Data are inadequate to test whale falls as chemosynthetic stepping-stones using network analysis: faunal overlaps do support a stepping-stone role

© 2017 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited

Enhancing the kinetics of hydrazone exchange processes: an experimental and computational study

The capacity of hydrazone bonds to readily undergo component exchange processes sees their extensive utilization in dynamic combinatorial chemistry. The kinetics of hydrazone exchange are optimal at pH ∼4.5, which limits the use of hydrazone-based dynamic combinatorial libraries, particularly for biological targets which are only stable at near-neutral pH values. It would thus be advantageous if hydrazone exchange proceeded with faster rates at pH values closer to neutral. We experimentally and computationally evaluated the hypothesis that hydrazones possessing neighbouring acidic or basic functional groups within the carbonyl-derived moitety of the hydrazone would enhance exchange rates. Our work suggests that judiciously placed N- or O-hydrogen bond acceptors within the carbonyl-derived moiety of the hydrazone stabilize transition states via hydrogen bonding interactions, providing a valuable boost to exchange kinetics at near-neutral pH values. We anticipate these findings will be of interest in dynamic combinatorial chemistry, dynamic covalent polymers/materials, functionalized nanoparticles and interlocked molecules, all of which may benefit from hydrazone exchange processes able to operate at near-neutral pH values

Constraining parameter space in type-II two-Higgs doublet model in light of a 126 GeV Higgs boson

We explore the implications of a 126 GeV Higgs boson indicated by the recent LHC results for two-Higgs doublet model (2HDM). Identifying the 126 GeV Higgs boson as either the lighter or heavier of CP even neutral Higgs bosons in 2HDM, we examine how the masses of Higgs fields and mixing parameters can be constrained by the theoretical conditions and experimental constraints. The theoretical conditions taken into account are the vacuum stability, perturbativity and unitarity required to be satisfied up to a cut-off scale. We also show how bounds on the masses of Higgs bosons and mixing parameters depend on the cut-off scale. In addition, we investigate whether the allowed regions of parameter space can accommodate particularly the enhanced di-photon signals, ZZ* and WW* decay modes of the Higgs boson, and examine the prediction of the signal strength of Z{\gamma} decay mode for the allowed regions of the parameter space.Comment: To be published in JHEP, 20 pages, 11 figures, Figures and results are updated for the recent LHC result

Episodic Memory and Appetite Regulation in Humans

Psychological and neurobiological evidence implicates hippocampal-dependent memory processes in the control of hunger and food intake. In humans, these have been revealed in the hyperphagia that is associated with amnesia. However, it remains unclear whether 'memory for recent eating' plays a significant role in neurologically intact humans. In this study we isolated the extent to which memory for a recently consumed meal influences hunger and fullness over a three-hour period. Before lunch, half of our volunteers were shown 300 ml of soup and half were shown 500 ml. Orthogonal to this, half consumed 300 ml and half consumed 500 ml. This process yielded four separate groups (25 volunteers in each). Independent manipulation of the 'actual' and 'perceived' soup portion was achieved using a computer-controlled peristaltic pump. This was designed to either refill or draw soup from a soup bowl in a covert manner. Immediately after lunch, self-reported hunger was influenced by the actual and not the perceived amount of soup consumed. However, two and three hours after meal termination this pattern was reversed - hunger was predicted by the perceived amount and not the actual amount. Participants who thought they had consumed the larger 500-ml portion reported significantly less hunger. This was also associated with an increase in the 'expected satiation' of the soup 24-hours later. For the first time, this manipulation exposes the independent and important contribution of memory processes to satiety. Opportunities exist to capitalise on this finding to reduce energy intake in humans

Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3)

BACKGROUND/AIMS: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. METHODS: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. RESULTS: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak

Long-term results of diaphragmatic plication in adults with unilateral diaphragm paralysis

<p>Abstract</p> <p>Background</p> <p>In this study we aimed to evaluate the long-term outcome of diaphragmatic plication for symptomatic unilateral diaphragm paralysis.</p> <p>Methods</p> <p>Thirteen patients who underwent unilateral diaphragmatic plication (2 patients had right, 11 left plication) between January 2003 and December 2006 were evaluated. One patient died postoperatively due to sepsis. The remaining 12 patients [9 males, 3 females; mean age 60 (36-66) years] were reevaluated with chest radiography, flouroscopy or ultrasonography, pulmonary function tests, computed tomography (CT) or magnetic resonance imaging (MRI), and the MRC/ATS dyspnea score at an average of 5.4 (4-7) years after diaphragmatic plication.</p> <p>Results</p> <p>The etiology of paralysis was trauma (9 patients), cardiac by pass surgery (3 patients), and idiopathic (1 patient). The principle symptom was progressive dyspnea with a mean duration of 32.9 (22-60) months before surgery. All patients had an elevated hemidiaphragm and paradoxical movement radiologically prior to surgery. There were partial atelectasis and reccurent infection of the lower lobe in the affected side on CT in 9 patients. Atelectasis was completely improved in 9 patients after plication. Preoperative spirometry showed a clear restrictive pattern. Mean preoperative FVC was 56.7 ± 11.6% and FEV1 65.3 ± 8.7%. FVC and FEV1 improved by 43.6 ± 30.6% (p < 0.001) and 27.3 ± 10.9% (p < 0.001) at late follow-up. MRC/ATS dyspnea scores improved 3 points in 11 patients and 1 point in 1 patient at long-term (p < 0.0001). Eight patients had returned to work at 3 months after surgery.</p> <p>Conclusions</p> <p>Diaphragmatic plication for unilateral diaphragm paralysis decreases lung compression, ensures remission of symptoms, and improves quality of life in long-term period.</p

Lessons from an international trial evaluating vaccination strategies for recovered inpatients with COVID-19 (VATICO)

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus

Laparoscopic sacrocolpopexy with bone anchor fixation: short-term anatomic and functional results

Contains fulltext : 108485.pdf (publisher's version ) (Open Access)INTRODUCTION AND HYPOTHESIS: The aim of this study was to evaluate short-term anatomic and functional outcomes and safety of laparoscopic sacrocolpopexy with bone anchor fixation. METHODS: A prospective cohort study of women undergoing laparoscopic sacrocolpopexy between 2004 and 2009. Anatomic outcome was assessed using the pelvic organ prolapse quantification score (POP-Q). Functional outcomes were assessed using the Urogenital Distress Inventory, Defecatory Distress Inventory, and the Incontinence Impact Questionnaire preoperatively and at 6 months postoperatively. The Wilcoxon signed rank test was used to test differences between related samples. RESULTS: Forty-nine women underwent laparoscopic sacrocolpopexy. The objective success rate in the apical compartment was 98%, subjective success rate was 79%. One mesh exposure (2%) was found. One conversion was necessary due to injury to the ileum. CONCLUSIONS: Laparoscopic sacrocolpopexy with bone anchor fixation is a safe and efficacious treatment for apical compartment prolapse. It provides excellent apical support and good functional outcome 6 months postoperatively.1 april 201

The Potent Respiratory System of Osedax mucofloris (Siboglinidae, Annelida) - A Prerequisite for the Origin of Bone-Eating Osedax?

Members of the conspicuous bone-eating genus, Osedax, are widely distributed on whale falls in the Pacific and Atlantic Oceans. These gutless annelids contain endosymbiotic heterotrophic bacteria in a branching root system embedded in the bones of vertebrates, whereas a trunk and anterior palps extend into the surrounding water. The unique life style within a bone environment is challenged by the high bacterial activity on, and within, the bone matrix possibly causing O2 depletion, and build-up of potentially toxic sulphide. We measured the O2 distribution around embedded Osedax and showed that the bone microenvironment is anoxic. Morphological studies showed that ventilation mechanisms in Osedax are restricted to the anterior palps, which are optimized for high O2 uptake by possessing a large surface area, large surface to volume ratio, and short diffusion distances. The blood vascular system comprises large vessels in the trunk, which facilitate an ample supply of oxygenated blood from the anterior crown to a highly vascularised root structure. Respirometry studies of O. mucofloris showed a high O2 consumption that exceeded the average O2 consumption of a broad line of resting annelids without endosymbionts. We regard this combination of features of the respiratory system of O. mucofloris as an adaptation to their unique nutrition strategy with roots embedded in anoxic bones and elevated O2 demand due to aerobic heterotrophic endosymbionts

Crystal Structure of the Formin mDia1 in Autoinhibited Conformation

Formin proteins utilize a conserved formin homology 2 (FH2) domain to nucleate new actin filaments. In mammalian diaphanous-related formins (DRFs) the FH2 domain is inhibited through an unknown mechanism by intramolecular binding of the diaphanous autoinhibitory domain (DAD) and the diaphanous inhibitory domain (DID).Here we report the crystal structure of a complex between DID and FH2-DAD fragments of the mammalian DRF, mDia1 (mammalian diaphanous 1 also called Drf1 or p140mDia). The structure shows a tetrameric configuration (4 FH2 + 4 DID) in which the actin-binding sites on the FH2 domain are sterically occluded. However biochemical data suggest the full-length mDia1 is a dimer in solution (2 FH2 + 2 DID). Based on the crystal structure, we have generated possible dimer models and found that architectures of all of these models are incompatible with binding to actin filament but not to actin monomer. Furthermore, we show that the minimal functional monomeric unit in the FH2 domain, termed the bridge element, can be inhibited by isolated monomeric DID. NMR data on the bridge-DID system revealed that at least one of the two actin-binding sites on the bridge element is accessible to actin monomer in the inhibited state.Our findings suggest that autoinhibition in the native DRF dimer involves steric hindrance with the actin filament. Although the structure of a full-length DRF would be required for clarification of the presented models, our work here provides the first structural insights into the mechanism of the DRF autoinhibition