A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect.

TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach.

Evaluation of a Cosmetic Formulation Containing Arginine Glutamate in Patients with Burn Scars: A Pilot Study.

Patients with burn scars require effective treatments able to alleviate dry skin and persistent itching. Ion pairing has been employed in cosmetic formulations to enhance solubility in solvents and improve skin permeability. To evaluate the efficacy and safety of the cosmetic formula "RE:pair (arginine-glutamate ion pair)", we analyzed scar size, itching and pain, skin barrier function, scar scale evaluation, and satisfaction in our study participants.

Mapping extrachromosomal DNA amplifications during cancer progression.

To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal amplifications in 8,060 newly diagnosed primary cancers, untreated metastases and heavily pretreated tumors. The ecDNAs were detected at significantly higher frequency in untreated metastatic and pretreated tumors compared to newly diagnosed cancers. Tumors from chemotherapy-pretreated patients showed significantly higher ecDNA frequency compared to untreated cancers.

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).

Large-scale map of RNA-binding protein interactomes across the mRNA life cycle.

mRNAs interact with RNA-binding proteins (RBPs) throughout their processing and maturation. While efforts have assigned RBPs to RNA substrates, less exploration has leveraged protein-protein interactions (PPIs) to study proteins in mRNA life-cycle stages. We generated an RNA-aware, RBP-centric PPI map across the mRNA life cycle in human cells by immunopurification-mass spectrometry (IP-MS) of ∼100 endogenous RBPs with and without RNase, augmented by size exclusion chromatography-mass spectrometry (SEC-MS).

Investigation Into the Subharmonic Response of Three Contrast Agents in Static and Dynamic Flow Environments Using a Commercially Available Diagnostic Ultrasound Scanner.

Objective: The objective of this study was to investigate the subharmonic response of Lumason (also known as SonoVue; Bracco, Milan, Italy) to static and dynamic ambient pressures, with a direct comparison to Sonazoid (GE HealthCare, Oslo, Norway) and Definity (Lantheus Medical Imaging, MA, USA). The subharmonic responses of contrast agents can be exploited to perform subharmonic-aided pressure estimation.

Methods: The subharmonic response of each ultrasound contrast agent was evaluated in both a static and dynamic tank using a commercially available Logiq E10 clinical ultrasound scanner (GE HealthCare) equipped with subharmonic imaging (SHI) and an acoustic power-optimization algorithm.

Material strengths of shear-induced platelet aggregation clots and coagulation clots.

Arterial occlusion by thrombosis is the immediate cause of some strokes, heart attacks, and peripheral artery disease. Most prior studies assume that coagulation creates the thrombus. However, a contradiction arises as whole blood (WB) clots from coagulation are too weak to stop arterial blood pressures (> 150 mmHg).

Nonepithelial Gene Expression Correlates With Symptom Severity in Adults With Eosinophilic Esophagitis.

Background: The mechanistic basis of the variable symptomatology seen in eosinophilic esophagitis (EoE) remains poorly understood.

Objective: We examined the correlation of a validated, patient-reported outcome metric with a broad spectrum of esophageal transcripts to uncover potential symptom pathogenesis.

Methods: We extracted data from 146 adults with EoE through the Consortium of Eosinophilic Gastrointestinal Disease Researchers.

Cluster-Based Pairwise Contrastive Loss for Noise-Robust Speech Recognition.

This paper addresses a joint training approach applied to a pipeline comprising speech enhancement (SE) and automatic speech recognition (ASR) models, where an acoustic tokenizer is included in the pipeline to leverage the linguistic information from the ASR model to the SE model. The acoustic tokenizer takes the outputs of the ASR encoder and provides a pseudo-label through K-means clustering. To transfer the linguistic information, represented by pseudo-labels, from the acoustic tokenizer to the SE model, a cluster-based pairwise contrastive (CBPC) loss function is proposed, which is a self-supervised contrastive loss function, and combined with an information noise contrastive estimation (infoNCE) loss function.

Complete Mitochondrial Genome and Its Phylogenetic Position in Red Algae from South Korea.

The mitogenome is an important tool in taxonomic and evolutionary studies. Only a few complete mitogenomes have been reported for red algae. Herein, we reported the complete mitochondrial genome sequence of (Harvey) Filloramo, G.

