Molecular theory of elastic constants of liquid crystals. III. Application to smectic phases with tilted orientational order

Using the density functional formalism we derive expression for the distortion free energy for systems with continuous broken symmetry and use it to derive expression for the elastic constants of smectic phases in which director is tilted with respect to the smectic layer normal. As in the previous papers of the series (Phys. Rev. A {\bf 45}, 974 (1992), E {\bf 49}, 501, (1994)) the expressions for the elastic constants are written in terms of order and structural parameters. The structural parameters involve the generalised spherical harmonic coefficients of the direct pair correlation function of an effective isotropic liquid. The density of this effective isotropic liquid depends on the nature and amount of ordering present in the system and is evaluated self- consistently. We estimate the value of elastic constants using reasonable guess for the order and structural- parameters.Comment: 31 pages; 1 Fig. in GIF format, To be appear in Phys. Rev.

Biophysical studies of protein misfolding and aggregation in in vivo models of Alzheimer's and Parkinson's diseases.

Neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's diseases (PD), are characterised by the formation of aberrant assemblies of misfolded proteins. The discovery of disease-modifying drugs for these disorders is challenging, in part because we still have a limited understanding of their molecular origins. In this review, we discuss how biophysical approaches can help explain the formation of the aberrant conformational states of proteins whose neurotoxic effects underlie these diseases. We discuss in particular models based on the transgenic expression of amyloid-β (Aβ) and tau in AD, and α-synuclein in PD. Because biophysical methods have enabled an accurate quantification and a detailed understanding of the molecular mechanisms underlying protein misfolding and aggregation in vitro, we expect that the further development of these methods to probe directly the corresponding mechanisms in vivo will open effective routes for diagnostic and therapeutic interventions

Towards Responsible Research Career Assessment

Contact: [email protected] Policy brief Growing evidence suggests that the evaluation of researchers’ careers on the basis of narrow definitions of excellence is restricting diversity in academia, both in the development of its labour force and its approaches to address societal challenges. The current research evaluation system is hampering diverse career pathways spanning research, teaching and (community) service. It inhibits the inclusion and retention of minorities, women, people from lower socio-economic backgrounds and meaningful public engagement with research. Improving the evaluation system in a concerted effort with research institutes and other funders will help fully realize a European Research Area (ERA) that is open to all talents. This diversity is essential to sustain academic careers, to strengthen the relevance and impact of science for society, and to enhance the resilience of our society and environment. Advice to MSCA policymakers Increasing attention to responsibility in, of and for research practices (as evidenced in Responsible Research and Innovation and Open Science in the ERA), has galvanized researchers and organisations to call for a change in the research evaluation system. While the academic evaluation landscape is shifting (as documented in the following pages), much remains to be done. The Marie Skłodowska-Curie Actions (MSCA) can spearhead these developments by implementing the following recommendations: Broaden current evaluation criteria of MSCA calls in dialogue with all relevant stakeholders, making responsible use of the options outlined below, to enlarge and modernize the notion of excellence (as done with the Gender dimension). Reward applicants and organisations that engage in open and responsible research through public engagement, science education, open science and ethical research; Provide (online) training for evaluators on implicit bias to reduce the risks of perpetuating narrow interpretations of research excellence in their evaluations; Offer training within the MSCA programme, such as via Innovative Training Networks, to prepare researchers and organizations for open and responsible, academic as well as non-academic careers. This includes a focus on transferable skills such as leadership and community engagement and attention to societal challenges; Reward and showcase MSCA grantees who excel in multiple dimensions of research, teaching, and service by showcasing and rewarding their work prominently on the MSCA website and social media; Support knowledge exchange and communities of practice around diverse and inclusive forms of excellence by involving a wide range of stakeholders (including civil society) in the ongoing discussion around modernizing and diversifying the concepts of excellence, and what counts as good and impactful academic practice. [ this is an excerpt, see pdf below for full policy brief ] For more from the Marie Curie Alumni Association, please see: https://zenodo.org/communities/mca

Dimensional crossover of the fundamental-measure functional for parallel hard cubes

We present a regularization of the recently proposed fundamental-measure functional for a mixture of parallel hard cubes. The regularized functional is shown to have right dimensional crossovers to any smaller dimension, thus allowing to use it to study highly inhomogeneous phases (such as the solid phase). Furthermore, it is shown how the functional of the slightly more general model of parallel hard parallelepipeds can be obtained using the zero-dimensional functional as a generating functional. The multicomponent version of the latter system is also given, and it is suggested how to reformulate it as a restricted-orientation model for liquid crystals. Finally, the method is further extended to build a functional for a mixture of parallel hard cylinders.Comment: 4 pages, no figures, uses revtex style files and multicol.sty, for a PostScript version see http://dulcinea.uc3m.es/users/cuesta/cross.p

Equation of State for Parallel Rigid Spherocylinders

The pair distribution function of monodisperse rigid spherocylinders is calculated by Shinomoto's method, which was originally proposed for hard spheres. The equation of state is derived by two different routes: Shinomoto's original route, in which a hard wall is introduced to estimate the pressure exerted on it, and the virial route. The pressure from Shinomoto's original route is valid only when the length-to-width ratio is less than or equal to 0.25 (i.e., when the spherocylinders are nearly spherical). The virial equation of state is shown to agree very well with the results of numerical simulations of spherocylinders with length-to-width ratio greater than or equal to 2

