Miracle-dz/UniFAR-FTUs huggingface dataset:
Analyse des phénomènes de vieillissement des matériaux d’isolation électrique de machines de traction électrique

La conception et la validation d’un nouveau moteur electrique necessitent d’examiner les comportements dans le temps des differents materiaux d’isolation electrique face aux multiples contraintes qu’ils subissent. Les caracterisations au cours des vieillissements thermiques, hygrothermiques, thermomecaniques et electriques, ont porte sur les materiaux seuls , avec un focus particulier sur les resines d’impregnation : une a base de polyesterimide et une a base d’epoxy charge, mais egalement sur les systemes d’isolation electrique complets. Les autres materiaux sont l’email des fils de cuivre, constitue de polyesterimide et de polyamide-imide, et deux papiers d’isolation tri-couches a base de Nomex® et de Kapton® pour l’un, et de Nomex® et de PET pour l’autre. Des caracterisations physico-chimiques (suivi de masse, spectroscopies IR et dielectrique, microscopie optique) et mecanique (flexion 3 points) ont permis de mettre en evidence des mecanismes de degradations des materiaux lors des vieillissements thermiques et hygrothermiques tels que la perte d’adherence de l’email ou bien la delamination de la resine epoxy. La caracterisation electrique des motorettes par des mesures de decharges partielles, a permis une evaluation des impacts des differents vieillissements et egalement de les correler avec certains comportements des materiaux. L’influence de la forme d’onde sur la TADP a ete etudiee. Il n’apparait aucune difference significative dans nos conditions entre des mesures sous signaux sinusoidaux et sous signaux carres. Les simulations de champs electriques sur les motorettes sont en accord avec les tensions d’apparition de decharges partielles (TADP) mesurees et avec l’influence de la temperature sur ces TADP.
Role of Protein Phosphatase1 Regulatory Subunit3 in Mediating the Abscisic Acid Response.

Protein phosphatase1 (PP1) plays important roles in eukaryotes, including in plant hormone responses, and functions as a holoenzyme that consists of catalytic and regulatory subunits. Animal genomes encode ∼200 PP1-interacting proteins; by contrast, only a few have been reported in plants. In this study, PP1 Regulatory Subunit3 (PP1R3), a protein that interacts with PP1 in Arabidopsis (Arabidopsis thaliana), was characterized by mass spectrometry. PP1R3 was widely expressed in various plant tissues and PP1R3 colocalized with Type One Protein Phosphatases (TOPPs) in the nucleus and cytoplasm. The pp1r3 mutants were hypersensitive to abscisic acid (ABA), similar to the dominant-negative mutant topp4-1 or the loss-of-function multiple mutants topp1 topp4-3, topp8 topp9, topp6/7/9, topp1/2/4-3/6/7/9, and topp1/4-3/5/6/7/8/9 (topp-7m). About two-thirds of differentially expressed genes in topp-7m showed the same gene expression changes as in pp1r3-2. In response to ABA, the phenotypes of pp1r3 topp1 topp4-3 and pp1r3 topp4-1 were consistent with those of pp1r3, while pp1r3 abi1-1 showed an additive effect of the pp1r3 and abi1-1 (mutation in Abscisic Acid Insensitive1 [ABI1]) single mutants. Moreover, pp1r3 could partially recover the ABA response-related phenotype, gene expression, and plant morphology of topp4-1. PP1R3 inhibited TOPP enzyme activity and facilitated the nuclear localization of TOPP4. By contrast, ABA treatment increased the amounts of TOPP1 and TOPP4 in the cytoplasm. Importantly, nuclear localization of TOPP4 partially restored the ABA-hypersensitive phenotype of topp4-1. Overall, our results suggest that the PP1R3:TOPP holoenzyme functions in parallel with ABI1 in the nucleus to regulate ABA signaling.
Continuous Crystallization of Cyclosporine: Effect of Operating Conditions on Yield and Purity

