Evidence of a low-temperature dynamical transition in concentrated microgels

A low-temperature dynamical transition has been reported in several proteins. We provide the first observation of a `protein-like' dynamical transition in nonbiological aqueous environments. To this aim we exploit the popular colloidal system of poly-N-isopropylacrylamide (PNIPAM) microgels, extending their investigation to unprecedentedly high concentrations. Owing to the heterogeneous architecture of the microgels, water crystallization is avoided in concentrated samples, allowing us to monitor atomic dynamics at low temperatures. By elastic incoherent neutron scattering and molecular dynamics simulations, we find that a dynamical transition occurs at a temperature $T_d\sim250$~K, independently from PNIPAM mass fraction. However, the transition is smeared out on approaching dry conditions. The quantitative agreement between experiments and simulations provides evidence that the transition occurs simultaneously for PNIPAM and water dynamics. The similarity of these results with hydrated protein powders suggests that the dynamical transition is a generic feature in complex macromolecular systems, independently from their biological function

Analysis of gene expression levels and their impact on survival in 31 cancer-types patients identifies novel prognostic markers and suggests unexplored immunotherapy treatment options in a wide range of malignancies

Background Immunotherapy has dramatically improved cancer treatment by inhibiting or activating specific cell receptors, thus unleashing the host anti-tumor response. However, the engagement of the three main immune checkpoints so far identified, CTLA4, PD-1 and PD-L1, is effective in a fraction of patients, therefore novel targets must be identified and tested. Methods We focused our attention on the following nine highly relevant immune checkpoint (ICR) receptors: CTLA4, PD1, PD-L1, LAG3, TIM3, OX40, GITR, 4-1BB and TIGIT. All of them are targets of existing drugs currently under clinical scrutiny in several malignancies. Their expression levels were evaluated in patient tissues of 31 different cancer types vs. proper controls, in a total of 15,038 individuals. This analysis was carried out by interrogating public databases available on GEPIA2 portal and UALCAN portal. By the Principal Component Analysis (PCA) their ability to effectively discriminate patients form controls was then investigated. Expression of the nine ICRs was also related to overall survival in 31 cancer types and expressed as Hazard Ratio, on the GEPIA2 portal and validated, for melanoma patients, in patients-datasets available on PROGgene V2 portal. Results Significant differential expression was observed for each ICR molecule in many cancer types. A 7-molecules profile was found to specifically discriminate melanoma patients from controls, while two different 6-molecules profiles discriminate pancreatic cancer patients and Testicular Germ Cell Tumors from matched controls. Highly significant survival improvement was found to be related to the expression levels of all nine ICRs in a wide spectrum of malignancies. For melanoma analysis, the relation with survival observed in TCGA datasets was validated in independent GSE melanoma datasets. Conclusion Analysis the nine ICR molecules demonstrates that their expression patterns may be considered as markers of disease and strong survival predictors in a variety of malignancies frequently associated to poor prognosis. Thus, the present findings are strongly advocating that exploratory clinical trials are worth to be performed, using available drugs, targeting these molecules

Endothelin-1 decreases gap junctional intercellular communication by inducing phosphorylation of connexin 43 in human ovarian carcinoma cells

Endothelin-1 (ET-1) is overexpressed in ovarian carcinoma and acts as an autocrine factor selectively through the ETA receptor (ETAR) to promote tumor cell proliferation, survival, neovascularization, and invasiveness. Loss of gap junctional intercellular communication (GJIC) is critical for tumor progression by allowing the cells to escape growth control. Exposure of HEY and OVCA 433 ovarian carcinoma cell lines to ET-1 led to a 50–75% inhibition in intercellular communication and to a decrease in the connexin 43 (Cx43)-based gap junction plaques. To investigate the phosphorylation state of Cx43, ovarian carcinoma cell lysates were immunoprecipitated and transient tyrosine phosphorylation of Cx43 was detected in ET-1-treated cells. BQ 123, a selective ETAR antagonist, blocked the ET-1-induced Cx43 phosphorylation and cellular uncoupling. Gap junction closure was prevented by tyrphostin 25 and by the selective c-Src inhibitor, PP2. Furthermore, the increased Cx43 tyrosine phosphorylation was correlated with ET-1-induced increase of c-Src activity, and PP2 suppressed the ET-1-induced Cx43 tyrosine phosphorylation, indicating that inhibition of Cx43-based GJIC is mainly mediated by the Src tyrosine kinase pathway. In vivo, the inhibition of human ovarian tumor growth in nude mice induced by the potent ETAR antagonist, ABT-627, was associated with a reduction of Cx43 phosphorylation. These findings indicate that the signaling mechanisms involved in GJIC disruption on ovarian carcinoma cells depend on ETAR activation, which leads to the Cx43 tyrosine phosphorylation mediated by c-Src, suggesting that ETAR blockade may contribute to the control of ovarian carcinoma growth and progression also by preventing the loss of GJIC

