Fluorinated Co-Solvents Enable Excellent Performances of Practical Cells Comprising LixSiO-Graphite Composite Anodes and LiNi0.89Co0.05Mn0.05Al0.01O2 (NCMA) Cathodes.

Li-ion batteries based on high specific capacity LixSiO-Graphite anodes and LiNi0.89Co0.05 Mn0.05Al0.01O2 (NCMA) cathodes may have numerous practical applications owing to high energy density without a necessary compromise on safety. SiO, which is an attractive Li insertion anode material, offers more cycling stability than Si and a higher capacity than graphite. Therefore, a new trend has emerged for developing composite C-Si anodes, possessing the excellent cyclability of graphite coupled with high capacity SiO. The composite structure described herein prevents the volume expansion of SiO and maintains the structural integrity during prolonged cycling. However, graphite electrodes suffer from exfoliation in propylene carbonate (PC) based electrolyte solutions, which avoids well known safety benefits related to a possible use of PC based electrolyte solutions in all kinds of Li batteries. Herein, it is reported that trifluoro propylene carbonate (TFPC) is compatible with graphite anodes. New electrolyte formulations are developed and tested containing fluorinated co-solvents and compared the performance of several electrolyte solutions, including conventional alkyl carbonates-based solutions in full Li-ion cells, which included LixSiO-Graphite anodes and LiNi0.89Co0.05Mn0.05Al0.01O2 (NCMA) cathodes. Cells with new electrolyte solutions developed herein demonstrated nearly twice capacity retention in prolonged cycling experiments compared to similar reference cells containing conventional electrolyte solutions.

The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.

Clinical features and outcomes in adults with COVID-19 during the pre-Omicron and Omicron waves.

OBJECTIVES: We conducted a single-center retrospective study to compare patient characteristics and death rates during the Omicron (O, December 01, 2021, to September 30, 2022) and pre-Omicron (PO, March 01, 1920, to October 31, 2021) periods. PATIENTS AND METHODS: We retrospectively analyzed the data of 2932 patients (1242 (O) and 1690 (PO)) hospitalized (>24 h) with laboratory-confirmed COVID. RESULTS: Compared to the PO period, O period patients were less frequently men, had a lower body mass index and fewer comorbidities except for immunosuppression and pregnancy. Nosocomial COVID-19 accounted for 18.2 % (O) and 15.4 % (PO) of cases (p = 0.05). Patient mortality rates during the O and PO periods were 11.0 % and 16.9 % (p < 0.001), respectively. Unvaccinated status (p < 0.001), existence of comorbidities, (p < 0.001) and high LDH value at baseline (p = 0.015), but not the period, were identified as factors likely to explain death. CONCLUSION: During the Omicron period, the inpatient death rate remained > 10 %, especially among unvaccinated and comorbid patients. Nosocomial cases were more frequent.

Quantitative Operando 7Li NMR Investigations of Silicon Anode Evolution during Fast Charging and Extended Cycling.

The development and optimization of fast battery charging protocols require detailed information regarding lithium speciation inside a battery. Nuclear magnetic resonance (NMR) spectroscopy has the unique capability of identifying the Li phases formed in an anode during Li-ion cell operation and quantifying their relative amounts. In addition, both Li metal films and dendrites are readily detected and quantified. Here, our recently reported parallel-plate resonator radio frequency (RF) probe and the cartridge-type single-layer full cell were used to track the behavior of Si electrodes during cycling and during fast charging. The LixSi compounds formed during electrochemical cycling exhibit an unexpected intrinsic nonequilibrium behavior at both slow and fast rates, evolving toward increasingly disordered local environments. The evolution with time of lithiated phases is nonlinear during both charging and discharging at constant current, unlike the case for pure graphite, and asymmetric between charge and discharge. During charging at rates of 1C, 2C, and 3C, metallic Li in both films and (to a lesser extent) dendritic forms are deposited on the Si anode. Part of the Li metal film formation is reversible, but a fraction remains on the electrode surface as dead Li, while all of the dendritic Li, even though formed in a considerably smaller amount, is entirely irreversible. Such performance-governing properties are critical to the development of fast-charging protocols for lithium-ion batteries (LIBs) and are exceptionally well evaluated and quantified by 7Li magnetic resonance strategies such as those presented here.

Oversewing and Gastropexy in Laparoscopic Sleeve Gastrectomy - Two Futile Steps of the Procedure? An Observational Case-Control Study.

PURPOSE: Laparoscopic sleeve gastrectomy (LSG) is the most popular primary bariatric metabolic procedure worldwide but severe complications are still reported, and there is no ideal technique to avoid them. This study analyses the impact of oversewing (OS) and gastropexy (GP) on complication rate, early dyspeptic and late de novo GERD symptoms after LSG. MATERIAL AND METHOD: A case-control study was conducted on patients with obesity who underwent LSG. The total cohort was divided in group A (control group) - patients with no oversewing (OS) or gastropexy (GP), group B - patients with OS but no gastropexy and group C - patients with both OS and GP performed during LSG. RESULTS: We included 272 patients with obesity with a mean BMI 42.9±6.94 kg/m2, 96 patients in group A, 90 patients in group B and 86 in group C with no statistical differences between them. We had 5 cases of postoperative hemorrhage (4 in group A) and three patients who developed leaks (2 in group A and one in group B). Prolonged and severe early dyspeptic episodes and after 6 months reflux symptoms were significantly more in groups A and B (p<0.05). The operative time was longer in group B and C (p<0.05) but with no difference in procedure -related morbidity and in hospital length of stay. CONCLUSION: Adding both OS and GP to LSG reduce complications rate with no influence on procedure-related postoperative morbidity and in-hospital length of stay. GP reduces early postoperative dyspeptic and de novo GERD symptoms after LSG.

Glucocorticoid receptor and RAS: an unexpected couple in cancer.

Constitutively activated rat sarcoma (RAS) GTPases are one of the major drivers of tumor growth and are difficult drug targets. The glucocorticoid receptor (GR), a nuclear receptor primarily acting in the nucleus, is a potent modulator of inflammation and regulator of metabolism and cell growth. Emerging evidence has revealed that GR modulates RAS-dependent signaling and RAS activation. The unliganded GR decreases RAS activation, and, upon ligand binding, GR leaves RAS complexes, is translocated into the nucleus, and unleashes the activation of RAS and its downstream pathways. GR forms a complex with RAS and RAF1 and their associated proteins, such as members of the 14-3-3 family of adapter proteins. The exploration of RAS-GR complex formation and maintenance will help to develop much-needed breakthroughs in oncogenic RAS biology and thus help to alleviate tumor growth and burden.

Characteristic and outcome changes in inpatients with COVID-19 during the four pre - Omicron waves.

Background: Four waves of Coronavirus disease 2019 (COVID-19) occurred in France between March 2020 and September 2021. COVID-19 inpatient characteristics change because of the influence of numerous parameters, especially immunization and circulating severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) variants. Methods: This retrospective single-center study analyzed patients with laboratory-proven COVID-19 admitted from 1/3/2020 to 30/6/2020 (wave one), 1/7/2020 to 31/12/2020 (wave two), 1/1/2021 to 30/6/2021 (wave three), and 1/7/2021 to 30/11/2021 (wave four). We compared the outcomes and baseline characteristics between these waves. Results: In our center, 1,762 patients were hospitalized for COVID-19: 666 (37.8 %), 425 (24.1 %), 482 (27.3 %), and 189 (10.7 %) during waves 1, 2, 3, and 4, respectively. Patients during the first wave were hospitalized later after the onset of COVID-19 symptoms, had more severe disease conditions at baseline, and suffered higher intensive care unit (ICU) hospitalization rates. Most patients from waves 1-3 were >70 years old, with 88-93 % having ≥1 comorbidity, whereas those from wave four were younger (68.0 years) with less comorbidities. The first two waves showed higher mortality rates (16.8 % and 20.0 %) than the latter (16.6 % and 9.5 %). Conclusion: Patients during the first wave had more severe disease conditions at baseline and higher mortality and ICU hospitalization rates. Despite the more virulent circulating Delta variant during wave four, the death and hospitalization rates were markedly decreased during wave four. HIPPOKRATIA 2023, 27 (1):1-6.

Granulomatosis with Polyangiitis (GPA)-A Multidisciplinary Approach of a Case Report.

Granulomatosis with polyangiitis is an atypical, multisystem disease with unknown etiology that generally affects both genders equally, with a predominance in the Caucasian racial group for individuals in their fourth decade. The disease affects the small vessels of the respiratory system, lungs, and kidneys. ENT manifestations are common, but ocular involvement is also frequent and can occur as an initial harbinger of the disease. The signs and symptoms of the disease are non-pathognomonic and sometimes localized, but it carries a poor prognosis if left untreated. Early diagnosis of granulomatosis with polyangiitis can be difficult and is established by a clinical examination along with laboratory tests for anti-neutrophil cytoplasmic antibodies (ANCA) and anatomopathological exam results that showcase necrosis, granulomatous inflammation, and vasculitis. Although the ocular involvement is not life threatening, it can cause blindness and may also be a sign of the active form of this systemic fatal disease. Treatment strategies involving immunosuppression and adjuvant therapies improve the prognosis. In this article we present a rare case of a patient diagnosed with granulomatosis with polyangiitis in our ENT department in 2003, with a follow-up for19 years in our clinic.

Evolution of baseline characteristics and severe outcomes in COVID-19 inpatients during the first and second waves in Northeastern France.

OBJECTIVES: Two COVID-19 epidemic waves occurred in France in 2020. This single-center retrospective study compared patients' characteristics and outcomes. PATIENTS AND METHODS: We included all patients with confirmed COVID-19 admitted to Colmar Hospital in March (n=600) and October/November (n=205) 2020. RESULTS: Median ages, sex ratio, body mass index, and number of comorbidities were similar in wave 1 and 2 patients. Significant differences were found for temperature (38°C vs. 37.2), need for oxygen (38.6% vs. 26.8%), high-flow cannula (0% vs. 8.3%), and steroid use (6.3% vs. 54.1%). Intensive care unit (ICU) hospitalizations (25.5% vs. 15.1%, OR: 0.44, 95% CI [0.28; 0.68], P=0.002) and deaths (19.2% vs. 12.7%, OR: 0.61, 95% CI [0.37; 0.98], P=0.04) decreased during the second wave. Except for cardiovascular events (5.5% vs. 10.2%), no change was observed in extrapulmonary events. CONCLUSIONS: Deaths and ICU hospitalizations were significantly reduced during the second epidemic wave.

A novel in vitro assay to study chondrocyte-to-osteoblast transdifferentiation.

PURPOSE: Endochondral ossification, which involves transdifferentiation of chondrocytes into osteoblasts, is an important process involved in the development and postnatal growth of most vertebrate bones as well as in bone fracture healing. To study the basic molecular mechanisms of this process, a robust and easy-to-use in vitro model is desirable. Therefore, we aimed to develop a standardized in vitro assay for the transdifferentiation of chondrogenic cells towards the osteogenic lineage. METHODS: Murine chondrogenic ATDC5 cells were differentiated into the chondrogenic lineage for seven days and subsequently differentiated towards the osteogenic direction. Gene expression analysis of pluripotency, as well as chondrogenic and osteogenic markers, cell-matrix staining, and immunofluorescent staining, were performed to assess the differentiation. In addition, the effects of Wnt3a and lipopolysaccharides (LPS) on the transdifferentiation were tested by their addition to the osteogenic differentiation medium. RESULTS: Following osteogenic differentiation, chondrogenically pe-differentiated cells displayed the expression of pluripotency and osteogenic marker genes as well as alkaline phosphatase activity and a mineralized matrix. Co-expression of Col2a1 and Col1a1 after one day of osteogenic differentiation indicated that osteogenic cells had differentiated from chondrogenic cells. Wnt3a increased and LPS decreased transdifferentiation towards the osteogenic lineage. CONCLUSION: We successfully established a rapid, standardized in vitro assay for the transdifferentiation of chondrogenic cells into osteogenic cells, which is suitable for testing the effects of different compounds on this cellular process.

Predictors of mortality, ICU hospitalization, and extrapulmonary complications in COVID-19 patients.

OBJECTIVE: A major coronavirus disease 2019 (COVID-19) outbreak occurred in Northeastern France in spring 2020. This single-center retrospective observational cohort study aimed to compare patients with severe COVID-19 and those with non-severe COVID-19 (survivors vs. non-survivors, ICU patients vs. non-ICU patients) and to describe extrapulmonary complications. PATIENTS AND METHODS: We included all patients with a confirmed diagnosis of COVID-19 admitted to Colmar Hospital in March 2020. RESULTS: We examined 600 patients (median age 71.09 years; median body mass index: 26.9 kg/m2); 57.7% were males, 86.3% had at least one comorbidity, 153 (25.5%) required ICU hospitalization, and 115 (19.1%) died. Baseline independent factors associated with death were older age (>75 vs. ≤75 years), male sex, oxygen supply, chronic neurological, renal, and pulmonary diseases, diabetes, cancer, low platelet and hemoglobin counts, and high levels of C-reactive protein (CRP) and serum creatinine. Factors associated with ICU hospitalization were age <75 years, oxygen supply, chronic pulmonary disease, absence of dementia, and high levels of CRP, hemoglobin, and serum creatinine. Among the 600 patients, 80 (13.3%) had an acute renal injury, 33 (5.5%) had a cardiovascular event, 27 (4.5%) had an acute liver injury, 24 (4%) had venous thromboembolism, eight (1.3%) had a neurological event, five (0.8%) had rhabdomyolysis, and one had acute pancreatitis. Most extrapulmonary complications occurred in ICU patients. CONCLUSION: This study highlighted the main risk factors for ICU hospitalization and death caused by severe COVID-19 and the frequency of numerous extrapulmonary complications in France.

Deregulation of Hepatic Mek1/2⁻Erk1/2 Signaling Module in Iron Overload Conditions.

The liver, through the production of iron hormone hepcidin, controls body iron levels. High liver iron levels and deregulated hepcidin expression are commonly observed in many liver diseases including highly prevalent genetic iron overload disorders. In spite of a number of breakthrough investigations into the signals that control hepcidin expression, little progress has been made towards investigations into intracellular signaling in the liver under excess of iron. This study examined hepatic signaling pathways underlying acquired and genetic iron overload conditions. Our data demonstrate that hepatic iron overload associates with a decline in the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) kinase (Mek1/2) pathway by selectively affecting the phosphorylation of Erk1/2. We propose that Mek1/2-Erk1/2 signaling is uncoupled from iron-Bmp-Smad-mediated hepcidin induction and that it may contribute to a number of liver pathologies in addition to toxic effects of iron. We believe that our findings will advance the understanding of cellular signaling events in the liver during iron overload of different etiologies.

Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling.

Noonan syndrome (NS), the most common RASopathy, is caused by mutations affecting signaling through RAS and the MAPK cascade. Recently, genome scanning has discovered novel genes implicated in NS, whose function in RAS-MAPK signaling remains obscure, suggesting the existence of unrecognized circuits contributing to signal modulation in this pathway. Among these genes, leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a functionally poorly characterized member of the BTB/POZ protein superfamily. Two classes of germline LZTR1 mutations underlie dominant and recessive forms of NS, while constitutional monoallelic, mostly inactivating, mutations in the same gene cause schwannomatosis, a cancer-prone disorder clinically distinct from NS. Here we show that dominant NS-causing LZTR1 mutations do not affect significantly protein stability and subcellular localization. We provide the first evidence that these mutations, but not the missense changes occurring as biallelic mutations in recessive NS, enhance stimulus-dependent RAS-MAPK signaling, which is triggered, at least in part, by an increased RAS protein pool. Moreover, we document that dominant NS-causing mutations do not perturb binding of LZTR1 to CUL3, a scaffold coordinating the assembly of a multimeric complex catalyzing protein ubiquitination but are predicted to affect the surface of the Kelch domain mediating substrate binding to the complex. Collectively, our data suggest a model in which LZTR1 contributes to the ubiquitinationof protein(s) functioning as positive modulator(s) of the RAS-MAPK signaling pathway. In this model, LZTR1 mutations are predicted to variably impair binding of these substrates to the multi-component ligase complex and their efficient ubiquitination and degradation, resulting in MAPK signaling upregulation.

Horizons for Li-Ion Batteries Relevant to Electro-Mobility: High-Specific-Energy Cathodes and Chemically Active Separators.

Li-ion batteries (LIBs) today face the challenge of application in electrified vehicles (xEVs) which require increased energy density, improved abuse tolerance, prolonged life, and low cost. LIB technology can significantly advance through more realistic approaches such as: i) stable high-specific-energy cathodes based on Li1+ x Niy Coz Mnw O2 (NCM) compounds with either Ni-rich (x = 0, y → 1), or Li- and Mn-rich (0.1 < x < 0.2, w > 0.5) compositions, and ii) chemically active separators and binders that mitigate battery performance degradation. While the stability of such cathode materials during cell operation tends to decrease with increasing specific capacity, active material doping and coatings, together with carefully designed cell-formation protocols, can enable both high specific capacities and good long-term stability. It has also been shown that major LIB capacity fading mechanisms can be reduced by multifunctional separators and binders that trap transition metal ions and/or scavenge acid species. Here, recent progress on improving Ni-rich and Mn-rich NCM cathode materials is reviewed, as well as in the search for inexpensive, multifunctional, chemically active separators. A realistic overview regarding some of the most promising approaches to improving the performance of rechargeable batteries for xEV applications is also presented.

Observation of Electron Coherence and Fabry-Perot Standing Waves at a Graphene Edge.

Electron surface states in solids are typically confined to the outermost atomic layers and, due to surface disorder, have negligible impact on electronic transport. Here, we demonstrate a very different behavior for surface states in graphene. We probe the wavelike character of these states by Fabry-Perot (FP) interferometry and find that, in contrast to theoretical predictions, these states can propagate ballistically over micron-scale distances. This is achieved by embedding a graphene resonator formed by gate-defined p-n junctions within a graphene superconductor-normal-superconductor structure. By combining superconducting Aharanov-Bohm interferometry with Fourier methods, we visualize spatially resolved current flow and image FP resonances due to p-n-p cavity modes. The coherence of the standing-wave edge states is revealed by observing a new family of FP resonances, which coexist with the bulk resonances. The edge resonances have periodicity distinct from that of the bulk states manifest in a repeated spatial redistribution of current on and off the FP resonances. This behavior is accompanied by a modulation of the multiple Andreev reflection amplitude on-and-off resonance, indicating that electrons propagate ballistically in a fully coherent fashion. These results, which were not anticipated by theory, provide a practical route to developing electron analog of optical FP resonators at the graphene edge.

Aberrant HRAS transcript processing underlies a distinctive phenotype within the RASopathy clinical spectrum.

RASopathies are a group of rare, clinically related conditions affecting development and growth, and are caused by germline mutations in genes encoding signal transducers and modulators with a role in the RAS signaling network. These disorders share facial dysmorphia, short stature, variable cognitive deficits, skeletal and cardiac defects, and a variable predisposition to malignancies. Here, we report on a de novo 10-nucleotide-long deletion in HRAS (c.481_490delGGGACCCTCT, NM_176795.4; p.Leu163ProfsTer52, NP_789765.1) affecting transcript processing as a novel event underlying a RASopathy characterized by developmental delay, intellectual disability and autistic features, distinctive coarse facies, reduced growth, and ectodermal anomalies. Molecular and biochemical studies demonstrated that the deletion promotes constitutive retention of exon IDX, which is generally skipped during HRAS transcript processing, and results in a stable and mildly hyperactive GDP/GTP-bound protein that is constitutively targeted to the plasma membrane. Our findings document a new mechanism leading to altered HRAS function that underlies a previously unappreciated phenotype within the RASopathy spectrum.

On the Oxidation State of Manganese Ions in Li-Ion Battery Electrolyte Solutions.

We demonstrate herein that Mn3+ and not Mn2+, as commonly accepted, is the dominant dissolved manganese cation in LiPF6-based electrolyte solutions of Li-ion batteries with lithium manganate spinel positive and graphite negative electrodes chemistry. The Mn3+ fractions in solution, derived from a combined analysis of electron paramagnetic resonance and inductively coupled plasma spectroscopy data, are ∼80% for either fully discharged (3.0 V hold) or fully charged (4.2 V hold) cells, and ∼60% for galvanostatically cycled cells. These findings agree with the average oxidation state of dissolved Mn ions determined from X-ray absorption near-edge spectroscopy data, as verified through a speciation diagram analysis. We also show that the fractions of Mn3+ in the aprotic nonaqueous electrolyte solution are constant over the duration of our experiments and that disproportionation of Mn3+ occurs at a very slow rate.

Ferrocenyl-Coupled N-Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs.

Four gold(I) carbene complexes featuring 4-ferrocenyl-substituted imidazol-2-ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug-resistant ones, with low micromolar or nanomolar IC50 (72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F-actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular-disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %.