Reintroducing electrostatics into protein X-ray structure refinement: bulk solvent treated as a dielectric continuum.
Structural refinement of proteins involves the minimization of a target function that combines X-ray data with a set of restraints enforcing stereochemistry and packing. Electrostatic interactions are not ordinarily included in the target function, partly because they cannot be calculated reliably without a description of dielectric screening by solvent in the crystal. With the recent development of accurate implicit solvent models to describe this screening, the question arises as to whether a more detailed target function including electrostatic and solvation terms can yield more accurate structures or somewhat different structures of equivalent accuracy. The Generalized Born (GB) model is one such model that describes the solvent as a dielectric continuum, taking into account its heterogeneous distribution within the crystal. It is used here for X-ray refinements of three protein structures with experimental diffraction data to 2.4, 2.9 and 3.2 A, respectively. In each case, a higher resolution structure is available for comparison. The new target function includes stereochemical restraints, van der Waals, Coulomb and solvation interactions, along with the usual X-ray pseudo-energy term, which employs the likelihood estimator of Pannu and Read. Multiple simulated-annealing refinements were performed in torsion-angle space with a conventional target function and the new GB target function, yielding ensembles of refined structures. The new target function yields structures of similar accuracy, as measured by the free R factor, map/model correlations and deviations from the high-resolution structures. About 10% of side-chain conformations differ between the two sets of refinements, in the sense that the two ensembles of conformations do not completely overlap. Over 75% of the differences correspond to surface side chains. For one of the proteins, the GB set has a greater dispersion, indicating that for this case the conventional target function overestimates the true precision. As GB parameterization continues to improve, we expect that this approach will become increasingly useful.


Cytophagic histiocytic panniculitis. Systemic histiocytosis presenting as chronic, nonhealing, ulcerative skin lesions.
Systemic histiocytosis was found in a patient who presented with chronic, nodular, and ulcerative skin lesions. The patient's hospital course was complicated by persistent fever, thrombocytopenia, severe neutropenia, and coagulation abnormalities. Treatment consisted only of splenectomy and supportive care. Postoperatively, the patient's skin lesions and the fever, pancytopenia, and coagulopathy resolved. Marked proliferation of histologically benign macrophages was observed in dermal, splenic, hepatic, and lymphoid tissues; leukophagocytosis and erythrophagocytosis were clearly demonstrated. This illness is most consistent with cytophagic histiocytic panniculitis, a newly described syndrome.


A new efficient data structure for storage and retrieval of multiple biosequences.
Today's genome analysis applications require sequence representations allowing for fast access to their contents while also being memory-efficient enough to facilitate analyses of large-scale data. While a wide variety of sequence representations exist, lack of a generic implementation of efficient sequence storage has led to a plethora of poorly reusable or programming language-specific implementations. We present a novel, space-efficient data structure (GtEncseq) for storing multiple biological sequences of variable alphabet size, with customizable character transformations, wildcard support and an assortment of internal representations optimized for different distributions of wildcards and sequence lengths. For the human genome (3.1 gigabases, including 237 million wildcard characters) our representation requires only 2 + 8 × 10^-6bits per character. Implemented in C, our portable software implementation provides a variety of methods for random and sequential access to characters and substrings (including different reading directions) using an object-oriented interface. In addition, it includes access to metadata like sequence descriptions or character distributions. The library is extensible to be used from various scripting languages. GtEncseq is much more versatile than previous solutions, adding features that were previously unavailable. Benchmarks show that it is competitive with respect to space and time requirements.


Atypical meningoma: current management dilemmas and prospective clinical trials.
Atypical meningioma is an intermediate grade tumour with a greater risk of recurrence following surgical resection. Changes to the WHO classification have resulted in an increased reporting of these tumours. The role of early adjuvant radiotherapy after gross total resection has not been clearly defined and the literature evidence is of poor quality providing conflicting information. This review assesses the evidence for current clinical practice, management dilemmas and the need for prospective clinical trials for atypical meningioma.


The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling.
Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies.


Diagnostic Accuracy and Usability of the ECG247 Smart Heart Sensor Compared to Conventional Holter Technology.
Heart rhythm disorders, especially atrial fibrillation (AF), are increasing global health challenges. Conventional diagnostic tools for assessment of rhythm disorders suffer from limited availability, limited test duration time, and usability challenges. There is also a need for out-of-hospital investigation of arrhythmias. Therefore, the Norwegian ECG247 Smart Heart Sensor has been developed to simplify the assessment of heart rhythm disorders. The current study aimed to evaluate the diagnostic accuracy and usability of the ECG247 Smart Heart Sensor compared to conventional Holter monitors. Parallel tests with ECG247 Smart Heart Sensor and a Holter monitor were performed in 151 consecutive patients referred for out-of-hospital long-term ECG recording at Sorlandet Hospital Arendal, Norway. All ECG data were automatically analysed by both systems and evaluated by hospital physicians. Participants were asked to complete a questionnaire scoring usability parameters after the test. A total of 150 patients (62% men, age 54 (±17) years) completed the study. The ECG quality from both monitors was considered satisfactory for rhythm analysis in all patients. AF was identified in 9 (6%) patients during the period with parallel tests. The diagnostic accuracy for automatic AF detection was 95% (95% CI 91-98) for the ECG247 Smart Heart Sensor and 81% (95% CI 74-87) for the Holter system. The proportion of false-positive AF was 4% in tests analysed by the ECG247 algorithm and 16% in tests analysed by the Holter algorithm. Other arrhythmias were absent/rare. The system usability score was significantly better for ECG247 Smart Heart Sensor compared to traditional Holter technology (score 87.4 vs. 67.5, p < 0.001). The ECG247 Smart Heart Sensor showed at least comparable diagnostic accuracy for AF and improved usability compared to conventional Holter technology. ECG247 allows for prolonged monitoring and may improve detection of AF. This trial is registered with https://clinicaltrials.gov/ct2/show/NCT04700865.


[General concepts and pathogenesis of the spondyloarthropathies].
The spondyloarthritides are a group of interrelated diseases with a close association with the HLA-B27 antigen that share many common articular and extra-articular features. This paper summarizes the different classification criteria that are currently in use. While the exact pathogenesis of these diseases is not yet clearly elucidated, there are a number of hypotheses relating to HLA-B27, modifications of the microbiome and biomechanical stresses. This in turn leads to upregulation of various proinflammatory cytokines such as TNF-alpha, IL-17, IL-22 and IL-23, which results in further inflammation and osteoproliferation.


Adipose-Derived Stem Cells to Treat Ischemic Diseases: The Case of Peripheral Artery Disease.
Critical limb ischemia incidence and prevalence have increased over the years. However, there are no successful treatments to improve quality of life and to reduce the risk of cardiovascular and limb events in these patients. Advanced regenerative therapies have focused their interest on the generation of new blood vessels to repair tissue damage through the use of stem cells. One of the most promising sources of stem cells with high potential in cell-based therapy is adipose-derived stem cells (ASCs). ASCs are adult mesenchymal stem cells that are relatively abundant and ubiquitous and are characterized by a multilineage capacity and low immunogenicity. The proangiogenic benefits of ASCs may be ascribed to: (a) paracrine secretion of proangiogenic molecules that may stimulate angiogenesis; (b) secretion of microvesicles/exosomes that are also considered as a novel therapeutic prospect for treating ischemic diseases; and (c) their differentiation capability toward endothelial cells (ECs). Although we know the proangiogenic effects of ASCs, the therapeutic efficacy of ASCs after transplantation in peripheral artery diseases patients is still relatively low. In this review, we evidence the potential therapeutic use of ASCs in ischemic regenerative medicine. We also highlight the main challenges in the differentiation of these cells into functional ECs. However, significant efforts are still needed to ascertain relevant transcription factors, intracellular signaling and interlinking pathways in endothelial differentiation.


Effect of Oral Nutritional Supplementation With and Without Exercise on Nutritional Status and Physical Function of Adult Hemodialysis Patients: A Parallel Controlled Clinical Trial (AVANTE-HEMO Study).
Protein energy wasting affects the nutritional status (NS) and physical function (PF) of dialysis patients. Among the different anabolic strategies to improve NS and PF, oral nutritional supplementation (ONS) and resistance exercise (RE) or aerobic exercise (AE) have been shown to be effective. Nevertheless, the combination of both anabolic strategies has not been completely evaluated. The aim of this study is to assess the effect of exercise combined with ONS versus ONS without exercise during hemodialysis sessions on PF and NS indicators. Young hemodialysis patients (29 ± 9.3 years) with predominantly unknown causes of renal disease (80%) were divided into the following 3 groups during a period of 12 weeks: (1) ONS (n = 15), (2) ONS + RE (n = 15), and (3) ONS + AE (n = 15). Anthropometric, biochemical, PF, and quality of life measurements were recorded at baseline and after 3 months. Repeated measures analysis of variance and effect sizes (Cohen's d) were used to assess the effect of exercise and nutrition (ISRCTN registry 10251828). At the completion of the study, the ONS and ONS + RE groups exhibited statistically significant increases in body weight, body mass index, and in the percentage of fat mass (P < .05); the greatest effect sizes were observed in the ONS + RE group (d = 0.30 for body weight, d = 0.63 for body mass index, and d = 0.90 for the percentage of fat mass). Groups with RE and AE had statistically significant increases and large effect sizes in the six-minute walk test (RE: d = 0.94, P = .02; AE: d = 1.11, P = .03), sit-to-stand test (RE: d = 0.81, P = .041; AE: d = 1.20, P = .002), timed up and go test (RE: d = 1.04, P = .036; AE: d = 1.6, P = .000), and muscle strength (RE: d = 1.01, P = .000; AE: d = 0.60, P = .003). Regarding quality of life, the ONS + RE group had more areas of improvement at the end of the study, followed by the ONS + AE group. No statistically significant differences were found in the repeated measures ANOVA. The combination of exercise with ONS had larger effects on PF than on ONS alone. Further studies to examine the impact of exercise on the effect of oral nutritional supplementation in dialysis patients are indicated.


The cost of health professionals' brain drain in Kenya.
Past attempts to estimate the cost of migration were limited to education costs only and did not include the lost returns from investment. The objectives of this study were: (i) to estimate the financial cost of emigration of Kenyan doctors to the United Kingdom (UK) and the United States of America (USA); (ii) to estimate the financial cost of emigration of nurses to seven OECD countries (Canada, Denmark, Finland, Ireland, Portugal, UK, USA); and (iii) to describe other losses from brain drain. The costs of primary, secondary, medical and nursing schools were estimated in 2005. The cost information used in this study was obtained from one non-profit primary and secondary school and one public university in Kenya. The cost estimates represent unsubsidized cost. The loss incurred by Kenya through emigration was obtained by compounding the cost of educating a medical doctor and a nurse over the period between the average age of emigration (30 years) and the age of retirement (62 years) in recipient countries. The total cost of educating a single medical doctor from primary school to university is 65,997 US dollars; and for every doctor who emigrates, a country loses about 517,931 US dollars worth of returns from investment. The total cost of educating one nurse from primary school to college of health sciences is 43,180 US dollars; and for every nurse that emigrates, a country loses about 338,868 US dollars worth of returns from investment. Developed countries continue to deprive Kenya of millions of dollars worth of investments embodied in her human resources for health. If the current trend of poaching of scarce human resources for health (and other professionals) from Kenya is not curtailed, the chances of achieving the Millennium Development Goals would remain bleak. Such continued plunder of investments embodied in human resources contributes to further underdevelopment of Kenya and to keeping a majority of her people in the vicious circle of ill-health and poverty. Therefore, both developed and developing countries need to urgently develop and implement strategies for addressing the health human resource crisis.


The impact of meal timing on performance, sleepiness, gastric upset, and hunger during simulated night shift.
This study examined the impact of eating during simulated night shift on performance and subjective complaints. Subjects were randomized to eating at night (n=5; 23.2 ± 5.5 y) or not eating at night (n=5; 26.2 ± 6.4 y). All participants were given one sleep opportunity of 8 h (22:00 h-06:00 h) before transitioning to the night shift protocol. During the four days of simulated night shift participants were awake from 16:00 h-10:00 h with a daytime sleep of 6 h (10:00 h-16:00 h). In the simulated night shift protocol, meals were provided at ≈0700 h, 1900 h and 0130 h (eating at night); or ≈0700 h, 0930 h, 1410 h and 1900 h (not eating at night). Subjects completed sleepiness, hunger and gastric complaint scales, a Digit Symbol Substitution Task and a 10-min Psychomotor Vigilance Task. Increased sleepiness and performance impairment was evident in both conditions at 0400 h (p<0.05). Performance impairment at 0400 h was exacerbated when eating at night. Not eating at night was associated with elevated hunger and a small but significant elevation in stomach upset across the night (p<0.026). Eating at night was associated with elevated bloating on night one, which decreased across the protocol. Restricting food intake may limit performance impairments at night. Dietary recommendations to improve night-shift performance must also consider worker comfort.


[Spatial resolution of digital systems: is the visual determination with a lead bar pattern meaningful?].
The factors influencing the spatial resolution of digital detectors are discussed and demonstrated on simulated bar pattern images. Lead bar patterns are often used in quality control procedures to test the spatial resolution of image detectors. In digital imaging systems the pixelization of the detector interferes with the periodic bar pattern and makes it difficult to determine the resolution limit. Bar pattern images seem to have only limited value for characterizing the imaging performance of digital detector systems.


Current Imaging Strategies in Patients with Abdominal Aortic Aneurysms.
An abdominal aortic aneurysm (AAA) is defined as a localized dilatation of the abdominal aorta of ≥ 3 cm. With a prevalence of 4-8 %, AAA is one of the most common vascular diseases in Western society. Radiological imaging is an elementary component in the diagnosis, monitoring, and treatment planning of AAA patients. This is a narrative review article on preoperative imaging strategies of AAA, incorporating expert opinions based on the current literature and standard-of-care practices from our own center. Examples are provided to illustrate clinical cases from our institution. Radiological imaging plays a pivotal role in the initial diagnosis and monitoring of patients with AAA. Ultrasound is the mainstay imaging modality for AAA screening and surveillance. Contrast-enhanced CT angiography is currently considered the gold standard for preoperative imaging and image-based treatment planning in AAA repair. New non-contrast MR angiography techniques are robustly applicable and allow precise determination of aortic diameters, which is of critical importance, particularly with regard to current diameter-based surgical treatment guidelines. 3D imaging with multiplanar reformation and automatic centerline positioning enables more accurate assessment of the maximum aortic diameter. Modern imaging techniques such as 4D flow MRI have the potential to further improve individualized risk stratification in patients with AAA. · Ultrasound is the mainstay imaging modality for AAA screening and monitoring. · Contrast-enhanced CT angiography is the gold standard for preoperative imaging in AAA repair. · Non-contrast MR angiography allows for accurate monitoring of aortic diameters in AAA patients. · Measurement of aortic diameters is more accurate with 3D-CT/MRI compared to ultrasound. · Research seeks new quantitative imaging biomarkers for AAA risk stratification, e. g., using 4D flow MRI.


The role of chemokines and their receptors in ocular disease.
The migration and infiltration of cells into the eye whether blood-borne leucocytes, endothelial or epithelial cells occurs in many ocular diseases. Dysregulation of this process is apparent in chronic inflammation, corneal graft rejection, allergic eye disease and other sight-threatening conditions. Under normal and inflammatory conditions, chemokines and their receptors are important contributors to cell migration. To date, 47 chemokines and 19 chemokine receptors have been identified and characterised. In recent years, investigations into the role of chemokines and their receptors in ocular disease have generated an increasing number of publications. In the eye, the best understood action of these molecules has arisen from the study of their ability to control the infiltration of leucocytes in uveitis. However, the involvement of chemokines in angiogenesis in several ocular conditions and in the survival of corneal transplants demonstrates the multifaceted nature of their effects. Interestingly, the constitutive expression of chemokines and their receptors in ocular tissues suggests that certain chemokines have a homeostatic function. In this review, we discuss the nature and function of chemokines in health and disease, and describe the role of chemokines in the pathogenesis of different ocular conditions.


Medical Foods: Science, Regulation, and Practical Aspects. Summary of a Workshop.
On August 13-14, 2019, the Healthcare Nutrition Council and the ASN held the Medical Foods Workshop: Science, Regulation, and Practical Aspects. Medical food products help patients manage their disease and improve their quality of life. Yet many hurdles exist to getting patients new products. In this workshop, participants addressed some of these hurdles, with specific emphasis on topics like the statutory term distinctive nutritional requirements, the regulatory term modification of the diet alone, the role of clinical guidelines, the requirement that medical foods be used under medical supervision, and differentiation of foods for special dietary use from medical foods, as well as product innovation and future research. Real-world examples were discussed for intractable epilepsy, diabetes, end-stage renal disease, and inflammatory bowel disease.


[Aripiprazole-induced parkinsonism in a 64-year-old female patient diagnosed with bipolar disorder].
A 64-year-old female patient, diagnosed with bipolar disorder, developed parkinsonism 18 days after aripiprazole had been initiated. Twenty-six days after the patient had stopped taking aripiprazole the parkinson syndrome disappeared completely. Aripiprazole is usually associated with a low incidence of extrapyramidal symptoms. So far, little is known about the pathophysiology of parkinsonism and the possible role of aripiprazole. The case-study includes some hypotheses and recommendations.


The 4q27 locus and prostate cancer risk.
Chronic inflammation is considered to be implicated in the development of prostate cancer. In this study we are the first to investigate a potential association between variants in an autoimmune related region on chromosome 4q27 and prostate cancer risk. This region harbors two cytokine genes IL-2 and the recently described IL-21. We genotyped six variants previously associated with autoimmune disease (namely rs13151961, rs13119723, rs17388568, rs3136534, rs6822844 and rs6840978) and one functional IL-2 promoter variant (rs2069762) for possible association with prostate cancer risk using the Australian Risk Factors for Prostate Cancer case-control Study. Overall, our results do not support an association between the seven variants at position 4q27 and prostate cancer risk. Per allele odds ratios (ORs) were not significantly different from 1 (all P-values = 0.06). However, we found suggestive evidence for a significant association between the presence of the rs13119723 variant (located in a protein of unknown function) and men with a family history of prostate cancer in first-degree relatives (P-value for interaction 0.02). The per allele OR associated with this variant was significantly higher than 1 (2.37; 95% C.I. = 1.01-5.57). We suggest that genetic variation within the chromosome 4q27 locus might be associated with prostate cancer susceptibility in men with a family history of the disease. Furthermore, our study alludes to a potential role of unknown protein KIAA1109 in conferring this risk.


Functional morphological adaptations of the bony labyrinth in marsupials (Mammalia, Theria).
Diprotodontia represents the largest and ecologically most distinct order of marsupials occurring in Australasian being highly divers in size, locomotion, habitat preferences, feeding, and activity pattern. The spatial orientation in the habitat and therefore the three-dimensional space is detected by the vestibular system of the inner ear, more precisely by the three semicircular canals. In this study, we investigated the bony labyrinth of diprotodontian and selected non-diprotodontian marsupial mammals of almost all genera with noninvasive micro-CT scanning and 3D-reconstructions. In principal component analyses, the subterranean taxon can be separated from gliding and saltatorial taxa, whereas arboreal species can be separated from saltatorial specimens. The highest PCA loadings of this functional distinction are clearly found in the diameter of the semicircular canals, whereas the overall shape (height, width, length) of the semicircular canals is less important. Additionally, the investigated arboreal and fossorial species of South America are nested in the morphospace of the Australasian taxa. Even if a phylogenetic signal in the anatomy of the bony labyrinth cannot be excluded entirely, the main functional morphological signal of the vestibular system is found in the diameter of the semicircular canals. With the large dataset of extant marsupial mammals analysed here, the locomotion mode of extinct taxa can be inferred in future studies independent of any evidence of postcranial material.


