Assays to measure small molecule Hsp70 agonist activity in vitro and in vivo.

Hsp70 prevents protein aggregation and is cytoprotective, but sustained Hsp70 overexpression is problematic. Therefore, we characterized small molecule agonists that augment Hsp70 activity. Because cumbersome assays were required to assay agonists, we developed cell-based and in vivo assays in which disease-associated consequences of Hsp70 activation can be quantified.

Non-Essential Amino Acid Availability Influences Proteostasis and Breast Cancer Cell Survival During Proteotoxic Stress.

Unlabelled: Protein homeostasis (proteostasis) regulates tumor growth and proliferation when cells are exposed to proteotoxic stress, such as during treatment with certain chemotherapeutics. Consequently, cancer cells depend to a greater extent on stress signaling, and require the integrated stress response (ISR), amino acid metabolism, and efficient protein folding and degradation pathways to survive. To define how these interconnected pathways are wired when cancer cells are challenged with proteotoxic stress, we investigated how amino acid abundance influences cell survival when Hsp70, a master proteostasis regulator, is inhibited.

Single feature constrained manual registration method for Augmented Reality applications in gynecological laparoscopic interventions.

Augmented Reality (AR) can avoid some of the drawbacks of Minimally Invasive Surgery and may provide opportunities for developing innovative tools to assist surgeons. In laparoscopic surgery, the achievement of easy and sufficiently accurate registration is an open challenge. This is particularly true in procedures, such as laparoscopic abdominal Sacro-Colpopexy, where there is a lack of a sufficient number of visible anatomical landmarks to be used as a reference for registration.

A campaign targeting a conserved Hsp70 binding site uncovers how subcellular localization is linked to distinct biological activities.

The potential of small molecules to localize within subcellular compartments is rarely explored. To probe this question, we measured the localization of Hsp70 inhibitors using fluorescence microscopy. We found that even closely related analogs had dramatically different distributions, with some residing predominantly in the mitochondria and others in the ER.

Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised.

Molecular chaperones, such as Hsp70, prevent proteotoxicity and maintain homeostasis. This is perhaps most evident in cancer cells, which overexpress Hsp70 and thrive even when harboring high levels of misfolded proteins. To define the response to proteotoxic challenges, we examined adaptive responses in breast cancer cells in the presence of an Hsp70 inhibitor.

Synthesis and evaluation of bifunctional PTP4A3 phosphatase inhibitors activating the ER stress pathway.

We developed JMS-053, a potent inhibitor of the dual specificity phosphatase PTP4A3 that is potentially suitable for cancer therapy. Due to the emerging role of the unfolded protein response (UPR) in cancer pathology, we sought to identify derivatives that combine PTP4A3 inhibition with induction of endoplasmatic reticulum (ER) stress, with the goal to generate more potent anticancer agents. We have now generated bifunctional analogs that link the JMS-053 pharmacophore to an adamantyl moiety and act in concert with the phosphatase inhibitor to induce ER stress and cell death.

The Effects of COVID-19 and Quarantine Measures on the Lifestyles and Mental Health of People Over 60 at Increased Risk of Dementia.

The lockdown strategies adopted to limit the spread of COVID-19 infection may lead to adopt unhealthy lifestyles which may impact on the mental well-being and future risk of dementia. Older adults with mild cognitive impairment (MCI) or subjective cognitive decline (SCD) may suffer important mental health consequences from measures of quarantine and confinement. The study aimed to explore the effects of COVID-19 and quarantine measures on lifestyles and mental health of elderly at increased risk of dementia.

Return on Investment (ROI) and Development of a Workplace Disability Management Program in a Hospital-A Pilot Evaluation Study.

The progressive ageing of the working population and the increase in related chronic diseases tend to affect working capacity. The aim of this study was to evaluate a Workplace Disability Management Program (WDMP) within a pediatric hospital. Absenteeism due to healthcare workers' (HCWs) pre- and post- WDMP and the related costs were used for the program evaluation.

Synthesis and Selective Functionalization of Thiadiazine 1,1-Dioxides with Efficacy in a Model of Huntington's Disease.

The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington's disease.

Seasonal influenza vaccination and absenteeism in health-care workers in two subsequent influenza seasons (2016/17 and 2017/18) in an Italian pediatric hospital.

Background: Seasonal influenza in Health-Care Workers (HCWs) is a topic of growing interest in public health for its organizational implications. The study aims at measuring absenteeism due to influenza in HCWs of an Italian pediatric hospital.

Research Design And Methods: A retrospective observational study on absenteeism for influenza and influenza-like illness was carried out on all hospital HCWs.

Zinc regulates ERp44-dependent protein quality control in the early secretory pathway.

Zinc ions (Zn) are imported into the early secretory pathway by Golgi-resident transporters, but their handling and functions are not fully understood. Here, we show that Zn binds with high affinity to the pH-sensitive chaperone ERp44, modulating its localization and ability to retrieve clients like Ero1α and ERAP1 to the endoplasmic reticulum (ER). Silencing the Zn transporters that uptake Zn into the Golgi led to ERp44 dysfunction and increased secretion of Ero1α and ERAP1.

