Breaking the translational barriers: the value of integrating biomedical informatics and translational research.
The conduct of translational health research has become a vital national enterprise. However, multiple barriers prevent the effective translation of basic science discoveries into clinical and community practice. New information technology (IT) applications could help address these barriers. Unfortunately, owing to a combination of organizational, technical, and social factors, neither physician-investigators and research staff nor their clinical and community counterparts have harnessed such applications. Recently, at the request of the Institute of Medicine's Clinical Research Roundtable, a qualitative study of these factors was conducted at several leading academic medical centers. We explore the current status of IT in the translational research domain, describe the qualitative results, and conclude with a proposed set of initiatives to further increase the integration of IT into translational research.


The 2018 correlative microscopy techniques roadmap.
Developments in microscopy have been instrumental to progress in the life sciences, and many new techniques have been introduced and led to new discoveries throughout the last century. A wide and diverse range of methodologies is now available, including electron microscopy, atomic force microscopy, magnetic resonance imaging, small-angle x-ray scattering and multiple super-resolution fluorescence techniques, and each of these methods provides valuable read-outs to meet the demands set by the samples under study. Yet, the investigation of cell development requires a multi-parametric approach to address both the structure and spatio-temporal organization of organelles, and also the transduction of chemical signals and forces involved in cell-cell interactions. Although the microscopy technologies for observing each of these characteristics are well developed, none of them can offer read-out of all characteristics simultaneously, which limits the information content of a measurement. For example, while electron microscopy is able to disclose the structural layout of cells and the macromolecular arrangement of proteins, it cannot directly follow dynamics in living cells. The latter can be achieved with fluorescence microscopy which, however, requires labelling and lacks spatial resolution. A remedy is to combine and correlate different readouts from the same specimen, which opens new avenues to understand structure-function relations in biomedical research. At the same time, such correlative approaches pose new challenges concerning sample preparation, instrument stability, region of interest retrieval, and data analysis. Because the field of correlative microscopy is relatively young, the capabilities of the various approaches have yet to be fully explored, and uncertainties remain when considering the best choice of strategy and workflow for the correlative experiment. With this in mind, the Journal of Physics D: Applied Physics presents a special roadmap on the correlative microscopy techniques, giving a comprehensive overview from various leading scientists in this field, via a collection of multiple short viewpoints.


Fitness of transgenic mosquito Aedes aegypti males carrying a dominant lethal genetic system.
OX513A is a transgenic strain of Aedes aegypti engineered to carry a dominant, non-sex-specific, late-acting lethal genetic system that is repressed in the presence of tetracycline. It was designed for use in a sterile-insect (SIT) pest control system called RIDL® (Release of Insects carrying a Dominant Lethal gene) by which transgenic males are released in the field to mate with wild females; in the absence of tetracycline, the progeny from such matings will not survive. We investigated the mating fitness of OX513A in the laboratory. Male OX513A were as effective as Rockefeller (ROCK) males at inducing refractoriness to further mating in wild type females and there was no reduction in their ability to inseminate multiple females. They had a lower mating success but yielded more progeny than the wild-type comparator strain (ROCK) when one male of each strain was caged with a ROCK female. Mating success and fertility of groups of 10 males-with different ratios of RIDL to ROCK-competing for five ROCK females was similar, but the median longevity of RIDL males was somewhat (18%) lower. We conclude that the fitness under laboratory conditions of OX513A males carrying a tetracycline repressible lethal gene is comparable to that of males of the wild-type comparator strain.


Description of three new species of Moenkhausia (Teleostei, Characiformes, Characidae) with the definition of the Moenkhausia jamesi species complex.
From the examination of extensive comparative material currently identified as M. jamesi we verified that there are, at least, three new species under this name. These, along with M. jamesi and M. justae, form what we herein called the M. jamesi species complex, by sharing the following group of characters: a short maxilla, with its distal margin not exceeding anterior third of the second infraorbital; first through third teeth of the inner row of premaxilla and first and second dentary teeth with cusps arranged in a pronounced arch, humeral spot positioned between the fourth and seventh scales of the lateral line and extending up to four scale rows above the lateral line and one scale row below the lateral line, and a vertically oval to round spot at the base of the caudal fin rays. Moenkhausia ischyognatha sp. n., from Rio Xingu basin, differs from the other species of the complex by its lower head depth. Moenkhausia alesis sp. n., from the river system Tocantins-Araguaia, differs from M. jamesi, M. ischyognatha, and M. sthenosthoma by the number of scale rows above the lateral line. Moenkhausia sthenosthoma sp. n., from the Rio Madeira basin, differs from M. jamesi by the number of scale rows between the lateral line and the midventral scale series. Moenkhausia justae can be diagnosed from the other species of the complex by having a tri to pentacuspidate tooth on the maxilla.


Absence of IL-10 production by human PBMCs co-cultivated with human cells expressing or secreting retroviral immunosuppressive domains.
Immunosuppression by retroviruses including the human immunodeficiency virus-1 (HIV-1) is well known, however the mechanisms how retroviruses induce this immunosuppression is not fully investigated. It was shown that non-infectious retroviral particles as well as retroviral or recombinant retroviral transmembrane envelope (TM) proteins demonstrated immunosuppressive properties. The same was shown for peptides corresponding to a highly conserved domain in the TM protein. This domain is called immunosuppressive (ISU) domain and it induces modulation of the cytokine release of peripheral blood mononuclear cells (PBMCs) from healthy donors. In addition, it changes the gene expression of these cells. Common indications for the immunosuppressive activity were tumour growth in vivo and interleukin-10 (IL-10) release from human PBMCs in vitro. Single mutations in the ISU domain abrogated the immunosuppressive activity. In order to develop a new model system for the expression of the ISU domain and presentation to PBMCs which is not prone to possible endotoxin contaminations, two expression systems were developed. In the first system, designated pOUT, retroviral proteins containing the ISU domain were expressed and released into the cell culture medium, and in the second system, tANCHOR, the ISU domain was presented by a tetraspanin-anchored sequence on the cell surface of human cells. Both systems were exploited to express the wild-type (wt) ISU domains of HIV-1, of the porcine endogenous retrovirus (PERV) and of the murine leukaemia virus (MuLV) as well as to express mutants (mut) of these ISU domains. PERV is of special interest in the context of virus safety of xenotransplantation using pig organs. Expression of the TM proteins was demonstrated by confocal laser scanning microscopy, ELISA and Western blot analyses using specific antibodies. However, when cells expressing and releasing the ISU were co-incubated with human PBMCs, no increased production of IL-10 was observed when compared with the mutants. Similar results were obtained when the released TM proteins were concentrated by immunoprecipitation and added to PBMCs. We suggest that the absence of IL-10 induction can be explained by a low amount of protein, by the lack of a biologically active conformation or the absence of additional factors.


Hepatitis E virus sequences in swine related to sequences in humans, The Netherlands.
Hepatitis E virus (HEV), a major cause of viral hepatitis in much of the developing world, has recently been detected in swine in North America and Asia, raising concern about potential for zoonotic transmission. To investigate if HEV is commonly present in swine in the Netherlands, pooled stool samples from 115 swine farms and nine individual pigs with diarrhea were assayed by reverse transcription-polymerase chain reaction (RT-PCR) amplification. HEV RNA was detected by RT-PCR and hybridization in 25 (22%) of the pooled specimens, but in none of the individual samples. RT-PCR amplification products of open reading frames 1 and 2 were sequenced, and the results were compared with published sequences of HEV genotypes from humans and swine. HEV strains from swine in the Netherlands were clustered in at least two groups, together with European and American isolates from swine and humans. Our data show that HEV in swine in the Netherlands are genetically closely related to HEV isolates from humans. Although zoonotic transmission has not been proven, these findings suggest that swine may be reservoir hosts of HEV.