Notoginsenoside R1 attenuates glucose-induced podocyte injury via the inhibition of apoptosis and the activation of autophagy through the PI3K/Akt/mTOR signaling pathway.
Injury to terminally differentiated podocytes contributes ignificantly to proteinuria and glomerulosclerosis. The aim of this study was to examine the protective effects of notoginsenoside R1 (NR1) on the maintenance of podocyte number and foot process architecture via the inhibition of apoptosis, the induction of autophagy and the maintenance pf podocyte biology in target cells. The effects of NR1 on conditionally immortalized human podocytes under high glucose conditions were evaluated by determining the percentage apoptosis, the percentage autophagy and the expression levels of slit diaphragm proteins. Our results revealed that NR1 protected the podocytes against high glucose-induced injury by decreasing apoptosis, increasing autophagy and by promoting cytoskeletal recovery. The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was further investigated in order to elucidate the mechanisms responsible for the protective effects of NR1 on podocytes. Our data indicated that treatment with NR increased the phosphorylation levels of PI3K, Akt and mTOR, leading to the activation of the PI3K/Akt/mTOR signaling pathway in podocytes. To the best of our knowledge, this is the first in vitro study to demonstrate that NR1 protects podocytes by activating the PI3K/Akt/mTOR pathway.


Folic acid-modified mesoporous silica nanoparticles with pH-responsiveness loaded with Amp for an enhanced effect against anti-drug-resistant bacteria by overcoming efflux pump systems.
Efflux pump system-mediated bacterial multidrug resistance is one of the main causes of antibiotic failure. Therefore, it is necessary to develop a novel nanocarrier that could effectively inhibit drug-resistant bacteria by increasing the intake and retention time of antibiotics. Herein, we constructed a pH-responsive nanocarrier (MSN@FA@CaP@FA) with double folic acid (FA) and calcium phosphate (CaP) covered on the surface of mesoporous silica (MSN) by electrostatic attraction and biomineralization, respectively. Afterward, loading the nanocomposites with ampicillin (Amp) effectively increased the uptake and reduced the efflux effect in Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by the specific targeting of FA. Moreover, Amp-MSN@FA@CaP@FA could specifically transport Amp to the bacterial infection site. Similarly, antibacterial experiments revealed that the Amp-MSN@FA@CaP@FA could significantly enhance the activity of Amp for inhibiting drug-resistant bacteria, without producing drug resistance. Additionally, the Amp-MSN@FA@CaP@FA could reduce the content of protein and inhibit the protein activity in drug-resistant bacteria, so that it destroyed the bacterial membrane and led to the bacteria death. In vivo antibacterial experiments showed that the Amp-MSN@FA@CaP@FA could effectively reduce the mortality of drug-resistant E. coli infection and promote wound healing of drug-resistant S. aureus infection. In summary, Amp-MSN@FA@CaP@FA has a potential for application in sustained-release nanostructures and to inhibit drug-resistant bacteria.


Promoting Physical Activity in Japanese Older Adults Using a Social Pervasive Game: Randomized Controlled Trial.
Pervasive games aim to create more fun and engaging experiences by mixing elements from the real world into the game world. Because they intermingle with players' lives and naturally promote more casual gameplay, they could be a powerful strategy to stimulate physical activity among older adults. However, to use these games more effectively, it is necessary to understand how design elements of the game affect player behavior. The aim of this study was to evaluate how the presence of a specific design element, namely social interaction, would affect levels of physical activity. Participants were recruited offline and randomly assigned to control and intervention groups in a single-blind design. Over 4 weeks, two variations of the same pervasive game were compared: with social interaction (intervention group) and with no social interaction (control group). In both versions, players had to walk to physical locations and collect virtual cards, but the social interaction version allowed people to collaborate to obtain more cards. Changes in the weekly step counts were used to evaluate the effect on each group, and the number of places visited was used as an indicator of play activity. A total of 20 participants were recruited (no social interaction group, n=10; social interaction group, n=10); 18 participants remained active until the end of the study (no social interaction group, n=9; social interaction group, n=9). Step counts during the first week were used as the baseline level of physical activity (no social interaction group: mean 46,697.2, SE 7905.4; social interaction group: mean 45,967.3, SE 8260.7). For the subsequent weeks, changes to individual baseline values (absolute/proportional) for the no social interaction group were as follows: 1583.3 (SE 3108.3)/4.6% (SE 7.2%) (week 2), 591.5 (SE 2414.5)/2.4% (SE 4.7%) (week 3), and -1041.8 (SE 1992.7)/0.6% (SE 4.4%) (week 4). For the social interaction group, changes to individual baseline values were as follows: 11520.0 (SE 3941.5)/28.0% (SE 8.7%) (week 2), 9567.3 (SE 2631.5)/23.0% (SE 5.1%) (week 3), and 7648.7 (SE 3900.9)/13.9% (SE 8.0%) (week 4). The result of the analysis of the group effect was significant (absolute change: η2=0.31, P=.04; proportional change: η2=0.30, P=.03). Correlations between both absolute and proportional change and the play activity were significant (absolute change: r=0.59, 95% CI 0.32 to 0.77; proportional change: r=0.39, 95% CI 0.08 to 0.64). The presence of social interaction design elements in pervasive games appears to have a positive effect on levels of physical activity. Japan Medical Association Clinical Trial Registration Number JMA-IIA00314; https://tinyurl.com/y5nh6ylr (Archived by WebCite at http://www.webcitation.org/761a6MVAy).


Medicinal plants for the prevention and treatment of bacterial infections.
Infectious diseases are a significant cause of morbidity and mortality worldwide, accounting for approximately 50% of all deaths in tropical countries and as much as 20% of deaths in the Americas. Despite the significant progress made in microbiology and the control of microorganisms, sporadic incidents of epidemics due to drug resistant microorganisms and hitherto unknown disease-causing microbes pose an enormous threat to public health. These negative health trends call for a global initiative for the development of new strategies for the prevention and treatment of infectious disease. For over 100 years chemical compounds isolated from medicinal plants have served as the models for many clinically proven drugs, and are now being re-assessed as antimicrobial agents. The reasons for this renaissance include a reduction in the new antibacterial drugs in the pharmaceutical pipeline, an increase in antimicrobial resistance, and the need of treatments for new emerging pathogens. Literally thousands of plant species have been tested against hundreds of bacterial strains in vitro and many medicinal plants are active against a wide range of gram positive and gram negative bacteria. However, very few of these medicinal plant extracts have been tested in animal or human studies to determine safety and efficacy. This review focuses on the medicinal plants and bacteria for which there is significant published in vitro, in vivo and clinical data available. The examples provided in this review indicate that medicinal plants offer significant potential for the development of novel antibacterial therapies and adjunct treatments (i.e. MDR pump inhibitors).


Mouse Trophoblast Cells Have Attenuated Responses to TNF-α and IFN-γ and Can Avoid Synergic Cytotoxicity of the Two Cytokines.
TNF-α and IFN-γ are two inflammatory cytokines that play critical roles in immune responses, but they can also negatively affect cell proliferation and viability. In particular, the combination of the two cytokines (TNF-α/IFN-γ) synergistically causes cytotoxicity in many cell types. We recently reported that mouse embryonic stem cells (ESCs) isolated from the blastocyst stage embryo do not respond to TNF-α and have limited response to IFN-γ, thereby avoiding TNF-α/IFN-γ cytotoxicity. The current study expanded our investigation to mouse trophoblast stem cells (TSCs) and their differentiated trophoblasts (TSC-TBs), the precursors and the differentiated cells of the placenta, respectively. In this study, we report that the combination of TNF-α/IFN-γ does not show the cytotoxicity to TSCs and TSC-TBs that otherwise effectively kills fibroblasts, similar to ESCs. Although ESCs, TSCs, and TSC-TBs are dramatically different in their growth rate, morphology, and physiological functions, they nevertheless share a similarity in being able to avoid TNF-α/IFN-γ cytotoxicity. We propose that this unique immune property may serve as a protective mechanism that limits cytokine cytotoxicity in the blastocyst. With molecular and cellular approaches and genome-wide transcriptomic analysis, we have demonstrated that the attenuated NF-κB and STAT1 transcription activation is a limiting factor that restricts the effect of TNF-α/IFN-γ on TSCs and TSC-TBs.


Network-based vaccination improves prospects for disease control in wild chimpanzees.
Many endangered wildlife populations are vulnerable to infectious diseases for which vaccines exist; yet, pragmatic considerations often preclude large-scale vaccination efforts. These barriers could be reduced by focusing on individuals with the highest contact rates. However, the question then becomes whether targeted vaccination is sufficient to prevent large outbreaks. To evaluate the efficacy of targeted wildlife vaccinations, we simulate pathogen transmission and control on monthly association networks informed by behavioural data from a wild chimpanzee community (Kanyawara N = 37, Kibale National Park, Uganda). Despite considerable variation across monthly networks, our simulations indicate that targeting the most connected individuals can prevent large outbreaks with up to 35% fewer vaccines than random vaccination. Transmission heterogeneities might be attributed to biological differences among individuals (e.g. sex, age, dominance and family size). Thus, we also evaluate the effectiveness of a trait-based vaccination strategy, as trait data are often easier to collect than interaction data. Our simulations indicate that a trait-based strategy can prevent large outbreaks with up to 18% fewer vaccines than random vaccination, demonstrating that individual traits can serve as effective estimates of connectivity. Overall, these results suggest that fine-scale behavioural data can help optimize pathogen control efforts for endangered wildlife.


