FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models.

Background: We developed the FORCE platform to overcome limitations of oligonucleotide delivery to muscle and enable their applicability to neuromuscular disorders. The platform consists of an antigen-binding fragment, highly specific for the human transferrin receptor 1 (TfR1), conjugated to an oligonucleotide via a cleavable valine-citrulline linker. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by expanded CUG triplets in the DMPK RNA, which sequester splicing proteins in the nucleus, lead to spliceopathy, and drive disease progression.

Explainable human-centered traits from head motion and facial expression dynamics.

We explore the efficacy of multimodal behavioral cues for explainable prediction of personality and interview-specific traits. We utilize elementary head-motion units named kinemes, atomic facial movements termed action units and speech features to estimate these human-centered traits. Empirical results confirm that kinemes and action units enable discovery of multiple trait-specific behaviors while also enabling explainability in support of the predictions.

Artificial Liver Support Systems in Acute Liver Failure and Acute-on-Chronic Liver Failure: Systematic Review and Meta-Analysis.

Objectives: To systematically review the safety and efficacy of nonbiological (NBAL) or biological artificial liver support systems (BAL) and whole-organ extracorporeal liver perfusion (W-ECLP) systems, in adults with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF).

Data Sources: Eligible NBAL/BAL studies from PubMed/Embase searches were randomized controlled trials (RCTs) in adult patients with ALF/ACLF, greater than or equal to ten patients per group, reporting outcomes related to survival, adverse events, transplantation rate, and hepatic encephalopathy, and published in English from January 2000 to July 2023. Separately, we searched for studies evaluating W-ECLP in adult patients with ALF or ACLF published between January1990 and July 2023.

The effect of cancer cell-derived exosomal proteins on macrophage polarization: An in-depth review.

Cancer is characterized by unregulated cell proliferation, enabling it to invade and spread to different organs and tissues in the body. Cancer progression is intricately influenced by the complex dynamics within the tumor microenvironment (TME). The TME is a composite and dynamic network comprising cancer cells and various immune cells, including tumor-associated macrophages.

Mechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist.

ATP-activated P2X3 receptors play a pivotal role in chronic cough, affecting more than 10% of the population. Despite the challenges posed by the highly conserved structure of P2X receptors, efforts to develop selective drugs targeting P2X3 have led to the development of camlipixant, a potent, selective P2X3 antagonist. However, the mechanisms of receptor desensitization, ion permeation, and structural basis of camlipixant binding to P2X3 remain unclear.

Non-canonical CDK6 activity promotes cilia disassembly by suppressing axoneme polyglutamylation.

Tubulin polyglutamylation is a posttranslational modification that occurs primarily along the axoneme of cilia. Defective axoneme polyglutamylation impairs cilia function and has been correlated with ciliopathies, including Joubert Syndrome (JBTS). However, the precise mechanisms regulating proper axoneme polyglutamylation remain vague.

Formulation of Asiatic acid-loaded polymeric chitosan-based hydrogel for effective MRSA infection control and enhanced wound healing in zebrafish models.

Background: Wound healing relies on a controlled inflammatory process vital for tissue regeneration. Chronic wounds, characterized by persistent inflammation and high infection risk, pose significant challenges in healthcare. Hydrogel dressings offer promise in wound care; however, the understanding of their role in managing inflammation and infection remains unclear.

The Effect of a Tailored Educational Flyer on Colorectal Cancer Screening Among Rural Residents: Lessons Learned from a Pilot Randomized Trial.

: Stool-based tests, such as the fecal immunochemical test (FIT), have been widely used for increasing colorectal cancer (CRC) screening. Small media, such as printed materials or flyers, are known to be an effective intervention to increase CRC screening by fecal tests. However, more evidence is needed to determine whether such small media are effective in improving screening uptake of a mailed FIT intervention targeted at rural populations in the USA.

Samelisant (SUVN-G3031), a histamine 3 receptor inverse agonist: Results from the phase 2 double-blind randomized placebo-controlled study for the treatment of excessive daytime sleepiness in adult patients with narcolepsy.

