EHR-Safe: generating high-fidelity and privacy-preserving synthetic electronic health records.

Privacy concerns often arise as the key bottleneck for the sharing of data between consumers and data holders, particularly for sensitive data such as Electronic Health Records (EHR). This impedes the application of data analytics and ML-based innovations with tremendous potential. One promising approach for such privacy concerns is to instead use synthetic data.

Phylogenetic and Ancestral Sequence Reconstruction of SARS-CoV-2 Reveals Latent Capacity to Bind Human ACE2 Receptor.

SARS-CoV-2 is a unique event, having emerged suddenly as a highly infectious viral pathogen for human populations. Previous phylogenetic analyses show its closest known evolutionary relative to be a virus detected in bats (RaTG13), with a common assumption that SARS-CoV-2 evolved from a zoonotic ancestor via recent genetic changes (likely in the Spike protein receptor-binding domain or RBD) that enabled it to infect humans. We used detailed phylogenetic analysis, ancestral sequence reconstruction, and in situ molecular dynamics simulations to examine the Spike-RBD's functional evolution, finding that the common ancestral virus with RaTG13, dating to no later than 2013, possessed high binding affinity to the human ACE2 receptor.

Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study.

Background & Aims: Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S).

Comparison of technical errors in pediatric bitewing radiographs acquired with round vs rectangular collimation.

Objective: To compare technical errors in bitewing radiographs acquired with round vs rectangular collimation in a hospital-based pediatric dentistry training program.

Study Design: A retrospective chart review was conducted of 176 digital bitewing radiographs exposed with round collimation and 106 exposed with rectangular collimation. The number of re-exposures was calculated, and errors in central ray entry (CRE; "cone cuts"), horizontal and vertical positioning, and angulation were measured.

The adaptive landscape of a metallo-enzyme is shaped by environment-dependent epistasis.

Enzymes can evolve new catalytic activity when environmental changes present them with novel substrates. Despite this seemingly straightforward relationship, factors other than the direct catalytic target can also impact adaptation. Here, we characterize the catalytic activity of a recently evolved bacterial methyl-parathion hydrolase for all possible combinations of the five functionally relevant mutations under eight different laboratory conditions (in which an alternative divalent metal is supplemented).

Uncovering DNA-PKcs ancient phylogeny, unique sequence motifs and insights for human disease.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key member of the phosphatidylinositol-3 kinase-like (PIKK) family of protein kinases with critical roles in DNA-double strand break repair, transcription, metastasis, mitosis, RNA processing, and innate and adaptive immunity. The absence of DNA-PKcs from many model organisms has led to the assumption that DNA-PKcs is a vertebrate-specific PIKK. Here, we find that DNA-PKcs is widely distributed in invertebrates, fungi, plants, and protists, and that threonines 2609, 2638, and 2647 of the ABCDE cluster of phosphorylation sites are highly conserved amongst most Eukaryotes.

Statistical analysis of mutational epistasis to reveal intramolecular interaction networks in proteins.

Epistasis occurs when the combined effect of two or more mutations differs from the sum of their individual effects, and reflects molecular interactions that affect the function and fitness of a protein. Epistasis is widely recognized as a key phenomenon that drives the dynamics of evolution. It can profoundly affect our ability to understand sequence-structure-function relationships, and thus has important implications for protein engineering and design.

Author Correction: Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Engaging in building the educational support needed to deliver precision health in Canada.

Canadian healthcare facilities are poised to benefit from the tools of precision health. To do so effectively, however, it is crucial that we align changes in how healthcare professionals are educated in order to ensure they have the skills, knowledge, and training to fully engage with its tools. Here, we propose that the design, development, and delivery of novel educational programs focused on precision health should be prioritized for healthcare professionals, and we suggest some essential curricular considerations to that end.

Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme.

Characterizing the adaptive landscapes that encompass the emergence of novel enzyme functions can provide molecular insights into both enzymatic and evolutionary mechanisms. Here, we combine ancestral protein reconstruction with biochemical, structural and mutational analyses to characterize the functional evolution of methyl-parathion hydrolase (MPH), an organophosphate-degrading enzyme. We identify five mutations that are necessary and sufficient for the evolution of MPH from an ancestral dihydrocoumarin hydrolase.

Exploring the sequence, function, and evolutionary space of protein superfamilies using sequence similarity networks and phylogenetic reconstructions.

Integrative computational methods can facilitate the discovery of new protein functions and enzymatic reactions by enabling the observation and investigation of complex sequence-structure-function and evolutionary relationships within protein superfamilies. Here, we highlight the use of sequence similarity networks (SSNs) and phylogenetic reconstructions to map the functional divergence and evolutionary history of protein superfamilies. We exemplify this approach using the nitroreductase (NTR) flavoenzyme superfamily, demonstrating that SSN investigations can provide a rapid and effective means to classify groups of proteins, expose sequence similarity relationships across the global scale of a protein superfamily, and efficiently support detailed phylogenetic analyses.

A non-randomised controlled pilot study of clinical pharmacist collaborative intervention for community dwelling patients with COPD.

UK, home-based patients with COPD receive specialist care from respiratory physicians, nurses, and general practitioners (GPs), but increasing complexity of therapeutic options and a GP/Nurse workforce crisis suggests merit in testing the role of home visits by a clinical pharmacist. We conducted a non-randomised intervention study with a contemporaneous comparator group, in Glasgow (Scotland). A clinical pharmacist (working closely with a consultant respiratory physician) visited patients with COPD living at home, assessing respiratory and other co-morbid conditions, and medicines then, with patient approval, agreed treatment modifications with a consultant physician.