A continuous crystallization process has potential advantages such as lower cost and improved flexibility in pharmaceutical production when compared to batch crystallization. In this work, multistage continuous cooling crystallization processes for cyclosporine were developed. The approach demonstrated that optimization of stage conditions can be used to improve yield and purity. For a multi-impurity system such as cyclosporine, the segregation of each impurity should be estimated separately due to their different behaviors. The effective distribution coefficients of the impurities were calculated and related to the steady state mother liquor concentrations. A population balance and mass balance model including distribution coefficients for impurities was used to estimate maximum yields and purities that could be obtained at various operating conditions. The results showed the limitation in yield and purity improvement using a mixed-suspension, mixed-product removal cascade. In addition, optimization alon.
General Trends in Core–Shell Preferences for Bimetallic Nanoparticles

Surface segregation phenomena dictate core–shell preference of bimetallic nanoparticles and thus play a crucial role in the nanoparticle synthesis and applications. Although it is generally agreed that surface segregation depends on the constituent materials’ physical properties, a comprehensive picture of the phenomena on the nanoscale is not yet complete. Here we use a combination of molecular dynamics (MD) and Monte Carlo (MC) simulations on 45 bimetallic combinations to determine the general trend on the core–shell preference and the effects of size and composition. From the extensive studies over sizes and compositions, we find that the surface segregation and degree of the core–shell tendency of the bimetallic combinations depend on the sufficiency or scarcity of the surface-preferring material. Principal component analysis (PCA) and linear discriminant analysis (LDA) on the molecular dynamics simulations results reveal that cohesive energy and Wigner–Seitz radius are the two primary factors that have an “additive” effect on the segregation level and core–shell preference in the bimetallic nanoparticles studied. When the element with the higher cohesive energy also has the larger Wigner–Seitz radius, its core preference decreases, and thus this combination forms less segregated structures than what one would expect from the cohesive energy difference alone. Highly segregated structures (highly segregated core–shell or Janus-like) are expected to form when both the relative cohesive energy difference is greater than ∼20%, and the relative Wigner–Seitz radius difference is greater than ∼4%. Practical guides for predicting core–shell preference and degree of segregation level are presented.
Current challenges to underpinning the genetic basis for cholangiocarcinoma

ABSTRACT Introduction: Cholangiocarcinoma (CCA) is an aggressive cancer type with a dismal prognosis. CCA typically presents at an advanced stage when surgical resection is not feasible, and systemic chemotherapy is generally of limited benefit. Thus, developing effective therapies against this deadly tumor is imperative and remains an unmet need. The advent of high-throughput approaches has led to a better delineation of each CCA subtype’s molecular landscape and the identification of promising candidates for targeted therapies. In this scenario, the recent approval of pemigatinib, a pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, for the treatment of the CCA subtype characterized by FGFR2 mutations, represents the first of numerous novel therapies against this disease. Areas covered This review provides an overview regarding the current scenario and knowledge of the CCA genomic landscape and the potentially actionable molecular aberrations in each CCA subtype. Expert opinion The establishment and advances of high-throughput methodologies applied to genetic and epigenetic profiling are changing many cancer types' therapeutic landscape , including CCA.The large body of data generated must be interpreted appropriately and eventually implemented in clinical practice. The following advancements toward precision medicine in CCA management will require designing better clinical trials with improved methods to stratify biliary tumor patients.
Rationale and design of the AMULET study: A new Model of telemedical care in patients with heart failure

Heart failure (HF) is characterized by high mortality and hospital readmission rates. Limited access to cardiologists restricts the application of guideline‐directed, patient‐tailored medical therapy. Some telemedicine solutions and novel non‐invasive diagnostic tools may facilitate real‐time detection of early HF decompensation symptoms, prompt initiation of appropriate treatment, and optimal management of medical resources. We describe the rationale and design of the AMULET trial, which investigates the effect of comprehensive outpatient intervention, based on individualized haemodynamic assessment and teleconsultations, on cardiovascular mortality and unplanned hospitalizations in HF patients.
Structural characterization of the antiapoptotic protein Bcl-x\(_{L}\) and the NDH-1 complex subunit CupS by X-ray crystallography and NMR spectroscopy

