Effects of lithium isotopes on sodium/lithium co-transport and calcium efflux through the sodium/calcium/lithium exchanger in mitochondria.

The effects of lithium (Li) isotopes and their impact on biological processes have recently gained increased attention due to the significance of Li as a pharmacological agent and the potential that Li isotopic effects in neuroscience contexts may constitute a new example of quantum effects in biology. Previous studies have shown that the two Li isotopes, which differ in mass and nuclear spin, have unusual different effects in vivo and in vitro and, although some molecular targets for Li isotope fractionation have been proposed, it is not known whether those result in observable downstream neurophysiological effects. In this work we studied fluxes of Li+, sodium (Na+) and calcium (Ca2+) ions in the mitochondrial sodium/calcium/lithium exchanger (NCLX), the only transporter known with recognized specificity for Li+. We studied the effect of Li+ isotopes on Ca2+ efflux from heart mitochondria in comparison to natural Li+ and Na+ using Ca2+-induced fluorescence and investigated a possible Li isotope fractionation in mitochondria using inductively coupled plasma mass spectrometry (ICP-MS). Our fluorescence data indicate that Ca2+ efflux increases with higher concentrations of either Li+ or Na+. We found that the simultaneous presence of Li+ and Na+ increases Ca2+ efflux compared to Ca2+ efflux caused by the same concentration of Li+ alone. However, no differentiation in the Ca2+ efflux between the two Li+ isotopes was observed, either for Li+ alone or in mixtures of Li+ and Na+. Our ICP-MS data demonstrate that there is selectivity between Na+ and Li+ (greater Na+ than Li+ uptake) and, most interestingly, between the Li+ isotopes (greater 6Li+ than 7Li+ uptake) by the inner mitochondrial membrane. In summary, we observed no Li+ isotope differentiation for Ca2+ efflux in mitochondria via NCLX but found a Li+ isotope fractionation during Li+ uptake by mitochondria with NCLX active or blocked. Our results suggest that the transport of Li+ via NCLX is not the main pathway for Li+ isotope fractionation and that this differentiation does not affect Ca2+ efflux in mitochondria. Therefore, explaining the puzzling effects of Li+ isotopes observed in other contexts will require further investigation to identify the molecular targets for Li+ isotope differentiation.

Lithium isotopes differentially modify mitochondrial amorphous calcium phosphate cluster size distribution and calcium capacity.

Lithium is commonly prescribed as a mood stabilizer in a variety of mental health conditions, yet its molecular mode of action is incompletely understood. Many cellular events associated with lithium appear tied to mitochondrial function. Further, recent evidence suggests that lithium bioactivities are isotope specific. Here we focus on lithium effects related to mitochondrial calcium handling. Lithium protected against calcium-induced permeability transition and decreased the calcium capacity of liver mitochondria at a clinically relevant concentration. In contrast, brain mitochondrial calcium capacity was increased by lithium. Surprisingly, 7Li acted more potently than 6Li on calcium capacity, yet 6Li was more effective at delaying permeability transition. The size distribution of amorphous calcium phosphate colloids formed in vitro was differentially affected by lithium isotopes, providing a mechanistic basis for the observed isotope specific effects on mitochondrial calcium handling. This work highlights a need to better understand how mitochondrial calcium stores are structurally regulated and provides key considerations for future formulations of lithium-based therapeutics.

Pseudo-Goldstone Modes and Dynamical Gap Generation from Order by Thermal Disorder.

Accidental ground state degeneracies-those not a consequence of global symmetries of the Hamiltonian-are inevitably lifted by fluctuations, often leading to long-range order, a phenomenon known as "order-by-disorder" (ObD). The detection and characterization of ObD in real materials currently lacks clear, qualitative signatures that distinguish ObD from conventional energetic selection. We show that for order by thermal disorder (ObTD) such a signature exists: a characteristic temperature dependence of the fluctuation-induced pseudo-Goldstone gap. We demonstrate this in a minimal two-dimensional model that exhibits ObTD, the ferromagnetic Heisenberg-compass model on a square lattice. Using spin-dynamics simulations and self-consistent mean-field calculations, we determine the pseudo-Goldstone gap, Δ, and show that at low temperatures it scales as the square root of temperature, sqrt[T]. We establish that a power-law temperature dependence of the gap is a general consequence of ObTD, showing that all key features of this physics can be captured in a simple model of a particle moving in an effective potential generated by the fluctuation-induced free energy.

Search for lithium isotope effects in neuronal HT22 cells.

Lithium has been used as a treatment for bipolar disorder for over half a century, but there has thus far been no clinical differentiation made between the two naturally occurring stable isotopes (6Li and 7Li). While the natural lithium salts commonly used in treatments are composed of a mixture of these two stable isotopes (approximately 7.59% 6Li and 92.41% 7Li), some preliminary research indicates the above two stable isotopes of lithium may have differential effects on rat behaviour and neurophysiology. Here, we evaluate whether lithium isotopes may have distinct effects on HT22 neuronal cell viability, GSK-3-ß phosphorylation in HT22 cells, and GSK-3-ß kinase activity. We report no significant difference in lithium isotope toxicity on HT22 cells, nor in GSK-3-ß phosphorylation, nor in GSK-3-ß kinase activity between the two isotopes of lithium.

[After the COVID crisis, what solutions for the future nursing home?] / Rapport 22-02. Après la crise COVID, quelles solutions pour l'EHPAD de demain ?

The ageing of the population induces situations of large vulnerability and dependence. Home care usually remains the best response to comply with the person's wish, the family's desire, and the civil society's interest. However, there are circumstances where patient management in a nursing home (EHPAD) is the only solution. The present pandemic of coronavirus COVID-19 has highlighted the issue of EHPAD and their limitations to provide high quality care. To analyze the current position of EHPAD into the care chain and to understand difficulties to their functioning, it seems essential to seek out accelerated changes in the EHPAD since their establishment in 1999 and then in the light of the current crisis, propose possible solutions with a positive view of the role which each EHPAD will have to ensure for future.

Education, Healthy Ageing and Vaccine Literacy.

Importance and Objective: The Covid pandemic is a timely opportunity to try to broaden our understanding of the links between education and health literacy and explore the vaccine-decision process with a view to identifying interventions that will positively influence vaccine uptake. EVIDENCE: Health and vaccine literacy encompass people's knowledge, motivation, and competence to access, understand, appraise and apply health information in order to make judgements and take decisions in everyday life concerning health care, disease prevention and health promotion. FINDINGS: Appropriate vaccine communication, which depends greatly on personal and contextual determinants, as well as on societal and environmental circumstances, is essential to reassure people about vaccine efficacy, safety, and possible side effects. However, vaccine confidence is not solely a question of trust in the vaccine's efficacy, safety. and individual protective benefit of vaccination. It also encompasses the mechanism(s) of vaccine activity, immunization schedules, organization and trust in the healthcare system that promotes and delivers the vaccines, and at what costs. When healthcare professionals as science brokers of vaccine knowledge attempt to increase vaccine knowledge and confidence, they must adjust their communication to the educational or health literacy level of their intended audience. Even if their messages are apparently clear and simple, they absolutely need to verify that they are properly understood. RELEVANCE: Specific vaccine communication training appears essential to increase vaccine communication skills among healthcare providers. Moreover, further randomized controlled studies are warranted to improve vaccine empowerment among different populations, from a variety of educational backgrounds.

From Langmuir-Blodgett to Grafted Films.

A locally organized monolayer film strongly attached to a gold surface is obtained by transfer of a Langmuir-Blodgett (LB) film of octadecylamine (ODA) or alcohol (ODOH) onto a Au surface and simultaneous oxidative electrografting of this film still in contact with the aqueous subphase. As opposed to LB films, these films resist ultrasonication; and unlike electrografted films, they are organized monolayers by construction. They are characterized by AFM (atomic force microscopy), water contact angle, ellipsometry, XPS (X-ray photoelectron spectroscopy), IRRAS (infrared reflection absorption spectroscopy), and GIXD (grazing incidence X-ray diffraction).

Influence of Sociodemographic, Behavioral and Other Health-Related Factors on Healthy Ageing Based on Three Operative Definitions.

OBJECTIVES: Healthy ageing (HA) is a key concept and highly desirable phenomenon in every ageing and already old societies. The aim of our study was to evaluate the influence of socio-economic conditions as well as life-style and other health-related factors on the WHO definition of HA. DESIGN, SETTING, PARTICIPANTS: The study used cross-sectional data of the PolSenior Project - nationwide research evaluating different aspects of ageing in Poland - which included 4'653 respondents aged 65 years and over. MEASUREMENTS: Data were collected by trained interviewers in respondents' homes. Three definitions of HA including or not the participants' chronic conditions were analyzed. RESULTS: The prevalence of HA appeared as high as 17.6% if none or 1 chronic disease was present and 42.8% if no information about chronic diseases was taken into account. The association between known health predictors (age, marital status, education, income) and HA was observed. Moreover, HA appeared in relation with indicators of physical functioning and lifestyle. There was a strong concordance between HA and the fair self-rated health (OR = 1.87; 1.99, and 2.74 for the 1st, 2nd and 3rd definitions, respectively) and opposite relation with self-reported need for help (OR = 0.15; 0.15; and 0.13, respectively). CONCLUSIONS: The HA definition based on no functional activity limitations, no cognitive impairment, no depressive symptoms, no more than one disease and being socially active seems to be a useful approach of HA.

Wind erosion as a driver for transport of light density microplastics.

Microplastic pollution in the environment is a growing concern in today's world. Wind-eroded sediment, as an environmental transport pathway of microplastics, can result in environmental and human exposure far beyond its sources. For the first time, this study investigates the presence of microplastics in wind-eroded sediments from different land uses in the Fars Province, Iran. Eleven test plots were selected based on land use and wind erosion risk. On each plot, wind erosion was simulated using a portable wind tunnel and the eroded sediment was collected for further analysis aimed at measuring light density microplastics (LDMP). The LDMPs were extracted in both soil and wind-eroded sediment using a floatation method and then further examined using microscopy. Annual LDMP transport by wind erosion was estimated using wind data from the study areas. LDMPs were detected in six study areas in the Fars Province which are highly prone to wind erosion. Although LDMPs were found mostly in agricultural land, it was also detected in the soils and sediments from two natural areas. The total concentrations of LDMPs in polluted areas were 6.91 and 20.27 mg kg-1 of microplastics in soil and wind-eroded sediments, respectively. The enrichment ratio for LDMP ranged from 2.83 to 7.63 in different areas. The erosion rate of LDMP ranged from 0.08 to 1.48 mg m-2 min-1. The results of this study confirmed the key role of wind erosion in the spread of microplastics in terrestrial environments which could form an exposure risk to humans via direct inhalation of the particles transported with the dust.

Mobile Application Removes Societal Barriers to P4 Medicine.

The overlap between one innovative paradigm (P4 medicine: predictive, personalized, participatory and preventive) and another (a new definition of "Healthy ageing") is fertile ground for new technologies; a new mobile application (app) that could broaden our scientific knowledge of the ageing process and help us to better analyse the impact of possible interventions in slowing the ageing decline. A novel mobile application is here presented as a game including questions and tests will allow in 10 minutes the assessment of the following domains: robustness, flexibility (lower muscle strength), balance, mental and memory complaints, semantic memory and visual retention. This game is completed by specific measurements, which could allow establishing precise information on functional and cognitive abilities. A global evaluation precedes advice and different types of exercises. The repetition of the tests and measures will allow a long follow up of the individual performances which could be shared (on specific request) with family members and general practitioners.

