DCD – a novel plant specific domain in proteins involved in development and programmed cell death

BACKGROUND: Recognition of microbial pathogens by plants triggers the hypersensitive reaction, a common form of programmed cell death in plants. These dying cells generate signals that activate the plant immune system and alarm the neighboring cells as well as the whole plant to activate defense responses to limit the spread of the pathogen. The molecular mechanisms behind the hypersensitive reaction are largely unknown except for the recognition process of pathogens. We delineate the NRP-gene in soybean, which is specifically induced during this programmed cell death and contains a novel protein domain, which is commonly found in different plant proteins. RESULTS: The sequence analysis of the protein, encoded by the NRP-gene from soybean, led to the identification of a novel domain, which we named DCD, because it is found in plant proteins involved in development and cell death. The domain is shared by several proteins in the Arabidopsis and the rice genomes, which otherwise show a different protein architecture. Biological studies indicate a role of these proteins in phytohormone response, embryo development and programmed cell by pathogens or ozone. CONCLUSION: It is tempting to speculate, that the DCD domain mediates signaling in plant development and programmed cell death and could thus be used to identify interacting proteins to gain further molecular insights into these processes

Generic 3D Representation via Pose Estimation and Matching

Though a large body of computer vision research has investigated developing generic semantic representations, efforts towards developing a similar representation for 3D has been limited. In this paper, we learn a generic 3D representation through solving a set of foundational proxy 3D tasks: object-centric camera pose estimation and wide baseline feature matching. Our method is based upon the premise that by providing supervision over a set of carefully selected foundational tasks, generalization to novel tasks and abstraction capabilities can be achieved. We empirically show that the internal representation of a multi-task ConvNet trained to solve the above core problems generalizes to novel 3D tasks (e.g., scene layout estimation, object pose estimation, surface normal estimation) without the need for fine-tuning and shows traits of abstraction abilities (e.g., cross-modality pose estimation). In the context of the core supervised tasks, we demonstrate our representation achieves state-of-the-art wide baseline feature matching results without requiring apriori rectification (unlike SIFT and the majority of learned features). We also show 6DOF camera pose estimation given a pair local image patches. The accuracy of both supervised tasks come comparable to humans. Finally, we contribute a large-scale dataset composed of object-centric street view scenes along with point correspondences and camera pose information, and conclude with a discussion on the learned representation and open research questions.Comment: Published in ECCV16. See the project website http://3drepresentation.stanford.edu/ and dataset website https://github.com/amir32002/3D_Street_Vie

Efficacy and safety of intravenous ferric carboxymaltose compared with oral iron for the treatment of iron deficiency anaemia in women after childbirth in Tanzania: a parallelgroup, open-label, randomised controlled phase 3 trial

Background: Iron deficiency anaemia is of major concern in low-income settings, especially for women of childbearing age. Oral iron substitution efficacy is limited by poor compliance and iron depletion severity. We aimed to assess the efficacy and safety of intravenous ferric carboxymaltose versus oral iron substitution following childbirth in women with iron deficiency anaemia in Tanzania. Methods: This parallel-group, open-label, randomised controlled phase 3 trial was done at Bagamoyo District Hospital and Mwananyamala Hospital, Tanzania. Eligible participants were close to delivery and had iron deficiency anaemia defined as a haemoglobin concentration of less than 110 g/L and a ferritin concentration of less than 50 μg/L measured within 14 days before childbirth. Participants were randomly assigned 1:1 to receive intravenous ferric carboxymaltose or oral iron, stratified by haemoglobin concentration and site. Intravenous ferric carboxymaltose was administered at a dose determined by the haemoglobin concentration and bodyweight (bodyweight 35 kg to <70 kg and haemoglobin ≥100 g/L: 1000 mg in one dose; bodyweight 35 kg to <70 kg and haemoglobin <100 g/L, or bodyweight ≥70 kg and haemoglobin ≥100 g/L: 1500 mg in two doses at least 7 days apart; bodyweight ≥70 kg and haemoglobin 115 g/L) at 6 weeks. Follow-up visits were at 6 weeks, and 3, 6, and 12 months. Analyses were done in the modified intention-totreat population of participants who had a 6-week haemoglobin concentration result, using logistic and linear regression models for binary and continuous outcomes, adjusted for baseline haemoglobin concentration and site. This trial is registered with ClinicalTrials.gov, NCT02541708. Findings: Between Oct 8, 2015, and March 14, 2017, 533 individuals were screened and 230 were enrolled and randomly assigned to a study group (114 to intravenous iron, 116 to oral iron). At 6 weeks, 94 (82%) participants in the intravenous iron group and 92 (79%) in the oral iron group were assessed for the primary outcome. 75 (80%) participants in the intravenous iron group and 47 (51%) in the oral iron group had normalised haemoglobin (odds ratio 4·65, 95% CI 2·33-9·27). There were two mild to moderate infusion-related adverse events; and five serious adverse events (three in the intravenous iron group, two in the oral iron group), unrelated to the study medication. Interpretation: Intravenous iron substitution with ferric carboxymaltose was safe and yielded a better haemoglobin response than oral iron. To our knowledge, this is the first study to provide evidence of the benefits and safety of intravenous iron substitution in a low-income setting

Design, Synthesis and Biological Evaluation of Novel Triazole N-acylhydrazone Hybrids for Alzheimer's Disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Aβ42 oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics

International cohort study for pediatric Behçet’s Disease: update 2011

PubMe

Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial

Background The administration of broadly neutralising anti-HIV-1 antibodies before latency reversal could facilitate elimination of HIV-1-infected CD4 T cells. We tested this concept by combining the broadly neutralising antibody 3BNC117 in combination with the latency-reversing agent romidepsin in people with HIV-1 who were taking suppressive antiretroviral therapy (ART). Methods We did a randomised, open-label, phase 2A trial at three university hospital centres in Denmark, Germany, and the USA. Eligible participants were virologically suppressed adults aged 18-65 years who were infected with HIV-1 and on ART for at least 18 months, with plasma HIV-1 RNA concentrations of less than 50 copies per mL for at least 12 months, and a CD4 T-cell count of greater than 500 cells per mu L. Participants were randomly assigned (1:1) to receive 3BNC117 plus romidepsin or romidepsin alone in two cycles. All participants received intravenous infusions of romidepsin (5 mg/m(2) given over 120 min) at weeks 0, 1, and 2 (treatment cycle 1) and weeks 8, 9, and 10 (treatment cycle 2). Those in the 3BNC117 plus romidepsin group received an intravenous infusion of 3BNC117 (30 mg/kg given over 60 min) 2 days before each treatment cycle. An analytic treatment interruption (ATI) of ART was done at week 24 in both groups. Our primary endpoint was time to viral rebound during analytic treatment interruption, which was assessed in all participants who completed both treatment cycles and ATI. We used a log-rank test to compare time to viral rebound during analytic treatment interruption between the two groups. This trial is registered with ClinicalTrials. gov, NCT02850016. It is closed to new participants, and all follow-up is complete. Findings Between March 20, 2017, and Aug 14, 2018, 22 people were enrolled and randomly assigned, 11 to the 3BNC117 plus romidepsin group and 11 to the romidepsin group. 19 participants completed both treatment cycles and the ATI: 11 in the 3BNC117 plus romidepsin group and 8 in the romidepsin group. The median time to viral rebound during ATI was 18 days (IQR 14-28) in the 3BNC117 plus romidepsin group and 28 days (21-35) in the romidepsin group B (p=0.0016). Although this difference was significant, prolongation of time to viral rebound was not clinically meaningful in either group. All participants in both groups reported adverse events, but overall the combination of 3BNC117 and romidepsin was safe. Two severe adverse events were observed in the romidepsin group during 48 weeks of follow-up, one of which-increased direct bilirubin-was judged to be related to treatment. Interpretation The combination of 3BNC117 and romidepsin was safe but did not delay viral rebound during analytic treatment interruptions in individuals on long-term ART. The results of our trial could serve as a benchmark for further optimisation of HIV-1 curative strategies among people with HIV-1 who are taking suppressive ART. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd

From Acting What’s next to Speeding Trap: Co-Evolutionary Dynamics of an Emerging Technology-Leader

JEL Classifications: O33, O53, L63[[abstract]]How does technological innovation emerge and evolve? We approach such an inquiry by synthesizing the perspectives of dynamic capabilities and co-evolutionary dynamics to portray organizational routines and multi-phase strategic renewals of an emerging technology-leader. To untangle the emergence of technological innovation, we conducted a longitudinal case study on the first and the largest dedicated semiconductor foundry, TSMC, located in the emerging economy of Taiwan. The firm-case of TSMC illustrates two unique co-evolutionary paths, that is, transforming from industry-latecomer to technology-leader and from process innovation to product innovation. We found multi-motor co-evolutionary dynamics between TSMC and the semiconductor industry, where its co-evolutionary mechanism of managed selection in its creating phase of mature process-innovation (1987-1998) has migrated to hierarchical renewal in its extending phase of advanced process-innovation (1999-2001), and then to holistic renewal in its modifying phase of product-innovation (2002-2007). During such paths, our research discovered a unique type of organizational routines, acting what’s next because TSMC has proactively searched for potential problems sooner than its competitors. However, such routines, although driving technological innovation, also lead to a unique type of success-trap, that is, speeding trap. When an emerging technology-leader fundamentally changes the industrial structures to over-specs, the growth driven by technology speeding may trap such a leader in a loop of over-exploration.[[sponsorship]]The authors are grateful to the research grant from the National Science Council (NSC) in Taiwan. The earlier manuscript of this paper was presented at the 2009 Annual Meeting of Academy of International Business (AIB) in San Diego, USA.[[notice]]補正完畢[[journaltype]]國外[[ispeerreviewed]]Y[[booktype]]紙本[[booktype]]電子版[[countrycodes]]CA

Design, synthesis, and biological evaluation of new thalidomide–donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation

A new series of eight multifunctional thalidomide–donepezil hybrids were synthesized based on the multi target-directed ligand strategy and evaluated as potential neuroprotective, cholinesterase inhibitors and anti neuroinflammatory agents against neurodegenerative diseases. A molecular hybridization approach was used for structural design by combining the N-benzylpiperidine pharmacophore of donepezil and the isoindoline 1,3-dione fragment from the thalidomide structure. The most promising compound, PQM-189 (3g), showed good AChE inhibitory activity with an IC50 value of 3.15 μM, which was predicted by docking studies as interacting with the enzyme in the same orientation observed in the AChE–donepezil complex and a similar profile of interaction. Additionally, compound 3g significantly decreased iNOS and IL-1β levels by 43% and 39%, respectively, after 24 h of incubation with lipopolysaccharide. In vivo data confirmed the ability of 3g to prevent locomotor impairment and changes in feeding behavior elicited by lipopolysaccharide. Moreover, the PAMPA assay evidenced adequate blood–brain barrier and gastrointestinal tract permeabilities with an Fa value of 69.8%. Altogether, these biological data suggest that compound 3g can treat the inflammatory process and oxidative stress resulting from the overexpression of iNOS and therefore the increase in reactive nitrogen species, and regulate the release of pro-inflammatory cytokines such as IL-1β. In this regard, compound PQM-189 (3g) was revealed to be a promising neuroprotective and anti-neuroinflammatory agent with an innovative thalidomide–donepezil-based hybrid molecular architectur

Quantification of uncertainties in global grazing systems assessments

Livestock systems play a key role in global sustainability challenges like food security and climate change, yet, many unknowns and large uncertainties prevail. We present a systematic, spatially explicit assessment of uncertainties related to grazing intensity (GI), a key metric for assessing ecological impacts of grazing, by combining existing datasets on a) grazing feed intake, b) the spatial distribution of livestock, c) the extent of grazing land, and d) its net primary productivity (NPP). An analysis of the resulting 96 maps implies that on average 15% of the grazing land NPP is consumed by livestock. GI is low in most of worlds grazing lands but hotspots of very high GI prevail in 1% of the total grazing area. The agreement between GI maps is good on one fifth of the world's grazing area, while on the remainder it is low to very low. Largest uncertainties are found in global drylands and where grazing land bears trees (e.g., the Amazon basin or the Taiga belt). In some regions like India or Western Europe massive uncertainties even result in GI > 100% estimates. Our sensitivity analysis indicates that the input-data for NPP, animal distribution and grazing area contribute about equally to the total variability in GI maps, while grazing feed intake is a less critical variable. We argue that a general improvement in quality of the available global level datasets is a precondition for improving the understanding of the role of livestock systems in the context of global environmental change or food security

Surgery for benign insulinoma: An international review

In a multiinstitutional review, data on 396 patients with benign solitary or multiple insulinomas operated on in 15 centers were collected. In these 396 patients, 419 laparotomies (375 primary procedures and 44 reoperations) were performed. The rate of unnecessary laparotomies was 1.7%. Complications occurred after 132 operations (31.5%), requiring 27 reinterventions (6.4%). Ten (2%) patients died within 30 days of surgery. The success rate of first procedures in the centers was 94.9%. After reoperation, all but 2 (99.5%) of these patients were cured. The overall cure rate including those patients who had their primary operations elsewhere was 97.5% . Compilant les dossiers de 15 établissements internationaux, nous avons colligé les données concernant 396 patients présentant un insulinome bénin unique ou multiple, opérés. Chez ces 396 patients, 419 laparotomies (375 interventions de première intention et 44 reprises) ont été effectuées. Le taux de laparotomie inutile était de 1.7%. Des complications sont intervenues à la suite de 132 opérations (31.5%), nécessitant 27 réinterventions (6.4%). Dix (2%) patients sont morts dans les trente jours après l'acte chirurgical. Le taux de succès des interventions de première intention dans les centres de l'étude était de 94.9%. Après réinterventions, tous les patients sauf 2 (99.5%) ont été guéris. Le taux global de guérison, y compris les patients ayant été opérés une première fois ailleurs, était de 97.5%. En una revisión multiinstitucional se recolectaron los datos sobre 396 pacientes con insulinomas benignos solitarios o múltiples operados en 15 centros. En estos 396 pacientes se efectuaron 419 laparotomías (375 procedimientos primarios y 44 reoperaciones). Se registró una tasa de laparotomías innecesarias de 1.7%; se presentaron complicaciones después de 132 operaciones (31.5%), las cuales requirieron 27 reintervenciones (6.4%). Diez (2%) pacientes murieron dentro de los primeras 30 días después de la cirugía. La tasa de éxito del procedimiento primario realizado en estos centros fue 94.9%. Después de las reoperaciones la totalidad de los pacientes, menos 2 (99.5%), fueron curados. La tasa global de curación, incluyendo los que tuvieron su operación primaria por fuera de los centros del estudio, fue 97.5%.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41289/1/268_2005_Article_BF01658536.pd