Ehbp1 orchestrates orderly sorting of Wnt/Wingless to the basolateral and apical cell membranes.

Wingless (Wg)/Wnt signaling plays a critical role in both development and adult tissue homeostasis. In the Drosophila larval wing disc epithelium, the orderly delivery of Wg/Wnt to the apical and basal cell surfaces is essential for wing development. Here, we identified Ehbp1 as the switch that dictates the direction of Wg/Wnt polarized intracellular transport: the Adaptor Protein complex 1 (AP-1) delivers Wg/Wnt to the basolateral cell surface, and its sequestration by Ehbp1 redirects Wg/Wnt for apical delivery.

Therapeutic siRNA targeting PLIN2 ameliorates steatosis, inflammation, and fibrosis in steatotic liver disease models.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. If left untreated, MASLD can progress from simple hepatic steatosis to metabolic dysfunction-associated steatohepatitis, which is characterized by inflammation and fibrosis. Current treatment options for MASLD remain limited, leaving substantial unmet medical needs for innovative therapeutic approaches.

Stereotactic central/core ablative radiation therapy: results of a phase I study of a novel strategy to treat bulky tumor.

Purpose: Bulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT).

Breast Cancer Method of Detection: 5-Year Outcomes Across a Multisite Health Care Enterprise.

Purpose: To investigate the feasibility and accuracy of radiologists categorizing the method of detection (MOD) when performing image-guided breast biopsies.

Methods: This retrospective, observational study was conducted across a health care enterprise that provides breast imaging services at 18 imaging sites across four US states. Radiologists used standardized templates to categorize the MOD, defined as the first test, sign, or symptom that triggered the subsequent workup and recommendation for biopsy.

Combining spatially fractionated radiation therapy (SFRT) and immunotherapy opens new rays of hope for enhancing therapeutic ratio.

Spatially Fractionated Radiation Therapy (SFRT) is a form of radiotherapy that delivers a single large dose of radiation within the target volume in a heterogeneous pattern with regions of peak dosage and regions of under dosage. SFRT types can be defined by how the heterogeneous pattern of radiation is obtained. Immune checkpoint inhibitors (ICIs) have been approved for various malignant tumors and are widely used to treat patients with metastatic cancer.

Stuxnet fine-tunes Notch dose during development using a functional Polycomb response element.

Evolutionarily conserved Notch signaling is highly sensitive to changes in Notch receptor dose caused by intrinsic and environmental fluctuations. It is well known that epigenetic regulation responds dynamically to genetic, cellular and environmental stresses. However, it is unclear whether the Notch receptor dose is directly regulated at the epigenetic level.

Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle.

Background: Malnutrition is implicated in human metabolic disorders, including hepatic steatosis and myosteatosis. The corresponding nutrient signals and sensors as well as signalling pathways have not yet been well studied. This study aimed to unravel the nutrient-sensing mechanisms in the pathogenesis of steatosis.

Dissection of the microRNA Network Regulating Hedgehog Signaling in .

The evolutionarily conserved Hedgehog (Hh) signaling plays a critical role in embryogenesis and adult tissue homeostasis. Aberrant Hh signaling often leads to various forms of developmental anomalies and cancer. Since altered microRNA (miRNA) expression is associated with developmental defects and tumorigenesis, it is not surprising that several miRNAs have been found to regulate Hh signaling.

Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with no approved drugs. High-protein dietary intervention is currently the most effective treatment. However, its underlying mechanism is unknown.

Protein modifications in Hedgehog signaling: Cross talk and feedback regulation confer divergent Hedgehog signaling activity.

The complexity of the Hedgehog (Hh) signaling cascade has increased over the course of evolution; however, it does not suffice to accommodate the dynamic yet robust requirements of differential Hh signaling activity needed for embryonic development and adult homeostatic maintenance. One solution to solve this dilemma is to apply multiple forms of post-translational modifications (PTMs) to the core Hh signaling components, modulating their abundance, localization, and signaling activity. This review summarizes various forms of protein modifications utilized to regulate Hh signaling, with a special emphasis on crosstalk between different forms of PTMs and their feedback regulation by Hh signaling.

Vitrectomy versus Combined Vitrectomy and Scleral Buckle for Repair of Primary Rhegmatogenous Retinal Detachment with Vitreous Hemorrhage.

Purpose: To compare pars plana vitrectomy (PPV) with combined PPV and scleral buckle (PPV/SB) for repair of primary rhegmatogenous retinal detachment (RRD) with associated vitreous hemorrhage (VH).

Design: Retrospective, observational study.

Participants: Patients with RRD and associated VH who underwent PPV or PPV/SB from January 1, 2010, through August 31, 2020, were analyzed.

A widely diverged locus involved in locomotor adaptation in butterflies.

butterflies have undergone adaptive radiation and therefore serve as an excellent system for exploring the continuum of speciation and adaptive evolution. However, there is a long-lasting paradox between their convergent mimetic wing patterns and rapid divergence in speciation. Here, we characterize a locus that consistently displays high divergence among butterflies and acts as an introgression hotspot.

Epigenetic regulator Stuxnet modulates octopamine effect on sleep through a Stuxnet-Polycomb-Octβ2R cascade.

Sleep homeostasis is crucial for sleep regulation. The role of epigenetic regulation in sleep homeostasis is unestablished. Previous studies showed that octopamine is important for sleep homeostasis.

Competition between two phosphatases fine-tunes Hedgehog signaling.