Das antiapoptotische Protein Bcl-xL wird in einigen Tumoren uberexprimiert und spielt daher eine wichtige Rolle in der Medikamentenforschung. Es kommt sowohl im Cytosol als auch an der Mitochondrienmembran vor. Fur die Membranlokalisation ist der C-Terminus wichtig, der die Funktion einer Transmembrandomane ubernimmt. Allerdings wurden die meisten strukturellen Studien ohne den C-Terminus durchgefuhrt. Diese Arbeit beschreibt die Expression von full-length Bcl-xL, erste rontgenkristallographische und NMR-Experimente, sowie Studien in einer membranahnlichen Umgebung (LDAO-Mizellen). Das cyanobakterielle Protein CupS ist Untereinheit des NAD(P)H-Dehydrogenase Typ 1 (NDH-1) Komplexes. Diese Arbeit beschaftigt sich mit der strukturellen Untersuchung von CupS aus \(\textit {Thermosynechococcus elongatus}\) mittels NMR-Spektroskopie. Die chemischen Verschiebungen des Protein-Backbones und der Seitenketten wurden bestimmt und die Struktur des Proteins wurde berechnet.
APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE‐TR mice

The impact of sex and menopausal status in Alzheimer’s disease remains understudied despite increasing evidence of greater female risk, particularly in APOE4 carriers. Utilizing female APOE‐TR mice maintained on a high‐fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months of age, recognition memory and spatial memory were assessed using object recognition, Y‐maze spontaneous alternation, and Barnes maze. A VCD*genotype interaction reduced the recognition memory (P < .05), with APOE4 VCD‐treated animals unable to distinguish between novel and familiar objects. APOE4 mice displayed an additional 37% and 12% reduction in Barnes (P < .01) and Y‐maze (P < .01) performance, indicative of genotype‐specific spatial memory impairment. Molecular analysis indicated both VCD and genotype‐related deficits in synaptic plasticity with BDNF, Akt, mTOR, and ERK signaling compromised. Subsequent reductions in the transcription factors Creb1 and Atf4 were also evident. Furthermore, the VCD*genotype interaction specifically diminished Ephb2 expression, while Fos, and Cnr1 expression reduced as a consequence of APOE4 genotype. Brain DHA levels were 13% lower in VCD‐treated animals independent of genotype. Consistent with this, we detected alterations in the expression of the DHA transporters Acsl6 and Fatp4. Our results indicate that the combination of ovarian failure and APOE4 leads to an exacerbation of cognitive and neurological deficits.
Marrow Stimulation Has Relatively Inferior Patient-Reported Outcomes in Cartilage Restoration Surgery of the Knee: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background: Multiple cartilage repair techniques are available for chondral defects in the knee. Optimal treatment is controversial. Purpose: To evaluate change from baseline in the 5 Knee injury and Osteoarthritis Outcome Score (KOOS) subscales among different cartilage repair techniques of the knee. Study Design: Systematic review and meta-analysis; Level of evidence, 1A. Methods: Medline and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for randomized controlled trials with minimum 1 year follow-up reporting change from baseline KOOS (delta KOOS) subscale values. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. A meta-analysis was performed on the following surgery types: microfracture (Mfx); augmented microfracture techniques (Mfx+Augment); and culture-based therapies, including autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI). A random-effects metaregression model was used. Results: A total of 14 randomized trials with a total of 775 patients were included. The KOOS Sport and Recreation (Sport) and KOOS Quality of Life (QOL) were the 2 most responsive subscales after operative intervention. Outcomes from Mfx and Mfx+Augment were not different in any of the 5 KOOS subscales (minimum P > .3). The mean delta KOOS Sport after ACI/MACI was 9.9 points greater than after Mfx (P = .021) and 11.7 points greater than after Mfx+Augment (P = .027). Longer follow-up time correlated with greater delta KOOS Sport (P = .028). Larger body mass index led to greater delta KOOS QOL (P = .045). Larger cartilage defect size correlated with greater delta KOOS Pain and KOOS Activities of Daily Living scores (P = .023 and P = .002, respectively). Conclusion: The KOOS Sport and QOL were the most responsive subscales after cartilage restoration surgery of the knee. Culture-based therapies (ACI/MACI) led to clinically relevant improvements in the KOOS Sport score compared with marrow stimulation and may be a more appropriate treatment in younger and more active individuals. There were no benefits to Mfx+Augment over Mfx alone in any of the KOOS subscales.
Loss of enteric neuronal Ndrg4 promotes colorectal cancer via increased release of Nid1 and Fbln2