Design control considerations for biologic-device combination products.

Combination products are therapeutic and diagnostic medical products that combine drugs, devices, and/or biological products with one another. Historically, biologics development involved identifying efficacious doses administered to patients intravenously or perhaps by a syringe. Until fairly recently, there has been limited focus on developing an accompanying medical device, such as a prefilled syringe or auto-injector, to enable easy and more efficient delivery.

Intermolecular epistasis shaped the function and evolution of an ancient transcription factor and its DNA binding sites.

Complexes of specifically interacting molecules, such as transcription factor proteins (TFs) and the DNA response elements (REs) they recognize, control most biological processes, but little is known concerning the functional and evolutionary effects of epistatic interactions across molecular interfaces. We experimentally characterized all combinations of genotypes in the joint protein-DNA sequence space defined by an historical transition in TF-RE specificity that occurred some 500 million years ago in the DNA-binding domain of an ancient steroid hormone receptor. We found that rampant epistasis within and between the two molecules was essential to specific TF-RE recognition and to the evolution of a novel TF-RE complex with unique derived specificity.

Evolution of DNA specificity in a transcription factor family produced a new gene regulatory module.

Complex gene regulatory networks require transcription factors (TFs) to bind distinct DNA sequences. To understand how novel TF specificity evolves, we combined phylogenetic, biochemical, and biophysical approaches to interrogate how DNA recognition diversified in the steroid hormone receptor (SR) family. After duplication of the ancestral SR, three mutations in one copy radically weakened binding to the ancestral estrogen response element (ERE) and improved binding to a new set of DNA sequences (steroid response elements, SREs).

Blood pressure after recent stroke: baseline findings from the secondary prevention of small subcortical strokes trial.

Background: Hypertension is the most powerful risk factor for stroke. The aim of this study was to characterize baseline blood pressure in participants in the Secondary Prevention of Small Subcortical Strokes trial.

Methods: For this cross-sectional analysis, participants were categorized by baseline systolic blood pressure (SBP) < 120, 120-139, 140-159, 160-179, and ≥ 180 mm Hg and compared on demographic and clinical characteristics.

Serum biomarkers reveal long-term cardiac injury in isoproterenol-treated African green monkeys.

The assessment of cardiac toxicity is a major challenge in both drug development and clinical trials, and numerous marketed pharmaceuticals have been removed from the market due to unpredicted cardiac effects. Serum troponins are widely used indicators of cardiac injury; however, they are short-lived and have not been validated in preclinical animal models. In this study, we have used filter-aided sample preparation (FASP) and tandem mass tag (TMT) labeling to investigate serum protein alterations in isoproterenol-treated African green monkeys.

Evolution of the closely related, sex-related genes DM-W and DMRT1 in African clawed frogs (Xenopus).

DM-W is a dominant, female-specific, regulator of sex determination in the African clawed frog Xenopus laevis. This gene is derived from partial duplication of DMRT1, a male-related autosomal gene. We set out to better understand sex determination in Xenopus by studying this pair of genes.

The chaperone-like protein HYPK acts together with NatA in cotranslational N-terminal acetylation and prevention of Huntingtin aggregation.

The human NatA protein N(alpha)-terminal-acetyltransferase complex is responsible for cotranslational N-terminal acetylation of proteins with Ser, Ala, Thr, Gly, and Val N termini. The NatA complex is composed of the catalytic subunit hNaa10p (hArd1) and the auxiliary subunit hNaa15p (hNat1/NATH). Using immunoprecipitation coupled with mass spectrometry, we identified endogenous HYPK, a Huntingtin (Htt)-interacting protein, as a novel stable interactor of NatA.

A novel human NatA Nalpha-terminal acetyltransferase complex: hNaa16p-hNaa10p (hNat2-hArd1).

Background: Protein acetylation is among the most common protein modifications. The two major types are post-translational Nepsilon-lysine acetylation catalyzed by KATs (Lysine acetyltransferases, previously named HATs (histone acetyltransferases) and co-translational Nalpha-terminal acetylation catalyzed by NATs (N-terminal acetyltransferases). The major NAT complex in yeast, NatA, is composed of the catalytic subunit Naa10p (N alpha acetyltransferase 10 protein) (Ard1p) and the auxiliary subunit Naa15p (Nat1p).

Regulatory evolution of a duplicated heterodimer across species and tissues of allopolyploid clawed frogs (Xenopus).

Changes in gene expression contribute to reproductive isolation of species, adaptation, and development and may impact the genetic fate of duplicated genes. African clawed frogs (genus Xenopus) offer a useful model for examining regulatory evolution, particularly after gene duplication, because species in this genus are polyploid. Additionally, these species can produce viable hybrids, and expression divergence between coexpressed species-specific alleles in hybrids can be attributed exclusively to cis-acting mechanisms.

Characterization of hARD2, a processed hARD1 gene duplicate, encoding a human protein N-alpha-acetyltransferase.

Background: Protein acetylation is increasingly recognized as an important mechanism regulating a variety of cellular functions. Several human protein acetyltransferases have been characterized, most of them catalyzing epsilon-acetylation of histones and transcription factors. We recently described the human protein acetyltransferase hARD1 (human Arrest Defective 1).

Cloning and characterization of hNAT5/hSAN: an evolutionarily conserved component of the NatA protein N-alpha-acetyltransferase complex.

The human hARD1-NATH complex, cotranslationally acetylating the alpha-amino groups of proteins, was recently described. In S. cerevisiae and D.