Vimentin is a ubiquitination and degradation substrate of the ubiquitin ligase KPC1.

The ubiquitin proteasome system (UPS), driven by ubiquitin as a degradation signal, eliminates, in a highly specific manner, 'abnormal' proteins and proteins that completed their function. This process involves a hierarchical cascade of E1, E2, and E3 enzymes. The E3 ubiquitin ligases, act as specific receptors that bind their cognate substrates.

CXCL12 restricts tumor growth by suppressing the Ras, ERK1/2, c-Myc, and the immune checkpoint PD-L1 pathways.

Cytokines constitute a family of proteins that modulate the immune system and are secreted by many cells. CXCL12, along with its receptor CXCR4, are essential players in numerous processes. Dysregulation of their function underlie the mechanism(s) of several pathologies, including malignancies.

Nuclear p62 condensates stabilize the promyelocytic leukemia nuclear bodies by sequestering their ubiquitin ligase RNF4.

Liquid-liquid phase separation has emerged as a crucial mechanism driving the formation of membraneless biomolecular condensates, which play important roles in numerous cellular processes. These condensates, found both in the nucleus and cytoplasm, are formed through multivalent, low-affinity interactions between various molecules. P62-containing condensates serve, among other functions, as proteolytic hubs for the ubiquitin-proteasome system.

Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination.

Huntington's disease (HD) is caused by a glutamine repeat expansion in the protein huntingtin. Mutated huntingtin (mHtt) forms aggregates whose impacts on neuronal survival are still debated. Using weeks-long, continual imaging of cortical neurons, we find that mHtt is gradually sequestrated into peripheral, mainly axonal aggregates, concomitant with dramatic reductions in cytosolic mHtt levels and enhanced neuronal survival.

The Interplay between Extracellular Matrix Remodeling and Cancer Therapeutics.

The extracellular matrix (ECM) is an abundant noncellular component of most solid tumors known to support tumor progression and metastasis. The interplay between the ECM and cancer therapeutics opens up new avenues in understanding cancer biology. While the ECM is known to protect the tumor from anticancer agents by serving as a biomechanical barrier, emerging studies show that various cancer therapies induce ECM remodeling, resulting in therapy resistance and tumor progression.

Spatial features of skip lesions in Crohn's disease.

Skip lesions are an enigmatic spatial feature characterizing Crohn's disease (CD). They comprise inflamed and adjacent non-inflamed tissue sections with a clear demarcation. Currently, spatial features of the human gastrointestinal (GI) system lack clarity regarding the organization of microbes, mucus, tissue, and host cells during inflammation.

Stress-Induced Proteasome Sub-Cellular Translocation in Cardiomyocytes Causes Altered Intracellular Calcium Handling and Arrhythmias.

The ubiquitin-proteasome system (UPS) is an essential mechanism responsible for the selective degradation of substrate proteins via their conjugation with ubiquitin. Since cardiomyocytes have very limited self-renewal capacity, as they are prone to protein damage due to constant mechanical and metabolic stress, the UPS has a key role in cardiac physiology and pathophysiology. While altered proteasomal activity contributes to a variety of cardiac pathologies, such as heart failure and ischemia/reperfusion injury (IRI), the environmental cues affecting its activity are still unknown, and they are the focus of this work.

Microbiome and infectious disease: diagnostics to therapeutics.

Over 300 years of research on the microbial world has revealed their importance in human health and disease. This review explores the impact and potential of microbial-based detection methods and therapeutic interventions, integrating research of early microbiologists, current findings, and future perspectives.

Inflammation and bacteriophages affect DNA inversion states and functionality of the gut microbiota.

Reversible genomic DNA inversions control the expression of numerous gut bacterial molecules, but how this impacts disease remains uncertain. By analyzing metagenomic samples from inflammatory bowel disease (IBD) cohorts, we identified multiple invertible regions where a particular orientation correlated with disease. These include the promoter of polysaccharide A (PSA) of Bacteroides fragilis, which induces regulatory T cells (Tregs) and ameliorates experimental colitis.

Tryptophanyl-Transfer RNA Synthetase Is Involved in a Negative Feedback Loop Mitigating Interferon-γ-Induced Gene Expression.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes responsible for linking a transfer RNA (tRNA) with its cognate amino acid present in all the kingdoms of life. Besides their aminoacyl-tRNA synthetase activity, it was described that many of these enzymes can carry out non-canonical functions. They were shown to be involved in important biological processes such as metabolism, immunity, development, angiogenesis and tumorigenesis.

Gut microbial signatures are associated with Lynch syndrome (LS) and cancer history in Druze communities in Israel.

Lynch syndrome (LS) is a hereditary cancer syndrome caused by autosomal dominant mutations, with high probability of early onset for several cancers, mainly colorectal cancer (CRC). The gut microbiome was shown to be influenced by host genetics and to be altered during cancer development. Therefore, we aimed to determine alterations in gut microbiome compositions of LS patients with and without cancer.

The role of host response to chemotherapy: resistance, metastasis and clinical implications.