The N‐Myc Downstream‐Regulated Gene 4 (NDRG4), a prominent biomarker for colorectal cancer (CRC), is specifically expressed by enteric neurons. Considering that nerves are important members of the tumor microenvironment, we here establish different Ndrg4 knockout (Ndrg4−/−) CRC models and an indirect co‐culture of primary enteric nervous system (ENS) cells and intestinal organoids to identify whether the ENS, via NDRG4, affects intestinal tumorigenesis. Linking immunostainings and gastrointestinal motility (GI) assays, we show that the absence of Ndrg4 does not trigger any functional or morphological GI abnormalities. However, combining in vivo, in vitro, and quantitative proteomics data, we uncover that Ndrg4 knockdown is associated with enlarged intestinal adenoma development and that organoid growth is boosted by the Ndrg4−/− ENS cell secretome, which is enriched for Nidogen‐1 (Nid1) and Fibulin‐2 (Fbln2). Moreover, NID1 and FBLN2 are expressed in enteric neurons, enhance migration capacities of CRC cells, and are enriched in human CRC secretomes. Hence, we provide evidence that the ENS, via loss of Ndrg4, is involved in colorectal pathogenesis and that ENS‐derived Nidogen‐1 and Fibulin‐2 enhance colorectal carcinogenesis.
Overexpression of DPGR -type KEA3 Resulted in Retarded Plant Growth

50 The thylakoid K + efflux antiporter 3 (KEA3) is required for regulating components of the 52 proton motive force ( pmf ), proton concentration gradient (ΔpH), and membrane potential 53 (Δψ). The Arabidopsis ( Arabidopsis thaliana ) dpgr ( disturbed proton gradient regulation ) 54 mutant is a dominant allele of KEA3 conferring disturbed transport activity. Here, we show 55 that overexpressing the DPGR-type KEA3 (DPGRox) retarded plant growth, whereas 56 overexpressing the wild-type KEA3 (KEA3ox) did not. In KEA3ox lines, the contribution 57 of Δψ to pmf was enhanced, but in DPGRox lines, the size of pmf was reduced. In DPGRox 58 plants, proton conductivity of the thylakoid membrane ( g H+ ) was elevated under high light, 59 implying disturbed stoichiometry of H + /K + antiport through DPGR-type KEA3 rather than 60 simply enhanced activity. The ΔpH-dependent regulation consisting of thermal dissipation 61 of excessively absorbed light energy and down-regulation of cytochrome b 6 f complex 62 activity was severely and mildly affected in DPGRox and KEA3ox plants, respectively. 63 Consequently, photosystem I was sensitive to fluctuating light in both transgenic plants. 64 Both photosystems were sensitive to constant high light and were slightly photodamaged 65 even at standard growth light intensity in DPGRox plants. KEA3 regulates the components 66 of pmf and optimizes the operation of ∆pH-dependent regulation of electron transport.
HPLC-UV/HRMS methods for the unambiguous detection of adulterations of Ginkgo biloba leaves with Sophora japonica fruits on an extract level

Abstract Context Ginkgo biloba L. (Ginkgoaceae) leaf extract is one of the most frequently sold herbal extracts. There have been reports on poor quality and adulteration of ginkgo leaf extracts or the powdered plant material with extracts or powder of Styphnolobium japonicum (L.) Schott (Fabaceae) (syn. Sophora japonica L.) fruits, which is rich in flavone glycosides. Objective The study investigates whether ginkgo leaves genuinely contain genistein and sophoricoside and whether these two substances could be used as markers to detect adulterations with sophora fruits. Materials and methods A total of 33 samples of dried ginkgo leaves were sourced from controlled plantations in China, the USA, and France. After extraction, the samples were analyzed using two high-performance liquid chromatography (HPLC) coupled with UV/HRMS methods for the detection of genistein and sophoricoside, respectively. Chromatograms were compared to standard reference materials. Results In none of the tested ginkgo samples, neither genistein nor sophoricoside could be detected. The applied method was designed to separate genistein from apigenin. The latter is a genuine compound of ginkgo leaves, and its peak may have been previously misidentified as genistein because of the same molecular mass. The method for the detection of sophoricoside allows identification of the adulteration with sophora fruit without prior hydrolysis. By both HPLC methods, it was possible to detect adulterations of ≥2% sophora fruits in the investigated ginkgo extract. Conclusion The methods allow unambiguous detection of adulterations of ginkgo leaves with sophora fruits, using genistein and sophoricoside as marker compounds.
Engram Size Varies with Learning and Reflects Memory Content and Precision

