Development of rare earth element-based hybrid aluminium composites using stir casting process.

Aerospace and marine industries are constantly in search of materials that can provide good strength and durability while also being lightweight. Aluminium composites with adequate reinforcements have been proven to be effective in achieving incredible mechanical properties while also maintaining a good strength to weight ratio. Numerous studies have been done to study the various possibilities of matrix reinforcement combinations in aluminium composites.

Zebrafish reveal new roles for Fam83f in hatching and the DNA damage-mediated autophagic response.

The FAM83 (ily with sequence similarity ) family is highly conserved in vertebrates, but little is known of the functions of these proteins beyond their association with oncogenesis. Of the family, FAM83F is of particular interest because it is the only membrane-targeted FAM83 protein. When overexpressed, FAM83F activates the canonical Wnt signalling pathway and binds to and stabilizes p53; it therefore interacts with two pathways often dysregulated in disease.

Targeted dephosphorylation of SMAD3 as an approach to impede TGF-β signaling.

TGF-β (transforming growth factor-β) signaling is involved in a myriad of cellular processes and its dysregulation has been implicated in many human diseases, including fibrosis and cancer. TGF-β transcriptional responses are controlled by tail phosphorylation of transcription factors SMAD2 and SMAD3 (mothers against decapentaplegic homolog 2/3). Therefore, targeted dephosphorylation of phospho-SMAD3 could provide an innovative mechanism to block some TGF-β-induced transcriptional responses, such as the transcription of , which encodes plasminogen activator inhibitor 1 (PAI-1).

Targeted dephosphorylation of TFEB promotes its nuclear translocation.

Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localized to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity.

Mapping the substrate landscape of protein phosphatase 2A catalytic subunit PPP2CA.

Protein phosphatase 2A (PP2A) is an essential Ser/Thr phosphatase. The PP2A holoenzyme complex comprises a scaffolding (A), regulatory (B), and catalytic (C) subunit, with PPP2CA being the principal catalytic subunit. The full scope of PP2A substrates in cells remains to be defined.

Proteomic approaches advancing targeted protein degradation.

Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings.

Identification of KLHDC2 as an efficient proximity-induced degrader of K-RAS, STK33, β-catenin, and FoxP3.

Targeted protein degradation (TPD), induced by enforcing target proximity to an E3 ubiquitin ligase using small molecules has become an important drug discovery approach for targeting previously undruggable disease-causing proteins. However, out of over 600 E3 ligases encoded by the human genome, just over 10 E3 ligases are currently utilized for TPD. Here, using the affinity-directed protein missile (AdPROM) system, in which an anti-GFP nanobody was linked to an E3 ligase, we screened over 30 E3 ligases for their ability to degrade 4 target proteins, K-RAS, STK33, β-catenin, and FoxP3, which were endogenously GFP-tagged.

Preservation of Phenols, Antioxidant Activity, and Cyclic Adenosine Monophosphate in Jujube ( Mill.) Fruits with Different Drying Methods.

Jujube, commonly known as the Chinese date, is a nutritious fruit with medicinal importance. Fresh jujube fruits have a shelf life of about ten days in ambient conditions that can be extended by drying. However, nutrition preservation varies with the drying method and parameters selected.

Harnessing nanobodies for target protein degradation through the Affinity-directed PROtein Missile (AdPROM) system.

Targeted protein degradation (TPD) is a useful approach in dissecting protein function and therapeutics. Technologies such as RNA interference or gene knockout that are routinely used rely on protein turnover. However, RNA interference takes a long time to deplete target proteins and is not suitable for long-lived proteins, while a genetic knockout is irreversible, takes a long time to achieve and is not suitable for essential genes.

Target protein localization and its impact on PROTAC-mediated degradation.

Proteolysis-targeting chimeras (PROTACs) bring a protein of interest (POI) into spatial proximity of an E3 ubiquitin ligase, promoting POI ubiquitylation and proteasomal degradation. PROTACs rely on endogenous cellular machinery to mediate POI degradation, therefore the subcellular location of the POI and access to the E3 ligase being recruited potentially impacts PROTAC efficacy. To interrogate whether the subcellular context of the POI influences PROTAC-mediated degradation, we expressed either Halo or FKBP12 (dTAG) constructs consisting of varying localization signals and tested the efficacy of their degradation by von Hippel-Lindau (VHL)- or cereblon (CRBN)-recruiting PROTACs targeting either Halo or dTAG.

Case Report of an 18 Year Old Girl with Solid Pseudo-papillary Tumor of Pancreas.

Solid Pseudo-papillary Tumor (SPT) of the pancreas is a rare tumor which typically affects young women without any significant clinical symptoms. Solid Pseudopapillary Tumor usually shows an indolent behavior and only rare cases recur and/or metastasize after complete resection. Here is a case report of 18 years old girl who presented to our centre with complaints of severe epigastric pain and underwent pancreatic parenchyma saving surgery for a large pancreatic head mass.