Contrasting flowering phenology and species richness in abiotically and biotically pollinated angiosperms.
Biotic pollination is thought to correlate with increased interspecific competition for pollination among plants and a higher speciation rate. In this study we compared patterns of flowering phenology and species richness between abiotically (wind) and biotically pollinated plants, using phylogenetically independent contrasts. We compiled phenological data from eight local seasonal floras, in which we found geographically overlapping sister clades. Of 65 documented origins of wind pollination, we were able to use up to 17 independent contrasts. In contrast to previous studies we found no difference in global species richness between wind- and biotically pollinated sister clades. Regarding phenology, we found wider phenological spread in biotically pollinated clades, earlier flowering onset in wind-pollinated trees, but no difference in duration of flowering between pollination modes. These results corroborate previous views that niche space is more constrained for wind-pollinated species, and that niche partitioning is less important between wind-pollinated plants compared to plants pollinated by animals.


Assessing the sensitivity of habitats to fishing: from seabed maps to sensitivity maps.
In the Welsh part of the Irish Sea, a method was developed for assessing the sensitivity of different seabed habitats to existing fishing activities, across a range of potential fishing intensities. The resistance of 31 habitats and their associated biological assemblage to damage by 14 categories of fishing activity were assessed along with the rate at which each habitat would recover following impact (resilience). Sensitivity was scored based on a combination of the resistance of a habitat to damage and its subsequent rate of recovery. The assessments were based, wherever possible, on scientific literature, with expert judgement used to extrapolate results to habitat and gear combinations not directly examined in the published literature. The resulting sensitivity matrices were then subject to further peer review at a series of workshops. Following consensus on the habitat sensitivity, these data were combined with the most resolved sea-floor habitat maps. These habitat sensitivity maps can help inform the development of site-specific management plans, as well as having a place in spatial planning and aiding managers in developing dialogue with other stakeholders. A case study of their application is provided.


Anatomy and functionality of leptomeningeal anastomoses: a review.
This review seeks to provide a structured presentation of existing knowledge of leptomeningeal anastomoses from anatomic and functional points of view and to identify problems and possible research directions to foster a better understanding of the subject and of stroke mechanisms. Available data show that leptomeningeal anastomoses may be important in understanding stroke mechanisms and that leptomeningeal anastomoses play an important role in penumbra outcome. However, the literature shows no consensus between statements on the existence of leptomeningeal anastomoses and compensatory capacity. By analyzing the available literature and identifying the factors that contribute to this confusion, we found that variability and the functional consequences thereof are important but that quantitative data are lacking. Moreover, vascular remodeling is an issue to consider.


Cytomorphology of crystal storing histiocytosis in the breast associated with lymphoma: a case report.
Crystal storing histiocytosis (CSH) is a very rare immunoglobulin (Ig) deposition disorder in which macrophages accumulate light chains or Ig crystalline inclusions. It is frequently associated with lymphoproliferative disorders, but can be seen in some reactive conditions too. This article reports the cytomorphologic, histopathologic, and ancillary study findings of a marginal zone B cell lymphoma of the breast with CSH in a 54-year-old woman. To the best of our knowledge, this is the first report describing CSH in the breast and one of a few reports describing the cytomorphology of CSH. In breast fine-needle aspiration biopsies, CSH can be confused with benign processes such as fat necrosis and histiocytic lesions. Thus, awareness of this rare entity and its frequent association with lymphoproliferative disorders is useful in order to triage a specimen appropriately and exclude the possibility of a lymphoproliferative process.


Predicting the effect of prandial stage and particle size on absorption of ODM-204.
The prediction of absorption properties plays a key role in formulation development when the compound under development shows poor solubility and its absorption is therefore presumed to be solubility limited. In our work, we combined and compared data obtained from in vitro dissolution tests, transit intestinal model studies (TIM-1) and physiologically based pharmacokinetic modelling. Our aim was to determine the ability of these methods to predict performance of poorly soluble lipophilic weak base in vivo. The validity of the predictive methods was evaluated against the in vivo clinical pharmacokinetic (PK) data obtained after administration of the first test formulation, T1. The aim of our study was to utilize the models in evaluating absorption properties of the second test formulation, T2, which has not yet been clinically administered. The compound in the studies was ODM-204, which is a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. Owing to its physicochemical properties ODM-204 is prone to low or variable bioavailability. The models examined provided congruent data on dose dependent absorption, food effect at a dose of 200 mg and on the effect of API (active pharmaceutical ingredient) particle size on absorption. Our study shows that the predictive tools of in vitro dissolution, TIM-1 system and the PBPK (physiologically based pharmacokinetic) simulation, showed predictive power of different mechanisms of bioavailability and together provided valuable information for decision making.


The effect on patency of type, shape and volume of a vein collar used at the distal anastomis of PTFE-bypass to arteries below-knee.
The aim of this paper was to study the effect on patency rate of different types of vein collar (Miller's original or St Mary's boot), different length/height shapes of vein collar, and different vein collar volumes at the distal anastomosis of PTFE-bypass grafts to below-knee arteries in patients with critical limb ischemia. One hundred eighty patients operated on with PTFE-bypass to below-knee arteries with a vein collar at the distal anastomosis were analyzed. They were recruited from a prospective randomized trial evaluating the effect of adding a vein collar to the distal anastomosis. Primary patency rate of the reconstructions were assessed against three factors: the type, shape, and volume of the vein collar. Univariate analysis was performed with the help of plotted Kaplan-Meier lifetable curves and log-rank tests and multivariate analysis with Cox proportional hazards regression. Type of vein collar had no influence on primary patency (logrank-test, χ(2)=0.8, df=1, P=0.377, N.=180). A length/height ratio of the vein collar between 1.18 and 1.63 were advantageous for primary patency but the effect was not statistically significant (logrank-test, chisq=5.5, df=2, P=0.063, N.=177). A large volume of the vein collar enhanced primary patency (logrank-test, chisq=6, df=2, P=0.050, N.=173). In the multivariate analysis, however, a larger volume and a length/height ratio between 1.18 and 1.63 as well as > 1.63 reduce the risk of graft failure with 48% (P=0.00006), 58% (P=0.007), 58% (P=0.004), respectively, while vein collar type had no effect on primary patency. This prospective observational study indicates that if a vein collar is used at the distal anastomosis of a PTFE-bypass to below-knee arteries it should be long compared to height and large in volume to improve primary patency rate, while the type of vein collar does not appear to matter.


Contraindications to metformin therapy among patients with type 2 diabetes mellitus.
The biguanide, metformin, is a commonly prescribed oral antihyperglycemic agent. However, there are several clinical conditions that are considered as contraindications to the use of metformin among patients with type 2 diabetes mellitus. The aim of this study was to investigate the presence and nature of contraindications to metformin therapy among patients with type 2 diabetes mellitus. A retrospective study of the medical files of diabetic patients available at Alwosta clinic, north Palestine was carried out. Information about disease and medication profile of the patients was retrieved and analyzed using SPSS during the study period in 2004/2005. Focus was on metformin users who have contraindications to metfromin therapy. Presence and number of contraindications to metformin therapy. Two hundred and seventy-two type 2 diabetic patients were identified. One hundred and twenty four of those diabetic patients were metformin users. Approximately, 60% of patients in the metformin group had a least one contraindication. Congestive heart failure and renal impairment were the most quantitatively present contraindications. Contraindications to metformin therapy are common among type 2 diabetic patients and mostly disregarded. Patients have to be critically assessed before starting therapy and in case of metformin prescribing; dose should be adjusted based on the presence of risk factors for metformin adverse effects.


Associations between skill perceptions and young children's actual fundamental movement skills.
Given that children with low movement skill competence engage in less physical activity, it is important to understand how children's perceptions relate to actual movement competence. This study examined relationships between (i) children's self-perception and objective assessments of their movement skills (object control and locomotor) and (ii) parents' perceptions of the children's movement skills and objective assessment. Children's skill perceptions were assessed using the Pictorial Scale of Perceived Movement Skill Competence for Young Children. Parent perceptions of their child's skills were assessed using a modified version of this instrument. The Test of Gross Motor Development-2nd edition assessed children's skills objectively. Participants were 136 Australian children (51% boys; M=6.5 yr., SD=1.1) and 133 parents. Regression analyses (by sex) examined the relationship between perceptions and children's scores for actual skilled performance. Boys' perceptions were associated with their actual object control ability. Parents accurately perceived boys' object control ability and girls' locomotor ability, but not the reverse. This suggests interventions aiming to improve children's movement skills could target parents and be designed to teach parents how to recognize good and poor skill performance in their children.


Identification of introduced and stably inherited DNA methylation variants in soybean associated with soybean cyst nematode parasitism.
DNA methylation is a widespread epigenetic mark that contributes to transcriptome reprogramming during plant-pathogen interactions. However, the distinct role of DNA methylation in establishing resistant and susceptible responses remains largely unexplored. Here, we developed and used a pair of near-isogenic lines (NILs) to characterize DNA methylome landscapes of soybean roots during the susceptible and resistant interactions with soybean cyst nematode (SCN; Heterodera glycines). We also compared the methylomes of the NILs and their parents to identify introduced and stably inherited methylation variants. The genomes of the NILs were substantially differentially methylated under uninfected conditions. This difference was associated with differential gene expression that may prime the NIL responses to SCN infection. In response to SCN infection, the susceptible line exhibited reduced global methylation levels in both protein-coding genes and transposable elements, whereas the resistant line showed the opposite response, increased global methylation levels. Heritable and novel nonparental differentially methylated regions overlapping with genes associated with soybean response to SCN infection were identified and validated using transgenic hairy root system. Our analyses indicate that DNA methylation patterns associated with the susceptible and resistant interactions are highly specific and that novel and stably inherited methylation variants are of biological significance.


A physically motivated constitutive model for 3D numerical simulation of skeletal muscles.
A detailed numerical implementation within the FEM is presented for a physically motivated three-dimensional constitutive model describing the passive and active mechanical behaviors of the skeletal muscle. The derivations for the Cauchy stress tensor and the consistent material tangent are provided. For nearly incompressible skeletal muscle tissue, the strain energy function may be represented either by a coupling or a decoupling of the distortional and volumetric material response. In the present paper, both functionally different formulations are introduced allowing for a direct comparison between the coupled and decoupled isochoric-volumetric approach. The numerical validation of both implementations revealed significant limitations for the decoupled approach. For an extensive characterization of the model response to different muscle contraction modes, a benchmark model is introduced. Finally, the proposed implementation is shown to provide a reliable tool for the analysis of complex and highly nonlinear problems through the example of the human mastication system by studying bite force and three-dimensional muscle shape changes during mastication.


The role of the prostacyclin receptor antagonist RO3244019 in treating neurogenic detrusor overactivity after spinal cord injury in rats.
To determine the effects of the prostacyclin receptor (IP) antagonist RO3244019 on neurogenic detrusor overactivity (NDO) in spinal cord-injured (SCI) neurogenic bladder of the rat. Female Sprague-Dawley rats with SCI were divided into four treatment groups of eight each: vehicle (200 mm Tris base), indomethacin (3 mg/kg), RO3244019 (at 1 and 5 mg/kg). The conscious rats were assessed by cystometry, by slowly infusing the bladder with physiological normal saline at 0.04 mL/min. After 1 h of cystometry one of the four compounds was administered intravenously to the rats and changes in cystometrogram tracings recorded. Seven voiding variables were calculated before and after administering each compound: the intercontractile interval (ICI) for all contractions, voiding ICI, amplitude of all contractions, amplitude of voiding contractions, time to first void (TFV), voided volumes (VVs), and first VV. Data were analysed using a paired t-test for each of the experiments. At 1 mg/kg, the RO compound was associated with a statistically significant difference in the voiding ICI and VVs (both P < 0.05). The mean (sd) voiding ICI increased from 621 (140) to 889 (119) s (43% increase) and the VVs from 0.53 (0.13) to 0.72 (0.09) mL (36% increase). However, there was no statistically significant difference in the TFV or the first VVs. Increasing the dose to 5 mg/kg was more effective in improving the voiding ICI and the VVs (both P < 0.01). The voiding ICI increased from 716 (130) to 1346 (159) s (88% increase) and the VVs from 0.60 (0.11) to 1.05 (0.12) mL (75% increase). In addition, the higher dose had a statistically significant difference in the TFV (P < 0.05). There was more than a four-fold increase in the TFV, from 807 (138) to 3239 (883) s. At 5 mg/kg, the difference in the first VV before and after administering the compound was also almost statistically significant (P = 0.057); the first VV increased from 0.56 (0.14) to 1.01 (0.21) mL. There were no statistically significant differences in the amplitude of contractions or the ICI for all contractions for either of the dosages. Indomethacin at 3 mg/kg was the most effective compound for improving all of the voiding variables and was the only one to show a significant difference in the first VV. However, the IP antagonist at 5 mg/kg was almost as effective as indomethacin when comparing other variables, e.g. the voiding ICI and the VV. There was no statistically significant difference in any of the seven voiding variables before and after administering the vehicle. The IP antagonist RO3244019 was effective in treating NDO in SCI bladders. While RO3244019 at 1 mg/kg significantly increased the voiding ICI and VVs, 5 mg/kg appeared to be more effective, suggesting a dose-dependent effect of the drug. The RO compound at 5 mg/kg was almost as effective as indomethacin in improving all of the voiding variables.


Cultivating famine: data, experimentation and food security, 1795-1848.
Collecting seeds and specimens was an integral aspect of botany and natural history in the eighteenth century. Historians have until recently paid less attention to the importance of collecting, trading and compiling knowledge of their cultivation, but knowing how to grow and maintain plants free from disease was crucial to agricultural and botanical projects. This is particularly true in the case of food security. At the close of the eighteenth century, European diets (particularly among the poor) began shifting from wheat- to potato-dependence. In Britain and Ireland during these decades, extensive crop damage was caused by diseases like 'curl' and 'dry rot' - leading many agriculturists and journal editors to begin collecting data on potato cultivation in order to answer practical questions about the causes of disease and methods that might mitigate or even eliminate their appearance. Citizens not only produced the bulk of these data, but also used agricultural print culture and participation in surveys to shape and direct the interpretation of these data. This article explores this forgotten scientific ambition to harness agricultural citizen science in order to bring stability and renewed vitality to the potato plant and its cultivation. I argue that while many agriculturists did recognize that reliance upon the potato brought with it unique threats to the food supplies of Britain and Ireland, their views on this threat were wholly determined by the belief that the diseases attacking potato plants in Europe had largely been produced or encouraged by erroneous cultivation methods.


First serosurvey of Besnoitia spp. infection in wild European ruminants in Spain.
Besnoitia besnoiti has been reported to affect cattle, wildebeest, kudu and impala, and B. tarandi other wild ruminants (caribou, reindeer, mule deer and musk ox), causing similar characteristic clinical signs and lesions. However, both Besnoitia species have been reported in different geographical areas and the link between the sylvatic and domestic life cycles of Besnoita spp. in wild ruminants and cattle remains unknown. The aim of this study was to evaluate the presence of specific antibodies against Besnoitia spp. in wild ruminants in Spain. A wide panel of sera from red deer (Cervus elaphus) (n=734), roe deer (Capreolus capreolus) (n=124), chamois (Rupicapra pyrenaica) (n=170) and mouflon (Ovis musimon) (n=20) collected from different locations of Spain was analyzed. Beef cattle were present in all sampled areas and, interestingly, bovine besnoitiosis has been widely reported in some of them (e.g., Pyrenees and Central Spain). Sera samples were first examined with an Enzyme-Linked Immunosorbent Assay (ELISA). For red deer and roe deer, the ELISA was standardized with positive and negative control sera from several Cervidae species (100% Se and 98% Sp). Chamois and mouflon sera samples were tested with a previously reported ELISA validated for bovine sera (97% Se and 95% Sp) using protein G as a conjugate. Positive results by ELISA were confirmed a posteriori with a tachyzoite-based Western blot. Sixty-one sera samples from red deer and 17 sera samples from roe-deer were seropositive or doubtful by ELISA. All samples from mouflon were seronegative and 15 sera samples from chamois were considered doubtful. B. besnoiti exposure was only confirmed clearly by Western blot in one red deer and one roe deer from the Spanish Pyrenees where the disease is traditionally endemic. This is the first serological report of Besnoitia spp. infection carried out in European wild ruminants and the results show that specific antibodies are present at least in red deer and roe-deer. Thus, wild ruminants from endemic regions of bovine besnoitiosis should be further studied because they may be putative reservoirs of the parasite.


High-throughput microplate technique for enzymatic hydrolysis of lignocellulosic biomass.
Several factors will influence the viability of a biochemical platform for manufacturing lignocellulosic based fuels and chemicals, for example, genetically engineering energy crops, reducing pre-treatment severity, and minimizing enzyme loading. Past research on biomass conversion has focused largely on acid based pre-treatment technologies that fractionate lignin and hemicellulose from cellulose. However, for alkaline based (e.g., AFEX) and other lower severity pre-treatments it becomes critical to co-hydrolyze cellulose and hemicellulose using an optimized enzyme cocktail. Lignocellulosics are appropriate substrates to assess hydrolytic activity of enzyme mixtures compared to conventional unrealistic substrates (e.g., filter paper, chromogenic, and fluorigenic compounds) for studying synergistic hydrolysis. However, there are few, if any, high-throughput lignocellulosic digestibility analytical platforms for optimizing biomass conversion. The 96-well Biomass Conversion Research Lab (BCRL) microplate method is a high-throughput assay to study digestibility of lignocellulosic biomass as a function of biomass composition, pre-treatment severity, and enzyme composition. The most suitable method for delivering milled biomass to the microplate was through multi-pipetting slurry suspensions. A rapid bio-enzymatic, spectrophotometric assay was used to determine fermentable sugars. The entire procedure was automated using a robotic pipetting workstation. Several parameters that affect hydrolysis in the microplate were studied and optimized (i.e., particle size reduction, slurry solids concentration, glucan loading, mass transfer issues, and time period for hydrolysis). The microplate method was optimized for crystalline cellulose (Avicel) and ammonia fiber expansion (AFEX) pre-treated corn stover.


Quasi-stellar objects: possible local origin.
Many difficulties face the conventional interpretation of the red shift of quasars as a Hubble shift, with associated immense distances. These objects are not of galactic size or nature, and are not associated with galaxies or clusters of galaxies. The continuing energy source for such enormous powers for a period of 10(6) to 10(7) years has not been clearly revealed. The absence of the expected absorption for the Lyman-alpha spectral line of hydrogen is a new difficulty. Because of the relativistic limit on the diameter which can produce rapid fluctuations of light output, there may not be enough surface to radiate the required light.A similar and perhaps more serious difficulty exists for the fluctuating radio output. Calculations given here for synchrotron radiation self-absorption lead to a reasonably accurate formula for the angular diameter of a radio source. For the quasar 3C 273B these relations indicate a conflict with the usually assumed distance. However, the discrepancy may be explained in terms of strong variation of radio diameter with frequency. For CTA 102 the conflict is more serious, and could be explained -for cosmological distance-only by rejecting the data of Sholomitskii. These difficulties are removed by the hypothesis that the observed quasars were ejected from a gravitational collapse at the center of our own galaxy, which may have occurred roughly 5 million years ago. The resultant distances, of the order of a million lightyears, reduce the energy problem by a factor of 10(6) or 10(7). On this basis the optical diameter would be less than a light-hour, about the size of the earth's orbit. A rotating mass of a few thousand solar masses with this diameter would account for the unusual line width, could easily produce the required radiated energy, and could readily account for observed short fluctuation periods and variations in spectrum. It is suggested that the radio output may be produced by high-speed passage of the quasar through intergalactic gas. This would probably correspond to a radio size of a few light-years or less, in agreement with the fluctuations. Since the radio power would be considerably less than that of radio galaxies, it is suggested that radio galaxies may have ejected groups of quasars. This would explain the peculiarly distant locations of the radio sources for many such galaxies. The objections to this model that have been raised are apparently not fatal. In particular, the receding hydrogen cloud discovered by Koehler to be in the line of sight to 3C 273 is more plausibly interpreted as having been ejected from our own galaxy, in the manner observed for other galaxies, than as being associated with the Virgo cluster of galaxies. The latter interpretation, which would place 3C 273 further away, is in conflict with Lyman-alpha absorption data for 3C 9 and other quasars. Thus the local model seems to give a reasonable explanation not only of quasars but also of radio galaxies, bothv of which seem largely to defy explanation on other grounds. Whether or not this model is valid, it is clear that an understanding of quasars will radically change our understanding of the universe.


A wearable vibrotactile biofeedback system improves balance control of healthy young adults following perturbations from quiet stance.
Maintaining postural equilibrium requires fast reactions and constant adjustments of the center of mass (CoM) position to prevent falls, especially when there is a sudden perturbation of the support surface. During this study, a newly developed wearable feedback system provided immediate vibrotactile clues to users based on plantar force measurement, in an attempt to reduce reaction time and CoM displacement in response to a perturbation of the floor. Ten healthy young adults participated in this study. They stood on a support surface, which suddenly moved in one of four horizontal directions (forward, backward, left and right), with the biofeedback system turned on or off. The testing sequence of the four perturbation directions and the two system conditions (turned on or off) was randomized. The resulting reaction time and CoM displacement were analysed. Results showed that the vibrotactile feedback system significantly improved balance control during translational perturbations. The positive results of this preliminary study highlight the potential of a plantar force measurement based biofeedback system in improving balance under perturbations of the support surface. Future system optimizations could facilitate its application in fall prevention in real life conditions, such as standing in buses or trains that suddenly decelerate or accelerate.


Structural basis for allosteric regulation of GPCRs by sodium ions.
Pharmacological responses of G protein-coupled receptors (GPCRs) can be fine-tuned by allosteric modulators. Structural studies of such effects have been limited due to the medium resolution of GPCR structures. We reengineered the human A(2A) adenosine receptor by replacing its third intracellular loop with apocytochrome b(562)RIL and solved the structure at 1.8 angstrom resolution. The high-resolution structure allowed us to identify 57 ordered water molecules inside the receptor comprising three major clusters. The central cluster harbors a putative sodium ion bound to the highly conserved aspartate residue Asp(2.50). Additionally, two cholesterols stabilize the conformation of helix VI, and one of 23 ordered lipids intercalates inside the ligand-binding pocket. These high-resolution details shed light on the potential role of structured water molecules, sodium ions, and lipids/cholesterol in GPCR stabilization and function.


Losing a dime with a satisfied mind: positive affect predicts less search in sequential decision making.
We investigated the contribution of cognitive ability and affect to age differences in sequential decision making by asking younger and older adults to shop for items in a computerized sequential decision-making task. Older adults performed poorly compared to younger adults partly due to searching too few options. An analysis of the decision process with a formal model suggested that older adults set lower thresholds for accepting an option than younger participants. Further analyses suggested that positive affect, but not fluid abilities, was related to search in the sequential decision task. A second study that manipulated affect in younger adults supported the causal role of affect: Increased positive affect lowered the initial threshold for accepting an attractive option. In sum, our results suggest that positive affect is a key factor determining search in sequential decision making. Consequently, increased positive affect in older age may contribute to poorer sequential decisions by leading to insufficient search.


[Efficacy of antioxidant therapy in patients with acute and chronic purulent otitis media].
The examination of 90 patients referred to hospital for otitis media purulenta (OMP) and 25 healthy subjects included assessment of lipid peroxidation by content of malonic dialdehyde and intensity of chemoluminescence. Enzymes of antioxidant system were also measured (superoxide dismutase and catalase in blood plasma and wash-offs from the acoustic meatus and postoperative cavities). The measurements gave different values for the above parameters for healthy and OMP subjects. Conventional treatment reduced levels of LPO products and raised the activity of antioxidant enzymes, but control values were reached only in adjuvant parenteral administration of lipostabil and local administration of alpha-tocopherol. Also, earlier relief of clinical symptoms shortened the hospital stay.


MicroRNA Profiling Reveals Distinct Signatures in Degenerative Rotator Cuff Pathologies.
MicroRNAs (miRNAs) have emerged as key regulators orchestrating a wide range of inflammatory and fibrotic diseases. However, the role of miRNAs in degenerative shoulder joint disorders is poorly understood. The aim of this explorative case-control study was to identify pathology-related, circulating miRNAs in patients with chronic rotator cuff tendinopathy and degenerative rotator cuff tears (RCT). In 2017, 15 patients were prospectively enrolled and assigned to three groups based on the diagnosed pathology: (i) no shoulder pathology, (ii) chronic rotator cuff tendinopathy, and (iii) degenerative RCTs. In total, 14 patients were included. Venous blood samples ("liquid biopsies") were collected from each patient and serum levels of 187 miRNAs were determined. Subsequently, the change in expression of nine candidate miRNAs was verified in tendon biopsy samples, collected from patients who underwent arthroscopic shoulder surgery between 2015 and 2018. Overall, we identified several miRNAs to be progressively deregulated in sera from patients with either chronic rotator cuff tendinopathy or degenerative RCTs. Importantly, for the several of these miRNAs candidates repression was also evident in tendon biopsies harvested from patients who were treated for a supraspinatus tendon tear. As similar expression profiles were determined for tendon samples, the newly identified systemic miRNA signature has potential as novel diagnostic or prognostic biomarkers for degenerative rotator cuff pathologies. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. Inc. J Orthop Res 38:202-211, 2020.


Mechanisms of cell signaling and inflammation in Alzheimer's disease.
Alzheimer's disease, the most common neurodegenerative dementia in the elderly, affects cognition, behavior and functioning, and a prominent neuroinflammatory component likely contributes to disease pathogenesis. The epidemiology of AD has previously shown that NSAID use decreases the incidence of AD, and evidence from tissue culture, in vivo models, and Alzheimer brain tissue studies indicate that inflammation in AD is mediated by the production of proinflammatory molecules, leading to microglial activation and neuronal damage. Preliminary clinical drug trials of anti-inflammatory agents, such as indomethacin, suggest slowing of cognitive decline in AD, further supporting a role for inflammation. The basic mechanisms underlying the AD neuroinflammatory cascade, which might accelerate the development of AD neuropathology, are poorly understood, but several recent studies implicate a number of established signaling pathways in this process. Microglial activation might involve beta-amyloid binding and activation of cell surface immune and adhesion molecules such as CD45, CD40, CD36 and integrins, with the subsequent recruitment of Src family tyrosine kinases such as Fyn, Lyn and Syk kinases. ERK and MAPK pathways are then activated, which induces proinflammatory gene expression and leads to the production of cytokines and chemokines. These molecules may then contribute to synaptic pruning, damage and loss, while TNFalpha can induce neuronal apoptosis and injury. The production of interleukins and other cytokines and chemokines also may lead to microglial activation, astrogliosis, and further secretion of proinflammatory molecules and amyloid, thus perpetuating the cascade. Simultaneously, direct neuronal injury from amyloid-induced signaling also contributes to neurodegeneration. Of clinical relevance, components of these pathways may be suitable targets for therapeutic modulation in AD and for the development of novel disease-modifying anti-inflammatory therapy.


Transcriptome analysis reveals gene expression changes of pigs infected with non-lethal African swine fever virus.
African swine fever (ASF) is an important viral disease of swine caused by the African swine fever virus (ASFV), which threatens swine production profoundly. To better understand the gene expression changes when pig infected with ASFV, RNA sequencing was performed to characterize differentially expressed genes (DEGs) of six tissues from Kenya domestic pigs and Landrace × Yorkshire (L/Y) pigs infected with ASFV Kenya1033 in vivo. As results, a total of 209, 522, 34, 505, 634 and 138 DEGs (q-value < 0.05 and |Log2foldchange| values >2) were detected in the kidney, liver, mesenteric lymph node, peripheral blood mononuclear cell, submandibular lymph node and spleen, respectively. The expression profiles of DEGs shared in the multiple tissues illustrated variation in regulation function in the different tissues. Functional annotation analysis and interaction of proteins encoded by DEGs revealed that genes including IFIT1, IFITM1, MX1, OASL, ISG15, SAMHD1, IFINA1, S100A12 and S100A8 enriched in the immune and antivirus pathways were significantly changed when the hosts were infected with ASFV. The genes mentioned could play crucial roles in the process of the reaction to non-lethal ASF infection, which may will help to improve the ASF tolerance in the pig population through molecular breeding strategies.


