Glioblastoma (GBM) is the most common and aggressive primary brain tumor. To better understand how GBM evolves, we analyzed longitudinal genomic and transcriptomic data from 114 patients. The ...analysis shows a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern, together with estimates of evolutionary rate, suggests that relapse-associated clones typically existed years before diagnosis. Fifteen percent of tumors present hypermutation at relapse in highly expressed genes, with a clear mutational signature. We find that 11% of recurrence tumors harbor mutations in LTBP4, which encodes a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to suppression of TGF-β activity and decreased cell proliferation. In recurrent GBM with wild-type IDH1, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM.
This paper reports a simple, one-pot, template-free synthesis of flower-like Au nanoparticles (three-dimensional branched nanoparticles with more than 10 tips) with high yield and good size ...monodispersity at room temperature. The size of the Au nanoflowers could be tuned by controlling the composition of the starting reaction mixture. The key synthesis strategy was to use a common Good’s buffer, HEPES, as a weak reducing and particle stabilizing agent to confine the growth of the Au nanocrystals in the special reaction region of limited ligand protection (LLP). Time-course measurements by UV−vis spectroscopy and TEM were used to follow the reaction progress and the evolution of the flower-like shape. The Au nanoflowers exhibited strong surface-enhanced effects which were utilized in the design of an efficient, stable, and nontoxic Raman-active tag for in vivo applications.
Peptides are multifunctional reagents (reducing and capping agents) that can be used for the synthesis of biocompatible metal nanoparticles under relatively mild conditions. However, the progress in ...peptide synthesis of metal nanoparticles has been slow due to the lack of peptide design rules. It is difficult to establish sequence−reactivity relationships from peptides isolated from biological sources (e.g., biomineralizing organisms) or selected by combinatorial display libraries because of their widely varying compositions and structures. The abundance of random and inactive amino acid sequences in the peptides also increases the difficulty in knowledge extraction. In this study, a “bottom-up” approach was used to formulate a set of rudimentary rules for the size- and shape-controlled peptide synthesis of gold nanoparticles from the properties of the 20 natural α-amino acids for AuCl4 − reduction and binding to Au0. It was discovered that the reduction capability of a peptide depends on the presence of certain reducing amino acid residues, whose activity may be regulated by neighboring residues with different Au0 binding strengths. Another finding is the effect of peptide net charge on the nucleation and growth of the Au nanoparticles. On the basis of these understandings, several multifunctional peptides were designed to synthesize gold nanoparticles in different morphologies (nanospheres and nanoplates) and with sizes tunable by the strategic placement of selected amino acid residues in the peptide sequence. The methodology presented here and the findings are useful for establishing the scientific basis for the rational design of peptides for the synthesis of metal nanostructures.
Abstract
Introduction
Noncombat injuries (“injuries”) greatly impact soldier health and United States (U.S.) Army readiness; they are the leading cause of outpatient medical encounters (more than two ...million annually) among active component (AC) soldiers. Noncombat musculoskeletal injuries (“MSKIs”) may account for nearly 60% of soldiers’ limited duty days and 65% of soldiers who cannot deploy for medical reasons. Injuries primarily affect readiness through increased limited duty days, decreased deployability rates, and increased medical separation rates. MSKIs are also responsible for exorbitant medical costs to the U.S. government, including service-connected disability compensation. A significant subset of soldiers develops chronic pain or long-term disability after injury; this may increase their risk for chronic disease or secondary health deficits potentially associated with MSKIs. The authors will review trends in U.S. Army MSKI rates, summarize MSKI readiness-related impacts, and highlight the importance of standardizing surveillance approaches, including injury definitions used in injury surveillance.
Materials/Methods
This review summarizes current reports and U.S. Department of Defense internal policy documents. MSKIs are defined as musculoskeletal disorders resulting from mechanical energy transfer, including traumatic and overuse injuries, which may cause pain and/or limit function. This review focuses on various U.S. Army populations, based on setting, sex, and age; the review excludes combat or battle injuries.
Results
More than half of all AC soldiers sustained at least one injury (MSKI or non-MSKI) in 2017. Overuse injuries comprise at least 70% of all injuries among AC soldiers. Female soldiers are at greater risk for MSKI than men. Female soldiers’ aerobic and muscular fitness performances are typically lower than men’s performances, which could account for their higher injury rates. Older soldiers are at greater injury risk than younger soldiers. Soldiers in noncombat arms units tend to have higher incidences of reported MSKIs, more limited duty days, and higher rates of limited duty days for chronic MSKIs than soldiers in combat arms units. MSKIs account for 65% of medically nondeployable AC soldiers. At any time, 4% of AC soldiers cannot deploy because of MSKIs. Once deployed, nonbattle injuries accounted for approximately 30% of all medical evacuations, and were the largest category of soldier evacuations from both recent major combat theaters (Iraq and Afghanistan). More than 85% of service members medically evacuated for MSKIs failed to return to the theater. MSKIs factored into (1) nearly 70% of medical disability discharges across the Army from 2011 through 2016 and (2) more than 90% of disability discharges within enlisted soldiers’ first year of service from 2010 to 2015. MSKI-related, service-connected (SC) disabilities account for 44% of all SC disabilities (more than any other body system) among compensated U.S. Global War on Terrorism veterans.
Conclusions
MSKIs significantly impact soldier health and U.S. Army readiness. MSKIs also figure prominently in medical disability discharges and long-term, service-connected disability costs. MSKI patterns and trends vary between trainees and soldiers in operational units and among military occupations and types of operational units. Coordinated injury surveillance efforts are needed to provide standardized metrics and accurately measure temporal changes in injury rates.
This paper describes the synthesis of single-crystalline Ag nanoplates using the extract of unicellular green alga Chlorella vulgaris at room temperature. Proteins in the extract were involved in the ...biological synthesis, providing the dual function of Ag ion reduction and shape-controlled synthesis of nanosilver. Hydroxyl groups in Tyr residues and carboxyl groups in Asp and/or Glu residues were further identified as the most active functional groups for Ag ion reduction and for directing the anisotropic growth of Ag nanoplates, respectively. The kinetics of Ag ion reduction in biological systems was discussed and probed by using custom-designed peptides. The results showed the Tyr content (the reduction source) and the content of Ag complexers (the reaction inhibitors, e.g., His and Cys) in the protein molecules as important factors affecting the reduction kinetics. The comprehensive system identification effort has led to the design of a simple bifunctional tripeptide (DDY-OMe) with one Tyr residue as the reduction source and two carboxyl groups in the Asp residues as shape-directors, which could produce small Ag nanoplates with low polydispersivity in good yield (>55%). The roles of the carboxyl groups in the formation of Ag nanoplates were also discussed.
In this work, single‐crystalline gold nanoplates were produced by treating an aqueous solution of chloroauric acid with the extract of the unicellular green alga Chlorella vulgaris at room ...temperature. The results suggest proteins as the primary biomolecules involved in providing the dual function of AuIII reduction and the size‐ and shape‐controlled synthesis of the nanogold crystals. A protein with a molecular weight of approximately 28 kDa was isolated and purified by reversed‐phase HPLC; this protein tested positive for the reduction of chloroauric acid in aqueous solution. The isolated protein (named gold shape‐directing protein, or GSP for convenience) was then used to produce gold nanoplates with distinctive triangular and hexagonal shapes in high yields (≈90 %). The kinetics of the reduction reaction could be manipulated through changes in the GSP concentration to produce plates with lateral sizes ranging from nanometers to micrometers. The growth of gold nanoplates in the GSP solution with time was monitored by microscopic and spectroscopic techniques, thereby allowing the detection of several key intermediates in the growth process.
A protein to make plates: The active biomolecules in the algal synthesis of gold nanoplates have been identified. A protein with a molecular weight of approximately 28 kDa was isolated and purified and it was found to possess both reduction and shape‐directing functionalities. The protein could be used to produce plates with lateral sizes ranging from nanometers to micrometers (see image).
Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.
Patients were enrolled after ...they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding.
A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 95% confidence interval {CI}, 0.17 to 0.48; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 95% CI, 0.59 to 0.85; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 95% CI, 1.00 to 1.85; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.
Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.).
In this work, three-dimensional branched gold nanocrystals were produced at high yield by reacting an aqueous solution of chloroauric acid with a Good's buffer, HEPES, at room temperature. This ...particular method of preparation was scalable to gram-quantity. The branched nanocrystals containing one to eight tips were stable at room temperature and could be stored as a powder after freeze-drying. They were, however, unstable at higher temperatures and transformed into spherical particles upon boiling. The formation of the branched gold nanocrystals was kinetically controlled, as shown by the dependence of shapes on temperature and precursor salt concentration. The growth of branched gold nanocrystals in the HEPES buffer was monitored by microscopic and spectroscopic techniques, allowing the detection of several key intermediates in the growth process. Piperazine in HEPES molecule was identified as the principal moiety responsible for forming highly branched Au nanocrystals in the HEPES buffer.
Postoperative delirium occurs in 10% to 60% of elderly patients having major surgery and is associated with longer hospital stays, increased hospital costs, and 1-year mortality. Emerging literature ...suggests that dexmedetomidine sedation in critical care units is associated with reduced incidence of delirium. However, intraoperative use of dexmedetomidine for prevention of delirium has not been well studied.
To evaluate whether an intraoperative infusion of dexmedetomidine reduces postoperative delirium.
This study was a multicenter, double-blind, randomized, placebo-controlled trial that randomly assigned patients to dexmedetomidine or saline placebo infused during surgery and for 2 hours in the recovery room. Patients were assessed daily for postoperative delirium (primary outcome) and secondarily for postoperative cognitive decline. Participants were elderly (>68 years) patients undergoing major elective noncardiac surgery. The study dates were February 2008 to May 2014.
Dexmedetomidine infusion (0.5 µg/kg/h) during surgery and up to 2 hours in the recovery room.
The primary hypothesis tested was that intraoperative dexmedetomidine administration would reduce postoperative delirium. Secondarily, the study examined the correlation between dexmedetomidine use and postoperative cognitive change.
In total, 404 patients were randomized; 390 completed in-hospital delirium assessments (median interquartile range age, 74.0 71.0-78.0 years; 51.3% 200 of 390 female). There was no difference in postoperative delirium between the dexmedetomidine and placebo groups (12.2% 23 of 189 vs 11.4% 23 of 201, P = .94). After adjustment for age and educational level, there was no difference in the postoperative cognitive performance between treatment groups at 3 months and 6 months. Adverse events were comparably distributed in the treatment groups.
Intraoperative dexmedetomidine does not prevent postoperative delirium. The reduction in delirium previously demonstrated in numerous surgical intensive care unit studies was not observed, which underscores the importance of timing when administering the drug to prevent delirium.
clinicaltrials.gov Identifier NCT00561678.
Disruptive selection is often assumed to be relatively rare, because it is dynamically unstable and hence should be transient. However, frequency‐dependent interactions such as intraspecific ...competition may stabilize fitness minima and make disruptive selection more common. Such selection helps explain the maintenance of genetic variation and may even contribute to sympatric speciation. There is thus great interest in determining when and where disruptive selection is most likely. Here, we show that there is a general trend toward weak disruptive selection on trophic morphology in three‐spine stickleback (Gasterosteus aculeatus) in 14 lakes on Vancouver Island. Selection is inferred from the observation that, within a lake, fish with intermediate gill raker morphology exhibited slower growth than phenotypically extreme individuals. Such selection has previously been shown to arise from intraspecific competition for alternate resources. However, not all environments are equally conducive to disruptive selection, which was strongest in intermediate‐sized lakes where both littoral and pelagic prey are roughly balanced. Also, consistent with theory, we find that sexual dimorphism in trophic traits tends to mitigate disruptive selection. These results suggest that it may be possible to anticipate the kinds of environments and populations most likely to experience disruptive selection.
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