Hedgehog (Hh) signaling is essential for embryonic development and adult homeostasis. How its signaling activity is fine-tuned in response to fluctuated Hh gradient is less known. Here, we identify protein phosphatase V (PpV), the catalytic subunit of protein phosphatase 6, as a homeostatic regulator of Hh signaling.

Impact of Surfactants on Polymer Maintained Nifedipine Supersaturation in Aqueous Solution.

Purpose: To study the impact of different surfactants on the supersaturation of nifedipine stabilized with HPMC and PVP-VA.

Methods: Different kinds of surfactants, including one cationic surfactant, two anionic surfactants, and three nonionic surfactants, were used to evaluate their impacts on the supersaturation of nifedipine stabilized with HPMC and PVP-VA. Polymer-surfactant interaction was studied by nuclear magnetic resonance (NMR) and fluorescent method.

Recognition of early and late stages of bladder cancer using metabolites and machine learning.

Introduction: Bladder cancer (BCa) is one of the most common and aggressive cancers. It is the sixth most frequently occurring cancer in men and its rate of occurrence increases with age. The current method of BCa diagnosis includes a cystoscopy and biopsy.

Impact of a Single Hydrogen Substitution by Fluorine on the Molecular Interaction and Miscibility between Sorafenib and Polymers.

We aim to understand the potential impact of a modest chemical modification of a drug molecule on the downstream design of its amorphous solid dispersion (ASD) formulation. To this end, we used sorafenib (SOR) and its fluorinated form, regorafenib (REG), as model drugs, to assess the impact of a single hydrogen substitution by fluorine on the molecular interaction and miscibility between drug and PVP or PVP-VA, two commonly used polymers for ASDs. In this study, we observed that the T values of PVP or PVP-VA based ASDs of SOR deviated positively from the Gordon-Taylor prediction, which assumes ideal mixing, yet the T of REG ASDs deviated negatively from or matched well with the ideal mixing model, suggesting much stronger drug-polymer interactions in SOR ASDs compared with the REG ASDs.

Aggregation of Hydroxypropyl Methylcellulose Acetate Succinate under Its Dissolving pH and the Impact on Drug Supersaturation.

Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is one of the commonly selected polymers used in amorphous solid dispersions (ASD) with excellent capabilities to maintain aqueous supersaturation of poorly water-soluble drugs and inhibit their crystallization, but the underlying mechanisms remain elusive. In this study, posaconazole was chosen as the model drug to study the supersaturation maintaining and crystallization inhibition capabilities of different types of HPMC-AS under pH 5.5-7.

A high-sensitivity HPLC-ELSD method for HPMC-AS quantification and its application in elucidating the release mechanism of HPMC-AS based amorphous solid dispersions.

Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is one of the most widely used polymers used in amorphous solid dispersions (ASD) for solubility and bioavailability enhancement of poorly water-soluble drugs. Once released from ASDs, HPMC-AS was often found to be highly effective in maintaining drug supersaturation, and this capability is dependent on the concentration and substitution types of this pH-dependent polymer. Therefore, accurate quantification of different grades of HPMC-AS allows us to better understand the release and supersaturation mechanisms of HPMC-AS based ASDs.

Predictive Modeling of Micellar Solubilization by Single and Mixed Nonionic Surfactants.

Micellar solubilization is an important concept in the delivery of poorly water-soluble drugs. The rational selection of the type and the amount of surfactant to be incorporated in a formulation require comprehensive solubility studies. These studies are time and material demanding, both of which are scarce, especially during late discovery and early development stages.

Surface Enrichment and Depletion of the Active Ingredient in Spray Dried Amorphous Solid Dispersions.

Purpose: To study the effects of physicochemical properties of drug and polymer, as well as the drug-polymer interactions, on the surface composition of SDDs.

Methods: Ethanol solutions containing a model drug (IMC, NMP or FCZ) and a model polymer (PVPK12, PVPK30 or PVP-VA) were spray dried, and the surface composition of SDDs was analyzed by XPS. The surface tensions of pure components and their solutions were measured using Wilhelmy plate and/or calculated using ACD/Labs.

The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development.

Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila.

COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR.

Oestrogen receptor α (ERα) antagonists are used in endocrine therapies for ERα-positive (ERα+) breast cancer patients. Unfortunately the clinical benefit is limited due to intrinsic and acquired drug resistance. Here using integrated genomic and functional studies, we report that amplification and/or overexpression of COPS5 (CSN5/JAB1) confers resistance to tamoxifen.

Stuxnet Facilitates the Degradation of Polycomb Protein during Development.

Polycomb-group (PcG) proteins function to ensure correct deployment of developmental programs by epigenetically repressing target gene expression. Despite the importance, few studies have been focused on the regulation of PcG activity itself. Here, we report a Drosophila gene, stuxnet (stx), that controls Pc protein stability.

Ubpy controls the stability of the ESCRT-0 subunit Hrs in development.

Ubiquitylated developmental membrane signaling proteins are often internalized for endocytic trafficking, through which endosomal sorting complexes required for transport (ESCRT) act sequentially to deliver internalized cargos to lysosomes. The ESCRT function in endocytic sorting is well established; however, it is not fully understood how the sorting machinery itself is regulated. Here, we show that Ubiquitin isopeptidase Y (Ubpy) plays a conserved role in vivo in the homeostasis of an essential ESCRT-0 complex component Hrs.