Disruption of Asymmetric Lipid Bilayer Models Mimicking the Outer Membrane of Gram-Negative Bacteria by an Active Plasticin.

The outer membrane (OM) of Gram-negative bacteria is a complex and asymmetric bilayer that antimicrobial peptides must disrupt in order to provoke the cell lysis. The inner and external leaflets of the OM are mainly composed of phospholipids (PL), and lipopolysaccharide (LPS), respectively. Supported lipid bilayers are interesting model systems to mimic the lipid asymmetric scaffold of the OM and determine the quantitative and mechanistic effect of antimicrobial agents, using complementary physicochemical techniques. We report the formation of asymmetric PL/LPS bilayers using the Langmuir-Blodgett/Langmuir-Schaefer technique on two different surfaces (sapphire and mica) with synthetic phospholipids constituting the inner leaflet and bacteria-extracted mutant LPS making up the outer one. The combination of neutron reflectometry and atomic force microscopy techniques allowed the examination of the asymmetric scaffold structure along the normal to the interface and its surface morphology in buffer conditions. Our results allow discrimination of two structurally related peptides, one neutral and inactive, and the other cationic and active. The active cationic plasticin PTCDA1-KF disrupts the asymmetric OM at relevant concentrations through a carpeting scenario characterized by a dramatic removal of lipid molecules from the surface.

Spin slush in an extended spin ice model.

We present a new classical spin liquid on the pyrochlore lattice by extending spin ice with further neighbour interactions. We find that this disorder-free spin model exhibits a form of dynamical heterogeneity with extremely slow relaxation for some spins, while others fluctuate quickly down to zero temperature. We thus call this state spin slush, in analogy to the heterogeneous mixture of solid and liquid water. This behaviour is driven by the structure of the ground-state manifold which extends the celebrated two-in/two-out ice states to include branching structures built from three-in/one-out, three-out/one-in and all-in/all-out tetrahedra defects. Distinctive liquid-like patterns in the magnetic correlations serve as a signature of this intermediate range order. Possible applications to materials as well the effects of quantum tunnelling are discussed.

Nematicity in stripe-ordered cuprates probed via resonant x-ray scattering.

In underdoped cuprate superconductors, a rich competition occurs between superconductivity and charge density wave (CDW) order. Whether rotational symmetry-breaking (nematicity) occurs intrinsically and generically or as a consequence of other orders is under debate. Here, we employ resonant x-ray scattering in stripe-ordered superconductors (La,M)2CuO4 to probe the relationship between electronic nematicity of the Cu 3d orbitals, structure of the (La,M)2O2 layers, and CDW order. We find distinct temperature dependences for the structure of the (La,M)2O2 layers and the electronic nematicity of the CuO2 planes, with only the latter being enhanced by the onset of CDW order. These results identify electronic nematicity as an order parameter that is distinct from a purely structural order parameter in underdoped striped cuprates.

Operational Definition of Active and Healthy Ageing (AHA): A Conceptual Framework.

Health is a multi-dimensional concept, capturing how people feel and function. The broad concept of Active and Healthy Ageing was proposed by the World Health Organisation (WHO) as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal Active and Healthy Ageing definition is not available and it may differ depending on the purpose of the definition and/or the questions raised. While the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact, a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier, France, October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (Contre les Maladies Chroniques pour un Vieillissement Actif en Languedoc Roussillon) to propose an operational definition of Active and Healthy Ageing including tools that may be used for this. The current paper describes the rationale and the process by which the aims of the meeting will be reached.

Oral single-agent chemotherapy in older patients with solid tumours: A position paper from the International Society of Geriatric Oncology (SIOG).