Continuous flushing of the bladder in rodents reduces artifacts and improves quantification in molecular imaging

In this study, we evaluated the partial volume effect (PVE) of 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) tracer accumulation in the bladder on the positron emission tomographic (PET) image quantification in mice and rats suffering from inflammatory bowel disease. To improve the accuracy, we implemented continuous bladder flushing procedures. Female mice and rats were scanned using microPET/computed tomography (CT) at baseline and after induction of acute colitis by injecting 2,4,6-trinitrobenzene sulfonic acid (TNBS) intrarectally. During the scans, the bladder was continuously flushed in one group, whereas in the other group, no bladder flushing was performed. As a means of in vivo and ex vivo validation of the inflammation, animals also underwent colonoscopy and were sacrificed for gamma counting (subpopulation) and to score the colonic damage both micro- and macroscopically as well as biochemically. At baseline, the microPET signal in the colon of both mice and rats was significantly higher in the nonflushed group compared to the flushed group, caused by the PVE of tracer activity in the bladder. Hence, the colonoscopy and postmortem analyses showed no significant differences at baseline between the flushed and nonflushed animals. TNBS induced significant colonic inflammation, as revealed by colonoscopic and postmortem scores, which was not detected by microPET in the mice without bladder flushing, again because of spillover of bladder activity in the colonic area. MicroPET in bladder-flushed animals did reveal a significant increase in 18F-FDG uptake. Correlations between microPET and colonoscopy, macroscopy, microscopy, and myeloperoxidase yielded higher Spearman rho values in mice with continuously flushed bladders during imaging. Comparable, although somewhat less pronounced, results were shown in the rat. Continuous bladder flushing reduced image artifacts and is mandatory for accurate image quantification in the pelvic region for both mice and rats. We designed and validated experimental protocols to facilitate such.Steven Deleye, Marthe Heylen, Annemie Deiteren, Joris De Man, Sigrid Stroobants, Benedicte De Winter, and Steven Staelen

Enhanced stability of layered phases in parallel hard-spherocylinders due to the addition of hard spheres

There is increasing evidence that entropy can induce microphase separation in binary fluid mixtures interacting through hard particle potentials. One such phase consists of alternating two dimensional liquid-like layers of rods and spheres. We study the transition from a uniform miscible state to this ordered state using computer simulations and compare results to experiments and theory. We conclude that (1) there is stable entropy driven microphase separation in mixtures of parallel rods and spheres, (2) adding spheres smaller then the rod length decreases the total volume fraction needed for the formation of a layered phase, therefore small spheres effectively stabilize the layered phase; the opposite is true for large spheres and (3) the degree of this stabilization increases with increasing rod length.Comment: 11 pages, 9 figures. Submitted to Phys. Rev. E. See related website http://www.elsie.brandeis.ed

Involvement of peptidylarginine deiminase 4 in eosinophil extracellular trap formation and contribution to citrullinated histone signal in thrombi

Background: Extracellular traps formed by neutrophils (NETs) and eosinophils (EETs) have been described in coronary thrombi, contributing to thrombus stability. A key mechanism during NET formation is histone modification by the enzyme PAD4. Citrullinated histones, the product of PAD4 activity, are often attributed to neutrophils. Eosinophils also express high levels of PAD4. Objectives: We aimed to explore the contribution of PAD4 to EET formation. Methods: We performed immunohistological analyses on thrombi, including a large, intact, and eosinophil-containing thrombus retrieved from the right coronary artery using an aspiration catheter and stroke thrombi from thrombectomy retrieval. We studied eosinophils for their capability to form PAD4-dependent EETs in response to strong ET-inducing agonists as well as activated platelets and bacteria. Results: Histopathology and immunofluorescence microscopy identified a coronary thrombus rich in platelets and neutrophils, with distinct areas containing von Willebrand factor and citrullinated histone H3 (H3Cit). Eosinophils were also identified in leukocyte-rich areas. The majority of the H3Cit+ signal colocalized with myeloperoxidase, but some colocalized with eosinophil peroxidase, indicating EETs. Eosinophils isolated from healthy volunteers produced H3Cit+ EETs, indicating an involvement of PAD4 activity. The selective PAD4 inhibitor GSK484 blocked this process, supporting PAD4 dependence of H3Cit+ EET release. Citrullinated histones were also present in EETs produced in response to live Staphylococci. However, limited evidence for EETs was found in mouse models of venous thrombosis or infective endocarditis. Conclusion: As in NETosis, PAD4 can catalyze the formation of EETs. Inhibition of PAD4 decreases EET formation, supporting the future utility of PAD4 inhibitors as possible antithrombotic agents

Pulsed field studies of the magnetization reversal in molecular nanomagnets

We report experimental studies of crystals of Mn12 molecular magnetic clusters in pulsed magnetic fields with sweep rates up to 4x10^3 T/s. The steps in the magnetization curve are observed at fields that are shifted with respect to the resonant field values. The shift systematically increases as the rate of the field sweep goes up. These data are consistent with the theory of the collective dipolar relaxation in molecular magnets.Comment: 4 pages, 4 figure

Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins.

Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases