Patient and physician predictors of hyperlipidemia screening and statin prescription.
Appropriate lipid management has been demonstrated to reduce cardiovascular events, but rates of hyperlipidemia screening and statin therapy are suboptimal. We aimed to evaluate patient and physician predictors of guideline-concordant hyperlipidemia screening and statin prescription. Retrospective study of patients with primary care provider (PCP) visits from 2014 to 2016 at the University of Pennsylvania Health System. Data on patients, screening orders, and prescriptions were obtained from the electronic health record. Multivariate logistic regression models were fit to binary outcomes of lipid screening and statin prescription. Among 97,189 eligible patients, 79.9% had an order for hyperlipidemia screening. In adjusted models, significant patient predictors of greater odds of having screening ordered included a history of diabetes (odds ratio [OR], 1.19; 95% CI, 1.10-1.29; P <.001) or hypertension (OR, 1.16; 95% CI, 1.10-1.23; P <.001). Significant provider predictors of lower odds of having screening ordered were being a resident PCP (OR, 0.63; 95% CI, 0.43-0.93; P = .021) or being trained in family medicine (OR, 0.37; 95% CI, 0.30-0.47; P <.001). Among 40,845 eligible patients, 56.1% were prescribed a statin. In adjusted models, significant patient predictors of greater odds of being prescribed a statin were if they had a history of diabetes (OR, 2.70; 95% CI, 2.32-3.13; P <.001) or clinical cardiovascular disease (OR, 2.26; 95% CI, 1.85-2.76; P <.001). Significant provider predictors of lower odds of being prescribed a statin were being a physician assistant (OR, 0.65; 95% CI, 0.52-0.81; P <.001) or female (OR, 0.82; 95% CI, 0.70-0.96; P = .01). Both patient and provider factors significantly predicted guideline-concordant care for hyperlipidemia screening and statin therapy.


Can early endoscopic ultrasound predict pancreatic necrosis in acute pancreatitis?
Presence of pancreatic/extrapancreatic necroses (PN/EPN) is an important prognostic indicator in acute pancreatitis (AP) and their early detection is a challenge. Endoscopic ultrasound (EUS) provides high resolution images of pancreas but there is paucity of data on its role in AP. Consecutive patients with AP seen at our center from December 2012-November 2013 and presenting within 5 days of onset of symptoms were prospectively enrolled. EUS was done on the day of admission with a radial echoendoscope and pancreatic/peripancreatic findings were compared with the abdominal computed tomography (CT) findings performed on day 7. Of the 46 patients evaluated, 14 were excluded, and 32 patients (22 male; age 40.68±12.46 years) underwent EUS at admission. The etiology of AP was alcohol in 16, gallstones in 13, and idiopathic in 3 patients. Necrotizing pancreatitis was present in 20 (62%) patients, and mean CT severity index was 6.45±2.96. In patients without PN (n=12), EUS revealed normal echo pattern in 6 patients and diffusely hyperechoic and enlarged pancreas in 6 patients. In patients with PN/EPN, EUS revealed multiple hypoechoic areas (>5 mm) in 5 patients, multiple hyperechoic areas (>5 mm) in 7 patients and mixed hypo and hyperechoic areas in 8 patients. Also, 13 of these patients had peripancreatic hypoechoic areas that correlated with EPN. Moreover, EUS detected common bile duct (CBD) stones in two patients, pleural effusion in 17 patients, and ascites in 15 patients. EUS done at admission can reliably detect PN and co-existent disorders like CBD stones.


Topical silicone gel for the prevention and treatment of hypertrophic scar.
We studied the effects of a silicone gel bandage that was worn for at least 12 hours daily on the resolution of hypertrophic burn scar. In a second cohort, the prevention of hypertrophic scar formation in fresh surgical incisions by this bandage was also evaluated. In 19 patients with hypertrophic burn scars, elasticity of the scars was quantitated serially with the use of an elastometer. An adjacent or mirror-image hypertrophic burn scar served as a control. Scar elasticity was increased after both 1 and 2 months compared with that in controls. There was corresponding improvement clinically that persisted for at least 6 months. In the other cohort, scar volume changes in 21 surgical incisions were measured before and after 1 and 2 months. Gel-treated incisions gained less volume than control incisions after both intervals. Clinical assessment corroborated this quantitative demonstration of a decrement in scar volume. We concluded that topical silicone gel is efficacious, both in the prevention and in the treatment of hypertrophic scar.


Metabolic acidosis and strong ion gap in critically ill patients with acute kidney injury.
To determine the influence of physicochemical parameters on survival in metabolic acidosis (MA) and acute kidney injury (AKI) patients. Seventy-eight MA patients were collected and assigned to AKI or non-AKI group. We analyzed the physiochemical parameters on survival at 24 h, 72 h, 1 week, 1 month, and 3 months after AKI. Mortality rate was higher in the AKI group. AKI group had higher anion gap (AG), strong ion gap (SIG), and apparent strong ion difference (SIDa) values than non-AKI group. SIG value was higher in the AKI survivors than nonsurvivors and this value was correlated serum creatinine, phosphate, albumin, and chloride levels. SIG and serum albumin are negatively correlated with Acute Physiology and Chronic Health Evaluation IV scores. AG was associated with mortality at 1 and 3 months post-AKI, whereas SIG value was associated with mortality at 24 h, 72 h, 1 week, 1 month, and 3 months post-AKI. Whether high or low SIG values correlate with mortality in MA patients with AKI depends on its correlation with serum creatinine, chloride, albumin, and phosphate (P) levels. AG predicts short-term mortality and SIG value predicts both short- and long-term mortality among MA patients with AKI.


Engaging Physician Learners Through a Web-Based Platform: Individualized End-of-Life Education.
Web-based modules provide a convenient and low-cost education platform, yet should be carefully designed to ensure that learners are actively engaged. In order to improve attitudes and knowledge in end-of-life (EOL) care, we developed a web-based educational module that employed hyperlinks to allow users access to auxiliary resources: clinical guidelines and seminal research papers. Participants took pre-test evaluations of attitudes and knowledge regarding EOL care prior to accessing the educational module, and a post-test evaluation following the module intervention. We recorded the type of hyperlinks (guideline or paper) accessed by learners, and stratified participants into groups based on link type accessed (none, either, or both). We used demographic and educational data to develop a multivariate mixed-effects regression analysis to develop adjusted predictions of attitudes and knowledge. 114 individuals participated. The majority had some professional exposure to EOL care (prior instruction 62%; EOL referral 53%; EOL discussion 56%), though most had no family (68%) or personal experience (51%). On bivariate analysis, non-partnered (p = .04), medical student training level (p = .03), prior palliative care referral (p = .02), having a family member (p = .02) and personal experience of EOL care (p < .01) were all associated with linking to auxiliary resources via hyperlinks. When adjusting for confounders, β coefficient estimates and least squares estimation demonstrated that participants clicking on both hyperlink types were more likely to score higher on all knowledge and attitude items, and demonstrate increased score improvements. Auxiliary resources accessible by hyperlink are an effective adjunct to web-based learning in end-of-life care.


Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC).
In many cancers, including non-small cell lung cancer (NSCLC), tumor angiogenesis pathways have been identified as important therapeutic targets. Angiogenesis is essential in the process of primary tumor growth, proliferation and metastasis. One of the best characterized group of protein factors for angiogenesis include the members of the vascular endothelial growth factor (VEGF) family, consisting of VEGF-(A-D), and placenta growth factor (PIGF). Targeting tumor angiogenesis has been approached through two primary methods, monoclonal antibodies that block VEGF-vascular endothelial growth factor receptor (VEGFR) binding or small molecule tyrosine kinase inhibitors (TKIs) that inhibit the downstream VEGFR mediated signaling. Many TKIs inhibit multiple pro-angiogenic and pro-proliferative pathways such as the mitogen activated protein (MAP) kinase pathway. Bevacizumab and ramucirumab, monoclonal antibodies targeting VEGF and the VEGFR, respectively, have each led to improvements in overall survival (OS) for NSCLC when added to standard first and second line chemotherapy, respectively. Small incremental gains seen with both bevacizumab and ramucirumab may be further improved upon by incorporating novel agents and treatment strategies, and many additional trials are ongoing.


An FPGA Accelerator for High-Speed Moving Objects Detection and Tracking With a Spike Camera.
Ultra-high-speed object detection and tracking are crucial in fields such as fault detection and scientific observation. Existing solutions to this task have deficiencies in processing speeds. To deal with this difficulty, we propose a neural-inspired ultra-high-speed moving object filtering, detection, and tracking scheme, as well as a corresponding accelerator based on a high-speed spike camera. We parallelize the filtering module and divide the detection module to accelerate the algorithm and balance latency among modules for the benefit of the task-level pipeline. To be specific, a block-based parallel computation model is proposed to accelerate the filtering module, and the detection module is accelerated by a parallel connected component labeling algorithm modeling spike sparsity and spatial connectivity of moving objects with a searching tree. The hardware optimizations include processing the LIF layer with a group of multiplexers to reduce ADD operations and replacing expensive exponential operations with multiplications of preprocessed fixed-point values to increase processing speed and minimize resource consumption. We design an accelerator with the above techniques, achieving 19 times acceleration over the serial version after 25-way parallelization. A processing system for the accelerator is also implemented on the Xilinx ZCU-102 board to validate its functionality and performance. Our accelerator can process more than 20,000 spike images with 250 × 400 resolution per second with 1.618 W dynamic power consumption.