Compared with intravenous (i.v.) chemotherapy, oral administration is convenient, requires fewer healthcare resources, is generally preferred by patients, and may be appropriate in older people with breast, colorectal and lung cancers. The effects of organ dysfunction on drug metabolism and drug interactions in patients with multiple comorbidities must be considered but are not specific to oral chemotherapy. Single-agent oral chemotherapy with capecitabine or vinorelbine is active in older patients with advanced or metastatic breast cancer. Choice of treatment is based mainly on different safety profiles. In the adjuvant treatment of colorectal cancer (CRC), single-agent oral capecitabine is an effective alternative to i.v. fluorouracil (5-FU) regimens. In metastatic CRC, oral, single-agent capecitabine has recently shown encouraging median overall survival in combination with bevacizumab. In non-small cell lung cancer, fit older patients, like their younger counterparts, benefit from platinum-based doublets, with carboplatin preferred to cisplatin. Single agent vinorelbine is an option for those less suited to combination chemotherapy, and oral may be an alternative to i.v. administration. For elderly cancer patients in general, metronomic chemotherapy combines good tolerability with acceptable activity.

Charge and aggregation pattern govern the interaction of plasticins with LPS monolayers mimicking the external leaflet of the outer membrane of Gram-negative bacteria.

Bacterial resistance to antibiotics has become today a major public health issue. In the development of new anti-infectious therapies, antimicrobial peptides appear as promising candidates. However, their mechanisms of action against bacterial membranes are still poorly understood. We describe for the first time the interaction and penetration of plasticins into lipid monolayers and bilayers modeling the two leaflets of the asymmetrical outer membrane of Gram-negative bacteria. The lipid composition of these monolayers mimics that of each leaflet: mixtures of LPS Re 595 mutant and wild type S-form from Salmonella enterica for the external leaflet, and SOPE/SOPG/cardiolipin (80/15/5) for the inner one. The analysis of the interfacial behavior of native (PTCDA1) and modified (PTCDA1-KF) antimicrobial plasticins showed that PTCDA1-KF exhibited better surface properties than its unmodified counterpart. Both peptides could penetrate into the model monolayers at concentrations higher than 0.1 µM. The penetration was particularly enhanced for PTCDA1-KF into the mixed LPS monolayer, due to attractive electrostatic interactions. Grazing X-ray diffraction and atomic force microscopy studies revealed the changes in LPS monolayers organization upon peptide insertion. The interaction of plasticins with liposomes was also monitored by light scattering and circular dichroism techniques. Only the cationic plasticin achieved full disaggregation and structuration in α helices, whereas the native one remained aggregated and unstructured. The main steps of the penetration mechanism of the two plasticins into lipid models of the external leaflet of the outer membrane of Gram-negative bacteria have been established.

Fluctuation-driven selection at criticality in a frustrated magnetic system: the case of multiple-k partial order on the pyrochlore lattice.

We study the problem of partially ordered phases with periodically arranged disordered (paramagnetic) sites on the pyrochlore lattice, a network of corner-sharing tetrahedra. The periodicity of these phases is characterized by one or more wave vectors k={1/21/21/2}. Starting from a general microscopic Hamiltonian including anisotropic nearest-neighbor exchange, long-range dipolar interactions, and second- and third-nearest neighbor exchange, we use standard mean-field theory (SMFT) to identify an extended range of interaction parameters that support partially ordered phases. We demonstrate that thermal fluctuations ignored in SMFT are responsible for the selection of one particular partially ordered phase, e.g., the "4-k" phase over the "1-k" phase. We suggest that the transition into the 4-k phase is continuous with its critical properties controlled by the cubic fixed point of a Ginzburg-Landau theory with a four-component vector order parameter. By combining an extension of the Thouless-Anderson-Palmer method originally used to study fluctuations in spin glasses with parallel-tempering Monte Carlo simulations, we establish the phase diagram for different types of partially ordered phases. Our results elucidate the long-standing puzzle concerning the origin of the 4-k partially ordered phase observed in the Gd2Ti2O7 dipolar pyrochlore antiferromagnet below its paramagnetic phase transition temperature.