Evaluating the menopausal transition with the STRAW + 10 in a Brazilian cohort of women with HIV, 2015-2016.
Menopausal transition is a physiological process encompassing hormonal and body changes that impact women's health and life quality. This period may be characterized by the Stages of Reproductive Aging Workshop (STRAW + 10) criteria using menstrual patterns. Use of the STRAW + 10 is uncertain in HIV infection. We aimed to characterize menopausal transition in women with HIV (WWH) using the STRAW + 10 criteria, hormonal measures and menopause symptoms. We performed a cross-sectional study, nested to the HIV-Infected Women's Cohort, in Rio de Janeiro, Brazil. Eligible women included those aged 30 years or older, without clinical or surgical menopause, hormonal contraception, replacement therapy and ovarian disorders. We conducted face-to-face interviews and collected blood samples for follicle stimulating hormone (FSH) and estradiol measures. We enrolled 328 WWH (28.3% of women in the cohort). The distribution of age, hormonal levels and reported symptoms per each STRAW + 10 stage was consistent with the expected distribution in the menopausal transition. Age and FSH significantly increased and estradiol decreased from stage -2 (7 + days of menstrual delay) to stage +2 (8 + years of amenorrhea). The present results support use of the STRAW + 10 to characterize the menopausal transition of WWH with good clinical and immunological control.


A benchmark for dose-finding studies with unknown ordering.
An important tool to evaluate the performance of a dose-finding design is the nonparametric optimal benchmark that provides an upper bound on the performance of a design under a given scenario. A fundamental assumption of the benchmark is that the investigator can arrange doses in a monotonically increasing toxicity order. While the benchmark can be still applied to combination studies in which not all dose combinations can be ordered, it does not account for the uncertainty in the ordering. In this article, we propose a generalization of the benchmark that accounts for this uncertainty and, as a result, provides a sharper upper bound on the performance. The benchmark assesses how probable the occurrence of each ordering is, given the complete information about each patient. The proposed approach can be applied to trials with an arbitrary number of endpoints with discrete or continuous distributions. We illustrate the utility of the benchmark using recently proposed dose-finding designs for Phase I combination trials with a binary toxicity endpoint and Phase I/II combination trials with binary toxicity and continuous efficacy.


What's in an object file? Evidence from priming studies.
Six experiments were conducted to investigate the nature of the contents of object files, temporary representations that store information about objects. Experiment 1 used a lexical priming paradigm with a lexical decision task, in which the prime and target could appear in either the same or different locations. The results indicated a greater priming effect when the prime and target appeared in the same location than when they appeared in different locations (object-or location-specific priming). Experiment 2 replicated these findings for objects that changed position during the display. Experiment 3 demonstrated that these findings reflected the inclusion of abstract identity information, rather than physical form, in object files. Three additional experiments tested for the presence of three types of semantic information (related concepts, semantic features, and category membership) in object files. No object-specific priming effects were found. Taken together, these experiments suggest that an object file includes identity information, but not semantic information. Implications of the results for object file theory are discussed.


Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia.
Sarcopenia, the age-associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability, and health care planning. A group of geriatricians and scientists from academia and industry met in Rome, Italy, on November 18, 2009, to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia may be a component of sarcopenia, the 2 conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1 m/s(-1). Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m·s(-1) and an objectively measured low muscle mass (eg, appendicular mass relative to ht(2) that is ≤ 7.23 kg/m(2) in men and ≤ 5.67 kg/m(2) in women). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization, and death.


Validity and clinical utility of DSM and empirically derived prototype diagnosis for personality disorders in predicting adaptive functioning.
Prototype matching, which involves comparing a patient clinical presentation with a prototype description of the disorder addresses some of the clinical limitations of the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases symptom-count approach. Here, we investigated the validity and clinical utility of three diagnostic systems in predicting patient adaptive functioning using a multimethod multi-informant approach. Specifically, we compared a prototype matching approach based on DSM criteria, an empirically derived prototype matching approach, and DSM symptom count diagnostic systems. A convenience sample of clinicians (N = 80) and patients (N = 170) participated in the study. We imposed minimal exclusion criteria for patient participation to maximize generalizability. Clinicians completed assessment of their active patients using two prototype matching diagnoses, one based on DSM and another that was empirically derived. Independent interviewers completed the Structured Clinical Interview to provide DSM symptom count. Patient global composite assessment of adaptive functioning, rated across the clinician, patient self-report, and independent interviewer, served as outcome variable. Prototype diagnosis for personality disorders, both one that is based on DSM criteria and one that was empirically derived, demonstrates some incremental validity over and above the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition symptom count, in predicting patient's adaptive functioning. Specifically, avoidant personality disorder prototype diagnosis significantly contributed to prediction of adaptive functioning. Furthermore, clinicians rated the prototype-matching approach as more useful in clinical practice compared with the current DSM-IV categorical approach. Using a dimensional approach, which is based on prototype matching that also preserves the advantages of categorical system offers a valid and efficient approach to psychiatric assessment for personality disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Research Questions and Outcomes Prioritized by Patients With Dry Eye.
Dry eye is a common ocular surface condition with significant influence on patient quality of life and societal economic burden. There is an urgent need to prioritize new research for dry eye. To identify and rank research questions and outcomes important to patients with dry eye. This study was conducted using the following 6 steps: (1) identifying research questions from a previous survey of clinicians who treat patients with dry eye; (2) identifying outcomes from existing research (systematic reviews and their cited clinical trials in the Cochrane Eyes and Vision US Satellite database of eyes and vision reviews, and National Eye Institute-funded clinical trials registered on ClinicalTrials.gov) as of June 13, 2017; (3) identifying a sample of patients with dry eye from the email subscribers to the online newsletter KeratoScoop; (4) and (5) conducting a 2-round Delphi survey of those patients online in November and December 2017, respectively; and (6) designating and ranking questions and outcomes as important. Importance assigned to research questions and outcomes for dry eye. A research question or outcome ranked by at least 75% of patients as 6 or higher on a scale of 0 to 10 was considered important. Among the 420 patients from 15 countries who completed both rounds of the Delphi survey, most were 60 years of age or older (233 [56%]), female (348 [83%]), white (393 [94%]), and of non-Hispanic ethnicity (398 [95%]). Among the 12 questions that clinicians had previously prioritized, patients rated 8 as important. The top 3 questions pertained to effectiveness of patient education, environmental modifications, and topical anti-inflammatory eye drops for dry eye. Among the 109 outcomes identified in existing research on dry eye, patients rated 26 as important. Ten of these 26 were unpopular in existing research, with fewer than 10% of 158 studies reporting these outcomes. Of the 10 most important outcomes, 9 were associated with symptoms or quality of life. The 3 outcomes rated most important by patients were ocular burning or stinging, ocular discomfort, and ocular pain. This study identified research questions and outcomes important to patients with dry eye. A considerable gap was noted between outcomes in existing research on dry eye and outcomes patients consider important. Future research on dry eye should consider addressing the important research questions and outcomes identified herein, taking into account the patient perspective.


Associations Among Childhood Trauma, Childhood Mental Disorders, and Past-Year Posttraumatic Stress Disorder in Military and Civilian Men.
To identify early life factors associated with posttraumatic stress disorder (PTSD), we investigated the association between childhood trauma and mental disorders with International Classification of Diseases (ICD)-diagnosed past-year PTSD in employed military and civilian men. Data were derived from the 2010 Australian Defence Force (ADF) Mental Health Prevalence and Wellbeing Study (N = 1,356) and the 2007 Australian Bureau of Statistics (ABS) National Survey of Mental Health and Wellbeing Study (N = 2,120) and analyzed using logistic regression and generalized structural equation modeling. After controlling for demographics, PTSD was associated with childhood anxiety, adjusted odds ratio (AOR) = 3.94, 95% CI [2.36, 6.58]; and depression, AOR = 7.01, 95% CI [2.98, 16.49], but not alcohol use disorders, in the ADF. In civilians, PTSD was associated with childhood anxiety only, AOR = 7.06, 95% CI [3.50, 14.22]. These associations remained significant after controlling for childhood and adult trauma in both populations and service factors and deployment, combat, or adult trauma in the ADF. In both populations, PTSD was associated with more than three types of childhood trauma: AOR = 2.97, 95% CI [1.53, 5.75] for ADF and AOR = 5.92, 95% CI [3.00, 11.70] for ABS; and childhood interpersonal, but not noninterpersonal, trauma: AOR = 3.08, 95% CI [1.61, 5.90] for ADF and AOR = 6.63, 95% CI [2.74, 16.06] for ABS. The association between childhood trauma and PTSD was fully mediated by childhood disorder in the ADF only. Taking a lifetime perspective, we have identified that the risk of PTSD from childhood trauma and disorder is potentially predictable and, therefore, modifiable.


Lack of evidence for cytoplasmic effects for four traits of Polypay sheep.
Analyses of birth and weaning weights, fleece weights of ewes, and number born per litter of Polypay sheep collected at the U.S. Sheep Experimental Station from 1978 through 1998, confirmed previous analyses of three other dual-purpose breeds that cytoplasmic effects do not contribute to variation in these four traits. In general, estimates of genetic parameters that would be needed for national genetic evaluation were similar to previous estimates for Columbia, Rambouillet, and Targhee sheep, although estimates of direct heritability for Polypay were somewhat less for birth weight, slightly greater for weaning weight, significantly greater for fleece weight, and the same for number born as for those three breeds. For birth weight only, evidence was found for important dam x year or dam x number born interactions, which are essentially litter effects, as was found for the other dual-purpose breeds. There were 11,896, 11,104, 7,748, and 7,831 records for birth and weaning weights, fleece weight, and number born per litter, with 255 to 316 sires of animals with records. There were 260 and 261 cytoplasmic lines for fleece weight and number born, and 861 and 882 for weaning and birth weights.


