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.

[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.

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).

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.

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.

Are Multiphase Competition and Order by Disorder the Keys to Understanding Yb(2)Ti(2)O(7)?

If magnetic frustration is most commonly known for undermining long-range order, as famously illustrated by spin liquids, the ability of matter to develop new collective mechanisms in order to fight frustration is perhaps no less fascinating, providing an avenue for the exploration and discovery of unconventional behaviors. Here, we study a realistic minimal model where a number of such mechanisms converge, which, incidentally, pertain to the perplexing quantum spin ice candidate Yb(2)Ti(2)O(7). Specifically, we explain how thermal and quantum fluctuations, optimized by order-by-disorder selection, conspire to expand the stability region of a degenerate continuous U(1) manifold against the classical splayed ferromagnetic ground state that is displayed by the sister compound Yb(2)Ti(2)O(7). The resulting competition gives rise to multiple phase transitions, in striking similitude with recent experiments on Yb(2)Ti(2)O(7) [Lhotel et al., Phys. Rev. B 89, 224419 (2014)]. By combining a gamut of numerical techniques, we obtain compelling evidence that such multiphase competition is a natural engine for the substantial sample-to-sample variability observed in Yb(2)Ti(2)O(7) and is the missing key to ultimately understand the intrinsic properties of this material. As a corollary, our work offers a pertinent illustration of the influence of chemical pressure in rare-earth pyrochlores.

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.

Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in primary care.

PURPOSE: To determine whether treatment with nitrofurantoin in women with urinary tract infection (UTI) and renal impairment in primary care is associated with a higher risk of ineffectiveness and/or serious adverse events than in women without renal impairment. METHODS: A cohort of 21,317 women treated with nitrofurantoin and a cohort of 7,926 women treated with trimethoprim, identified from the Pharmo Record Linkage System, were analysed. The primary outcome was ineffectiveness of treatment of nitrofurantoin defined as the start of a second antibacterial within 1 month after the start of nitrofurantoin. The secondary outcome was the occurrence of serious adverse events of nitrofurantoin leading to hospitalization within 90 days. A cohort of trimethoprim users was used to determine if the associations found for nitrofurantoin were mainly related to nitrofurantoin itself. The association between renal impairment and the risk of these outcomes was determined with Cox regression and expressed as hazard ratios (HRs). RESULTS: Overall, the incidence density for ineffectiveness was 5.4 per 1,000 person-days, and moderate renal impairment was not associated with ineffective treatment [HR 1.1, 95 % confidence interval (CI) 0.74-1.51]. The overall incidence density for adverse events was 0.02 per 1,000 person-days. In patients with renal impairment (<50 ml/min/1.73 m²) the risk of pulmonary adverse events leading to hospitalization was significantly increased (HR 4.1, 95 % CI 1.31-13.09) CONCLUSIONS: Nitrofurantoin treatment was not associated with a higher risk of ineffectiveness in women with UTI and moderate renal impairment (30-50 ml/min/1.73 m²). However, we did find a significant association between renal impairment (<50 ml/min/1.73 m²) and pulmonary adverse events leading to hospitalization.

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.

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.

Biomimetic liposomes and planar supported bilayers for the assessment of glycodendrimeric porphyrins interaction with an immobilized lectin.

Photodynamic therapy is a potentially efficient treatment for various solid tumours, among which retinoblastoma. Its efficacy depends on the preferential accumulation of photosensitizers in the malignant tissues and their accessibility to light. The specificity of drugs for retinoblastoma cells can be improved by targeting a mannose receptor overexpressed at their surface. With the aim of assessing the recognition of newly synthesized glycodendrimeric porphyrins by such receptors, we have built and characterized an original synthetic biomimetic membrane having similar lipidic composition to that of the retinal cell membranes and bearing Concanavalin A, as a model of the mannose receptor. The interaction of the porphyrin derivatives with liposomes and supported planar bilayers has been studied by dynamic light scattering and quartz crystal microbalance with dissipation monitoring (QCM-D). Only mannosylated porphyrins interacted significantly with the membrane model. The methodology used proved to be efficient for the selection of potentially active compounds.

[Interfacial behaviour of glycoconjugated tetraphenylporphyrins and their interaction with biomimetic models of the cell membrane]. / Comportement interfacial de tétraphénylporphyrines glycoconjuguées et leur interaction avec des modèles biomimétiques de la membrane cellulaire.

INTRODUCTION: Porphyrins are photosensitizers usable in photodynamic therapy. Although these molecules are clinically effective, their low water solubility and their lack of specificity are major drawbacks to their development. Our study was aimed at analysing the interfacial behaviour of glycoconjugated tetraphenylporphyrins newly synthesized at the Curie Institute, and their interaction with model membranes bearing a specific lectin mimicking a mannose membrane receptor in retinoblastoma. MATERIAL AND METHODS: The interfacial behaviour of the porphyrins was analysed by surface pressure measurements, and their specific interaction with the lectin, by dynamic light scattering (liposomes) and the quartz crystal microbalance technique (supported bilayers). RESULTS: All porphyrin derivatives were able to organize at the air/liquid interface. The dendrimeric compounds formed more stable monolayers than the others, and generally showed good mixing properties with the phospholipid used for liposome preparation. In the presence of concanavalin A, the porphyrin bearing-liposomes behaved differently depending on the nature (mannosylated or not) of the porphyrins. DISCUSSION: The interfacial behaviour of the tetraphenylporphyrins is directly related to the orientation of the tetrapyrrolic macrocycle controlled by the grafted groups. Incorporated into a liposome bilayer, glycodendrimeric porphyrins expose their sugar moieties at the vesicle surface. The spacer length plays a crucial role by increasing sugars freedom and enhancing glycosylated liposomes interaction with the lectin. CONCLUSION: Compared to the other studied compounds, the glycodendrimeric porphyrins seem very promising compounds and are now evaluated on cell cultures.

