The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Through computational analyses of large-scale tissue transcriptomes, we unveil that the chaperone system is composed of core elements that are uniformly expressed across tissues, and variable elements that are differentially expressed to fit with tissue-specific requirements. We demonstrate via a proteomic analysis that the muscle-specific signature is functional and conserved. Core chaperones are significantly more abundant across tissues and more important for cell survival than variable chaperones. Together with variable chaperones, they form tissue-specific functional networks. Analysis of human organ development and aging brain transcriptomes reveals that these functional networks are established in development and decline with age. In this work, we expand the known functional organization of de novo versus stress-inducible eukaryotic chaperones into a layered core-variable architecture in multi-cellular organisms

Bosonization for Wigner-Jordan-like Transformation : Backscattering and Umklapp-processes on Fictitious Lattice

We analyze the asymptotic behavior of the exponential form in the fermionic density operators as the function of ruling parameter Q. In the particular case Q=\pi this exponential associates with the Wigner-Jordan transformation for XY spin chain model. We compare the bosonization approach and the evaluation via the Toeplitz determinant. The use of Szego-Kac theorem suggests that at Q>\pi/3 the divergent series for intrinsic logarithm provides a bosonized solution and faster decaying one, found as the logarithm's value on another sheet of the complex plane. The second solution is revealed as umklapp-process on the fictitious lattice while originates from backscattering terms in bosonized density. Our finding preserves in a wide range of fermion filling ratios.Comment: 8 pages, REVTEX, 3 eps figures, accepted to Phys.Rev.

The Self-Administered Witness Interview Tool (SAW-IT): Enhancing witness recall of workplace incidents

Given the often crucial role of witness evidence in Occupational Health and Safety investigation, statements should be obtained as soon as possible after an incident using best practice methods. The present research systematically tested the efficacy of a novel Self-Administered Witness Interview Tool (SAW-IT); an adapted version of the Self-Administered Interview (SAI©) designed to elicit comprehensive information from witnesses to industrial events. The present study also examined whether completing the SAW-IT mitigated the effect of schematic processing on witness recall. Results indicate that the SAW-IT elicited significantly more correct details, as well as more precise information than a traditional incident report form. Neither the traditional report from, nor the SAW-IT mitigated against biasing effects of contextual information about a worker’s safety history, confirming that witnesses should be shielded from extraneous post-event information prior to reporting. Importantly, these results demonstrate that the SAW-IT can enhance the quality of witness reports

Inhomogeneous Phases in a Double-Exchange Magnet with Long Range Coulomb Interactions

We consider a model with competing double-exchange (ferromagnetic) and super-exchange (anti-ferromagnetic) interactions in the regime where phase separation takes place. The presence of a long range Coulomb interaction frustrates a macroscopic phase separation, and favors microscopically inhomogeneous configurations. We use the variational Hartree-Fock approach, in conjunction with Monte-Carlo simulations to study the geometry of such configurations in a two-dimensional system. We find that an array of diamond shaped ferromagnetic droplets is the preferred configuration at low electronic densities, while alternating ferromagnetic and anti-ferromagnetic diagonal stripes emerge at higher densities. These findings are expected to be relevant for thin films of colossal magneto-resistive manganates.Comment: 15 pages, 9 figures. Journal Ref. added, errors correcte

Distinct routes of lineage development reshape the human blood hierarchy across ontogeny

In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a cell-sorting scheme to resolve myeloid (My), erythroid (Er), and megakaryocytic (Mk) fates from single CD34+ cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with intermingled My, Er and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult ‘two-tier’ hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.This work was supported by Postdoctoral Fellowship Awards from Canadian Institute of Health Research (CIHR) to FN and SZ. SZ is supported by (Aplastic Anemia). FN is a recipient of a scholar’s research award from the Ontario Institute of Cancer Research (OICR), through generous support from the Ontario Ministry of Research and Innovation. Research in EL laboratory is supported by a Wellcome Trust Sir Henry Dale Fellowship and core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute. Work in the Dick laboratory is supported by grants from the CIHR, Canadian Cancer Society, Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, OICR with funds from the province of Ontario, a Canada Research Chair and the Ontario Ministry of Health and Long Term Care (OMOHLTC).This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aab211

First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors

Agonistic 4-1BB monoclonal antibodies were preclinically validated as promising cancer immunotherapies, both as monotherapy and as potentiators of the activity of PD-(L) 1–blocking agents. However, toxicity and a narrow therapeutic window have hampered their clinical development. DuoBodyPD-L1×4-1BB, a first-in-class, bispecific, next-generation checkpoint immunotherapy, was designed to overcome these limitations by activating T cells through conditional 4-1BB costimulation, while simultaneously blocking the PD-L1 axis. We present preliminary data from the ongoing, first-in-human, open-label, phase I/IIa trial of DuoBody-PD-L1×4-1BB in advanced solid tumors (NCT03917381)

Acidic microenvironment plays a key role in human melanoma progression through a sustained exosome mediated transfer of clinically relevant metastatic molecules

