Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise.

Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson's disease and Huntington's disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as synthetic lethality in autophagy-null human cells using available data from yeast screens.

p37 regulates VCP/p97 shuttling and functions in the nucleus and cytosol.

The AAA-ATPase valosin-containing protein (VCP; also called p97 or Cdc48), a major protein unfolding machinery with a variety of essential functions, localizes to different subcellular compartments where it has different functions. However, the processes regulating the distribution of VCP between the cytosol and nucleus are not understood. Here, we identified p37 (also called UBXN2B) as a major factor regulating VCP nucleocytoplasmic shuttling.

The Influence of Body Mass Index on Growth Factor Composition in the Platelet-Rich Plasma in Patients with Knee Osteoarthritis.

Background: An abnormally high body mass index is strongly associated with knee osteoarthritis. Usually, obese patients are excluded from clinical trials involving PRP intra-articular injections. Growth factors have been demonstrated to have a disease-modifying effect on KOA treatment, even though data on their influence on treatment effectiveness in obese patients are lacking.

SMER28 binding to VCP/p97 enhances both autophagic and proteasomal neurotoxic protein clearance.

The ability to maintain a functional proteome by clearing damaged or misfolded proteins is critical for cell survival, and aggregate-prone proteins accumulate in many neurodegenerative diseases, such as Huntington, Alzheimer, and Parkinson diseases. The removal of such proteins is mainly mediated by the ubiquitin-proteasome system and autophagy, and the activity of these systems declines in disease or with age. We recently found that targeting VCP/p97 with compounds like SMER28 enhances macroautophagy/autophagy flux mediated by the increased activity of the PtdIns3K complex I.

Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance.

Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington's disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome.

Machine Learning Based Analysis of Relations between Antigen Expression and Genetic Aberrations in Childhood B-Cell Precursor Acute Lymphoblastic Leukaemia.

Flow cytometry technique (FC) is a standard diagnostic tool for diagnostics of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) assessing the immunophenotype of blast cells. BCP-ALL is often associated with underlying genetic aberrations, that have evidenced prognostic significance and can impact the disease outcome. Since the determination of patient prognosis is already important at the initial phase of BCP-ALL diagnostics, we aimed to reveal specific genetic aberrations by finding specific multiple antigen expression patterns with FC immunophenotyping.

Cholecalciferol supplementation lowers leptin and TMAO but increases NO and VEGF-A levels in obese vitamin D deficient patients: Is it one of the potential cardioprotective mechanisms of vitamin D?

Background: Vitamin D deficiency is one of the most common health issues in developed countries. Obese patients are most at risk of having serum 25-hydroxyvitamin D (25(OH)D) levels that are too low due to the accumulation of vitamin D in adipose tissue. While the effects of a deficiency on the skeletal or immune system are known, the effects on the cardiovascular system are not yet clear.

So similar yet so different: The distinct contributions of extrafascicular and fascicular phloem to transport and exudation in cucumber plants.

Cucurbits have been used as phloem research models for many decades because their exudates can be accessed with ease. However, cucurbit plants possess two distinct phloem systems known as the fascicular phloem (FP) and extrafascicular phloem (EFP). Therefore, the molecular composition and function of certain exudates can be misinterpreted due to their unclear origin.

The different autophagy degradation pathways and neurodegeneration.

The term autophagy encompasses different pathways that route cytoplasmic material to lysosomes for degradation and includes macroautophagy, chaperone-mediated autophagy, and microautophagy. Since these pathways are crucial for degradation of aggregate-prone proteins and dysfunctional organelles such as mitochondria, they help to maintain cellular homeostasis. As post-mitotic neurons cannot dilute unwanted protein and organelle accumulation by cell division, the nervous system is particularly dependent on autophagic pathways.

Sensor-Based Predictive Maintenance with Reduction of False Alarms-A Case Study in Heavy Industry.

In this paper, the problem of the identification of undesirable events is discussed. Such events can be poorly represented in the historical data, and it is predominantly impossible to learn from past examples. The discussed issue is considered in the work in the context of two use cases in which vibration and temperature measurements collected by wireless sensors are analysed.

MAINE: a web tool for multi-omics feature selection and rule-based data exploration.

Summary: Patient multi-omics datasets are often characterized by a high dimensionality; however, usually only a small fraction of the features is informative, that is change in their value is directly related to the disease outcome or patient survival. In medical sciences, in addition to a robust feature selection procedure, the ability to discover human-readable patterns in the analyzed data is also desirable. To address this need, we created MAINE-Multi-omics Analysis and Exploration.

Data on methane concentration collected by underground coal mine sensors.

Coal mining requires working in hazardous conditions. Miners in an underground coal mine can face several threats, such as, e.g.

Transient siRNA-mediated protein knockdown in mouse followed by feeding/starving cycle and liver tissue analysis.

We present a protocol for in vivo siRNA-mediated knockdown of a gene of interest in mouse liver using systemic delivery via intravenous injection. We describe a step-by-step protocol for delivery of siRNA particles, with tips on how to optimize dosage. We detail steps for feeding/starving cycles as well as for liver tissue isolation, followed by gene expression analysis, measured at the mRNA and protein levels.

VCP/p97 modulates PtdIns3P production and autophagy initiation.