Chemotherapy remains the primary treatment for most metastatic cancers. However, the response to chemotherapy and targeted agents is often transient, and concurrent development of resistance is the primary impediment to effective cancer therapy. Strategies to overcome resistance to treatment have focused on cancer cell intrinsic factors and the tumor microenvironment (TME).

Combinatorial fluorescent labeling of live anaerobic bacteria via the incorporation of azide-modified sugars into newly synthesized macromolecules.

The human gut microbiome modulates physiological functions and pathologies; however, a mechanistic understanding of microbe-host and microbe-microbe interactions remains elusive owing to a lack of suitable approaches to monitor obligate anaerobic bacterial populations. Common genetically encoded fluorescent protein reporters, derived from the green fluorescent protein, require an oxidation step for fluorescent light emission and therefore are not suitable for use in anaerobic microbes residing in the intestine. Fluorescence in situ hybridization is a useful alternative to visualize bacterial communities in their natural niche; however, it requires tissue fixation.

A sound mind in a sound body: Stress-induced glucocorticoids exacerbate gut inflammation.

The notion that psychological stress can deteriorate our health is widely accepted. However, the mechanisms at play are poorly understood. In this issue of Cell, Schneider et al.

Extracellular vesicles of the Gram-positive gut symbiont Bifidobacterium longum induce immune-modulatory, anti-inflammatory effects.

The gut microbiota is now well known to affect the host's immune system. One way of bacterial communication with host cells is via the secretion of vesicles, small membrane structures containing various cargo. Research on vesicles secreted by Gram-positive gut bacteria, their mechanisms of interaction with the host and their immune-modulatory effects are still relatively scarce.

The NF-ĸB p50 subunit generated by KPC1-mediated ubiquitination and limited proteasomal processing, suppresses tumor growth.

Nuclear factor-ĸB (NF-ĸB) is an important transcriptional regulator of key cellular processes, including cell cycle, immune response, and malignant transformation. We found that the ubiquitin ligase Kip1 ubiquitination-promoting complex subunit 1 (KPC1; also known as Ring finger protein 123 - RNF123) stimulates ubiquitination and limited proteasomal processing of the p105 NF-ĸB precursor to generate p50, the active subunit of the heterodimeric transcription factor. KPC1 binds to the ankyrin repeats' (AR) domain of NF-ĸB p105 via a short binding site of 7 amino acids-968-WILVRLW-974.

The Tumor Suppressor Functions of Ubiquitin Ligase KPC1: From Cell-Cycle Control to NF-κB Regulator.

The ubiquitin-proteasome system (UPS) is responsible for up to 90% of intracellular protein degradation. Alterations in UPS are extensively involved in the development and advancement of malignant pathologies. Thus, the components of the UPS can become potential targets for cancer therapeutics.

Chemotherapy-induced tumor immunogenicity is mediated in part by megakaryocyte-erythroid progenitors.

Chemotherapy remains one of the main treatment modalities for cancer. While chemotherapy is mainly known for its ability to kill tumor cells directly, accumulating evidence indicates that it also acts indirectly by enhancing T cell-mediated anti-tumor immunity sometimes through immunogenic cell death. However, the role of immature immune cells in chemotherapy-induced immunomodulation has not been studied.

Automated device for multi-stage paper-based assays enabled by an electroosmotic pumping valve.

We leverage electroosmotic-flow generation in porous media in combination with a hydrophobic air gap to create a controllable valve capable of operating in either finite dosing or continuous flow mode, enabling the implementation of multi-step assays on paper-based devices. The hydrophobic air gap between two paper pads creates a barrier keeping the valve nominally closed. Electroosmotic actuation, implemented using a pair of electrodes under the upstream pad, generates sufficient pressure to overcome the barrier and connect the two pads.

Bv8 Blockade Sensitizes Anti-PD1 Therapy Resistant Tumors.

Myeloid-derived suppressor cells (MDSCs) are known to promote tumor growth in part by their immunosuppressive activities and their angiogenesis support. It has been shown that Bv8 blockade inhibits the recruitment of MDSCs to tumors, thereby delaying tumor relapse associated with resistance to antiangiogenic therapy. However, the impact of Bv8 blockade on tumors resistant to the new immunotherapy drugs based on the blockade of immune checkpoints has not been investigated.

Exploiting the ubiquitin system in myeloid malignancies. From basic research to drug discovery in MDS and AML.

The ubiquitin-proteasome system is the crucial homeostatic mechanism responsible for the degradation and turnover of proteins. As such, alterations at this level are often associated with oncogenic processes, either through accumulation of undegraded pathway effectors or, conversely, excessive degradation of tumor-suppressing factors. Therefore, investigation of the ubiquitin- proteasome system has gained much attraction in recent years, especially in the context of hematological malignancies, giving rise to efficient therapeutics such as bortezomib for multiple myeloma.

Microbiome Characterization of Infected Diabetic Foot Ulcers in Association With Clinical Outcomes: Traditional Cultures Versus Molecular Sequencing Methods.

Background: Infected diabetic foot ulcers (IDFU) are a major complication of diabetes mellitus. These potentially limb-threatening ulcers are challenging to treat due to impaired wound healing characterizing diabetic patients and the complex microbial environment of these ulcers.

Aim: To analyze the microbiome of IDFU in association with clinical outcomes.