Molecular basis of human angiotensin-1 converting enzyme inhibition by a series of diprolyl-derived compounds.

Angiotensin-1-converting enzyme (ACE) is a zinc-dependent carboxypeptidase of therapeutic interest for the treatment of hypertension, inflammation and fibrosis. It consists of two homologous N and C catalytic domains, nACE and cACE, respectively. Unfortunately, the current clinically available ACE inhibitors produce undesirable side effects due to the nonselective inhibition of these domains.

2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Phosphatidylinositol-4-kinase and Hemozoin Formation with Efficacy.

Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of () phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of .

Implementing Multifactorial Risk Assessment with Polygenic Risk Scores for Personalized Breast Cancer Screening in the Population Setting: Challenges and Opportunities.

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40-69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment.

Breast Magnetic Resonance Imaging for Preoperative Evaluation of Breast Cancer: A Systematic Review and Meta-Analysis.

Preoperative breast magnetic resonance imaging (MRI) is known to detect additional cancers that are occult on mammography and ultrasound. There is debate as to whether these additional lesions affect clinical outcomes. The objective of this systematic review was to summarize the evidence on whether additional information on disease extent obtained with preoperative breast MRI in patients with newly diagnosed breast cancer affects surgical management, rates of recurrence, survival, re-excision, and early detection of bilateral cancer.

Preoperative Breast Magnetic Resonance Imaging: An Ontario Health (Cancer Care Ontario) Clinical Practice Guideline.

Background: The use of preoperative breast magnetic resonance imaging (MRI) after the diagnosis of breast cancer by mammography and/or ultrasound is inconsistent.

Methods: After conducting a systematic review and meta-analysis comparing preoperative breast MRI versus no MRI, we reconvened to prepare a clinical practice guideline on this topic.

Results: Based on the evidence that MRI improved recurrence, decreased the rates of reoperations (re-excisions or conversion mastectomy), and increased detection of synchronous contralateral breast cancer, we recommend that preoperative breast MRI should be considered on a case-by-case basis in patients diagnosed with breast cancer for whom additional information about disease extent could influence treatment.

1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in .

Alternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors of HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain of mycolic acids in (). Mutations in compound -resistant mutants mapped to HadC (Rv0637; K157R), while chemoproteomics confirmed the compound's binding to HadA (Rv0635), HadB (Rv0636), and HadC.

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity.

New antibiotics with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug-resistant (), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against DNA gyrase (e.

Adherence to guidance for prioritizing higher risk groups for breast cancer screening during the COVID-19 pandemic in the Ontario Breast Screening Program: a descriptive study.

Background: Breast cancer screening in Ontario, Canada, was deferred during the first wave of the COVID-19 pandemic, and a prioritization framework to resume services according to breast cancer risk was developed. The purpose of this study was to assess the impact of the pandemic within the Ontario Breast Screening Program (OBSP) by comparing total volumes of screening mammographic examinations and volumes of screening mammographic examinations with abnormal results before and during the pandemic, and to assess backlogs on the basis of adherence to the prioritization framework.

Methods: A descriptive study was conducted among women aged 50 to 74 years at average risk and women aged 30 to 69 years at high risk, who participated in the OBSP.

The Impact of Radiologist Screening Mammogram Reading Volume on Performance in the Ontario Breast Screening Program.

Purpose: Although some studies have shown increasing radiologists' mammography volumes improves performance, there is a lack of evidence specific to digital mammography and breast screening program performance targets. This study evaluates the relationship between digital screening volume and meeting performance targets.

Methods: This retrospective cohort study included 493 radiologists in the Ontario Breast Screening Program who interpreted 1,762,173 screening mammograms in participants ages 50-90 between 2014 and 2016.

1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in .

Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set of compounds against (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide as a moderately active hit. Structure-activity relationship (SAR) studies demonstrated a clear scope to improve whole cell potency to MIC values of <0.5 μM, and a plausible pharmacophore model was developed to describe the chemical space of active compounds.

Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation (PERSPECTIVE I&I).

Early detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g.

New Amidated 3,6-Diphenylated Imidazopyridazines with Potent Antiplasmodium Activity Are Dual Inhibitors of Phosphatidylinositol-4-kinase and cGMP-Dependent Protein Kinase.

Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive activity and efficacy in mouse models of malaria infection. Herein, we report the synthesis and antiplasmodium evaluation of a new series of amidated analogues and demonstrate that these compounds potently inhibit phosphatidylinositol-4-kinase (PI4K) type IIIβ while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) activity . Using docking, we predict key binding interactions for these analogues within the adenosine triphosphate (ATP)-binding site of PI4K and PKG, paving the way for structure-based optimization of imidazopyridazines targeting both PI4K and PKG.

Structural Basis for Inhibitor Potency and Selectivity of Phosphatidylinositol 4-Kinase Inhibitors.

phosphatidylinositol 4-kinase (PI4K) has emerged as a promising new drug target for novel antimalarial therapeutics. In the absence of a reliable high-resolution three-dimensional structure, a homology model of PI4K was built as a tool for structure-based drug design. This homology model has been validated against three distinct chemical series of potent inhibitors using docking and energy minimizations to elucidate the interactions crucial for PI4K inhibition and potent antiplasmodium activity.

The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme.

Angiotensin-I converting enzyme (ACE) is a zinc metalloprotease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both domains nonselectively, resulting in adverse effects such as cough and angioedema. Selectively inhibiting the individual domains is likely to reduce these effects and potentially treat fibrosis in addition to hypertension.

Forensic bitemark identification: weak foundations, exaggerated claims.

Several forensic sciences, especially of the pattern-matching kind, are increasingly seen to lack the scientific foundation needed to justify continuing admission as trial evidence. Indeed, several have been abolished in the recent past. A likely next candidate for elimination is bitemark identification.

Application of Eshelby's Solution to Elastography for Diagnosis of Breast Cancer.

Eshelby's solution is the analytical method that can derive the elastic field within and around an ellipsoidal inclusion embedded in a matrix. Since breast tumor can be regarded as an elastic inclusion with different elastic properties from those of surrounding matrix when the deformation is small, we applied Eshelby's solution to predict the stress and strain fields in the breast containing a suspicious lesion. The results were used to investigate the effectiveness of strain ratio (SR) from elastography in representing modulus ratio (MR) that may be the meaningful indicator of the malignancy of the lesion.

Scalable privacy-preserving data sharing methodology for genome-wide association studies.

The protection of privacy of individual-level information in genome-wide association study (GWAS) databases has been a major concern of researchers following the publication of "an attack" on GWAS data by Homer et al. (2008). Traditional statistical methods for confidentiality and privacy protection of statistical databases do not scale well to deal with GWAS data, especially in terms of guarantees regarding protection from linkage to external information.

Reconceptualizing the classification of PNAS articles.

PNAS article classification is rooted in long-standing disciplinary divisions that do not necessarily reflect the structure of modern scientific research. We reevaluate that structure using latent pattern models from statistical machine learning, also known as mixed-membership models, that identify semantic structure in co-occurrence of words in the abstracts and references. Our findings suggest that the latent dimensionality of patterns underlying PNAS research articles in the Biological Sciences is only slightly larger than the number of categories currently in use, but it differs substantially in the content of the categories.

Population size estimation using individual level mixture models.

We revisit the heterogeneous closed population multiple recapture problem, modeling individual-level heterogeneity using the Grade of Membership model (Woodbury et al., 1978). This strategy allows us to postulate the existence of homogeneous latent "ideal" or "pure" classes within the population, and construct a soft clustering of the individuals, where each one is allowed partial or mixed membership in all of these classes.