Memories are rarely acquired under ideal conditions, rendering them vulnerable to profound omissions, errors, and ambiguities. Consistent with this, recent work using context fear conditioning has shown that memories formed after inadequate learning time display a variety of maladaptive properties, including overgeneralization to similar contexts. However, the neuronal basis of such poor learning and memory imprecision remains unknown. Using c-fos to track neuronal activity in male mice, we examined how these learning-dependent changes in context fear memory precision are encoded in hippocampal ensembles. We found that the total number of c-fos-encoding cells did not correspond with learning history but instead more closely reflected the length of the session immediately preceding c-fos measurement. However, using a c-fos-driven tagging method (TRAP2 mouse line), we found that the degree of learning and memory specificity corresponded with neuronal activity in a subset of dentate gyrus cells that were active during both learning and recall. Comprehensive memories acquired after longer learning intervals were associated with more double-labeled cells. These were preferentially reactivated in the conditioning context compared with a similar context, paralleling behavioral discrimination. Conversely, impoverished memories acquired after shorter learning intervals were associated with fewer double-labeled cells. These were reactivated equally in both contexts, corresponding with overgeneralization. Together, these findings provide two surprising conclusions. First, engram size varies with learning. Second, larger engrams support better neuronal and behavioral discrimination. These findings are incorporated into a model that describes how neuronal activity is influenced by previous learning and present experience, thus driving behavior. SIGNIFICANCE STATEMENT Memories are not always formed under ideal circumstances. This is especially true in traumatic situations, such as car accidents, where individuals have insufficient time to process what happened around them. Such memories have the potential to overgeneralize to irrelevant situations, producing inappropriate fear and contributing to disorders, such as post-traumatic stress disorder. However, it is unknown how such poorly formed fear memories are encoded within the brain. We find that restricting learning time results in fear memories that are encoded by fewer hippocampal cells. Moreover, these fewer cells are inappropriately reactivated in both dangerous and safe contexts. These findings suggest that fear memories formed at brief periods overgeneralize because they lack the detail-rich information necessary to support neuronal discrimination.
CaVβ controls the endocytic turnover of CaV1.2 L‐type calcium channel

Membrane depolarization activates the multisubunit CaV1.2 L‐type calcium channel initiating various excitation coupling responses. Intracellular trafficking into and out of the plasma membrane regulates the channel's surface expression and stability, and thus, the strength of CaV1.2‐mediated Ca2+ signals. The mechanisms regulating the residency time of the channel at the cell membrane are unclear. Here, we coexpressed the channel core complex CaV1.2α1 pore‐forming and auxiliary CaVβ subunits and analyzed their trafficking dynamics from single‐particle‐tracking trajectories. Speed histograms obtained for each subunit were best fitted to a sum of diffusive and directed motion terms. The same mean speed for the highest‐mobility state underlying directed motion was found for all subunits. The frequency of this component increased by covalent linkage of CaVβ to CaV1.2α1 suggesting that high‐speed transport occurs in association with CaVβ. Selective tracking of CaV1.2α1 along the postendocytic pathway failed to show the highly mobile state, implying CaVβ‐independent retrograde transport. Retrograde speeds of CaV1.2α1 are compatible with myosin VI‐mediated backward transport. Moreover, residency time at the cell surface was significantly prolonged when CaV1.2α1 was covalently linked to CaVβ. Thus, CaVβ promotes fast transport speed along anterograde trafficking and acts as a molecular switch controlling the endocytic turnover of L‐type calcium channels.