Total synthesis and target identification of marine cyclopiane diterpenes.

Marine cyclopianes are a family of diterpenoid with novel carbon skeleton and diverse biological activities. Herein, we report our synthetic and chemical proteomics studies of cyclopiane diterpenes which culminate in the asymmetric total synthesis of conidiogenones C, K and 12β-hydroxy conidiogenone C, and identification of Immunity-related GTPase family M protein 1 (IRGM1) as a cellular target. Our asymmetric synthesis commences from Wieland-Miescher ketone and features a sequential intramolecular Pauson-Khand reaction and gold-catalyzed Nazarov cyclization to rapidly construct the 6-5-5-5 tetracyclic skeleton.

Patient-Derived Xenografts of Triple-Negative Breast Cancer Enable Deconvolution and Prediction of Chemotherapy Responses.

Combination chemotherapy remains essential for clinical management of triple-negative breast cancer (TNBC). Consequently, responses to individual agents cannot be easily delineated at the single patient level, even though some patients might not require all drugs in the combination. Herein, we conduct multi-omic analyses of orthotopic TNBC patient-derived xenografts (PDXs) treated with single agent carboplatin, docetaxel, or the combination.

A robust benchmark for detecting low-frequency variants in the HG002 Genome In A Bottle NIST reference material.

Somatic mosaicism is an important cause of disease, but mosaic and somatic variants are often challenging to detect because they exist in only a fraction of cells. To address the need for benchmarking subclonal variants in normal cell populations, we developed a benchmark containing mosaic variants in the Genome in a Bottle Consortium (GIAB) HG002 reference material DNA from a large batch of a normal lymphoblastoid cell line. First, we used a somatic variant caller with high coverage (300x) Illumina whole genome sequencing data from the Ashkenazi Jewish trio to detect variants in HG002 not detected in at least 5% of cells from the combined parental data.

Clinical and Genomic Prediction of Coronary Artery Disease Subtypes.

Background: Coronary artery disease (CAD) is a complex, heterogeneous disease with distinct etiological mechanisms. These different etiologies may give rise to multiple subtypes of CAD that could benefit from alternative preventions and treatments. However, so far, there have been no systematic efforts to predict CAD subtypes using clinical and genetic factors.

Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes.

Base editors create precise genomic edits by directing nucleobase deamination or removal without inducing double-stranded DNA breaks. However, a vast chemical space of other DNA modifications remains to be explored for genome editing. Here, we harness the bacterial anti-phage toxin DarT2 to append ADP-ribosyl moieties to DNA, unlocking distinct editing outcomes in bacteria versus eukaryotes.

Enhanced Piezoelectric Response Attained by Defect Dipoles in BiFeO-based Lead-Free Ceramics.

The impact of defects on the performance of piezoelectric materials has been a topic of considerable debate, due to the competing actions of the deteriorating effect of the defects themselves on the ceramic resistance and the positive effect on the piezoelectric performance resulting from the defect polarization. In order to probe its combined influence on piezoelectric properties, here, we designed BiFeO (BF)-based ceramics with different defect concentrations. It has been demonstrated that the incorporation of an appropriate concentration of defects into ceramics can effectively enhance their piezoelectric properties while maintaining their insulating properties.

Health Economic Evaluation of Antimicrobial Stewardship, Procalcitonin Testing, and Rapid Blood Culture Identification in Sepsis Care: A 90-Day Model-Based, Cost-Utility Analysis.

Objective: We evaluated the cost-effectiveness of a bundled intervention including an antimicrobial stewardship program (ASP), procalcitonin (PCT) testing, and rapid blood culture identification (BCID), compared with pre-implementation standard care in critically ill adult patients with sepsis.

Methods: We conducted a decision tree model-based cost-effectiveness analysis alongside a previously published pre- and post-implementation quality improvement study. We adopted a public Canadian healthcare payer's perspective.

The utility of personal wearable data in long COVID and personalized patient care.

Radin et al.’s recent study on patients with long COVID demonstrates that personal wearable data can provide critical insight into complex conditions. This editorial argues that research insights gained through personal wearables support the integration of personal wearables into healthcare.

Formononetin-Loaded Self-Microemulsion Drug Delivery Systems for Improved Solubility and Oral Bioavailability: Fabrication, Characterization, In Vitro and In Vivo Evaluation.

This study aimed to construct a self-microemulsion drug delivery system (SMEDDS) for Formononetin (FMN) to improve its solubility and bioavailability while combining the nanocrystals (NCs) technology. The SMEDDS prescription composition was optimized with a pseudo-three-phase diagram, followed by a series of in vitro and in vivo evaluations of the selected optimal prescriptions. FMN-NCs loaded SMEDDS showed a homogeneous spherical shape in the Transmission electron microscope and the particle size was measured as (20.

Bayesian inversion of bacterial physiology and dissolved organic carbon biodegradability on water incubation data.

In aquatic ecosystems, dissolved organic carbon (DOC) plays a significant role in the global carbon cycle. Microorganisms mineralize biodegradable DOC, releasing greenhouse gases (carbon dioxide, methane) into the atmosphere. Extensive research has focused on the concentrations and biodegradability of DOC in aquatic systems worldwide.

LPS binding caspase activation and recruitment domains (CARDs) are bipartite lipid binding modules.

Caspase-11 is an innate immune pattern recognition receptor (PRR) that detects cytosolic bacterial lipopolysaccharides (LPS) through its caspase activation and recruitment domain (CARD), triggering inflammatory cell death known as pyroptosis. Caspase-11 also detects eukaryotic ( self) lipids. This observation raises the question of whether common or distinct mechanisms govern the interactions with self and nonself lipids.

Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader.

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader.

The epithelial barrier theory and its associated diseases.

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide.

Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition.

Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells.

Calibrating Observational Health Record Data Against a Randomized Trial.

Importance: The conditions required for health record data sources to accurately assess treatment effectiveness remain unclear. Emulation of randomized clinical trials (RCTs) with health record data and subsequent calibration of the results can help elucidate this.

Objective: To pilot an emulation of the KEYNOTE-189 RCT using a commercially available electronic health record (EHR) data source.

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD).

Cigarette Smoking and Observed Growth of Unruptured Intracranial Aneurysms: A Systematic Literature Review and Meta-Analysis.

Background: Smoking and observed growth of intracranial aneurysms are known risk factors for rupture. The mechanism by which smoking increases this risk is not completely elucidated. Furthermore, an association between smoking and aneurysm growth has not been clearly defined in the literature.

Diameter-dependent classification of dermal vasculature using optical coherence tomography angiography.

Background: Dermal blood vessels beneath the epidermis play critical roles in epidermal homeostasis and are functionally divided into several types, such as capillaries. Optical coherence tomography angiography (OCTA) is a powerful tool for the non-invasive assessment of dermal vasculature. However, the classification of vessel types has been limited.