A Phenotypic Approach for the Identification of New Molecules for Targeted Protein Degradation Applications.

Targeted protein degradation is an emerging new strategy for the modulation of intracellular protein levels with applications in chemical biology and drug discovery. One approach to enable this strategy is to redirect the ubiquitin-proteasome system to mark and degrade target proteins of interest (POIs) through the use of proteolysis targeting chimeras (PROTACs). Although great progress has been made in enabling PROTACs as a platform, there are still a limited number of E3 ligases that have been employed for PROTAC design.

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling.

Immunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling the recruitment of neo-substrates, such as CK1α, and their degradation via the ubiquitinproteasome system. Here, we report FAM83F as such a neo-substrate. The eight FAM83 proteins (A-H) interact with and regulate the subcellular distribution of CK1α.

FAM83F regulates canonical Wnt signalling through an interaction with CK1α.

The function of the FAM83F protein, like the functions of many members of the FAM83 family, is poorly understood. Here, we show that injection of Fam83f mRNA into embryos causes axis duplication, a phenotype indicative of enhanced Wnt signalling. Consistent with this, overexpression of FAM83F activates Wnt signalling, whereas ablation of FAM83F from human colorectal cancer (CRC) cells attenuates it.

Functions and regulation of the serine/threonine protein kinase CK1 family: moving beyond promiscuity.

Regarded as constitutively active enzymes, known to participate in many, diverse biological processes, the intracellular regulation bestowed on the CK1 family of serine/threonine protein kinases is critically important, yet poorly understood. Here, we provide an overview of the known CK1-dependent cellular functions and review the emerging roles of CK1-regulating proteins in these processes. We go on to discuss the advances, limitations and pitfalls that CK1 researchers encounter when attempting to define relationships between CK1 isoforms and their substrates, and the challenges associated with ascertaining the correct physiological CK1 isoform for the substrate of interest.

Inducible Degradation of Target Proteins through a Tractable Affinity-Directed Protein Missile System.

The affinity-directed protein missile (AdPROM) system utilizes specific polypeptide binders of intracellular proteins of interest (POIs) conjugated to an E3 ubiquitin ligase moiety to enable targeted proteolysis of the POI. However, a chemically tuneable AdPROM system is more desirable. Here, we use Halo-tag/VHL-recruiting proteolysis-targeting chimera (HaloPROTAC) technology to develop a ligand-inducible AdPROM (L-AdPROM) system.

Targeting Endogenous K-RAS for Degradation through the Affinity-Directed Protein Missile System.

K-RAS is known as the most frequently mutated oncogene. However, the development of conventional K-RAS inhibitors has been extremely challenging, with a mutation-specific inhibitor reaching clinical trials only recently. Targeted proteolysis has emerged as a new modality in drug discovery to tackle undruggable targets.

Characterisation of the biochemical and cellular roles of native and pathogenic amelogenesis imperfecta mutants of FAM83H.

The majority of mutations identified in patients with amelogenesis imperfecta have been mapped to FAM83H. As FAM83H expression is not limited to the enamel, how FAM83H contributes to amelogenesis is still largely unknown. We previously reported that members of the FAM83 family of proteins interact with and regulate the subcellular distribution of the promiscuous serine-threonine protein kinase CK1 family, through their shared N-terminal DUF1669 domains.

Mitotic kinase anchoring proteins: the navigators of cell division.

The coordinated activities of many protein kinases, acting on multiple protein substrates, ensures the error-free progression through mitosis of eukaryotic cells. Enormous research effort has thus been devoted to studying the roles and regulation of these mitotic kinases, and to the identification of their physiological substrates. Central for the timely deployment of specific protein kinases to their appropriate substrates during the cell division cycle are the many anchoring proteins, which serve critical regulatory roles.

Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses.

The signalling pathways initiated by members of the transforming growth factor-β (TGFβ) family of cytokines control many metazoan cellular processes, including proliferation and differentiation, epithelial-mesenchymal transition (EMT) and apoptosis. TGFβ signalling is therefore strictly regulated to ensure appropriate context-dependent physiological responses. In an attempt to identify novel regulatory components of the TGFβ signalling pathway, we performed a pharmacological screen by using a cell line engineered to report the endogenous transcription of the TGFβ-responsive target gene PAI-1.

Pathogenic palmoplantar keratoderma mutations inhibit the PAWS1:CK1α association and attenuate Wnt signalling.

Two recessive mutations in the gene, causing A34E and R52P amino acid substitutions in the DUF1669 domain of the PAWS1 protein, are associated with palmoplantar keratoderma (PPK) in humans and dogs respectively. We have previously reported that PAWS1 associates with the Ser/Thr protein kinase CK1α through the DUF1669 domain to mediate canonical Wnt signalling. Co-immunoprecipitation was used to investigate possible changes to PAWS1 interactors caused by the mutations.

FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning.

The concerted action of many protein kinases helps orchestrate the error-free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin-dependent kinases, are well established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis.