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A bstract The discovery by the ATLAS and CMS experiments of a new boson with mass around 125 GeV and with measured properties compatible with those of a Standard-Model Higgs boson, coupled with the absence of discoveries of phenomena beyond the Standard Model at the TeV scale, has triggered interest in ideas for future Higgs factories. A new circular e + e − collider hosted in a 80 to 100 km tunnel, TLEP, is among the most attractive solutions proposed so far. It has a clean experimental environment, produces high luminosity for top-quark, Higgs boson, W and Z studies, accommodates multiple detectors, and can reach energies up to the threshold and beyond. It will enable measurements of the Higgs boson properties and of Electroweak Symmetry-Breaking (EWSB) parameters with unequalled precision, offering exploration of physics beyond the Standard Model in the multi-TeV range. Moreover, being the natural precursor of the VHE-LHC, a 100 TeV hadron machine in the same tunnel, it builds up a long-term vision for particle physics. Altogether, the combination of TLEP and the VHE-LHC offers, for a great cost effectiveness, the best precision and the best search reach of all options presently on the market. This paper presents a first appraisal of the salient features of the TLEP physics potential, to serve as a baseline for a more extensive design study.

Background In viticulture, rootstock genotype plays a critical role to improve scion physiology, berry quality and to adapt grapevine ( Vitis vinifera L.) to different environmental conditions. This study aimed at investigating the effect of two different rootstocks (1103 Paulsen - P - and Mgt 101–14 - M) in comparison with not grafted plants - NGC - on transcriptome (RNA-seq and small RNA-seq) and chemical composition of berry skin in Pinot noir , and exploring the influence of rootstock-scion interaction on grape quality. Berry samples, collected at veraison and maturity, were investigated at transcriptional and biochemical levels to depict the impact of rootstock on berry maturation. Results RNA- and miRNA-seq analyses highlighted that, at veraison, the transcriptomes of the berry skin are extremely similar, while variations associated with the different rootstocks become evident at maturity, suggesting a greater diversification at transcriptional level towards the end of the ripening process. In the experimental design, resembling standard agronomic growth conditions, the vines grafted on the two different rootstocks do not show a high degree of diversity. In general, the few genes differentially expressed at veraison were linked to photosynthesis, putatively because of a ripening delay in not grafted vines, while at maturity the differentially expressed genes were mainly involved in the synthesis and transport of phenylpropanoids (e.g. flavonoids), cell wall loosening, and stress response. These results were supported by some differences in berry phenolic composition detected between grafted and not grafted plants, in particular in resveratrol derivatives accumulation. Conclusions Transcriptomic and biochemical data demonstrate a stronger impact of 1103 Paulsen rootstock than Mgt 101–14 or not grafted plants on ripening processes related to the secondary metabolite accumulations in berry skin tissue. Interestingly, the MYB14 gene, involved in the feedback regulation of resveratrol biosynthesis was up-regulated in 1103 Paulsen thus supporting a putative greater accumulation of stilbenes in mature berries.

Patients with focal segmental glomerulosclerosis (FSGS) who are refractory to drug treatment may present progressive loss of kidney function, leading to chronic kidney disease stage 5 under dialysis treatment. The safety of systemic administration of bone marrow‐derived mononuclear cells (BMDMCs) has been shown in different preclinical models of kidney diseases. However, to date, no study has evaluated the safety and biodistribution of BMDMCs after infusion in renal arteries in patients with FSGS. We used a prospective, non‐randomized, single‐center longitudinal design to investigate this approach. Five patients with refractory FSGS and an estimated glomerular filtration rate (eGFR) between 20 and 40 ml/min/1.73 m 2 underwent bone marrow aspiration and received an arterial infusion of autologous BMDMCs (5 × 10 7 ) for each kidney. In addition, BMDMCs labeled with technetium‐99m ( 99m Tc‐BMDMCs) were used to assess the biodistribution by scintigraphy. All patients completed the 270‐day follow‐up protocol with no serious adverse events. A transient increase in creatinine was observed after the cell therapy, with improvement on day 30. 99m Tc‐BMDMCs were detected in both kidneys and counts were higher after 2 hr compared with 24 hr. The arterial infusion of BMDMCs in both kidneys of patients with FSGS was considered safe with stable eGFR at the end of follow‐up. This trial is registered with NCT02693366 .

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide health epidemic with a global occurrence of approximately 30%. The pathogenesis of MASLD is a complex, multisystem disorder driven by multiple factors, including genetics, lifestyle, and the environment. Patient heterogeneity presents challenges in developing MASLD therapeutics, creating patient cohorts for clinical trials, and optimizing therapeutic strategies for specific patient cohorts. Implementing pre-clinical experimental models for drug development creates a significant challenge as simple in vitro systems and animal models do not fully recapitulate critical steps in the pathogenesis and the complexity of MASLD progression. To address this, we implemented a precision medicine strategy that couples the use of our liver acinus microphysiology system (LAMPS) constructed with patient-derived primary cells. We investigated the MASLD-associated genetic variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M variant) in primary hepatocytes as it is associated with MASLD progression. We constructed the LAMPS with genotyped wild-type and variant PNPLA3 hepatocytes, together with key non-parenchymal cells, and quantified the reproducibility of the model. We altered media components to mimic blood chemistries, including insulin, glucose, free fatty acids, and immune-activating molecules to reflect normal fasting (NF), early metabolic syndrome (EMS), and late metabolic syndrome (LMS) conditions. Finally, we investigated the response to treatment with resmetirom, an approved drug for metabolic syndrome-associated steatohepatitis (MASH), the progressive form of MASLD. This study, using primary cells, serves as a benchmark for studies using “patient biomimetic twins” constructed with patient induced pluripotent stem cell (iPSC)-derived liver cells using a panel of reproducible metrics. We observed increased steatosis, immune activation, stellate cell activation, and secretion of pro-fibrotic markers in the PNPLA3 GG variant compared to the wild-type CC LAMPS, consistent with the clinical characterization of this variant. We also observed greater resmetirom efficacy in the PNPLA3 wild-type CC LAMPS compared to the GG variant in multiple MASLD metrics, including steatosis, stellate cell activation, and the secretion of pro-fibrotic markers. In conclusion, our study demonstrates the capability of the LAMPS platform for the development of MASLD precision therapeutics, enrichment of patient cohorts for clinical trials, and optimization of therapeutic strategies for patient subgroups with different clinical traits and disease stages.

Metabolic-dysfunction-associated steatotic liver disease (MASLD), which affects 30 million people in the US and is anticipated to reach over 100 million by 2030, places a significant financial strain on the healthcare system. There is presently no FDA-approved treatment for MASLD despite its public health significance and financial burden. Understanding the connection between point mutations, liver enzymes, and MASLD is important for comprehending drug toxicity in healthy or diseased individuals. Multiple genetic variations have been linked to MASLD susceptibility through genome-wide association studies (GWAS), either increasing MASLD risk or protecting against it, such as PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438. As the impact of genetic variants on the levels of drug-metabolizing cytochrome P450 (CYP) enzymes in human hepatocytes has not been thoroughly investigated, this study aims to describe the analysis of metabolic functions for selected phase I and phase II liver enzymes in human hepatocytes. For this purpose, fresh isolated primary hepatocytes were obtained from healthy liver donors (n = 126), and liquid chromatography–mass spectrometry (LC–MS) was performed. For the cohorts, participants were classified into minor homozygotes and nonminor homozygotes (major homozygotes + heterozygotes) for five gene polymorphisms. For phase I liver enzymes, we found a significant difference in the activity of CYP1A2 in human hepatocytes carrying MBOAT7 (p = 0.011) and of CYP2C8 in human hepatocytes carrying PNPLA3 (p = 0.004). It was also observed that the activity of CYP2C9 was significantly lower in human hepatocytes carrying HSD17B13 (p = 0.001) minor homozygous compared to nonminor homozygous. No significant difference in activity of CYP2E1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, ECOD, FMO, MAO, AO, and CES2 and in any of the phase II liver enzymes between human hepatocytes carrying genetic variants for PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438 were observed. These findings offer a preliminary assessment of the influence of genetic variations on drug-metabolizing cytochrome P450 (CYP) enzymes in healthy human hepatocytes, which may be useful for future drug discovery investigations.

We report on a measurement of Spin Density Matrix Elements (SDMEs) in hard exclusive $$\\rho ^0$$ ρ 0 meson muoproduction at COMPASS using 160 GeV/ c polarised $$ \\mu ^{+}$$ μ + and $$ \\mu ^{-}$$ μ - beams impinging on a liquid hydrogen target. The measurement covers the kinematic range 5.0 GeV/ $$c^2$$ c 2 $$< W<$$ < W < 17.0 GeV/ $$c^2$$ c 2 , 1.0 (GeV/ c ) $$^2$$ 2 $$< Q^2<$$ < Q 2 < 10.0 (GeV/ c ) $$^2$$ 2 and 0.01 (GeV/ c ) $$^2$$ 2 $$< p_{\\textrm{T}}^2<$$ < p T 2 < 0.5 (GeV/ c ) $$^2$$ 2 . Here, W denotes the mass of the final hadronic system, $$Q^2$$ Q 2 the virtuality of the exchanged photon, and $$p_{\\textrm{T}}$$ p T the transverse momentum of the $$\\rho ^0$$ ρ 0 meson with respect to the virtual-photon direction. The measured non-zero SDMEs for the transitions of transversely polarised virtual photons to longitudinally polarised vector mesons ( $$\\gamma ^*_T \\rightarrow V^{ }_L$$ γ T ∗ → V L ) indicate a violation of s -channel helicity conservation. Additionally, we observe a dominant contribution of natural-parity-exchange transitions and a very small contribution of unnatural-parity-exchange transitions, which is compatible with zero within experimental uncertainties. The results provide important input for modelling Generalised Parton Distributions (GPDs). In particular, they may allow one to evaluate in a model-dependent way the role of parton helicity-flip GPDs in exclusive $$\\rho ^0$$ ρ 0 production.

We report on a measurement of Spin Density Matrix Elements (SDMEs) in hard exclusive ω meson muoproduction on the proton at COMPASS using 160 GeV/c polarised μ+ and μ- beams impinging on a liquid hydrogen target. The measurement covers the range 5.0 GeV/c2

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