Vasoactive intestinal peptide-like immunoreactive nerve fibers in the pineal gland of the sheep.
Vasoactive intestinal peptide (VIP)-like immunoreactive nerve fibers were demonstrated by peroxidase antiperoxidase (PAP) immunohistochemistry to be distributed throughout the entire pineal gland of the sheep. VIP-containing fibers were observed along the blood vessels, penetrating into the gland from the pial capsule and also in the capsule itself. Some fibers left the perivascular position and entered the pineal parenchyma, where they were located among pinealocytes. This suggested that the VIPergic fibers might influence both pinealocytes and blood vessels of the gland. The location of VIP-containing fibers in the capsule of the pineal gland indicates that the fibers originate from perikarya located in a peripheral ganglion.


The effect of fourth-generation fluoroquinolones gatifloxacin and moxifloxacin on epithelial healing following photorefractive keratectomy.
To compare the rate of epithelial healing following photorefractive keratectomy (PRK) with two commercially available fourth-generation fluoroquinolones, gatifloxacin (Zymar, Allergan, Irvine, California) and moxifloxacin (Vigamox, Alcon Laboratories, Fort Worth, Texas). Double-masked, randomized, prospective trial. Thirty-five subjects received gatifloxacin in one eye and moxifloxacin in the fellow eye following PRK with a 9.0-mm epithelial defect. Patients were examined daily after surgery until the epithelium had healed completely in both eyes. Beginning on post-operative day 3, photos were taken and used to confirm epithelial healing or measure the area of residual epithelial defects. Healing times and defect sizes were compared using the Wilcoxon signed-ranks test. Both eyes healed on the same day in 18 of the 35 subjects (51.4%). In 13 of 35 (37.1%) subjects, the moxifloxacin-treated eye healed first, compared with only four of 35 (11.4%) subjects whose gatifloxacin-treated eye healed first. All six of the eyes that took 2 days longer than their fellow eye to heal were gatifloxacin-treated. Median healing time for both groups was 4 days (moxifloxacin range: 3 to 7 days; gatifloxacin range: 3 to 9 days; P = .01), but only 69% of gatifloxacin-treated eyes had healed by day 4 compared with 80% of the moxifloxacin-treated eyes. Overall, on each post-operative day, defect sizes were greater for the gatifloxacin-treated eyes. This difference was statistically significant on day 4 (P = .027). Eyes treated with moxifloxacin healed faster and had smaller defects compared with those treated with gatifloxacin. This provides another factor to consider in selecting antibiotic prophylaxis for corneal refractive surgery.


Timing of improvement after carpal tunnel release.
This prospective study of 52 patients from the authors' institutional carpal tunnel database investigated which patient subpopulations were most likely to benefit from carpal tunnel release and documented the time course of recovery. Preoperatively and postoperatively at 6 and 12 months, patients completed a Levine-Katz questionnaire, and NC-Stat studies and clinical parameters were recorded by a certified occupational therapist. For individual parameters from preoperative to 6 months postoperative, statistical improvements were found in Tinel's and Phalen's signs, pinch strength, delayed motor latency, and symptom severity and functional scores. None of these parameters changed significantly from 6 to 12 months. Grip strength did not change significantly postoperatively. Analysis based on age or carpal tunnel release technique showed no differences postoperatively. Preoperative symptom and functional scores correlated statistically with postoperative scores, peaking at 6 months postoperatively. The study concluded that most clinical signs and symptoms of carpal tunnel release fail to improve after 6 months postoperatively.


Association Between Match Activity, Endurance Levels and Maturity in Youth Football Players.
The aim of the study was to examine the associations between maximal and submaximal field tests with match physical activity and biological maturation in youth football players. Sixty-eight youth football players (U14, U15, U16, U17) performed maximal and submaximal field endurance tests. Biological maturity was estimated calculating the distance from peak height velocity (Y-PHV). Physical match activities were tracked using GPS units and players' post-match rate of perceived exertion (RPE) was recorded. Mainly moderate associations were found between field tests and match activities. Large correlations were found between Yo-Yo Intermittent Recovery test level 1, distance covered at high and very high-speed running, the quantity of very high and maximal metabolic power running. Small to moderate associations between match activities and Y-PHV were observed. The magnitude of correlation between match activities and field tests increased from moderate to large when matches with an RPE>5 were considered. The results provide further evidence of the association between young football players' aerobic performance and match work rate. Submaximal field tests demonstrate ecological validity and may constitute a practical alternative to performing maximal tests. Maturation was found to have a moderate effect on youth players' match work rate.


Time-of-flight secondary ion mass spectrometry-based molecular distribution distinguishing healthy and osteoarthritic human cartilage.
Osteoarthritis (OA) is a pathology that ultimately causes joint destruction. The cartilage is one of the principal affected tissues. Alterations in the lipid mediators and an imbalance in the metabolism of cells that form the cartilage (chondrocytes) have been described as contributors to the OA development. In this study, we have studied the distribution of lipids and chemical elements in healthy and OA human cartilage. Time of flight-secondary ion mass spectrometry (TOF-SIMS) allows us to study the spatial distribution of molecules at a high resolution on a tissue section. TOF-SIMS revealed a specific peak profile that distinguishes healthy from OA cartilages. The spatial distribution of cholesterol-related peaks exhibited a remarkable difference between healthy and OA cartilages. A distinctive colocalization of cholesterol and other lipids in the superficial area of the cartilage was found. A higher intensity of oleic acid and other fatty acids in the OA cartilages exhibited a similar localization. On the other hand, CN(-) was observed with a higher intensity in the healthy samples. Finally, we observed an accumulation of calcium and phosphate ions exclusively in areas surrounding the chondrocyte in OA tissues. To our knowledge, this is the first time that TOF-SIMS revealed combined changes in the molecular distribution in the OA human cartilage.


Low Molecular Weight Heparin: An Evaluation of Current and Potential Clinical Utility in Surgery.
Heparin, a mixture of glycosaminoglycans of various sizes, is a potent natural anticoagulant. Low molecular weight heparins (LMWH) contain only the polymers of smaller size, which appear to possess most of the antithrombotic potential. Pharmacological differences between the two suggest a number of advantages with LMWH therapy. Our objective was to establish the utility of LMWHs in comparison to the current practice of anticoagulation in surgical patients. Articles were obtained through MEDLINE and CURRENT CONTENTS queries. The searches were limited to English and French-language articles and included published overviews containing relevant individual trials. We examined the current literature, consisting of 1,730 published reports from 1979-1998, regarding the biochemistry, pharmacology, physiology, and clinical applications of LMWH in comparison with current therapy. Studies were selected based on their relevance to LMWHs, the size and methods of trials, and their application to clinical care. Peer-reviewed published data were critically evaluated by independent extraction by several authors. Established rules for levels of evidence were used to objectively evaluate the strength of evidence supporting recommendations in each clinical area. LMWHs provide superior anticoagulation in the prophylaxis of DVT following orthopedic, general, and trauma surgery. Further studies should establish which other patients may benefit from such prophylaxis. Current evidence does not support the use of LMWHs in patients with mechanical heart valves or those on mechanical cardiac support devices; however, it may have a role in the maintenance of vascular graft patency. Further studies should examine the role of LMWHs in transplant atherosclerosis, and in patients requiring long-term anticoagulation at high risk for bleeding with warfarin therapy. The economic implications of LMWH administration remain unclear. On the basis of the information presented in this review, LMWHs are promising new agents in prophylaxis and treatment of both arterial and venous thrombosis. In the near future, LMWHs are likely to supplant UFH and perhaps warfarin in many applications.http://link.springer-ny.com/link/service/journals/00547/bibs/8n4p203.html</hea


A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia.
Chronic myelomonocytic leukemia (CMML) is a complex clonal hematological disorder classified among myelodysplastic (MDS)/myeloproliferative neoplasms. Prognosis is poor and there is a lack of effective treatments. The hypomethylating agent decitabine has shown activity against MDS and elderly acute myeloid leukemia, but there is little data focusing specifically on its efficacy in CMML. In this prospective, phase 2 Italian study, CMML patients received intravenous decitabine 20 mg/m2 per day on Days 1-5 of a 28-day treatment cycle. Response was evaluated after four and six cycles; patients responding at the end of six cycles could continue treatment with decitabine. Forty-three patients were enrolled; >50% were high-risk according to four CMML-specific scoring systems. In the intent-to-treat population (n=42), the overall response rate after six cycles was 47.6%, with seven complete responses (16.6%), eight marrow responses (19%), one partial response (2.4%) and four hematological improvements (9.5%). After a median follow-up of 51.5 months (range: 44.4-57.2), median overall survival was 17 months, with responders having a significantly longer survival than non-responders (P=0.02). Grade 3/4 anemia, neutropenia and thrombocytopenia occurred in 28.6%, 50% and 38% of patients, respectively. Decitabine appears to be an effective and well-tolerated treatment for patients with high-risk CMML.


The development of an instrument to measure global dimensions of maternal care in rhesus macaques (Macaca mulatta).
One of the strongest predictors of healthy child development is the quality of maternal care. Although many measures of observation and self-report exist in humans to assess global aspects of maternal care, such qualitative measures are lacking in nonhuman primates. In this study, we developed an instrument to measure global aspects of maternal care in rhesus monkeys, with the goal of complementing the individual behavioral data collected using a well-established rhesus macaque ethogram during the first months postpartum. The 22 items of the instrument were adapted from human maternal sensitivity assessments and a maternal Q-sort instrument already published for macaques. The 22 items formed four dimensions with high levels of internal reliability that represented major constructs of maternal care: (1) Sensitivity/Responsivity, (2) Protectiveness, (3) Permissiveness, and (4) Irritability. These dimensions yielded high construct validity when correlated with mother-infant frequency and duration behavior that was collected from focal observations across the first 3 postnatal months. In addition, comparisons of two groups of mothers (Maltreating vs. Competent mothers) showed significant differences across the dimensions suggesting that this instrument has strong concurrent validity, even after controlling for focal observation variables that have been previously shown to significantly differentiate these groups. Our findings suggest that this Instrument of Macaque Maternal Care has the potential to capture global aspects of the mother-infant relationship that complement individual behaviors collected through focal observations.


A cognitive task analysis for dental hygiene.
To be an effective assessment tool, a simulation-based examination must be able to evoke and interpret observable evidence about targeted knowledge, strategies, and skills in a manner that is logical and defensible. Dental Interactive Simulations Corporation's first assessment effort is the development of a scoring algorithm for a simulation-based dental hygiene initial licensure examination. The first phase in developing a scoring system is the completion of a cognitive task analysis (CTA) of the dental hygiene domain. In the first step of the CTA, a specifications map was generated to provide a framework of the tasks and knowledge that are important to the practice of dental hygiene. Using this framework, broad classes of behaviors that would tend to distinguish along the dental hygiene expert-novice continuum were identified. Nine paper-based cases were then designed with the expectation that the solutions of expert, competent, and novice dental hygienists would differ. Interviews were conducted with thirty-one dental hygiene students/practitioners to capture solutions to the paper-based cases. Transcripts of the interviews were analyzed to identify performance features that distinguish among the interviewees on the basis of their expertise. These features were more detailed and empirically grounded than the originating broad classes and better serve to ground the design of a scoring system. The resulting performance features were collapsed into nine major categories: 1) gathering and using information, 2) formulating problems and investigating hypotheses, 3) communication and language, 4) scripting behavior, 5) ethics, 6) patient assessment, 7) treatment planning, 8) treatment, and 9) evaluation. The results of the CTA provide critical information for defining the necessary elements of a simulation-based dental hygiene examination.


Lung cancer and interstitial lung disease: a literature review.
The association between lung cancer (LC) and interstitial lung disease (ILD) can be explained by the shared risk factors like smoking and physiopathology of fibrogenesis and cancerogenesis. The relative LC risk is shown to be 3.5- to 7.3-times higher in ILD, with LC occurrence estimated at 10-20% in ILD, with >15% of ILD patients likely to die from LC. ILD incidence upon LC diagnosis varied from 2.4-10.9%. Primary radiological presentations consist of peripheral lesions, mostly in the inferior pulmonary lobes, either close to or within the ILD areas. There is a trend towards inverted proportion of adenocarcinomas and squamous-cell carcinomas, with EGFR mutations very rarely found. ILD negatively impacted LC prognosis, with surgery associated with increased morbidity-mortality, particularly due to acute exacerbation (AE) of ILD. Limited resection reduced this risk, whilst increasing that of cancer mortality. Studies on radiotherapy that can induce AE-ILD are scarce. Chemotherapy was associated with similar response rates to those in LC patients without ILD, yet worse survival. This difference may be accounted for by ILD patients' poorer health and higher risk of drug-induced pneumonitis. Further studies are warranted to better understand cancer physiopathology within the fibrotic areas, along with the therapeutic strategies required.


Topographic and morphologic analyses of retinal ganglion cell loss in old DBA/2NNia mice.
To evaluate the relationship between retinal ganglion cell (RGC) size, density distribution, and survival in senescent DBA2/NNia mice that develop pigmentary glaucoma. To evaluate the validity of nearest neighbor distance (NND), a measure of focal density for surviving RGCs in the retina, as a method to quantify RGC loss in mice. Fifteen-month-old DBA2/NNia mice were labeled retrogradely with fluorogold. Retinas were flat mounted and imaged in their entirety using an epifluorescence microscope with a motorized stage. Digital maps of the retinal wholemounts were constructed to automatically count and establish spatial coordinates for RGCs over the entire retina. RGC size and NND were determined from these maps. RGC counts in the group of 15-month-old DBA/2NNia animals ranged from 22,330 to 92,157 cells per retina. Mean RGC cell size per retina ranged from 22.35 to 35.64 microm2 and correlated linearly with total RGC counts. NND distribution histograms were compared for retinas with variable degrees of RGC loss. The distribution of NNDs in each retina was skewed toward larger distance values in more affected retinas. In partially damaged retinas, areas with severe pathology coincided with areas of maximal loss of large RGCs, and areas of preserved RGCs correlated with larger cell sizes. Damaged retinas have a smaller mean cell size, indicating preferential loss of larger RGCs or size reduction of surviving cells. NND analysis of the RGC population in a retina is a useful measure of glaucomatous RGC loss. The skewed NND distribution of surviving RGCs and the finding that RGC loss correlates with a shift/amplitude change in the mode of the histogram and its tail suggests two different patterns of RGC loss possibly attributable to different pathologic processes in glaucomatous DBA/2 mice.


Diversity of phytobeneficial traits revealed by whole-genome analysis of worldwide-isolated phenazine-producing Pseudomonas spp.
Plant-beneficial Pseudomonas spp. competitively colonize the rhizosphere and display plant-growth promotion and/or disease-suppression activities. Some strains within the P. fluorescens species complex produce phenazine derivatives, such as phenazine-1-carboxylic acid. These antimicrobial compounds are broadly inhibitory to numerous soil-dwelling plant pathogens and play a role in the ecological competence of phenazine-producing Pseudomonas spp. We assembled a collection encompassing 63 strains representative of the worldwide diversity of plant-beneficial phenazine-producing Pseudomonas spp. In this study, we report the sequencing of 58 complete genomes using PacBio RS II sequencing technology. Distributed among four subgroups within the P. fluorescens species complex, the diversity of our collection is reflected by the large pangenome which accounts for 25 413 protein-coding genes. We identified genes and clusters encoding for numerous phytobeneficial traits, including antibiotics, siderophores and cyclic lipopeptides biosynthesis, some of which were previously unknown in these microorganisms. Finally, we gained insight into the evolutionary history of the phenazine biosynthetic operon. Given its diverse genomic context, it is likely that this operon was relocated several times during Pseudomonas evolution. Our findings acknowledge the tremendous diversity of plant-beneficial phenazine-producing Pseudomonas spp., paving the way for comparative analyses to identify new genetic determinants involved in biocontrol, plant-growth promotion and rhizosphere competence.


Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease.
Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer's disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.


Development of an open-source, flexible framework for complex inter-institutional disparate data sharing and collaboration.
Clinical information, "-omic" datasets, and tissue samples are difficult to harmonize and manage for data mining. We have developed a platform for storing clinical research data while providing access to associated data from other information stores. Data on 34 metrics from 11,000 neuroblastoma patients were instantiated into a database. The Django web framework was used to create a model for rapid development of tools and views with a front-end interface for generating complex queries. Working with Nationwide Children's Hospital, we can now consume their tissue inventory data through an API. The end-user sees the number of patients who both match their search and have tissue available. Since initial implementation, the current tasks revolve around developing a governance structure and the necessary data use agreements. Efforts now are to (1) update the data with 5000 more patients, and (2) link to genomic data stores, facilitating disparate data acquisition for research studies.


Fouling and ships' hulls: how changing circumstances and spawning events may result in the spread of exotic species.
Organisms fouling ships' hulls are continually in transit worldwide. Although effective antifouling paints incorporating organotins have considerably reduced fouling biomass these paints have a limited period of effectiveness, which may be less than the ships' inter-docking period, depending on sea temperature and abrasion. Vessels immersed over several years can allow fouling communities to develop and spread beyond their native distribution. This process of establishment is not fully understood. This review proposes that short rapid turn-around of vessels with mature attached biota can result in synchronized spawnings and production of sufficient zygotes to form a founder population. Spawning may be induced by changes in temperature or salinity on entry into a port, according to season. The diversity of taxa in transit on ships' hulls includes commercial molluscs, which have the potential to transmit their diseases or pests to port regions. Several factors may act in the further enhancement of exotic species establishment including changes of in-port berthing regions to more marine conditions. Ships today are generally larger, and faster, and have a high frequency of port visits thereby increasing the number of spawning opportunities, perhaps with a larger inoculum size. With trade expansion, new trading routes, political events and changes in climate, new pathways for invasion will emerge. Greater controls on industrial discharges, improved treatments of urban wastes and better management of waste runoff into rivers as well as a phasing out of organotin antifoulants will mean a reduced toxicity in port regions. This may enable a smaller inoculum to colonize by creating opportunities for establishment not present in the previous 25 years. Some invaders will have unwanted consequences for the environment, economies and human health.


A reliable and easy to transport quality control method for chlamydia and gonorrhoea molecular point of care testing.
Quality control (QC) is an essential component of point-of-care testing programs. In the context of a randomised-controlled trial (TTANGO) using GeneXpert (Xpert) Chlamydia trachomatis and Neisseria gonorrhoeae (CT/NG) point-of-care testing in remote areas of Australia, we aimed to develop and utilise a stable positive control material. Bacterial cultures of CT and NG were resuspended together to provide cycle threshold (Ct) values of approximately 25 cycles for both CT and NG when tested on the Xpert CT/NG assay. These positive control suspensions were dried in aliquots, heat inactivated, and then provided to 12 participating health services as research-only QC samples in kit form. At each service, a QC sample was resuspended and tested each month on the Xpert. QC results, including Xpert Ct values, were analysed from each site over 30 months and we calculated costs per QC sample. Overall, at 12 health services there were 89 QC samples tested (average of 8 tests per site per year). Mean Ct values for the 89 controls samples were 25.25 cycles (SD = 1.15) for CT, 24.04 cycles (SD = 1.400) for one NG target and 23.35 cycles (SD = 1.55) for the other NG target. No significant differences in Ct value for CT or NG controls were observed over a trial period of 30 months. Positive QC samples for research use in a trial of a molecular point-of-care assay were inexpensive to produce and stable when stored at 2-8°C. For routine use, additional requirements such as meeting National Association of Testing Authority (NATA) regulations and Therapeutic Goods Administration (TGA) approval will need to be achieved.


Sit-to-walk and sit-to-stand-and-walk task dynamics are maintained during rising at an elevated seat-height independent of lead-limb in healthy individuals.
Sit-to-walk (STW) is a common transitional motor task not usually included in rehabilitation. Typically, sit-to-stand (STS), pause, then gait initiation (GI) before walking is used, which we term sit-to-stand-and-walk (STSW). Separation between centre-of-pressure (COP) and whole-body centre-of-mass (BCOM) during GI is associated with dynamic postural stability. Rising from seats higher than knee-height (KH) is more achievable for patients, but whether this and/or lead-limb significantly affects task dynamics is unclear. This study tested whether rising from seat-heights and lead-limb affects STW and STSW task dynamics in young healthy individuals. Ten (5F) young (29±7.7 years) participants performed STW and STSW from a standardised position. Five trials of each task were completed at 100 and 120%KH leading with dominant and non-dominant legs. Four force-plates and optical motion capture delineated key movement events and phases with effect of seat-height and lead-limb determined by 2-way ANOVA within tasks. At 120%KH, lower peak vertical ground-reaction-forces (vGRFs) and vertical BCOM velocities were observed during rising irrespective of lead-limb. No other parameters differed between seat-heights or lead-limbs. During GI in STSW there was more lateral, and less posterior, COP excursion than expected. Reduction in vGRFs and velocity during rising at 120%KH is consistent with reduced effort in young healthy individuals and is likely therefore to be an appropriate seat-height for patients. Lead-limb had no effect upon STSW or STW parameters suggesting that normative data independent of lead-limb can be utilised to monitor motor rehabilitation should differences be observed in patients. STSW should be considered an independent movement transition.


Left Ventricular Velocity of Propagation: A Useful Non-Invasive Measurement When Assessing Hemodynamic Alterations in Pulmonary Arterial Hypertension.
Left ventricular (LV) velocity of propagation (Vp) has been shown to be inversely related to the LV relaxation time constant. We sought to examine Vp from a group of chronic pulmonary hypertension (cPH) patients and compare these values to Vp obtained in normal individuals and patients with known LV diastolic dysfunction (LVDD). Echo-Doppler data and Vp measurements were retrospectively collected from all patients. The studied population was divided into four groups. Group I comprised of 15 patients with normal LV diastole, group II included 27 patients with stage 1 LVDD, group III was made up of 27 patients with stage 2 LVDD, and group IV included 66 patients with cPH. In the cPH population studied, patients had smaller end-diastolic LV cavities with the highest Vp values but their early mitral inflow to Vp ratios were not different from healthy controls. In addition, Vp values and pulmonary wedge capillary pressures were significantly associated in patients with LV dysfunction or pulmonary hypertension (P < 0.01). LVVp might be a useful non-invasive measurement to be routinely obtained in cPH patients as it probably not only reflects the compressive forces being exerted on the LV, known to increase Vp, but also might be quite useful for the non-invasive assessment of pulmonary capillary wedge pressures in these patients.


A sum-frequency generation spectroscopic study of the Gibbs analysis paradox: monolayer or sub-monolayer adsorption?
The Gibbs adsorption isotherm (GAI) has been considered as the foundation of surfactant adsorption studies for over a century; however, its application in determining the limiting surface excess has recently been intensively discussed, with contradictory experimental evidence either supporting or refuting the theory. The available arguments are based on monolayer adsorption models. In this paper, we experimentally and intellectually propose and validate the contribution of sub-monolayer adsorption to the GAI paradox. We utilize a powerful intrinsically surface-sensitive technique, vibrational sum-frequency generation spectroscopy (SFG), complementing with conventional tensiometric measurements to address these controversies both quantitatively and qualitatively. Our SFG results revealed that the precipitous decrease in surface tension directly corresponds to surface occupancy by adsorbates. In addition, the Gibbs analysis was successfully applied to the soluble monolayer of a surface-active alcohol to full saturation. However, the full saturation of the topmost monolayer does not necessarily mean that the surface adsorption was completed because the adsorption was observed to continuously occur in the sub-monolayer region soon after the topmost monolayer became saturated. Nonetheless, the Gibbs isotherm failed to account for the excess of alcohol adsorbed in this sub-monolayer region. This new concept of surface excess must therefore be treated thermodynamically.


Multiple influences of a heparin-binding growth factor on neuronal development.
Heparin-binding growth factor-2 (HBGF-2; also known as basic fibroblast growth factor) is mitogenic for most anchorage-dependent cells. It is shown here that HBGF-2 stimulates cell-substratum adhesion and neurite extension in the sympathetic nerve cell line PC12. When HBGF-2 is adsorbed to artificial extracellular matrices consisting of heparin or chondroitin sulfate, it causes the formation of cellular aggregates or circles of cells, respectively. HBGF-2 is also a nerve cell survival molecule, for it potentiates the survival of primary cultures of embryonic chick ciliary ganglion cells but not of embryonic neural retina cells. Finally, a series of synthetic peptides from the HBGF-2 sequence is described that selectively alter the biological effects of HBGF-2. The amphiphilic nature of one of these peptides is discussed with respect to its ability to stimulate cell adhesion.


Fish on steroids: Temperature-dependent effects of 17β-trenbolone on predator escape, boldness, and exploratory behaviors.
Hormonal growth promoters (HGPs), widely used in beef cattle production globally, make their way into the environment as agricultural effluent-with potential impacts on aquatic ecosystems. One HPG of particular concern is 17β-trenbolone, which is persistent in freshwater habitats and can affect the development, morphology and reproductive behaviors of aquatic organisms. Despite this, few studies have investigated impacts of 17β-trenbolone on non-reproductive behaviors linked to growth and survival, like boldness and predator avoidance. None consider the interaction between 17β-trenbolone and other environmental stressors, such as temperature, although environmental challenges confronting animals in the wild seldom, if ever, occur in isolation. Accordingly, this study aimed to test the interactive effects of trenbolone and temperature on organismal behavior. To do this, eastern mosquitofish (Gambusia holbrooki) were subjected to an environmentally-relevant concentration of 17β-trenbolone (average measured concentration 3.0 ± 0.2 ng/L) or freshwater (i.e. control) for 21 days under one of two temperatures (20 and 30 °C), after which the predator escape, boldness and exploration behavior of fish were tested. Predator escape behavior was assayed by subjecting fish to a simulated predator strike, while boldness and exploration were assessed in a separate maze experiment. We found that trenbolone exposure increased boldness behavior. Interestingly, some behavioral effects of trenbolone depended on temperature, sex, or both. Specifically, significant effects of trenbolone on male predator escape behavior were only noted at 30 °C, with males becoming less reactive to the simulated threat. Further, in the maze experiment, trenbolone-exposed fish explored the maze faster than control fish, but only at 20 °C. We conclude that field detected concentrations of 17β-trenbolone can impact ecologically important behaviors of fish, and such effects can be temperature dependent. Such findings underscore the importance of considering the potentially interactive effects of other environmental stressors when investigating behavioral effects of environmental contaminants.


Suicide numbers during the first 9-15 months of the COVID-19 pandemic compared with pre-existing trends: An interrupted time series analysis in 33 countries.
Predicted increases in suicide were not generally observed in the early months of the COVID-19 pandemic. However, the picture may be changing and patterns might vary across demographic groups. We aimed to provide a timely, granular picture of the pandemic's impact on suicides globally. We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation. We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries' COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries' income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well. Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue. None.


Anti-Proliferative Effect of Naringenin through p38-Dependent Downregulation of Cyclin D1 in Human Colorectal Cancer Cells.
Naringenin (NAR) as one of the flavonoids observed in grapefruit has been reported to exhibit an anti-cancer activity. However, more detailed mechanism by which NAR exerts anti-cancer properties still remains unanswered. Thus, in this study, we have shown that NAR down-regulates the level of cyclin D1 in human colorectal cancer cell lines, HCT116 and SW480. NAR inhibited the cell proliferation in HCT116 and SW480 cells and decreased the level of cyclin D1 protein. Inhibition of proteasomal degradation by MG132 blocked NAR-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with NAR. In addition, NAR increased the phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine blocked cyclin D1 downregulation by NAR. p38 inactivation attenuated cyclin D1 downregulation by NAR. From these results, we suggest that NAR-mediated cyclin D1 downregulation may result from proteasomal degradation through p38 activation. The current study provides new mechanistic link between NAR, cyclin D1 downregulation and cell growth in human colorectal cancer cells.


Application of k-space energy spectrum analysis to susceptibility field mapping and distortion correction in gradient-echo EPI.
Echo-planar imaging (EPI) is widely used in functional MRI studies. It is well known that EPI quality is usually degraded by geometric distortions, when there exist susceptibility field inhomogeneities. EPI distortions may be corrected if the field maps are available. It is possible to estimate the susceptibility field gradients from the phase reconstruction of a single-TE EPI image, after a successful phase-unwrapping procedure. However, in regions affected by pronounced field gradients, the phase-unwrapping of a single-TE image may fail, and therefore the estimated field maps may be incorrect. It has been reported that the field inhomogeneity may be calculated more reliably from T2*-weighted images corresponding to multiple TEs. However, the multi-TE MRI field mapping increases the scan time. Furthermore, the measured field maps may be invalid if the subject's position changes during dynamic scans. To overcome the limitations in conventional field mapping approaches, a novel k-space energy spectrum analysis algorithm is developed, which quantifies the spatially dependent echo-shifting effect and the susceptibility field gradients directly from the k-space data of single-TE gradient-echo EPI. Using the k-space energy spectrum analysis, susceptibility field gradients can be reliably measured without phase-unwrapping, and EPI distortions can be corrected without extra field mapping scans or pulse sequence modification. The reported technique can be used to retrospectively improve the image quality of the previously acquired EPI and functional MRI data, provided that the complex-domain k-space data are still available.


Loss of reproductive parasitism following transfer of male-killing Wolbachia to Drosophila melanogaster and Drosophila simulans.
Wolbachia manipulate insect host biology through a variety of means that result in increased production of infected females, enhancing its own transmission. A Wolbachia strain (wInn) naturally infecting Drosophila innubila induces male killing, while native strains of D. melanogaster and D. simulans usually induce cytoplasmic incompatibility (CI). In this study, we transferred wInn to D. melanogaster and D. simulans by embryonic microinjection, expecting conservation of the male-killing phenotype to the novel hosts, which are more suitable for genetic analysis. In contrast to our expectations, there was no effect on offspring sex ratio. Furthermore, no CI was observed in the transinfected flies. Overall, transinfected D. melanogaster lines displayed lower transmission rate and lower densities of Wolbachia than transinfected D. simulans lines, in which established infections were transmitted with near-perfect fidelity. In D. simulans, strain wInn had no effect on fecundity and egg-to-adult development. Surprisingly, one of the two transinfected lines tested showed increased longevity. We discuss our results in the context of host-symbiont co-evolution and the potential of symbionts to invade novel host species.


An international outbreak of Salmonella infections caused by alfalfa sprouts grown from contaminated seeds.
An outbreak of Salmonella serotype stanley infections occurred in the United States and Finland in 1995. The outbreak was investigated through case-control studies in Arizona, Michigan, and Finland; by isolate subtyping; and by tracing and culturing of the implicated food. Alfalfa sprout consumption was the only exposure associated with S. stanley infections in Arizona (matched odds ratio [MOR] = 11.1; 95% confidence interval [CI], 1.4-513), Michigan (MOR = 5.5; CI, 1.6-23), and Finland (MOR undefined; CI, 4.9-infinity). US and Finnish patient isolates were a unique outbreak strain distinct from S. stanley isolates not linked to the outbreak. Alfalfa sprouts eaten by patients in 6 US states and Finland were traced to seed shipped by a Dutch shipper. Thus, it was concluded that alfalfa sprouts grown from contaminated seed caused an international outbreak of > or =242 S. stanley infections in > or =17 US states and Finland. This outbreak illustrates a new mechanism through which contamination of fresh produce can cause large, widely dispersed outbreaks.


Pre-Exercise Carbohydrate or Protein Ingestion Influences Substrate Oxidation but Not Performance or Hunger Compared with Cycling in the Fasted State.
Nutritional intake can influence exercise metabolism and performance, but there is a lack of research comparing protein-rich pre-exercise meals with endurance exercise performed both in the fasted state and following a carbohydrate-rich breakfast. The purpose of this study was to determine the effects of three pre-exercise nutrition strategies on metabolism and exercise capacity during cycling. On three occasions, seventeen trained male cyclists (VO2peak 62.2 ± 5.8 mL·kg-1·min-1, 31.2 ± 12.4 years, 74.8 ± 9.6 kg) performed twenty minutes of submaximal cycling (4 × 5 min stages at 60%, 80%, and 100% of ventilatory threshold (VT), and 20% of the difference between power at the VT and peak power), followed by 3 × 3 min intervals at 80% peak aerobic power and 3 × 3 min intervals at maximal effort, 30 min after consuming a carbohydrate-rich meal (CARB; 1 g/kg CHO), a protein-rich meal (PROTEIN; 0.45 g/kg protein + 0.24 g/kg fat), or water (FASTED), in a randomized and counter-balanced order. Fat oxidation was lower for CARB compared with FASTED at and below the VT, and compared with PROTEIN at 60% VT. There were no differences between trials for average power during high-intensity intervals (367 ± 51 W, p = 0.516). Oxidative stress (F2-Isoprostanes), perceived exertion, and hunger were not different between trials. Overall, exercising in the overnight-fasted state increased fat oxidation during submaximal exercise compared with exercise following a CHO-rich breakfast, and pre-exercise protein ingestion allowed similarly high levels of fat oxidation. There were no differences in perceived exertion, hunger, or performance, and we provide novel data showing no influence of pre-exercise nutrition ingestion on exercise-induced oxidative stress.


The excretion of NaCl and KCl loads in mosquitoes. 1. Control data.
The handling of Na(+) and K(+) loads was investigated in isolated Malpighian tubules and in whole mosquitoes of Aedes aegypti. Isolated Malpighian tubules bathed in Na(+)-rich Ringer solution secreted Na(+)-rich fluid, and tubules bathed in K(+)-rich Ringer solution secreted K(+)-rich fluid. Upon Na(+) loading the hemolymph, the mosquito removed 77% the injected Na(+) within the next 30 min. The rapid onset and magnitude of this diuresis and the excretion of more Na(+) than can be accounted for by tubular secretion in vitro is consistent with the release of the calcitonin-like diuretic hormone in the mosquito to remove the Na(+) load from the hemolymph. Downstream, K(+) was reabsorbed with water in the hindgut, which concentrated Na(+) in excreted urine hyperosmotic to the hemolymph. Upon K(+) loading the hemolymph, the mosquito took 2 h to remove 100% of the injected K(+) from the hemolymph. The excretion of K(+)-rich isosmotic urine was limited to clearing the injected K(+) from the hemolymph with a minimum of Cl(-) and water. As a result, 43.3% of the injected Cl(-) and 48.1% of the injected water were conserved. The cation retained in the hemolymph with Cl(-) was probably N-methyl-d-glucamine, which replaced Na(+) in the hemolymph injection of the K(+) load. Since the tubular secretion of K(+) accounts for the removal of the K(+) load from the hemolymph, the reabsorption of K(+), Na(+), Cl(-), and water must be inhibited in the hindgut. The agents mediating this inhibition are unknown.


What characterizes people who have an unclear classification using a treatment-based classification algorithm for low back pain? A cross-sectional study.
A treatment-based classification algorithm for low back pain (LBP) was created to help clinicians select treatments to which people are most likely to respond. To allow the algorithm to classify all people with LBP, additional criteria can help therapists make decisions for people who do not clearly fit into a subgroup (ie, unclear classifications). Recent studies indicated that classifications are unclear for approximately 34% of people with LBP. To guide improvements in the algorithm, it is imperative to determine whether people with unclear classifications are different from those with clear classifications. This study was a secondary analysis of data from 3 previous studies investigating the algorithm. Baseline data from 529 people who had LBP were used (3 discrete cohorts). The primary outcome was type of classification, that is, clear or unclear. Univariate logistic regression was used to determine which participant variables were related to having an unclear classification. People with unclear classifications had greater odds of being older (odds ratio [OR]=1.01, 95% confidence interval [CI]=1.003-1.033), having a longer duration of LBP (OR=1.001, 95% CI=1.000-1.001), having had a previous episode(s) of LBP (OR=1.61, 95% CI=1.04-2.49), having fewer fear-avoidance beliefs related to both work (OR=0.98, 95% CI=0.96-0.99) and physical activity (OR=0.98, 95% CI=0.96-0.996), and having less LBP-related disability (OR=0.98, 95% CI=0.96-0.99) than people with clear classifications. Studies from which participant data were drawn had different inclusion criteria and clinical settings. People with unclear classifications appeared to be less affected by LBP (less disability and fewer fear avoidance beliefs), despite typically having a longer duration of LBP. Future studies should investigate whether modifying the algorithm to exclude such people or provide them with different interventions improves outcomes.


Total respiratory resistance and reactance in patients with diffuse interstitial lung disease.
In 54 patients with interstitial lung diseases and no signs of airway obstruction we measured lung volumes, maximal expiratory flows, diffusing capacity (DLCO), total respiratory resistance (Rrs) and reactance (Xrs) between 4 and 26 Hz by means of the forced oscillation technique. In all patients DLCO was less than 75% of the expected value. Patients were classified into two groups depending on total lung capacity (TLC): group A with TLC less than 80% of expected, and group B with TLC of 80% or more. Group A demonstrated a decrease of Xrs especially at low frequencies, with small, not significant changes in Rrs. In the patients in this group with the lowest values of TLC (less than 50%), we observed an increase of Rrs at low frequencies causing a negative frequency dependence of Rrs. In group B no distinct changes of Rrs and Xrs occurred. Canonical correlation analysis between routine lung function data and forced oscillation parameters, showed tight correlations between TLC in absolute value or VC in percent of the predicted value on the one hand and average level of Xrs and average slope of Xrs (and Rrs) vs frequency curves on the other hand. Measurements of lung mechanics in five additional patients and comparison with a model of the respiratory system suggest that the changes of Rrs and Xrs are not explained totally by the observed increase in lung tissue resistance and decrease in lung compliance. The observed changes in Rrs and Xrs are not specific for restrictive lung disorders; similar changes are met also in moderately advanced obstructive diseases.


The Fas signaling pathway: more than a paradigm.
Apoptosis and related forms of cell death have central importance in development, homeostasis, tumor surveillance, and the function of the immune system. Apoptosis is initiated by two principal pathways. The intrinsic pathway emerges from mitochondria, whereas the extrinsic pathway is activated by the ligation of death receptors. This Viewpoint introduces the basic mechanisms of the extrinsic pathway, using the example of the prototypical death receptor Fas and its role in apoptosis, but it also points out the increasingly understood importance of this receptor as a non-apoptotic signal transducer.


Proinflammatory responses and higher IL-10 production by T cells correlate with protection against malaria during pregnancy and delivery outcomes.
Pregnancy triggers immunological changes aimed to tolerate the fetus. However, it has not been properly addressed whether similar changes occur in tropical areas with high infection pressure and whether these changes render women more susceptible to infectious diseases. We compared the frequencies of T cell subsets, including regulatory T cells, in pregnant and nonpregnant women from Papua New Guinea, a high malaria transmission area, and from Spain, a malaria-free country. We also assessed the relationship among these cellular subsets, malaria infection, and delivery outcomes. CD4(+)FOXP3(+)CD127(low) T cells (Tregs) were decreased in pregnant women in both countries but were not associated with malaria infection or poor delivery outcomes. An expansion of IFN-γ-producing cells and intracytoplasmic IFN-γ levels was found in pregnant compared with nonpregnant women only in Papua New Guinea. Increased CD4(+)IL-10(+)IFN-γ(+) frequencies and Treg-IFN-γ production were found in women with current Plasmodium falciparum infection. Higher CD4(+)IL-10(-)IFN-γ(+) T cells frequencies and production of proinflammatory cytokines (including TNF and IL-2) at recruitment (first antenatal visit) had a protective association with birth weight and future (delivery) P. falciparum infection, respectively. Higher intracellular IL-10 levels in T cells had a protective association with future P. falciparum infection and hemoglobin levels at delivery. The protective associations were found also with nonmalaria-specific T cell responses. Treg frequencies positively correlated with plasma eotaxin concentrations, but this subset did not express eotaxin receptor CCR3. Thus, an activated immune system during pregnancy might contribute to protection against malaria during pregnancy and poor delivery outcomes.


The effects and underlying mechanism of excessive iodide on excessive fluoride-induced thyroid cytotoxicity.
In many regions, excessive fluoride and excessive iodide coexist in groundwater, which may lead to biphasic hazards to human thyroid. To explore fluoride-induced thyroid cytotoxicity and the mechanism underlying the effects of excessive iodide on fluoride-induced cytotoxicity, a thyroid cell line (Nthy-ori 3-1) was exposed to excessive fluoride and/or excessive iodide. Cell viability, lactate dehydrogenase (LDH) leakage, reactive oxygen species (ROS) formation, apoptosis, and the expression levels of inositol-requiring enzyme 1 (IRE1) pathway-related molecules were detected. Fluoride and/or iodide decreased cell viability and increased LDH leakage and apoptosis. ROS, the expression levels of glucose-regulated protein 78 (GRP78), IRE1, C/EBP homologous protein (CHOP), and spliced X-box-binding protein-1 (sXBP-1) were enhanced by fluoride or the combination of the two elements. Collectively, excessive fluoride and excessive iodide have detrimental influences on human thyroid cells. Furthermore, an antagonistic interaction between fluoride and excessive iodide exists, and cytotoxicity may be related to IRE1 pathway-induced apoptosis.


Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice.
Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE(-/-) mice (6-8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12,500+/-700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2,700+/-830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17+/-0.03 vs. 0.31+/-0.05 mm(2), P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by approximately 53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.


A Techno-Economic Analysis of Methane Mitigation Potential from Reported Venting at Oil Production Sites in Alberta.
The technical and economic potential for reducing methane emissions from reported venting and flaring volumes in 2015 at 9422 upstream oil production sites in Alberta, Canada was evaluated in a comprehensive site-by-site analysis. For each site, up to six different technologies for mitigation were considered, based on conserving gas into pipelines, combusting gas on site, or using gas for on-site fuel. Economic viability of mitigation was calculated using current economic parameters and gas price projections on a net present cost basis. Monte Carlo simulations suggest that a 45% reduction in methane emissions (consistent with current federal and provincial targets) from reported flaring and venting is technically and economically feasible at overall average costs ranging from $-2.98 CAD/tCO2e (i.e., a profit) to $2.51 CAD/tCO2e with no one site paying more than $11.02 CAD/tCO2e. If the reported baseline emissions are augmented to reflect results of recent airborne measurements, overall economics of mitigation generally improve due to larger available gas volumes at many sites. Considering federal carbon price targets of $50 CAD/tCO2e by 2022, there are relevant economic opportunities for mitigating methane from reported venting and flaring volumes well beyond a 45% reduction. This could partially offset the challenge in addressing the additional methane emissions from fugitive and unreported venting sources.


PLK1 inhibition down-regulates polycomb group protein BMI1 via modulation of the miR-200c/141 cluster.
The polycomb group protein BMI1 is an important regulator of cancer stem cell (CSC) phenotype and is often overexpressed in cancer cells. Its overexpression leads to increase in CSC fraction and therapy resistance in tumors. BMI1 functions via polycomb repressive complex 1 (PRC1)-mediated gene silencing and also via PRC1-independent transcriptional activities. At present, very little is known about the therapy reagents that can efficiently inhibit BMI1 expression, and the CSC phenotype. Here, we report that the polo-like kinase 1 (PLK1) regulates BMI1 expression, and that its inhibition can efficiently down-regulate BMI1 expression and PRC1 activity, and induce premature senescence in breast cancer cells. We also show that the exogenous BMI1 overexpression mitigates anti-oncogenic effects of PLK1 inhibition and overcomes senescence induction by PLK1 inhibitors. We further show that PLK1 inhibition down-regulates BMI1 by upregulating the miRNA-200c/141 cluster, which encodes miR-200c and miR-141, both of which are known to post-transcriptionally downregulate BMI1 expression. Thus, our data suggest that PLK1 inhibitors can be successfully used to inhibit growth of tumors in which PcG protein BMI1 is overexpressed or the PRC1 activity is deregulated.


Novel Factors of Viral Origin Inhibit TOR Pathway Gene Expression.
Polydnaviruses (PDVs) are obligate symbionts of endoparasitoid wasps, which exclusively attack the larval stages of their lepidopteran hosts. The Polydnavirus is injected by the parasitoid female during oviposition to selectively infect host tissues by the expression of viral genes without undergoing replication. Toxoneuron nigriceps bracovirus (TnBV) is associated with Toxoneuron nigriceps (Hymenoptera: Braconidae) wasp, an endoparasitoid of the tobacco budworm larval stages, Heliothis virescens (Lepidoptera: Noctuidae). Previous studies showed that TnBV is responsible for alterations in host physiology. The arrest of ecdysteroidogenesis is the main alteration which occurs in last (fifth) instar larvae and, as a consequence, prevents pupation. TnBV induces the functional inactivation of H. virescens prothoracic glands (PGs), resulting in decreased protein synthesis and phosphorylation. Previous work showed the involvement of the PI3K/Akt/TOR pathway in H. virescens PG ecdysteroidogenesis. Here, we demonstrate that this cellular signaling is one of the targets of TnBV infection. Western blot analysis and enzyme immunoassay (EIA) showed that parasitism inhibits ecdysteroidogenesis and the phosphorylation of the two targets of TOR (4E-BP and S6K), despite the stimulation of PTTH contained in the brain extract. Using a transcriptomic approach, we identified viral genes selectively expressed in last instar H. virescens PGs, 48 h after parasitization, and evaluated expression levels of PI3K/Akt/TOR pathway genes in these tissues. The relative expression of selected genes belonging to the TOR pathway (tor, 4e-bp, and s6k) in PGs of parasitized larvae was further confirmed by qRT-PCR. The down-regulation of these genes in PGs of parasitized larvae supports the hypothesis of TnBV involvement in blocking ecdysteroidogenesis, through alterations of the PI3K/Akt/TOR pathway at the transcriptional level.


Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE Study Group.
New evidence shows that older adults need more dietary protein than do younger adults to support good health, promote recovery from illness, and maintain functionality. Older people need to make up for age-related changes in protein metabolism, such as high splanchnic extraction and declining anabolic responses to ingested protein. They also need more protein to offset inflammatory and catabolic conditions associated with chronic and acute diseases that occur commonly with aging. With the goal of developing updated, evidence-based recommendations for optimal protein intake by older people, the European Union Geriatric Medicine Society (EUGMS), in cooperation with other scientific organizations, appointed an international study group to review dietary protein needs with aging (PROT-AGE Study Group). To help older people (>65 years) maintain and regain lean body mass and function, the PROT-AGE study group recommends average daily intake at least in the range of 1.0 to 1.2 g protein per kilogram of body weight per day. Both endurance- and resistance-type exercises are recommended at individualized levels that are safe and tolerated, and higher protein intake (ie, ≥ 1.2 g/kg body weight/d) is advised for those who are exercising and otherwise active. Most older adults who have acute or chronic diseases need even more dietary protein (ie, 1.2-1.5 g/kg body weight/d). Older people with severe kidney disease (ie, estimated GFR <30 mL/min/1.73 m(2)), but who are not on dialysis, are an exception to this rule; these individuals may need to limit protein intake. Protein quality, timing of ingestion, and intake of other nutritional supplements may be relevant, but evidence is not yet sufficient to support specific recommendations. Older people are vulnerable to losses in physical function capacity, and such losses predict loss of independence, falls, and even mortality. Thus, future studies aimed at pinpointing optimal protein intake in specific populations of older people need to include measures of physical function.


Short-interval observational data to inform clinical trial design in Huntington's disease.
To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials. 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months.


Mechanical behavior of a soft hydrogel reinforced with three-dimensional printed microfibre scaffolds.
Reinforcing hydrogels with micro-fibre scaffolds obtained by a Melt-Electrospinning Writing (MEW) process has demonstrated great promise for developing tissue engineered (TE) constructs with mechanical properties compatible to native tissues. However, the mechanical performance and reinforcement mechanism of the micro-fibre reinforced hydrogels is not yet fully understood. In this study, FE models, implementing material properties measured experimentally, were used to explore the reinforcement mechanism of fibre-hydrogel composites. First, a continuum FE model based on idealized scaffold geometry was used to capture reinforcement effects related to the suppression of lateral gel expansion by the scaffold, while a second micro-FE model based on micro-CT images of the real construct geometry during compaction captured the effects of load transfer through the scaffold interconnections. Results demonstrate that the reinforcement mechanism at higher scaffold volume fractions was dominated by the load carrying-ability of the fibre scaffold interconnections, which was much higher than expected based on testing scaffolds alone because the hydrogel provides resistance against buckling of the scaffold. We propose that the theoretical understanding presented in this work will assist the design of more effective composite constructs with potential applications in a wide range of TE conditions.


The principal of dynamic contrast enhanced MRI, the method of pharmacokinetic analysis, and its application in the head and neck region.
Many researchers have established the utility of the dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) in the differential diagnosis in the head and neck region, especially in the salivary gland tumors. The subjective assessment of the pattern of the time-intensity curve (TIC) or the simple quantification of the TIC, such as the time to peak enhancement (T(peak)) and the wash-out ratio (WR), is commonly used. Although the semiquantitative evaluations described above have been widely applied, they do not provide information on the underlying pharmacokinetic analysis in tissue. The quantification of DCE-MRI is preferable; therefore, many compartment model analyses have been proposed. The Toft and Kermode (TK) model is one of the most popular compartment models, which provide information about the influx forward volume transfer constant from plasma into the extravascular-extracellular space (EES) and the fractional volume of EES per unit volume of tissue is used in many clinical studies. This paper will introduce the method of pharmacokinetic analysis and also describe the clinical application of this technique in the head and neck region.


The proliferative potential of human pituitary tumors in situ.
At the start of transsphenoidal microsurgery for removal of various types of pituitary adenomas, 21 patients received a 1-hour intravenous infusion of 5-bromodeoxyuridine (BUdR, 200 mg/sq m) to label tumor cells in the deoxyribonucleic acid (DNA) synthesis phase (S-phase). Excised tumor specimens were fixed in 70% ethanol and stained by the indirect peroxidase method using anti-BUdR monoclonal antibody as the first antibody. The percentage of BUdR-labeled cells, or S-phase fraction, was calculated for each specimen. The S-phase fraction was less than 0.1% in nine cases, 0.1% to 0.5% in seven, and greater than 0.5% in five. Except in two cases of Nelson's syndrome, in which it was greater than 1%, the S-phase fraction did not correlate with any other variable, including patient age, tumor size, or the duration of signs and symptoms. The small S-phase fraction of most of the pituitary adenomas correlates well with the clinical behavior of these tumors, which grow much more slowly than other kinds of brain tumors such as gliomas. However, the S-phase fractions varied by as much as one order of magnitude. The higher S-phase fractions may reflect aggressive and invasive growth. These results indicate that immunohistochemical studies of cell kinetics using BUdR and anti-BUdR monoclonal antibodies may provide information about the biological characteristics of pituitary adenomas which could lead to the design of appropriate treatment regimens (including surgery, radiation therapy, and chemotherapy) for individual patients.


Objectively measured physical activity and the subsequent risk of incident dysglycemia: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab).
To investigate pedometer-measured physical activity (PA) in 2000 and change in PA over 5 years with subsequent risk of dysglycemia by 2005. This prospective cohort study in Tasmania, Australia, analyzed 458 adults with normal glucose tolerance and a mean (SD) age of 49.7 (12.1) years in 2000. Variables assessed in 2000 and 2005 included PA, by pedometer and questionnaire, nutrient intake, and other lifestyle factors. Incident dysglycemia was defined as the development of impaired fasting glucose or impaired glucose tolerance revealed by oral glucose tolerance testing in 2005, without type 2 diabetes. Incident dysglycemia developed in 26 participants during the 5-year period. Higher daily steps in 2000 were independently associated with a lower 5-year risk of incident dysglycemia (adjusted odds ratio [AOR] 0.87 [95% CI 0.77-0.97] per 1,000-step increment). Higher daily steps in 2005, after controlling for baseline steps in 2000 (thus reflecting change in steps over 5 years), were not associated with incident dysglycemia (AOR 1.02 [0.92-1.14]). Higher daily steps in 2000 were also associated with lower fasting blood glucose, but not 2-h plasma glucose by 2005. Further adjustment for BMI or waist circumference did not remove these associations. Among community-dwelling adults, a higher rate of daily steps is associated with a reduced risk of incident dysglycemia. This effect appears to be not fully mediated through reduced adiposity.


Proteomes and signalling pathways of antler stem cells.
As the only known example of complete organ regeneration in mammals, deer antler in the growing or velvet phase is of major interest in developmental biology. This regeneration event initiates from self-renewing antler stem cells that exhibit pluripotency. At present, it remains unclear how the activation and quiescence of antler stem cells are regulated. Therefore, in the present study proteins that were differentially expressed between the antler stem cells and somatic cells (facial periosteum) were identified by a gel-based proteomic technique, and analysed using Ingenuity Pathway Analysis software. Several molecular pathways (PI3K/Akt, ERK/MAPK, p38 MAPK, etc.) were found to be activated during proliferation. Also expressed were the transcription factors POU5F1, SOX2, NANOG and MYC, which are key markers of embryonic stem cells. Expression of these proteins was confirmed in both cultured cells and fresh tissues by Western blot analysis. Therefore, the molecular pathways and transcription factors identified in the current study are common to embryonic and adult stem cells. However, expression of embryonic stem cell transcription factors would suggest that antler stem cells are, potentially, an intermediary stem cell type between embryonic and the more specialized tissue-specific stem cells like those residing in muscle, fat or from a hematopoietic origin. The retention of this embryonic, pluripotent lineage may be of fundamental importance for the subsequent regenerative capacity of antlers.


Tug-of-war between corrugation and binding energy: revealing the formation of multiple moiré patterns on a strongly interacting graphene-metal system.
The formation of multidomain epitaxial graphene on Rh(111) under ultra-high vacuum (UHV) conditions has been characterized by scanning tunnelling microscopy (STM) measurements and density functional theory (DFT) calculations. At variance with the accepted view for strongly interacting graphene-metal systems, we clearly demonstrate the formation of different rotational domains leading to multiple moiré structures with a wide distribution of surface periodicities. Experiments reveal a correlation between the STM apparent corrugation and the lattice parameter of the moiré unit cell, with corrugations of just 30-40 pm for the smallest moirés. DFT calculations for a relevant selection of these moiré patterns show much larger height differences and a non-monotonic behaviour with the moiré size. Simulations based on non-equilibrium Green's function (NEGF) methods reproduce quantitatively the experimental trend and provide a detailed understanding of the interplay between electronic and geometric contributions in the STM contrast of graphene systems. Our study sheds light on the subtle energy balance among strain, corrugation and binding that drives the formation of the moiré patterns in all graphene/metal systems and suggests an explanation for the success of an effective model only based on the lattice mismatch. Although low values of the strain energy are a necessary condition, it is the ability of graphene to corrugate in order to maximize the areas of favourable graphene-metal interactions that finally selects the stable configurations.


Medication adherence of patients with selected rheumatic conditions: a systematic review of the literature.
Nonadherence with medication treatment has been found to occur in large proportions of patients with a broad range of chronic conditions. Our aim was to perform a systematic review of the literature examining adherence with treatments for inflammatory rheumatic conditions to assess the magnitude of the problem in this patient population. A MEDLINE search of English language literature was performed to identify studies published between January 1, 1985 and November 30, 2007 that evaluated adherence with chronic medications needed in the treatment of rheumatic conditions. A total of 20 articles met the criteria for evaluation, the majority of which focused on the treatment of rheumatoid arthritis. Most of the studies examined the use of nonsteroidal anti-inflammatory medications and disease-modifying antirheumatic drugs. Adherence was assessed based on self-report, pill counts, pharmacy dispensings, openings of pill containers using electronic devices, laboratory assays, and physician assessment. Adherence varied greatly based on the adherence measure used, arthritic condition evaluated, and medication under study. Overall, the highest rates of adherence were based on self-reports for a wide variety of medications and conditions (range of persons reporting adherence was 30 to 99%), while the lowest adherence rates were for allopurinol based on pharmacy dispensings (18-26%). Adherence has not been widely examined for most chronic inflammatory rheumatic conditions and the few studies that exist used different definitions and populations, thus limiting any conclusions. However, the current literature does suggest that nonadherence is a substantial problem.


Drug-resistant malaria in Bangui, Central African Republic: an in vitro assessment.
We used an in vitro isotopic drug sensitivity assay to assess the sensitivity of Plasmodium falciparum isolates collected in Bangui, Central African Republic between March and July 2004. We tested antimalarials that are currently in use in this country (chloroquine, amodiaquine, quinine, and pyrimethamine), antimalarials that will become available in this region in the future (artemisinin and halofantrine), and prophylactic antimalarials (mefloquine, doxycycline, and atovaquone). The proportions of resistant isolates were 37% for chloroquine, 15.9% for amodiaquine, 0% for quinine, 0% for dihydroartemisinin, 1.6% for mefloquine, 3.8% for halofantrine, 4.0% for atovaquone, and 38.3% for pyrimethamine. No multi-resistant isolates (showing resistance to more than three drugs) were found. A positive correlation was found between the 50% inhibitory concentrations values for the following drugs: chloroquine and amodiaquine; quinine and halofantrine; chloroquine and dihydroartemisinin; chloroquine and halofantrine; amodiaquine and dihydroartemisinin; dihydroartemisinin and mefloquine; chloroquine and quinine; and quinine and dihydroartemisinin. These findings suggest that the Ministry of Health should recommend a interim policy with the amodiaquine plus sulfadoxine-pyrimethamine combination as the first-line antimalarial drug in Bangui until better alternative treatments such as artemisinin-based combination therapies become available at low prices in the Central African Republic.


Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.


Optogenetic dissection of descending behavioral control in Drosophila.
In most animals, the brain makes behavioral decisions that are transmitted by descending neurons to the nerve cord circuitry that produces behaviors. In insects, only a few descending neurons have been associated with specific behaviors. To explore how descending neurons control an insect's movements, we developed a novel method to systematically assay the behavioral effects of activating individual neurons on freely behaving terrestrial D. melanogaster. We calculated a two-dimensional representation of the entire behavior space explored by these flies, and we associated descending neurons with specific behaviors by identifying regions of this space that were visited with increased frequency during optogenetic activation. Applying this approach across a large collection of descending neurons, we found that (1) activation of most of the descending neurons drove stereotyped behaviors, (2) in many cases multiple descending neurons activated similar behaviors, and (3) optogenetically activated behaviors were often dependent on the behavioral state prior to activation.


Connectivity of the subthalamic nucleus and globus pallidus pars interna to regions within the speech network: a meta-analytic connectivity study.
Cortico-basal ganglia connections are involved in a range of behaviors within motor, cognitive, and emotional domains; however, the whole-brain functional connections of individual nuclei are poorly understood in humans. The first aim of this study was to characterize and compare the connectivity of the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) using meta-analytic connectivity modeling. Structure-based activation likelihood estimation meta-analyses were performed for STN and GPi seeds using archived functional imaging coordinates from the BrainMap database. Both regions coactivated with caudate, putamen, thalamus, STN, GPi, and GPe, SMA, IFG, and insula. Contrast analyses also revealed coactivation differences within SMA, IFG, insula, and premotor cortex. The second aim of this study was to examine the degree of overlap between the connectivity maps derived for STN and GPi and a functional activation map representing the speech network. To do this, we examined the intersection of coactivation maps and their respective contrasts (STN > GPi and GPi > STN) with a coordinate-based meta-analysis of speech function. In conjunction with the speech map, both STN and GPi coactivation maps revealed overlap in the anterior insula with GPi map additionally showing overlap in the supplementary motor area (SMA). Among cortical regions activated by speech tasks, STN was found to have stronger connectivity than GPi with regions involved in cognitive linguistic processes (pre-SMA, dorsal anterior insula, and inferior frontal gyrus), while GPi demonstrated stronger connectivity to regions involved in motor speech processes (middle insula, SMA, and premotor cortex).


Spinal cord injury-induced changes in breathing are not due to supraspinal plasticity in turtles (Pseudemys scripta).
After occurrence of spinal cord injury, it is not known whether the respiratory rhythm generator undergoes plasticity to compensate for respiratory insufficiency. To test this hypothesis, respiratory variables were measured in adult semiaquatic turtles using a pneumotachograph attached to a breathing chamber on a water-filled tank. Turtles breathed room air (2 h) before being challenged with two consecutive 2-h bouts of hypercapnia (2 and 6% CO2 or 4 and 8% CO2). Turtles were spinalized at dorsal segments D8-D10 so that only pectoral girdle movement was used for breathing. Measurements were repeated at 4 and 8 wk postinjury. For turtles breathing room air, breathing frequency, tidal volume, and ventilation were not altered by spinalization; single-breath (singlet) frequency increased sevenfold. Spinalized turtles breathing 6-8% CO2 had lower ventilation due to decreased frequency and tidal volume, episodic breathing (breaths/episode) was reduced, and singlet breathing was increased sevenfold. Respiratory variables in sham-operated turtles were unaltered by surgery. Isolated brain stems from control, spinalized, and sham turtles produced similar respiratory motor output and responded the same to increased bath pH. Thus spinalized turtles compensated for pelvic girdle loss while breathing room air but were unable to compensate during hypercapnic challenges. Because isolated brain stems from control and spinalized turtles had similar respiratory motor output and chemosensitivity, breathing changes in spinalized turtles in vivo were probably not due to plasticity within the respiratory rhythm generator. Instead, caudal spinal cord damage probably disrupts spinobulbar pathways that are necessary for normal breathing.


Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein-protein interaction.
The discovery of new Protein-Protein Interaction (PPI) modulators is currently limited by the difficulties associated with the design and synthesis of selective small molecule inhibitors. Peptides are a potential solution for disrupting PPIs; however, they typically suffer from poor stability in vivo and limited tissue penetration hampering their wide spread use as new chemical biology tools and potential therapeutics. In this work, a combination of CuAAC chemistry, molecular modelling, X-ray crystallography, and biological validation allowed us to develop highly functionalised peptide PPI inhibitors of the protein CK2. The lead peptide, CAM7117, prevents the formation of the holoenzyme assembly in vitro, slows down proliferation, induces apoptosis in cancer cells and is stable in human serum. CAM7117 could aid the development of novel CK2 inhibitors acting at the interface and help to fully understand the intracellular pathways involving CK2. Importantly, the approach adopted herein could be applied to many PPI targets and has the potential to ease the study of PPIs by efficiently providing access to functionalised peptides.


Managing the right tension.
Of all the competing objectives every company faces, three pairs stand out: profitability versus growth, the short term versus the long term, and the whole organization versus the units. In each case, progress on one front usually comes at the expense of progress on the other. The authors researched the performance of more than 1000 companies worldwide over the past two decades and found that most struggle to succeed across the three tensions. From 1983 to 2003, for example, only 32% of these companies more often than not achieved positive profitability and revenue growth at the same time. The problem, the authors discovered, is not so much that managers don't recognize the tensions--those are all too familiar to anyone who has ever run a business. Rather, it is that managers frequently don't focus on the tension that matters most to their company. Even when they do identify the right tension, they usually make the mistake of prioritizing a "lead" objective within it-for example, profitability over growth. As a result, companies often end up moving first in this direction, then in that, and then back again, never quite resolving the tension. The companies that performed best adopted a very different approach. Instead of setting a lead objective, they looked at how best to strengthen what the two sides of each tension have in common: For profitability and growth,the common bond is customer benefit; for the short term and the long, it is sustainable earnings; and for the whole and its parts, it is particular organizational resources and capabilities. The authors describe how companies can select the right tension, what traps they may fall into when they focus on one side over the other, and how to escape these traps by managing to the bonds between objectives.


The Working Well Trial: baseline dietary and smoking behaviors of employees and related worksite characteristics. The Working Well Research Group.
The Working Well Trial, the largest randomized worksite health promotion trial to date, tests the effects of cancer prevention and control interventions on dietary and smoking behaviors of employees and the worksite environment. The trial is a 5-year cooperative agreement conducted in 57 matched pairs of worksites in 16 states by four study centers, a coordinating center, and the National Cancer Institute. The dual aims of this paper are to: (a) present a baseline description of the dietary and smoking habits of 20,801 employees, who are predominantly blue-collar workers; and (b) describe the social and physical environments of their worksites that may facilitate or hinder health behavior changes. The self-administered baseline survey of individuals consisted of a core set of questions common across all study centers on diet and smoking. The organizational survey consisted of eight instruments administered via interviews with key informants in each worksite. Continuous variable were analyzed by a mixed linear model and binary data were analyzed by the Generalized Estimating Equation. The population represented is largely male (67.5%) and blue collar (53.5%). Mean levels of fat and fiber intakes were close to the national averages (36.6% of calories as fat and 13.1 g of fiber). Smoking prevalence (25.2%) was slightly lower than the national average. The worksites had a high level of health promotion activities (42% had nutrition programs, 53% had smoking control programs), but lacked environmental support for dietary behavior change and perceived support for smoking cessation. These findings replicate and extend previous research results to a large sample of diverse, largely blue-collar worksites. In addition the baseline results lay a foundation for the development of new insights into the relationship between individual and organizational level variables that may interact to influence behavioral and cultural norms.