Rods of neutron scattering intensity in Yb2Ti2O7: compelling evidence for significant anisotropic exchange in a magnetic pyrochlore oxide.

Paramagnetic correlations in the magnetic material Yb(2)Ti(2)O(7) have been investigated via neutron scattering, revealing a [111] rod of scattering intensity. Assuming interactions between the Yb(3+) ions composed of all symmetry-allowed nearest neighbor exchange interactions and long-range dipolar interactions, we construct a model Hamiltonian that allows for an excellent description of the neutron scattering data. Our results provide compelling evidence for significant anisotropic exchange interactions in an insulating magnetic pyrochlore oxide. We also compute the real space correlations leading to the [111] rod of scattering.

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.

Superglass phase of interacting bosons.

We introduce a Bose-Hubbard Hamiltonian with random disordered interactions as a model to study the interplay of superfluidity and glassiness in a system of three-dimensional hard-core bosons at half-filling. Solving the model using large-scale quantum Monte Carlo simulations, we show that these disordered interactions promote a stable superglass phase, where superflow and glassy density localization coexist in equilibrium without exhibiting phase separation. The robustness of the superglass phase is underlined by its existence in a replica mean-field calculation on the infinite-dimensional Hamiltonian.

Effect of cholesterol and sugar on the penetration of glycodendrimeric phenylporphyrins into biomimetic models of retinoblastoma cells membranes.

Photodynamic therapy (PDT) is considered one efficient treatment against retinoblastoma. The specificity of a photosensitizer and its penetration into cancerous cells are crucial for achieving tumor necrosis. The selection of photosensitizers such as porphyrin derivatives by tumor cells thus depends to a large extent on their ability to interact with the biological membrane. In this work, we have studied by surface pressure measurements and fluorescence spectroscopy the interaction between three newly synthesized dendrimeric phenylporphyrins and monolayers or liposomes with increasing cholesterol content mimicking the retinoblastoma cell membrane. The morphology of phospholipid-cholesterol-porphyrin mixed monolayers was also analyzed by Brewster angle microscopy. The results showed that the increase in cholesterol content in the model membranes had almost no effect on the effective penetration of the drugs into the lipid layers. Conversely, the chemical structure of the glycodendrimeric phenylporphyrins and the presence of sugar moieties especially appeared to play a crucial role. Although the non-glycoconjugated phenylporphyrin penetrated to a greater extent than glycodendrimeric ones into the liposome membrane, this could be achieved at a high lipid/porphyrin ratio only. Glycodendrimeric porphyrins exhibited improved surface properties compared to the non-glycoconjugated derivative and could penetrate into lipid layers even at low lipid/porphyrin ratios and high surface pressures. Our work highlights the role in the passive diffusion of porphyrins into biomimetic cancer cell membranes, of complex interactions among the lipid molecules, the sugar moieties, and the hydrophobic macrocycle of the porphyrins.

Evaluation of the specific interactions between glycodendrimeric porphyrins, free or incorporated into liposomes, and concanavalin A by fluorescence spectroscopy, surface pressure, and QCM-D measurements.

In photodynamic therapy, the specificity of a photosensitizer and its penetration into tumor cells are crucial. We have analyzed the ability of newly synthesized meso-(tetraphenyl)porphyrins to be recognized by a model of mannose-specific proteins overexpressed at the surface of retinoblastoma cells. The specific interaction of porphyrin with Con A was studied by surface pressure measurements, fluorescence spectroscopy, dynamic light scattering, and QCM-D. The extent of porphyrins binding to Con A was highly dependent upon their chemical structure. Glycodendrimeric porphyrins showed the higher binding constant to Con A. The length of the spacer separating the sugar from the tetrapyrrolic ring appeared to be crucial in controlling the interaction of the compounds with the lectin in solution or immobilized onto a solid substrate. The methodology used proved to be efficient for the selection of potentially active compounds. The glycodendrimeric porphyrins, especially the derivative having the longer spacer, interacted more significantly with the lectin than the compound devoid of any sugar.

Frail old patients as a target population for cancer trials.

The recent distinction between co-morbidity and multi-morbidity well stresses the difficulty of managing old patients with cancer whose complexity is not captured by a list of diagnoses or biological burden alone. The most adequate answer found by oncologists and geriatricians was to work together for better evaluating the physiological age and body reserve of the patient. The gold standard tool to assess old patient with cancer is named Comprehensive Geriatric Assessment. Its systematic application needs geriatric competences and time. In this context, a great number of cancer patients are considered as "frail" because they have reduced available physiological reserves. They might not withstand stress when challenged. Oncologists and geriatricians have imagined an innovative process to change the screening procedure of these patients, determine the prognosis, adapt the treatment strategy, to increase the patient's survival and his/her quality of life. The internet website "www.clinicaltrials.com" only lists 8 studies focused on frail elders with cancer. Six of them are focused on specific cancers or specific treatments, one was applied to all kind of cancers and the last was an opinion overview from oncologists and geriatricians. The selection criteria of frail patients are very diverse and probably include cancer patients who are not comparable. It is now time to try to identify new practical, reliable and accurate tools to facilitate the inclusion of the same kind of patients suffering from the same kind of cancer to be able to give more appropriate care and at the same time to constitute a valuable data base. Existing tools are reviewed and analyzed.