Fast exact gap-affine partial order alignment with POASTA.

Motivation: Partial order alignment is a widely used method for computing multiple sequence alignments, with applications in genome assembly and pangenomics, among many others. Current algorithms to compute the optimal, gap-affine partial order alignment do not scale well to larger graphs and sequences. While heuristic approaches exist, they do not guarantee optimal alignment and sacrifice alignment accuracy.

Basic Science and Pathogenesis.

Background: Emerging studies have identified changes in lipid processing in Alzheimer's disease patients. However, how the various brain cell types respond to these changes is unclear. Multiple Alzheimer's disease risk genes are expressed in microglia and involved in lipid sensing and processing.

Basic Science and Pathogenesis.

Background: Cerebrovascular pathology frequently co-occurs with Alzheimer's disease (AD) pathology and the combinations of these forms of pathology may underly AD dementia. Sex hormones influence many aspects of cerebrovascular systems and may contribute to cerebrovascular pathology, but many studies of aging and AD do not measure hormones. Therefore, in this study, we explored whether a polygenic score predicting sex hormone levels relates to cerebrovascular pathology in the AD brain.

Routine Prenatal cfDNA Screening for Autosomal Dominant Single-Gene Conditions.

Background: Genetic screening has advanced from prenatal cell-free DNA (cfDNA) screening for aneuploidies (cfDNA-ANP) to single-gene disorders (cfDNA-SGD). Clinical validation studies have been promising in pregnancies with anomalies but are limited in the general population.

Methods: Chart review and laboratory data identified pregnancies with cfDNA-SGD screening for 25 autosomal dominant conditions at our academic center.

Polygenic Risk Scores in Human Disease.

Background: Polygenic risk scores (PRS) are measures of genetic susceptibility to human health traits. With the advent of large data repositories combining genetic data and phenotypic information, PRS are providing valuable insights into the genetic architecture of complex diseases and are transforming the landscape of precision medicine.

Content: PRS have emerged as tools with clinical utility in human disease.

Impact of Higher Cell-Free DNA Yields on Liquid Biopsy Testing in Glioblastoma Patients.

Background: Minimally invasive molecular profiling using cell-free DNA (cfDNA) is increasingly important to the management of cancer patients; however, low sensitivity remains a major limitation, particularly for brain tumor patients. Transiently attenuating cfDNA clearance from the body-thereby, allowing more cfDNA to be sampled-has been proposed to improve the performance of liquid biopsy diagnostics. However, there is a paucity of clinical data on the effect of higher cfDNA recovery.

Rational engineering of minimally immunogenic nucleases for gene therapy.

Genome editing using CRISPR-Cas systems is a promising avenue for the treatment of genetic diseases. However, cellular and humoral immunogenicity of genome editing tools, which originate from bacteria, complicates their clinical use. Here we report reduced immunogenicity (Red)(i)-variants of two clinically relevant nucleases, SaCas9 and AsCas12a.

Profiling lateral gene transfer events in the human microbiome using WAAFLE.

Lateral gene transfer (LGT), also known as horizontal gene transfer, facilitates genomic diversification in microbial populations. While previous work has surveyed LGT in human-associated microbial isolate genomes, the landscape of LGT arising in personal microbiomes is not well understood, as there are no widely adopted methods to characterize LGT from complex communities. Here we developed, benchmarked and validated a computational algorithm (WAAFLE or Workflow to Annotate Assemblies and Find LGT Events) to profile LGT from assembled metagenomes.

Fine-mapping causal tissues and genes at disease-associated loci.

Complex diseases often have distinct mechanisms spanning multiple tissues. We propose tissue-gene fine-mapping (TGFM), which infers the posterior inclusion probability (PIP) for each gene-tissue pair to mediate a disease locus by analyzing summary statistics and expression quantitative trait loci (eQTL) data; TGFM also assigns PIPs to non-mediated variants. TGFM accounts for co-regulation across genes and tissues and models uncertainty in cis-predicted expression models, enabling correct calibration.

The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively.

Association between genetically predicted leisure and social activities and cardiovascular disease and other health outcomes.

Participation in leisure and social activities (LSA) is associated with better health outcomes and lower mortality. Previous observational studies demonstrated a relationship between engagement in LSA and both mental and physical health. Although several studies examined the association between LSA and health outcomes, including cardiovascular disease, their possible causal relationship has not been studied.

Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product.

Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.

Genetic Confounding of the Association Between Age at First Hormonal Contraception and Depression.

