Designing Cell-Type-Specific Promoter Sequences Using Conservative Model-Based Optimization.

Gene therapies have the potential to treat disease by delivering therapeutic genetic cargo to disease-associated cells. One limitation to their widespread use is the lack of short regulatory sequences, or promoters, that differentially induce the expression of delivered genetic cargo in target cells, minimizing side effects in other cell types. Such cell-type-specific promoters are difficult to discover using existing methods, requiring either manual curation or access to large datasets of promoter-driven expression from both targeted and untargeted cells.

Critical assessment of missense variant effect predictors on disease-relevant variant data.

Regular, systematic, and independent assessment of computational tools used to predict the pathogenicity of missense variants is necessary to evaluate their clinical and research utility and suggest directions for future improvement. Here, as part of the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, we assess missense variant effect predictors (or variant impact predictors) on an evaluation dataset of rare missense variants from disease-relevant databases. Our assessment evaluates predictors submitted to the CAGI6 Annotate-All-Missense challenge, predictors commonly used by the clinical genetics community, and recently developed deep learning methods for variant effect prediction.

Stress-related transcriptomic changes associated with GFP transgene expression and active transgene silencing in plants.

Plants respond to biotic and abiotic stress by activating and interacting with multiple defense pathways, allowing for an efficient global defense response. RNA silencing is a conserved mechanism of regulation of gene expression directed by small RNAs important in acquired plant immunity and especially virus and transgene repression. Several RNA silencing pathways in plants are crucial to control developmental processes and provide protection against abiotic and biotic stresses as well as invasive nucleic acids such as viruses and transposable elements.

Aggregation-Driven Photoinduced α-C(sp)-H Bond Hydroxylation/C(sp)-C(sp) Coupling of Boron Dipyrromethene Dye in Water Reported by Near-Infrared Emission.

Molecular aggregation is a powerful tool for tuning advanced materials' photophysical and electronic properties. Here we present a novel potential for the aqueous-solvated aggregated state of boron dipyrromethene (BODIPY) to facilitate phototransformations otherwise achievable only under harsh chemical conditions. We show that the photoinduced symmetry-breaking charge separation state can itself initiate catalyst-free redox chemistry, leading to selective α-C(sp)-H bond activation/C-C coupling on the BODIPY backbone.

Characterizing uncertainty in predictions of genomic sequence-to-activity models.

Genomic sequence-to-activity models are increasingly utilized to understand gene regulatory syntax and probe the functional consequences of regulatory variation. Current models make accurate predictions of relative activity levels across the human reference genome, but their performance is more limited for predicting the effects of genetic variants, such as explaining gene expression variation across individuals. To better understand the causes of these shortcomings, we examine the uncertainty in predictions of genomic sequence-to-activity models using an ensemble of Basenji2 model replicates.

Personal transcriptome variation is poorly explained by current genomic deep learning models.

Genomic deep learning models can predict genome-wide epigenetic features and gene expression levels directly from DNA sequence. While current models perform well at predicting gene expression levels across genes in different cell types from the reference genome, their ability to explain expression variation between individuals due to cis-regulatory genetic variants remains largely unexplored. Here, we evaluate four state-of-the-art models on paired personal genome and transcriptome data and find limited performance when explaining variation in expression across individuals.

GUANinE v1.0: Benchmark Datasets for Genomic AI Sequence-to-Function Models.

Computational genomics increasingly relies on machine learning methods for genome interpretation, and the recent adoption of neural sequence-to-function models highlights the need for rigorous model specification and controlled evaluation, problems familiar to other fields of AI. Research strategies that have greatly benefited other fields - including benchmarking, auditing, and algorithmic fairness - are also needed to advance the field of genomic AI and to facilitate model development. Here we propose a genomic AI benchmark, GUANinE, for evaluating model generalization across a number of distinct genomic tasks.

Photocatalytic degradation of organic micropollutants under UV-A and visible light irradiation by exfoliated g-CN catalysts.

In the present study, the photocatalytic performance of exfoliated graphitic carbon nitride (g-CN) catalysts, with enhanced properties and response in UV and visible light irradiation, was evaluated for the removal of selected contaminants i.e., diuron, bisphenol A and ethyl paraben.

The Impact of Stability Considerations on Genetic Fine-Mapping.

Fine-mapping methods, which aim to identify genetic variants responsible for complex traits following genetic association studies, typically assume that sufficient adjustments for confounding within the association study cohort have been made, e.g., through regressing out the top principal components (i.

Strategies for effectively modelling promoter-driven gene expression using transfer learning.

The ability to deliver genetic cargo to human cells is enabling rapid progress in molecular medicine, but designing this cargo for precise expression in specific cell types is a major challenge. Expression is driven by regulatory DNA sequences within short synthetic promoters, but relatively few of these promoters are cell-type-specific. The ability to design cell-type-specific promoters using model-based optimization would be impactful for research and therapeutic applications.

Tissue-specific impacts of aging and genetics on gene expression patterns in humans.

Age is the primary risk factor for many common human diseases. Here, we quantify the relative contributions of genetics and aging to gene expression patterns across 27 tissues from 948 humans. We show that the predictive power of expression quantitative trait loci is impacted by age in many tissues.

Copper Coordination and the Induced Morphological Changes in Covalent Organic Frameworks.

In this work, we reveal the coordination of copper ions absorbed by a series of covalent organic frameworks. The frameworks were synthesized through the nucleophilic substitution of either cyanuric chloride or phosphonitrilic chloride trimer by 4,4'-bipyridine, and they were utilized as absorbers for the removal of copper ions from aqueous solutions. The exfoliated counterpart of the layered network was compared to the bulk materials in terms of the copper retention capacity and efficiency.

A nonsymmetric Dy single-molecule magnet with two relaxation processes triggered by an external magnetic field: a theoretical and integrated EPR study of the role of magnetic-site dilution.

The 1 : 2 reaction between Dy(OCMe)·4HO and 1-acetyl-2-napthol (LH) in MeOH has provided access to the complex [DyL(MeOH)]·MeOH (1·MeOH) in a good yield. The structures of the isomorphous complex 1·MeOH and its doped diamagnetic yttrium analogue [DyYL(MeOH)]·MeOH (Dy@Y2) have been determined by single-crystal X-ray crystallography and characterized based on elemental analyses, IR spectra, and powder X-ray patterns. Combined dc and ac magnetic susceptibility and the magnetization data for 1 suggest that this complex shows slow magnetic relaxation.

Arrested Substrate Binding Resolves Catalytic Intermediates in Higher-Plant Water Oxidation.

Among the intermediate catalytic steps of the water-oxidizing Mn CaO cluster of photosystem II (PSII), the final metastable S state is critically important because it binds one substrate and precedes O evolution. Herein, we combine X- and Q-band EPR experiments on native and methanol-treated PSII of Spinacia oleracea and show that methanol-treated PSII preparations of the S state correspond to a previously uncharacterized high-spin (S=6) species. This is confirmed as a major component also in intact photosynthetic membranes, coexisting with the previously known intermediate-spin conformation (S=3).

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer.

Background: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.

Objective: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.

Design, Setting, And Participants: A two-stage design was used.

Kinetic and mechanistic investigation of water taste and odor compound 2-isopropyl-3-methoxy pyrazine degradation using UV-A/Chlorine process.

The present study was launched as a continuation of global efforts to tackle problems associated with two important aesthetic characteristics, taste and odor (T&O), of drinking water. The UV-A/Chlorine process, a promising advanced oxidation process (AOP), was evaluated for the first time for the removal of 2-isopropyl-3-methoxy pyrazine (IPMP), a widely reported compound in the literature that causes unpleasant taste and odor when present in water at or below the ng L level. It was found that the studied process was efficient for the removal of IPMP in both ultrapure and drinking water.

Predicting target genes of non-coding regulatory variants with IRT.

Summary: Interpreting genetic variants of unknown significance (VUS) is essential in clinical applications of genome sequencing for diagnosis and personalized care. Non-coding variants remain particularly difficult to interpret, despite making up a large majority of trait associations identified in genome-wide association studies (GWAS) analyses. Predicting the regulatory effects of non-coding variants on candidate genes is a key step in evaluating their clinical significance.

Comparative analysis of the medicinal compounds of the ship's "medicine chests" in European Union maritime countries. Need for improvement and harmonization.

Background: The contents of the ship pharmacy, namely "medicine chest" and its compliance with therespective regulations concerning the type of drugs to be provided for merchant vessels involved in long distance voyages and without a doctor on board were analysed. The current existing disparity between regulations can make medical assistance more complicated, and more often of low quality, due to frequent off-label use of supplied drugs. This study may represent a starting point leading to a model high-quality medicine chest on board ships.

Estimating prevalence for limb-girdle muscular dystrophy based on public sequencing databases.

Purpose: Limb-girdle muscular dystrophies (LGMD) are a genetically heterogeneous category of autosomal inherited muscle diseases. Many genes causing LGMD have been identified, and clinical trials are beginning for treatment of some genetic subtypes. However, even with the gene-level mechanisms known, it is still difficult to get a robust and generalizable prevalence estimation for each subtype due to the limited amount of epidemiology data and the low incidence of LGMDs.

Proton Translocation via Tautomerization of Asn298 During the S-S State Transition in the Oxygen-Evolving Complex of Photosystem II.

In biological water oxidation, a redox-active tyrosine residue (D1-Tyr161 or Y) mediates electron transfer between the MnCaO cluster of the oxygen-evolving complex and the charge-separation site of photosystem II (PSII), driving the cluster through progressively higher oxidation states S ( i = 0-4). In contrast to lower S-states (S, S), in higher S-states (S, S) of the MnCaO cluster, Y cannot be oxidized at cryogenic temperatures due to the accumulation of positive charge in the S → S transition. However, oxidation of Y by illumination of S at 77-190 K followed by rapid freezing and charge recombination between Y and the plastoquinone radical Q allows trapping of an S variant, the so-called S state (S), that is capable of forming Y at cryogenic temperature.