VCP/p97 is an essential multifunctional protein implicated in a plethora of intracellular quality control systems, and abnormal function of VCP is the underlying cause of several neurodegenerative disorders. We reported that VCP regulates the levels of the macroautophagy/autophagy-inducing lipid phosphatidylinositol-3-phosphate (PtdIns3P) by modulating the activity of the BECN1 (beclin 1)-containing phosphatidylinositol 3-kinase (PtdIns3K) complex. VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex.

VCP/p97 regulates Beclin-1-dependent autophagy initiation.

Autophagy is an essential cellular process that removes harmful protein species, and autophagy upregulation may be able to protect against neurodegeneration and various pathogens. Here, we have identified the essential protein VCP/p97 (VCP, valosin-containing protein) as a novel regulator of autophagosome biogenesis, where VCP regulates autophagy induction in two ways, both dependent on Beclin-1. Utilizing small-molecule inhibitors of VCP ATPase activity, we show that VCP stabilizes Beclin-1 levels by promoting the deubiquitinase activity of ataxin-3 towards Beclin-1.

mTORC2 Assembly Is Regulated by USP9X-Mediated Deubiquitination of RICTOR.

The mechanistic target of rapamycin complex 2 (mTORC2) controls cell metabolism and survival in response to environmental inputs. Dysregulation of mTORC2 signaling has been linked to diverse human diseases, including cancer and metabolic disorders, highlighting the importance of a tightly controlled mTORC2. While mTORC2 assembly is a critical determinant of its activity, the factors regulating this event are not well understood, and it is unclear whether this process is regulated by growth factors.

Operative outcome of hernia repair with synthetic mesh in immunocompromised patients.

Background: The safety of synthetic mesh in elective hernia repair in the setting of immunosuppression lacks national and international consensus. The aim of our analysis was to explore the effects of immunosuppression on the rates of wound complications.

Methods: Comparative analysis of immunocompetent and immunocompromised patients with elective mesh repair of inguinal, femoral, primary ventral, incisional or parastomal hernia between January 2001 and December 2013.

Erratum: Author Correction: Mendelian neurodegenerative disease genes involved in autophagy.

[This corrects the article DOI: 10.1038/s41421-020-0158-y.].

Mendelian neurodegenerative disease genes involved in autophagy.

The lysosomal degradation pathway of macroautophagy (herein referred to as autophagy) plays a crucial role in cellular physiology by regulating the removal of unwanted cargoes such as protein aggregates and damaged organelles. Over the last five decades, significant progress has been made in understanding the molecular mechanisms that regulate autophagy and its roles in human physiology and diseases. These advances, together with discoveries in human genetics linking autophagy-related gene mutations to specific diseases, provide a better understanding of the mechanisms by which autophagy-dependent pathways can be potentially targeted for treating human diseases.

Effects of Beta-Blockers on Melanoma Microenvironment and Disease Survival in Human.

The regulation of melanoma by noradrenergic signaling has gain attention since pre-clinical and clinical studies suggested a benefit of using beta-blockers to control disease progression. We need to confirm that human melanoma recapitulates the mechanisms described from pre-clinical models. The sources and targets of norepinephrine in the microenvironment of 20 human melanoma samples was investigated using immunostaining.

Patient-Specific Bone Multiscale Modelling, Fracture Simulation and Risk Analysis-A Survey.

This paper provides a starting point for researchers and practitioners from biology, medicine, physics and engineering who can benefit from an up-to-date literature survey on patient-specific bone fracture modelling, simulation and risk analysis. This survey hints at a framework for devising realistic patient-specific bone fracture simulations. This paper has 18 sections: presents the main interested parties; explains the organzation of the text; motivates further work on patient-specific bone fracture simulation; motivates this survey; concerns the collection of bibliographical references; motivates the physico-mathematical approach to bone fracture; presents the modelling of bone as a continuum; categorizes the surveyed literature into a continuum mechanics framework; concerns the computational modelling of bone geometry; concerns the estimation of bone mechanical properties; concerns the selection of boundary conditions representative of bone trauma; concerns bone fracture simulation; presents the multiscale structure of bone; concerns the multiscale mathematical modelling of bone; concerns the experimental validation of bone fracture simulations; concerns bone fracture risk assessment.

Numerical modelling of skin tumour tissue with temperature-dependent properties for dynamic thermography.

Dynamic thermography has been clinically proven to be a valuable diagnostic technique for skin tumour detection as well as for other medical applications, and shows many advantages over static thermography. Numerical modelling of heat transfer phenomena in biological tissue during dynamic thermography can aid the technique by improving process parameters or by estimating unknown tissue parameters based on measurement data. This paper presents a new non-linear numerical model of multilayer skin tissue containing a skin tumour together with thermoregulation response of the tissue during the cooling-rewarming process of dynamic thermography.

Drug-induced expression of the RNA-binding protein HuR attenuates the adaptive response to BRAF inhibition in melanoma.

Strategies that aim to limit the adaptive response to pathway inhibition in BRAF-mutated melanoma face the inherent limit of signaling redundancy and multiplicity of possible bypass mechanisms. Drug-induced expression of selected RNA-binding proteins, like the ubiquitously expressed HuR, has the potential to differentially stabilize the expression of many genes involved in the compensatory mechanisms of adaptive response. Here, we detect in BRAF-mutated melanoma cell lines having a higher propensity for adaptive response and in non-responding melanoma tumors, a larger proportion of HuR cells in the expression distribution of HuR.