Background: Previous research has shown that females who use hormonal contraception are at increased risk of developing depression, and that the risk is highest among adolescents. While this finding could reflect age-specific effects of exogenous hormones on mental health, genetic liability for mental disorders could be confounding the association. Our goal was to test the plausibility of this hypothesis by determining whether polygenic liabilities for major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SCZ), and attention deficit hyperactivity disorder (ADHD) are associated with younger age at hormonal contraception initiation.

Novel Phenotypes and Genotype-Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndrome.

Kleefstra syndrome (KLEFS) is a genetic neurodevelopmental disorder caused by haploinsufficiency of EHMT1. The full spectrum of clinical features and genotype-phenotype correlations is currently not fully understood. We performed a retrospective chart review of patients with KLEFS evaluated at the Boston Children's Hospital Kleefstra Clinic.

Rare germline structural variants increase risk for pediatric solid tumors.

Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and increased risk of solid tumors in male children.

Engineering synthetic phosphorylation signaling networks in human cells.

Protein phosphorylation signaling networks have a central role in how cells sense and respond to their environment. We engineered artificial phosphorylation networks in which reversible enzymatic phosphorylation cycles were assembled from modular protein domain parts and wired together to create synthetic phosphorylation circuits in human cells. Our design scheme enabled model-guided tuning of circuit function and the ability to make diverse network connections; synthetic phosphorylation circuits can be coupled to upstream cell surface receptors to enable fast-timescale sensing of extracellular ligands, and downstream connections can regulate gene expression.

High-dose intravenous BCG vaccination induces enhanced immune signaling in the airways.

Intradermal Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine, but it does not sufficiently protect adults against pulmonary tuberculosis. Recent studies in nonhuman primates show that intravenous BCG administration offers superior protection against (). We used single-cell analysis of bronchoalveolar lavage cells from rhesus macaques vaccinated via different routes and doses of BCG to identify alterations in the immune ecosystem in the airway following vaccination.

Aggregation pathway complexity in a simple perylene diimide.

This study characterizes the influence of self-assembly conditions on the aggregation pathway and resulting photophysical properties of one-dimensional aggregates of the simple imide-substituted perylene diimide, N, N'-didodecyl-3,4,9,10-perylenedicarboximide (ddPDI). We show that ddPDI, which has symmetric alkyl chains at the imide positions, assembles into fibers with distinct morphology, emission spectra, and temperature-dependent behavior as a function of preparation conditions. In all conditions explored, aggregates are one-dimensional; however, assembly conditions can bias formation to either J-like or H-like aggregates.

Cancer-specific innate and adaptive immune rewiring drives resistance to PD-1 blockade in classic Hodgkin lymphoma.

Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL), like many solid tumors, elicit ineffective immune responses. However, patients with cHL are highly responsive to PD-1 blockade, which largely depends on HRS cell-specific retention of MHC class II and implicates CD4 T cells and additional MHC class I-independent immune effectors. Here, we utilize single-cell RNA sequencing and spatial analysis to define shared circulating and microenvironmental features of the immune response to PD-1 blockade in cHL.

microT-CNN: an avant-garde deep convolutional neural network unravels functional miRNA targets beyond canonical sites.

microRNAs (miRNAs) are central post-transcriptional gene expression regulators in healthy and diseased states. Despite decades of effort, deciphering miRNA targets remains challenging, leading to an incomplete miRNA interactome and partially elucidated miRNA functions. Here, we introduce microT-CNN, an avant-garde deep convolutional neural network model that moves the needle by integrating hundreds of tissue-matched (in-)direct experiments from 26 distinct cell types, corresponding to a unique training and evaluation set of >60 000 miRNA binding events and ~30 000 unique miRNA-gene target pairs.

Therapeutic treatments targeting communication between angiogenic and immune microenvironments in thyroid cancers.

Thyroid cancer treatment has recently been revolutionized by the introduction of specific targeted therapies (e.g. BRAF or highly selective RET inhibitors), anti-angiogenic agents (e.

Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen.

The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging.

The T cell receptor sequence influences the likelihood of T cell memory formation.

The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells.

Family Genetic Risk Communication and Reverse Cascade Testing in the BabySeq Project.

Purpose: Genomic sequencing of newborns (NBSeq) can initiate disease surveillance and therapy for children, and may identify at-risk relatives through reverse cascade testing. We explored genetic risk communication and reverse cascade testing among families of newborns who underwent exome sequencing and had a risk for autosomal dominant disease identified.

Methods: We conducted semi-structured interviews with parents of newborns enrolled in the BabySeq Project who had a pathogenic or likely-pathogenic (P/LP) variant associated with an autosomal dominant (AD) childhood- and/or adult-onset disease returned.