Kinematics and observer-animator kinematic similarity predict mental state attribution from Heider-Simmel style animations.
The ability to ascribe mental states, such as beliefs or desires to oneself and other individuals forms an integral part of everyday social interaction. Animations tasks, in which observers watch videos of interacting triangles, have been extensively used to test mental state attribution in a variety of clinical populations. Compared to control participants, individuals with clinical conditions such as autism typically offer less appropriate mental state descriptions of such videos. Recent research suggests that stimulus kinematics and movement similarity (between the video and the observer) may contribute to mental state attribution difficulties. Here we present a novel adaptation of the animations task, suitable to track and compare animation generator and -observer kinematics. Using this task and a population-derived stimulus database, we confirmed the hypotheses that an animation's jerk and jerk similarity between observer and animator significantly contribute to the correct identification of an animation. By employing random forest analysis to explore other stimulus characteristics, we reveal that other indices of movement similarity, including acceleration- and rotation-based similarity, also predict performance. Our results highlight the importance of movement similarity between observer and animator and raise new questions about reasons why some clinical populations exhibit difficulties with this task.


Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness.
We amplified RNAs from 63 fine needle aspiration (FNA) samples from 37 s.c. melanoma metastases from 25 patients undergoing immunotherapy for hybridization to a 6108-gene human cDNA chip. By prospectively following the history of the lesions, we could correlate transcript patterns with clinical outcome. Cluster analysis revealed a tight relationship among autologous synchronously sampled tumors compared with unrelated lesions (average Pearson's r = 0.83 and 0.7, respectively, P < 0.0003). As reported previously, two subgroups of metastatic melanoma lesions were identified that, however, had no predictive correlation with clinical outcome. Ranking of gene expression data from pretreatment samples identified approximately 30 genes predictive of clinical response (P < 0.001). Analysis of their annotations denoted that approximately half of them were related to T-cell regulation, suggesting that immune responsiveness might be predetermined by a tumor microenvironment conducive to immune recognition.


Caffeine as an analgesic adjuvant.
Thirty clinical studies involving more than 10,000 patients conducted during the last 20 years have been analyzed to assess the value of caffeine as an analgesic adjuvant. Although most studies included patients with postpartum uterine cramping or episiotomy pain, some involved patients with pain from oral surgery or headache. In 21 of 26 studies, the relative potency estimates of an analgesic with caffeine to an analgesic without caffeine is greater than one. The pooled relative potency estimates in each of several major categories of combination analgesics are significantly greater than one. The overall pooled relative potency estimate is 1.41, with 95% confidence limits of 1.23 to 1.63; that is, to obtain the same amount of response from an analgesic without caffeine requires a dose that is approximately 40% greater than one with caffeine.


Mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells early in chronic myelogenous leukemia.
Mobilization of Philadelphia (Ph) chromosome-negative progenitors is now possible in many Ph1-positive chronic myelogenous leukemia (CML) patients who had received interferon alfa (IFN-alpha) with no cytogenetic response. In this pilot study, we used this approach in patients without prior IFN-alpha therapy to determine if the number and quality of mobilized progenitors would be increased and to evaluate the potential effect of these cells as autografts. Twenty-two untreated patients were mobilized within 12 months of diagnosis. The treatment regimen consisted of the mini-ICE protocol. Beginning on day +8, granulocyte colony-stimulating factor (G-CSF) was used in all patients. Leukophoresis was performed as the patients were recovering from aplasia, when WBC count exceeded 0.8 x 10(9)/L. In 14 patients, (63%) the leukophoresis product was entirely Ph1-negative and in four patients the Ph1-positive cell rate was < or = 7%. Significant numbers of long-term culture-initiating cells (LTC-IC) and CD34+ Thy1+Lin- cells were found in most of the Ph1-negative collections that were tested. Twelve patients underwent autografting with their mobilized peripheral-blood progenitor cells (PBPC) (Ph1-negative collections, 10 patients; major cytogenetic response, two patients). All patients engrafted and are alive; six have Ph1-negative marrow 7 to 15 months after autografting. Posttransplant treatment was IFN-alpha combined with interleukin (IL)-2 because of the recent demonstration of synergistic activity in augmenting cytolytic activity. Intensive chemotherapy given in early chronic phase of CML is well tolerated and results in high numbers of circulating Ph1-negative precursor cells.


Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells.
Autophagy is an evolutionarily conserved pathway in which cytoplasmic contents are degraded and recycled. This study found that submicromolar concentrations of urolithin A, a major polyphenol metabolite, induced autophagy in SW620 colorectal cancer (CRC) cells. Exposure to urolithin A also dose-dependently decreased cell proliferation, delayed cell migration, and decreased matrix metalloproteinas-9 (MMP-9) activity. In addition, inhibition of autophagy by Atg5-siRNA, caspases by Z-VAD-FMK suppressed urolithin A-stimulated cell death and anti-metastatic effects. Micromolar urolithin A concentrations induced both autophagy and apoptosis. Urolithin A suppressed cell cycle progression and inhibited DNA synthesis. These results suggest that dietary consumption of urolithin A could induce autophagy and inhibit human CRC cell metastasis. Urolithins may thus contribute to CRC treatment and offer an alternative or adjunct chemotherapeutic agent to combat this disease.


Opportunities for injury reduction in US frontal crashes: an overview by structural engagement, vehicle class, and occupant age.
An overview NASS study of US frontal crashes was performed to investigate crash involvement, driver injury distributions and rates in airbag equipped vehicles by vehicle class and structural engagement. Frontal crash bins were based on taxonomy of structural engagement, i.e., Full Engagement, Offset, Between Rails and Corner impact crashes. A new classification of Corner impacts included frontal small overlap impacts with side damage as coded by NASS CDS. Belted drivers of two age groups, between 16 and 50 and over 50 years old, were considered. Vehicles were grouped into light and heavy passenger cars and lights trucks, and vans. A method to identify and address overly influential NASS weights was developed based on considerations of weighting factor statistics. The new taxonomy, with an expanded definition of corner impacts, allowed a more comprehensive classification of frontal crash modes. Results highlight the need to address upper extremities injuries and to better address lower extremities injuries for both the younger and older drivers. For all body regions studied, the vast majority of all serious and moderate injuries occurred in Full Engagement and Offset crash modes for both the younger and older drivers. Corner impacts, which have been the focus of recent research and testing programs, are the smallest contributors to serious and moderate injuries in frontal crashes. Greater opportunities to mitigate injuries in frontal crashes for vehicles have been shown to exist in lower speed full frontal and offset crash modes.


Distinct effects of acute exercise and breaks in sitting on working memory and executive function in older adults: a three-arm, randomised cross-over trial to evaluate the effects of exercise with and without breaks in sitting on cognition.
Sedentary behaviour is associated with impaired cognition, whereas exercise can acutely improve cognition. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cognition in older adults. Sedentary overweight/obese older adults with normal cognitive function (n=67, 67±7 years, 31.2±4.1 kg/m2) completed three conditions (6-day washout): SIT (sitting): uninterrupted sitting (8 hours, control); EX+SIT (exercise + sitting): sitting (1 hour), moderate-intensity walking (30 min), uninterrupted sitting (6.5 hours); and EX+BR (exercise + breaks): sitting (1 hour), moderate-intensity walking (30 min), sitting interrupted every 30 min with 3 min of light-intensity walking (6.5 hours). Cognitive testing (Cogstate) was completed at four time points assessing psychomotor function, attention, executive function, visual learning and working memory. Serum brain-derived neurotrophic growth factor (BDNF) was assessed at six time points. The 8-hour net area under the curve (AUC) was calculated for each outcome. Working memory net AUC z-score·hour (95% CI) was improved in EX+BR with a z-score of +28 (-26 to +81), relative to SIT, -25 (-79 to +29, p=0.04 vs EX+BR). Executive function net AUC was improved in EX+SIT, -8 (- 71 to +55), relative to SIT, -80 (-142 to -17, p=0.03 vs EX+SIT). Serum BDNF net AUC ng/mL·hour (95% CI) was increased in both EX+SIT, +171 (-449 to +791, p=0.03 vs SIT), and EX+BR, +139 (-481 to +759, p=0.045 vs SIT), relative to SIT, -227 (-851 to +396). A morning bout of moderate-intensity exercise improves serum BDNF and working memory or executive function in older adults, depending on whether or not subsequent sitting is also interrupted with intermittent light-intensity walking. ACTRN12614000737639.


Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis.
Targeted therapies for lung adenocarcinoma (LUAD) have improved patient outcomes; however, drug resistance remains a major problem. One strategy to achieve durable response is to develop combination-based therapies that target both mutated oncogenes and key modifiers of oncogene-driven tumorigenesis. This is based on the premise that mutated oncogenes, although necessary, are not sufficient for malignant transformation. We aimed to uncover genetic alterations that cooperate with mutant EGFR during LUAD development. We performed integrative genomic analyses, combining copy number, gene expression and mutational information for over 500 LUAD tumors. Co-immunoprecipitation and Western blot analysis were performed in LUAD cell lines to confirm candidate interactions while RNA interference and gene overexpression were used for in vitro and in vivo functional assessment. We identified frequent amplifications/deletions of chromosomal regions affecting the activity of genes specifically in the context of EGFR mutation, including amplification of the mutant EGFR allele and deletion of dual specificity phosphatase 4 (DUSP4), which have both previously been reported. In addition, we identified the novel amplification of a segment of chromosome arm 16p in mutant-EGFR tumors corresponding to increased expression of Golgi Associated, Gamma Adaptin Ear Containing, ARF Binding Protein 2 (GGA2), which functions in protein trafficking and sorting. We found that GGA2 interacts with EGFR, increases EGFR protein levels and modifies EGFR degradation after ligand stimulation. Furthermore, we show that overexpression of GGA2 enhances EGFR mediated transformation while GGA2 knockdown reduces the colony and tumor forming ability of EGFR mutant LUAD. These data suggest that overexpression of GGA2 in LUAD tumors results in the accumulation of EGFR protein and increased EGFR signaling, which helps drive tumor progression. Thus, GGA2 plays a cooperative role with EGFR during LUAD development and is a potential therapeutic target for combination-based strategies in LUAD.