Airway injury induces alveolar epithelial and mesenchymal responses mediated by macrophages.

Acute injury in the airways or the lung activates local progenitors and stimulates changes in cell-cell interactions to restore homeostasis, but it is not appreciated how more distant niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar, immune, and mesenchymal responses. Single-cell transcriptomics and validation revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific ablation.

Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

Background: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.

A Computational Evaluation of Minimum Feature Size in Projection Two-Photon Lithography for Rapid Sub-100 nm Additive Manufacturing.

Two-photon lithography (TPL) is a laser-based additive manufacturing technique that enables the printing of arbitrarily complex cm-scale polymeric 3D structures with sub-micron features. Although various approaches have been investigated to enable the printing of fine features in TPL, it is still challenging to achieve rapid sub-100 nm 3D printing. A key limitation is that the physical phenomena that govern the theoretical and practical limits of the minimum feature size are not well known.

Switchable tribology of ferroelectrics.

Switchable tribological properties of ferroelectrics offer an alternative route to visualize and control ferroelectric domains. Here, we observe the switchable friction and wear behavior of ferroelectrics using a nanoscale scanning probe-down domains have lower friction coefficients and show slower wear rates than up domains and can be used as smart masks. This asymmetry is enabled by flexoelectrically coupled polarization in the up and down domains under a sufficiently high contact force.

Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer.

As a core chromatin-regulatory scaffolding protein, WDR5 mediates numerous protein-protein interactions (PPIs) with other partner oncoproteins. However, small-molecule inhibitors that block these PPIs exert limited cell-killing effects. Here, we report structure-activity relationship studies in pancreatic ductal adenocarcinoma (PDAC) cells that led to the discovery of several WDR5 proteolysis-targeting chimer (PROTAC) degraders, including (MS132), a highly potent and selective von Hippel-Lindau (VHL)-recruiting WDR5 degrader, which displayed positive binding cooperativity between WDR5 and VHL, effectively inhibited proliferation in PDAC cells, and was bioavailable in mice and , a cereblon (CRBN)-recruiting WDR5 degrader, which selectively degraded WDR5 over the CRBN neo-substrate IKZF1.

Microfibrillar-associated protein 4 as a potential marker of acute relapse in inflammatory demyelinating diseases of the central nervous system: Pathological and clinical aspects.

Background: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS).

Objectives: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels.

Methods: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) ( = 3), progressive MS ( = 3), neuromyelitis optica spectrum disorder (NMOSD) ( = 2), and controls ( = 9), including 6 healthy controls (HC).

The smallest functional antibody fragment: Ultralong CDR H3 antibody knob regions potently neutralize SARS-CoV-2.

Cows produce antibodies with a disulfide-bonded antigen-binding domain embedded within ultralong heavy chain third complementarity determining regions. This "knob" domain is analogous to natural cysteine-rich peptides such as knottins in that it is small and stable but can accommodate diverse loops and disulfide bonding patterns. We immunized cattle with SARS-CoV-2 spike and found ultralong CDR H3 antibodies that could neutralize several viral variants at picomolar IC potencies in vitro and could protect from disease in vivo.

Association of Depression and Cognitive Dysfunction With Patient-Centered Outcomes After Transcatheter Aortic Valve Replacement.

Background: Depression and cognitive dysfunction (CD) are not routinely screened for in patients before transcatheter aortic valve replacement (TAVR) and their association with postprocedural outcomes is poorly understood. The objectives of this study are to determine the prevalence of depression and CD in patients with aortic stenosis undergoing TAVR and evaluate their association with mortality and quality of life.

Methods: We analyzed a prospective, multicenter TAVR registry that systematically screened patients for preexisting depression and CD with the Patient Health Questionnaire-2 and Mini-Cog, respectively.

Rewiring cancer drivers to activate apoptosis.

Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers. Independent studies have identified cell death pathways that eliminate cells for the good of the organism. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs).

Impact of chronic kidney disease and diabetes on clinical outcomes in women undergoing PCI.

Background: For women undergoing drug-eluting stent (DES) implantation, the individual and combined impact of chronic kidney disease (CKD) and diabetes mellitus (DM) on outcomes is uncertain.

Aims: We sought to assess the impact of CKD and DM on prognosis in women after DES implantation.

Methods: We pooled patient-level data on women from 26 randomised controlled trials comparing stent types.