Background: Microenvironment cues involved in melanoma progression are largely unknown. Melanoma is highly influenced in its aggressive phenotype by the changes it determinates in its microenvironment, such as pH decrease, in turn influencing cancer cell invasiveness, progression and tissue remodelling through an abundant secretion of exosomes, dictating cancer strategy to the whole host. A role of exosomes in driving melanoma progression under microenvironmental acidity was never described. Methods: We studied four differently staged human melanoma lines, reflecting melanoma progression, under microenvironmental acidic pHs pressure ranging between pH 6.0-6.7. To estimate exosome secretion as a function of tumor stage and environmental pH, we applied a technique to generate native fluorescent exosomes characterized by vesicles integrity, size, density, markers expression, and quantifiable by direct FACS analysis. Functional roles of exosomes were tested in migration and invasion tests. Then we performed a comparative proteomic analysis of acid versus control exosomes to elucidate a specific signature involved in melanoma progression. Results: We found that metastatic melanoma secretes a higher exosome amount than primary melanoma, and that acidic pH increases exosome secretion when melanoma is in an intermediate stage, i.e. metastatic non-invasive. We were thus able to show that acidic pH influences the intercellular cross-talk mediated by exosomes. In fact when exposed to exosomes produced in an acidic medium, pH naïve melanoma cells acquire migratory and invasive capacities likely due to transfer of metastatic exosomal proteins, favoring cell motility and angiogenesis. A Prognoscan-based meta-analysis study of proteins enriched in acidic exosomes, identified 11 genes (HRAS, GANAB, CFL2, HSP90B1, HSP90AB1, GSN, HSPA1L, NRAS, HSPA5, TIMP3, HYOU1), significantly correlating with poor prognosis, whose high expression was in part confirmed in bioptic samples of lymph node metastases. Conclusions: A crucial step of melanoma progression does occur at melanoma intermediate -stage, when extracellular acidic pH induces an abundant release and intra-tumoral uptake of exosomes. Such exosomes are endowed with pro-invasive molecules of clinical relevance, which may provide a signature of melanoma advancement

Greenhushing: the deliberate under communicating of sustainability practices by tourism businesses

Greenhushing selectively communicates fewer pro-sustainability actions by businesses than are practiced; based on a perception of customers’ rights to consumerism. We first studied the gap between the communication of sustainability practices in the audits and websites of 31 small rural tourism businesses in the Peak District National Park (UK). The analysis showed that businesses only communicate 30% of all the sustainability actions practiced. Their websites emphasised customer benefits, using explicit, affective, experiential and active language that legitimises the customers’ hedonistic use of the landscape, while downplaying complex issues and normalising sustainability to reduce customer guilt. Just one website mentioned climate change. We found that greenhushing results from a low moral intensity, masking potentially negative consequences of perceived lower competence, whilst protecting business from more cynical consumers who may interpret their statements as hypocritical. Subsequent textual analysis and interviews were used to understand how communication constitutes these organisations. We propose that greenhushing reshapes and constitutes tourism businesses through their communications. Moreover, greenhushing is a form of public moralisation that adopts communication practices similar to greenwashing, reflecting the social norms expected from a business; however, in this case, located in a moral muteness, rather than moral hypocrisy, that businesses accept but resent

Characteristics of undernourished older medical patients and the identification of predictors for undernutrition status

<p>Abstract</p> <p>Background</p> <p>Undernutrition among older people is a continuing source of concern, particularly among acutely hospitalized patients. The purpose of the current study is to compare malnourished elderly patients with those at nutritional risk and identify factors contributing to the variability between the groups.</p> <p>Methods</p> <p>The study was carried out at the Soroka University Medical Center in the south of Israel. From September 2003 through December 2004, all patients 65 years-of-age or older admitted to any of the internal medicine departments, were screened within 72 hours of admission to determine nutritional status using the short version of the Mini Nutritional Assessment (MNA-SF). Patients at nutritional risk were entered the study and were divided into malnourished or 'at risk' based on the full version of the MNA. Data regarding medical, nutritional, functional, and emotional status were obtained by trained interviewers.</p> <p>Results</p> <p>Two hundred fifty-nine elderly patients, 43.6% men, participated in the study; 18.5% were identified as malnourished and 81.5% were at risk for malnutrition according to the MNA. The malnourished group was less educated, had a higher depression score and lower cognitive and physical functioning. Higher prevalence of chewing problems, nausea, and vomiting was detected among malnourished patients. There was no difference between the groups in health status indicators except for subjective health evaluation which was poorer among the malnourished group. Lower dietary score indicating lower intake of vegetables fruits and fluid, poor appetite and difficulties in eating distinguished between malnourished and at-risk populations with the highest sensitivity and specificity as compare with the anthropometric, global, and self-assessment of nutritional status parts of the MNA. In a multivariate analysis, lower cognitive function, education <12 years and chewing problems were all risk factors for malnutrition.</p> <p>Conclusion</p> <p>Our study indicates that low food consumption as well as poor appetite and chewing problems are associated with the development of malnutrition. Given the critical importance of nutritional status in the hospitalized elderly, further intervention trials are required to determine the best intervention strategies to overcome these problems.</p