Dynamical properties of water in living cells

With the aim of studying the effect of water dynamics on the properties of biological systems, in this paper, we present a quasi-elastic neutron scattering study on three different types of living cells, differing both in their morphological and tumor properties. The measured scattering signal, which essentially originates from hydrogen atoms present in the investigated systems, has been analyzed using a global fitting strategy using an optimized theoretical model that considers various classes of hydrogen atoms and allows disentangling diffusive and rotational motions. The approach has been carefully validated by checking the reliability of the calculation of parameters and their 99% confidence intervals. We demonstrate that quasi-elastic neutron scattering is a suitable experimental technique to characterize the dynamics of intracellular water in the angstrom/picosecond space/time scale and to investigate the effect of water dynamics on cellular biodiversity

Weather-Related Flood and Landslide Damage: A Risk Index for Italian Regions

The frequency of natural hazards has been increasing in the last decades in Europe and specifically in Mediterranean regions due to climate change. For example heavy precipitation events can lead to disasters through the interaction with exposed and vulnerable people and natural systems. It is therefore necessary a prevention planning to preserve human health and to reduce economic losses. Prevention should mainly be carried out with more adequate land management, also supported by the development of an appropriate risk prediction tool based on weather forecasts. The main aim of this study is to investigate the relationship between weather types (WTs) and the frequency of floods and landslides that have caused damage to properties, personal injuries, or deaths in the Italian regions over recent decades. In particular, a specific risk index (WT-FLARI) for each WT was developed at national and regional scale. This study has identified a specific risk index associated with each weather type, calibrated for each Italian region and applicable to both annual and seasonal levels. The risk index represents the seasonal and annual vulnerability of each Italian region and indicates that additional preventive actions are necessary for some regions. The results of this study represent a good starting point towards the development of a tool to support policy-makers, local authorities and health agencies in planning actions, mainly in the medium to long term, aimed at the weather damage reduction that represents an important issue of the World Meteorological Organization mission

Health Impact Assessment Practice and Potential for Integration within Environmental Impact and Strategic Environmental Assessments in Italy

Avoiding or minimizing potential environmental impact is the driving idea behind protecting a population\u27s health via Environmental Impact Assessments (EIAs) and Strategic Environmental Assessments (SEAs). However, both are often carried out without any systematic approach. This paper describes the findings of a review of HIA, EIA and SEA experiences carried out by the authors, who act as institutional competent subjects at the national and regional levels in Italy. The analysis of how health is tackled in EIA and SEA procedures could support the definition of a protocol for the integration of HIA with EIA and SEA. Although EIA and SEA approaches include the aim of protecting health, significant technical and methodological gaps are present when assessing health systematically, and their basic principles regarding assessment are unsatisfactory for promoting and addressing healthcare concepts stated by the WHO. HIA is still poorly integrated into the decision-making process, screening and monitoring phases are only occasionally implemented, and operational details are not well-defined. The collaborative approach of institutions involved in environment and health is a core element in a systematic advancement toward supporting effective decisions and effective protection of the environment and health. At the Italian national level, the definition of guidelines and tools for HIA, also in relation with EIA and SEA, is of great interest

Microscopic versus Macroscopic Glass Transitions and Relevant Length Scales in Mixtures of Industrial Interest

We have combined X-ray diffraction, neutron diffraction with polarization analysis, small-angle neutron scattering (SANS), neutron elastic fixed window scans (EFWS), and differential scanning calorimetry (DSC) to investigate polymeric blends of industrial interest composed by isotopically labeled styrene–butadiene rubber (SBR) and polystyrene (PS) oligomers of size smaller than the Kuhn length. The EFWS are sensitive to the onset of liquid-like motions across the calorimetric glass transition, allowing the selective determination of the “microscopic” effective glass transitions of the components. These are compared with the “macroscopic” counterparts disentangled by the analysis of the DSC results in terms of a model based on the effects of thermally driven concentration fluctuations and self-concentration. At the microscopic level, the mixtures are dynamically heterogeneous for blends with intermediate concentrations or rich in PS, while the sample with highest content of the fast SBR component looks as dynamically homogeneous. Moreover, the combination of SANS and DSC has allowed determining the relevant length scale for the α-relaxation through its loss of equilibrium to be ≈30 Å. This is compared with the different characteristic length scales that can be identified in these complex mixtures from structural, thermodynamical, and dynamical points of view because of the combined approach followed. We also discuss the sources of the non-Gaussian effects observed for the atomic displacements and the applicability of a Lindemann-like criterion in these materials.We thank Marc Couty for fruitful discussions and Karine Vernay (Michelin Advanced Research) for dSBR synthesis. The authors acknowledge Grant PID2021-123438NB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, as well as financial support of Eusko Jaurlaritza (code: IT1566-22) and from the IKUR Strategy under the collaboration agreement between Ikerbasque Foundation and the Materials Physics Center on behalf of the Department of Education of the Basque Government. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)

Kappa Index Versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders

Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID)

Innovative consolidating products for stone materials: field exposure tests as a valid approach for assessing durability

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Hepatitis B Surface Antigen Seropositive Men in Serodiscordant Couples: Effects on the Assisted Reproductive Outcomes

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