. The α- divergence is used in different frameworks to represent variants of RPCA approaches including orthogonal, non-orthogonal, and sparse methods. We show that the classical PCA is a special case of our proposed methods where the α- divergence is reduced to the Kullback-Leibler (KL) divergence. It is shown in simulations that the proposed approaches recover the underlying principal components (PCs) by down-weighting the importance of structured and unstructured outliers. Furthermore, using simulated data, it is shown that the proposed methods can be applied to fMRI signal recovery and Foreground-Background (FB) separation in video analysis. Results on real world problems of FB separation as well as image reconstruction are also provided.

Human antibody signatures towards the Chlamydia trachomatis major outer membrane protein after natural infection and vaccination.

BACKGROUND: Chlamydia trachomatis (CT) Major Outer Membrane Protein (MOMP) holds a neutralising epitope in the Variable Domain 4 (VD4), and this region's immune dominance during infection is well known. This study aimed to assess the antibody response induced after infection and compare it for specificity and functionality to the response following vaccination with the vaccine CTH522, which contains VD4's from serovars D, E, F, and G. METHODS: We assessed the antibody epitopes in MOMP by a high density peptide array. Furthermore, the role of the VD4 epitope in neutralisation was explored by competitive inhibition experiments with a fusion protein holding the neutralising VD4 linear epitope. This was done in two independent groups: 1) MOMP seropositive individuals infected with CT (n = 10, from case-control study) and 2) CTH522/CAF®01-vaccinated females (n = 14) from the CHLM-01 clinical trial. FINDINGS: We identified the major antigenic regions in MOMP as VD4 and the conserved region just before VD3 in individuals infected with CT. The same regions, with the addition of VD1, were identified in vaccine recipients. Overall, the VD4 peptide responses were uniform in vaccinated individuals and led to inhibition of infection in vitro in all tested samples, whereas the VD4 responses were more heterogenous in individuals infected with CT, and only 2 out of 10 samples had VD4-mediated neutralising antibody responses. INTERPRETATION: These data provide insights into the role of antibodies against MOMP VD4 induced after infection and vaccination, and show that their functionality differs. The induction of functional VD4-specific antibodies in vaccine recipients mimics previous results from animal models. FUNDING: This work was supported by the European Commission through contract FP7-HEALTH-2011.1.4-4-280873 (ADITEC) and Fonden til Lægevidenskabens Fremme.

Neuropsychiatric Manifestations and Cognitive Decline in Patients With Long-Standing Lyme Disease: A Scoping Review.

Lyme disease (LD), or Lyme borreliosis, is a vector-borne disease that is caused by the transmission of the bacterium Borrelia burgdorferi through a tick bite. The symptoms of LD can persist in individuals chronically, even after the treatment and resolution of the initial infection. These symptoms include various neuropsychiatric manifestations and cognitive decline. The purpose of this review was to report the neuropsychiatric manifestations, cognitive decline, and effects of a delayed diagnosis on symptom severity in patients with long-standing LD (LSLD). A scoping review was conducted utilizing the electronic databases Embase, Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science. A total of 744 articles were retrieved and considered for inclusion. After a rigorous screening process, 10 articles that met the inclusion criteria for this review were included (i.e., reported neuropsychiatric manifestations and cognitive decline in patients with LSLD and the effects of a delayed diagnosis). Neuropsychiatric manifestations in the patients consisted of suicidal ideation, homicidal tendencies, extreme anger, depressive symptoms, aggression, and anxiety. Cognitive symptoms included dysfunctions in working memory, verbal learning/memory, non-verbal learning/memory, alertness, visuoconstructive, and frontal executive functioning. A delayed LD diagnosis increased symptom severity in most patients. The findings of this review indicate that neuropsychiatric and cognitive symptoms tend to present for a chronic period, even after disease recovery. Although researchers have established a link between a delayed LD diagnosis and increased symptom severity, LSLD is often an overlooked diagnosis in patients with neuropsychiatric symptoms and cognitive decline. More research is needed to compare the time to diagnosis and symptom severity in patients with LSLD.

Natural 3,4-dihydro-2(1H)-quinolinones- Part I: plant sources.

While natural products have undoubtedly played a pivotal role in drug discovery, their potential as lead compounds has been hindered by challenges such as limited accessibility and complex synthesis processes. At the core of numerous natural and synthetic compounds, each exhibiting remarkable biological traits, lies the foundational structure of 3,4-dihydro-2(1H)-quinolinone, also known as 2-oxo-tetrahydroquinoline (2 O-THQ). This article extensively examines the occurrence of 2 O-THQ alkaloids across the plant kingdom, exploring their capacity to serve as a source for innovative bioactive natural products. Despite the undeniable significance of these compounds, the existing body of review literature has yet to provide comprehensive coverage, underscoring the pivotal contribution of this present article in investigating their prevalence in nature.

Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.