Narcolepsy is a rare, chronic neurological disorder characterized by a dysregulated sleep-wake cycle, with core clinical features including excessive daytime sleepiness (EDS), cataplexy, hypnopompic/hypnagogic hallucinations, and sleep paralysis. Several treatment options are available for the symptomatic management of narcolepsy, but they have limitations. Comorbidities of narcolepsy further limit the treatment choices.

Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of -Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.

Purpose: This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of -mutant metastatic colorectal cancer (mCRC).

Patients And Methods: This multicenter, open-label, single-arm study enrolled patients with -mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15).

Biologics and oral systemic treatment preferences in patients and physicians for moderate-to-severe atopic dermatitis: a discrete choice experiment in the United Kingdom and Germany.

As the available treatments for moderate-to-severe atopic dermatitis (AD) expand, understanding patient and physician preferences becomes crucial for informed decision-making. To quantify patient and physician preferences for biologics and oral systemic AD treatment attributes. We conducted a cross-sectional, online discrete choice experiment (DCE) involving 306 AD patients and 206 physicians throughout the United Kingdom and Germany.

Collaborative role of two distinct cilium-specific cytoskeletal systems in driving Hedgehog-responsive transcription factor trafficking.

Calibrated transcriptional outputs in cellular signaling require fine regulation of transcription factor activity. In vertebrate Hedgehog (Hh) signaling, the precise output of the final effectors, the GLI (Glioma-associated-oncogene) transcription factors, depends on the primary cilium. In particular, the formation of the activator form of GLI upon pathway initiation requires its concentration at the distal cilium tip.

Methods used to determine the structure of the oxygenase component of naphthalene 1,2 dioxygenase.

Rieske non-heme iron oxygenases are ubiquitously expressed in prokaryotes. These enzymes catalyze a wide variety of reactions, including cis-dihydroxylation, mono-hydroxylation, sulfoxidation, and demethylation. They contain a Rieske-type [2Fe-2S] cluster and an active site with a mono-nuclear iron bound to a 2-His carboxylate triad.

A comprehensive insight from molecular docking and dynamics with clinical investigation on the impact of direct oral anticoagulants on atheroprotective protein in atrial fibrillation.

Background: Direct oral anticoagulants (DOACs) have high potency against their therapeutic target and are widely used in the treatment of atrial fibrillation (AF). Most DOACs are often claimed to have adverse effects due to off-target inhibition of essential proteins. Human serum paraoxonase 1 (PON1), one of the essential proteins, known for its anti-inflammatory and antioxidant properties, could be affected by DOACs.

Patient-Centric Long-Acting Injectable and Implantable Platforms─An Industrial Perspective.

The increasing focus on patient centricity in the pharmaceutical industry over the past decade and the changing healthcare landscape, driven by factors such as increased access to information, social media, and evolving patient demands, has necessitated a shift toward greater connectivity and understanding of patients' unique treatment needs. One pharmaceutical technology that has supported these efforts is long acting injectables (LAIs), which lower the administration frequency for the patient's provided convenience, better compliance, and hence better therapeutical treatment for the patients. Furthermore, patients with conditions like the human immunodeficiency virus and schizophrenia have positively expressed the desire for less frequent dosing, such as that obtained through LAI formulations.

Architecture of native kinetochores revealed by structural studies utilizing a thermophilic yeast.

Eukaryotic chromosome segregation requires kinetochores, multi-megadalton protein machines that assemble on the centromeres of chromosomes and mediate attachments to dynamic spindle microtubules. Kinetochores are built from numerous complexes, and there has been progress in structural studies on recombinant subassemblies. However, there is limited structural information on native kinetochore architecture.

Synergistic berberine chloride and Curcumin-Loaded nanofiber therapies against Methicillin-Resistant Staphylococcus aureus Infection: Augmented immune and inflammatory responses in zebrafish wound healing.

Background: Wound healing pivots on a finely orchestrated inflammatory cascade, critical for tissue repair. Chronic wounds, compounded by persistent inflammation and susceptibility to infection, pose formidable clinical challenges. Nanofiber dressings offer promising avenues for wound care, yet their interaction with inflammation and infection remains elusive.