Publisher Correction: Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.

In the original version of this Article, references in the Methods section incorrectly referred to references in the Supplementary References section. The relevant references (now numbered 20, 27, 42, 47, 69-80) have been removed from the Supplementary References section of the Supplementary Information file and added to the References section of the main manuscript, in both the PDF and HTML versions of the Article.

Compensatory increases of select proteostasis networks after Hsp70 inhibition in cancer cells.

Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded protein response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition of Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction and apoptosis.

Visibility graphs for fMRI data: Multiplex temporal graphs and their modulations across resting-state networks.

Visibility algorithms are a family of methods that map time series into graphs, such that the tools of graph theory and network science can be used for the characterization of time series. This approach has proved a convenient tool, and visibility graphs have found applications across several disciplines. Recently, an approach has been proposed to extend this framework to multivariate time series, allowing a novel way to describe collective dynamics.

Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.

Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive.

Targeting protein quality control pathways in breast cancer.

The efficient production, folding, and secretion of proteins is critical for cancer cell survival. However, cancer cells thrive under stress conditions that damage proteins, so many cancer cells overexpress molecular chaperones that facilitate protein folding and target misfolded proteins for degradation via the ubiquitin-proteasome or autophagy pathway. Stress response pathway induction is also important for cancer cell survival.

-Acetyl-l-Cysteine Protects Astrocytes against Proteotoxicity without Recourse to Glutathione.

-acetyl-l-cysteine (NAC) exhibits protective properties in brain injury models and has undergone a number of clinical trials. Most studies of NAC have focused on neurons. However, neuroprotection may be complemented by the protection of astrocytes because healthier astrocytes can better support the viability of neurons.

Adolescence is the starting point of sex-dichotomous COMT genetic effects.

The catechol-o-methyltransferase (COMT) genetic variations produce pleiotropic behavioral/neuroanatomical effects. Some of these effects may vary among sexes. However, the developmental trajectories of COMT-by-sex interactions are unclear.

Lifespan oxytocin signaling: Maturation, flexibility, and stability in newborn, adolescent, and aged brain.

The hypothalamic neuropeptide oxytocin (OT) is a forefront molecule among neuropeptides due to its pronounced prosocial effects and its potential use in socioemotional deficits that characterize the most prevalent neurodevelopmental and psychiatric disorders (autism spectrum disorders and schizophrenia). The effects of OT have been studied in young and adult subjects (either animals or humans), while the complete lifespan trajectories of OT system development and activity have been far less investigated. In this (mini) review, we will primarily focus on three temporal distinct periods of life-early postnatal period, puberty/adolescence, and elderly.

Gradient COUP-TFI Expression Is Required for Functional Organization of the Hippocampal Septo-Temporal Longitudinal Axis.

The hippocampus (HP), a medial cortical structure, is subdivided into a distinct dorsal (septal) and ventral (temporal) portion, which is separated by an intermediate region lying on a longitudinal curvature. While the dorsal portion is more dedicated to spatial navigation and memory, the most ventral part processes emotional information. Genetic factors expressed in gradient during development seem to control the size and correct positioning of the HP along its longitudinal axis; however, their roles in regulating differential growth and in supporting its anatomical and functional dissociation remain unexplored.

Sex-dichotomous effects of functional COMT genetic variations on cognitive functions disappear after menopause in both health and schizophrenia.

Different genetic variations in the catechol-O-methyltransferase (COMT) gene have been indicated to functionally regulate the encoded enzyme. Despite the vast literature on the single nucleotide COMT ValMet polymorphism, the impact of complex haplotypes on cognitive functions has been overlooked. Here we contrasted the effects of complex COMT haplotypes with the ValMet polymorphism on cognitive functions and their interaction with menopause, in healthy subjects and patients with schizophrenia.

Effects of alpha1-blockers on urodynamic parameters of bladder outlet obstruction in patients with lower urinary tract symptoms suggestive of benign prostatic enlargement: a review.

α1-adrenergic receptors blockers (ABs) are recommended as first-line medical therapy in men with Lower Urinary Tract Symptoms suggestive of Benign Prostatic Enlargement (LUTS/BPE). Available ABs include: terazosin, doxazosin, tamsulosin, naftopidil, alfuzosin and silodosin. These agents have different profiles of selectivity for α1-adrenergic receptors subtypes.

Differential in vivo urodynamic measurement in a single thin catheter based on two optical fiber pressure sensors.

Urodynamic analysis is the predominant method for evaluating dysfunctions in the lower urinary tract. The exam measures the pressure during the filling and voiding process of the bladder and is mainly interested in the contraction of the bladder muscles. The data arising out of these pressure measurements enables the urologist to arrive at a precise diagnosis and prescribe an adequate treatment.

Proteostasis and "redoxtasis" in the secretory pathway: Tales of tails from ERp44 and immunoglobulins.

In multicellular organisms, some cells are given the task of secreting huge quantities of proteins. To comply with their duty, they generally equip themselves with a highly developed endoplasmic reticulum (ER) and downstream organelles in the secretory pathway. These professional secretors face paramount proteostatic challenges in that they need to couple efficiency and fidelity in their secretory processes.