346 research outputs found

    Towards greenhouse cultivation of Artemisia annua: The application of LEDs in regulating plant growth and secondary metabolism

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    Artemisinin is a sesquiterpene lactone produced in glandular trichomes of Artemisia annua, and is extensively used in the treatment of malaria. Growth and secondary metabolism of A. annua are strongly regulated by environmental conditions, causing unstable supply and quality of raw materials from field grown plants. This study aimed to bring A. annua into greenhouse cultivation and to increase artemisinin production by manipulating greenhouse light environment using LEDs. A. annua plants were grown in a greenhouse compartment for five weeks in vegetative stage with either supplemental photosynthetically active radiation (PAR) (blue, green, red or white) or supplemental radiation outside PAR wavelength (far-red, UV-B or both). The colour of supplemental PAR hardly affected plant morphology and biomass, except that supplemental green decreased plant biomass by 15% (both fresh and dry mass) compared to supplemental white. Supplemental far-red increased final plant height by 23% whereas it decreased leaf area, plant fresh and dry weight by 30%, 17% and 7%, respectively, compared to the treatment without supplemental radiation. Supplemental UV-B decreased plant leaf area and dry weight (both by 7%). Interestingly, supplemental green and UV-B increased leaf glandular trichome density by 11% and 9%, respectively. However, concentrations of artemisinin, arteannuin B, dihydroartemisinic acid and artemisinic acid only exhibited marginal differences between the light treatments. There were no interactive effects of far-red and UV-B on plant biomass, morphology, trichome density and secondary metabolite concentrations. Our results illustrate the potential of applying light treatments in greenhouse production of A. annua to increase trichome density in vegetative stage. However, the trade-off between light effects on plant growth and trichome initiation needs to be considered. Moreover, the underlying mechanisms of light spectrum regulation on artemisinin biosynthesis need further clarification to enhance artemisinin yield in greenhouse production of A. annua

    High-entropy materials for electrocatalytic applications: a review of first principles modeling and simulations

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    High-entropy materials, for both complexity in structure and superiority in performance, have been widely confirmed to be one possible kind of advanced electrocatalyst. Significant efforts have been dedicated to modeling the atomic-level details of high-entropy catalysts to improve the viability for bottom-up design of advanced electrocatalysts. In this review, first, we survey developments in various modeling methods that are based on density functional theory. We review progress in density functional theory simulations for emulating different high-entropy electrocatalysts. Then, we review the advancements in simulations of high-entropy materials for electrocatalytic applications. Finally, we present prospects in this field.Abbreviations: HEMs: high-entropy materials; CCMs: compositionally complex materials; DFT: density functional theory; LDA: local density approximation; GGA: generalized gradient approximation; VASP: Vienna Ab initio simulation package; ECP: effective core potential; PAW: projector-augmented wave potential; VCA: virtual crystal approximation; CPA: coherent potential approximation; SQS: special quasi-random structures; SSOS: small set of ordered structures; SLAE: similar local atomic environment; HEAs: high-entropy alloys; FCC: face-centered cubic; BCC: body-centered cubic; HCP: hexagonal close-packed; ORR: oxygen reduction reaction; OER: oxide evolution reaction; HER: hydrogen evolution reaction; RDS: rate-limiting step; AEM: adsorbate evolution mechanism; LOM: lattice oxygen oxidation mechanism; HEOs: high-entropy oxides; OVs: oxygen vacancies; PDOS: projected densities of states; ADR: ammonia decomposition reaction; NRR: nitrogen reduction reaction; CO2RR: CO2 reduction reaction; TMDC: transition metal dichalcogenide; TM: transition metal; AOR: alcohol oxidation reaction; GOR: glycerol oxidation reaction; UOR: urea oxidation reaction; HEI: high-entropy intermetallic

    Trans-pacific multicenter collaborative study of minimally invasive proximal versus total gastrectomy for proximal gastric and gastroesophageal junction cancers

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    Abstract Background The current standard operation for proximal gastric and gastroesophageal junction (P/GEJ) cancers with limited esophageal extension is total gastrectomy (TG). TG is associated with impaired appetite and weight loss¬†due to the loss of gastric functions such as production of ghrelin and with¬†anemia due to intrinsic factor loss and vitamin B12 malabsorption. Theoretically, proximal gastrectomy (PG) can mitigate these problems by preserving gastric function. However, PG with direct esophagogastric reconstruction is associated with severe postoperative reflux, delayed gastric emptying, and poor quality of life (QoL). Minimally invasive PG (MIPG) with antireflux techniques has been increasingly performed by experts but is technically demanding owing to its complexity. Moreover, the actual advantages of MIPG over minimally invasive TG (MITG) with regards to postoperative QoL are unknown. Our overall objective of this study is to determine the short-term QoL benefits of MIPG. Our central hypotheses are that MIPG is safe and that patients have improved appetite after MIPG with effective antireflux techniques, which leads to an overall QoL improvement when compared with MITG. Methods Enrollment of a total of 60 patients in this prospective survey-collection study is expected. Procedures (MITG versus MIPG, antireflux techniques for MIPG [double-tract reconstruction versus the double-flap technique]) will be chosen based on surgeon and/or patient preference. Randomization is not considered feasible because patients often have strong preferences regarding MITG and MIPG. The primary outcome is appetite level (reported on a 0-10 scale) at 3¬†months after surgery. With an expected 30 patients per cohort (MITG versus MIPG), this study will have 80% power to detect a one-point difference in appetite level. Patient-reported outcomes will be longitudinally collected (including questions about appetite and reflux), and specific QoL items, body weight, body mass index and ghrelin, albumin, and hemoglobin levels will be compared. Discussion Surgeons from the US, Japan, and South Korea formed this collaboration with the agreement that the surgical approach to P/GEJ cancers is an internationally important but controversial topic that requires immediate action. At the completion of the proposed research, our expected outcome is the establishment of the benefit and safety of MIPG. Trial registration This trial was registered with Clinical Trials Reporting Program Registration under the registration number NCI-2022‚Äď00267 on January 11, 2022, as well as with ClinicalTrials.gov under the registration number NCT05205343 on January 11, 2022

    Tepotinib in patients with non-small cell lung cancer with high-level<i> MET</i> amplification detected by liquid biopsy : VISION Cohort B

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    Abstract: High-level MET amplification (METamp) is a primary driver in-1%-2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1-63.4), and the median dura-tion of response is 14.3 months (95% CI, 2.8-not estimable). In exploratory biomarker analyses, focal METamp, RB1 wild-type, MYC diploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early mo-lecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides anti-tumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992)

    Patterns of oral anticoagulant use and outcomes in Asian patients with atrial fibrillation: a post-hoc analysis from the GLORIA-AF Registry

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    Background: Previous studies suggested potential ethnic differences in the management and outcomes of atrial fibrillation (AF). We aim to analyse oral anticoagulant (OAC) prescription, discontinuation, and risk of adverse outcomes in Asian patients with AF, using data from a global prospective cohort study. Methods: From the GLORIA-AF Registry Phase II-III (November 2011-December 2014 for Phase II, and January 2014-December 2016 for Phase III), we analysed patients according to their self-reported ethnicity (Asian vs. non-Asian), as well as according to Asian subgroups (Chinese, Japanese, Korean and other Asian). Logistic regression was used to analyse OAC prescription, while the risk of OAC discontinuation and adverse outcomes were analysed through Cox-regression model. Our primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). The original studies were registered with ClinicalTrials.gov, NCT01468701, NCT01671007, and NCT01937377. Findings: 34,421 patients were included (70.0&nbsp;¬Ī&nbsp;10.5 years, 45.1% females, 6900 (20.0%) Asian: 3829 (55.5%) Chinese, 814 (11.8%) Japanese, 1964 (28.5%) Korean and 293 (4.2%) other Asian). Most of the Asian patients were recruited in Asia (n&nbsp;=&nbsp;6701, 97.1%), while non-Asian patients were mainly recruited in Europe (n&nbsp;=&nbsp;15,449, 56.1%) and North America (n&nbsp;=&nbsp;8378, 30.4%). Compared to non-Asian individuals, prescription of OAC and non-vitamin K antagonist oral anticoagulant (NOAC) was lower in Asian patients (Odds Ratio [OR] and 95% Confidence Intervals (CI): 0.23 [0.22-0.25] and 0.66 [0.61-0.71], respectively), but higher in the Japanese subgroup. Asian ethnicity was also associated with higher risk of OAC discontinuation (Hazard Ratio [HR] and [95% CI]: 1.79 [1.67-1.92]), and lower risk of the primary composite outcome (HR [95% CI]: 0.86 [0.76-0.96]). Among the exploratory secondary outcomes, Asian ethnicity was associated with higher risks of thromboembolism and intracranial haemorrhage, and lower risk of major bleeding. Interpretation: Our results showed that Asian patients with AF showed suboptimal thromboembolic risk management and a specific risk profile of adverse outcomes; these differences may also reflect differences in country-specific factors. Ensuring integrated and appropriate treatment of these patients is crucial to improve their prognosis. Funding: The GLORIA-AF Registry was funded by Boehringer Ingelheim GmbH

    Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

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    Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ‚Č•18 years) with biopsy-proven IgA nephropathy and proteinuria of 1¬∑0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1¬∑75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49¬∑8%) than the irbesartan group (-15¬∑1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0¬∑59; 95% CI 0¬∑51-0¬∑69; p<0¬∑0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics

    Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

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    Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1¬∑0 g per day despite maximised renin‚Äďangiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6‚Äď110) was ‚ąí2¬∑7 mL/min per 1¬∑73 m2 per year versus ‚ąí3¬∑8 mL/min per 1¬∑73 m2 per year (difference 1¬∑1 mL/min per 1¬∑73 m2 per year, 95% CI 0¬∑1 to 2¬∑1; p=0¬∑037); total 2-year slope (day 1‚Äďweek 110) was ‚ąí2¬∑9 mL/min per 1¬∑73 m2 per year versus ‚ąí3¬∑9 mL/min per 1¬∑73 m2 per year (difference 1¬∑0 mL/min per 1¬∑73 m2 per year, 95% CI ‚ąí0¬∑03 to 1¬∑94; p=0¬∑058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (‚ąí42¬∑8%, 95% CI ‚ąí49¬∑8 to ‚ąí35¬∑0, with sparsentan versus ‚ąí4¬∑4%, ‚ąí15¬∑8 to 8¬∑7, with irbesartan; geometric least-squares mean ratio 0¬∑60, 95% CI 0¬∑50 to 0¬∑72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0¬∑7, 95% CI 0¬∑4 to 1¬∑2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.</p

    Correction to: Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

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    International audienceIn this article, the name of the GLORIA-AF investigator Anastasios Kollias was given incorrectly as Athanasios Kollias in the Acknowledgements. The original article has been corrected

    Gut microbiota of the young ameliorates physical fitness of the aged in mice

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    Abstract Background Aging is a natural process that an organism gradually loses its physical fitness and functionality. Great efforts have been made to understand and intervene in this deteriorating process. The gut microbiota affects host physiology, and dysbiosis of the microbial community often underlies the pathogenesis of host disorders. The commensal microbiota also changes with aging; however, the interplay between the microbiota and host aging remains largely unexplored. Here, we systematically examined the ameliorating effects of the gut microbiota derived from the young on the physiology and phenotypes of the aged. Results As the fecal microbiota was transplanted from young mice at 5 weeks after birth into 12-month-old ones, the thickness of the muscle fiber and grip strength were increased, and the water retention ability of the skin was enhanced with thickened stratum corneum. Muscle thickness was also marginally increased in 25-month-old mice after transferring the gut microbiota from the young. Bacteria enriched in 12-month-old mice that received the young-derived microbiota significantly correlated with the improved host fitness and altered gene expression. In the dermis of these mice, transcription of Dbn1 was most upregulated and DBN1-expressing cells increased twice. Dbn1-heterozygous mice exhibited impaired skin barrier function and hydration. Conclusions We revealed that the young-derived gut microbiota rejuvenates the physical fitness of the aged by altering the microbial composition of the gut and gene expression in muscle and skin. Dbn1, for the first time, was found to be induced by the young microbiota and to modulate skin hydration. Our results provide solid evidence that the gut microbiota from the young improves the vitality of the aged. Video Abstrac

    Brain substrates for automatic retrieval of value memory in the primate basal ganglia

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    Our behavior is often carried out automatically. Automatic behavior can be guided by past experiences, such as learned values associated with objects. Passive-viewing and free-viewing tasks with no immediate outcomes provide a testable condition in which monkeys and humans automatically retrieve value memories and perform habitual searching. Interestingly, in these tasks, caudal regions of the basal ganglia structures are involved in automatic retrieval of learned object values and habitual gaze. In contrast, rostral regions do not participate in these activities but instead monitor the changes in outcomes. These findings indicate that automatic behaviors based on the value memories are processed selectively by the caudal regions of the primate basal ganglia system. Understanding the distinct roles of the caudal basal ganglia may provide insight into finding selective causes of behavioral disorders in basal ganglia disease.N
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