Sedentary behaviour and health in adults: an overview of systematic reviews.
The purpose of this overview of systematic reviews was to determine the relationship between different types and patterns of sedentary behaviour and selected health outcomes in adults and older adults. Five electronic databases were last searched in May, 2019, with a 10-year search limit. Included reviews met the a priori population (community-dwelling adults aged 18 years and older), intervention/exposure/comparator (various types and/or patterns of sedentary behaviour), and outcomes criteria. Eighteen systematic reviews were included in the evidence synthesis. High levels of sedentary behaviour are unfavourably associated with cognitive function, depression, function and disability, physical activity levels, and physical health-related quality of life in adults. Reducing or breaking up sedentary behaviour may benefit body composition and markers of cardiometabolic risk. Total sedentary behaviour and TV viewing were most consistently associated with unfavourable health outcomes, while computer and Internet use may be favourably associated with cognitive function for older adults. The quality of evidence within individual reviews (as assessed by review authors) varied from low to high, while the certainty of evidence was low to very low. These findings have important public health implications, suggesting that adults should avoid high levels of sedentary behaviour and break-up periods of prolonged sitting. (PROSPERO registration nos.: CRD42019123121 and CRD42019127157.) Novelty High levels of sedentary behaviour are unfavourably associated with important health outcomes in adults. Reducing or breaking up sedentary behaviour may benefit body composition and markers of cardiometabolic risk. Computer and Internet use may be favourably associated with cognitive function in older adults.


Epidemiology of hepatitis E virus infection in a cohort of 4023 immunocompromised patients.
The prevalence of active, chronic, and former hepatitis E virus (HEV) infections was investigated in a cohort of immunocompromised patients. The association with transfusion transmitted HEV was evaluated, and the HEV seroprevalence was compared with that in healthy blood donors. Serum samples from 4023 immunocompromised patients at Rigshospitalet, Denmark were retrospectively tested for HEV RNA and anti-HEV IgG. HEV RNA-positive patients were followed up by HEV testing, clinical symptoms, and transfusion history. Factors associated with anti-HEV were explored by multivariable logistic regression analysis. Samples from 1226 blood donors were retrospectively tested for anti-HEV IgG. HEV RNA was detected in six patients (0.15%) with no indications of chronic HEV infection. HEV RNA prevalence rates among recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantation (SOT) were 0.58% and 0.21%, respectively. Transfusion transmitted infections were refuted, and transfusion history was not associated with anti-HEV positivity. The difference in HEV seroprevalence between patients (22.0%) and blood donors (10.9%) decreased when adjusting for age and sex (odds ratio 1.20, 95% confidence interval 0.97-1.48). HEV viremia among allo-HSCT and SOT recipients suggests that clinicians should be aware of this diagnosis. The lack of association of blood transfusion with anti-HEV positivity supports food-borne transmission as the main transmission route of HEV common to both patients and blood donors.


Pulmonary embolism: accuracy and safety of a negative CT pulmonary angiogram and value of a negative D-dimer assay to exclude CT pulmonary angiogram-detectable pulmonary embolism.
This is a retrospective study to determine the accuracy and safety of a negative CT pulmonary angiogram (CTPA) based on clinical outcome and to determine the usefulness of a negative D-dimer assay before CTPA. A total of 483 patients with a negative CTPA study were followed up for 3 months, with the aim of detecting episodes of venous thromboembolism and mortality. Three hundred and forty-nine patients had an immunochromatographic D-dimer assay called 'Simplify', carried out before a CTPA examination. Seventy-eight patients had a negative D-dimer assay and a negative CTPA. Three patients had a negative D-dimer assay and a positive CTPA. All three patients had a moderate pretest clinical probability. Of the 483 patients who had a negative CTPA and a 3-month follow up, 444 (92%) were alive and 39 (8%) had died. Of the 444 patients who were alive, none had any further suspected episode of thromboembolism or had received anticoagulation therapy within the follow-up period. Of those who died, none of the deaths was thought to be as a result of pulmonary embolism (PE). Single-detector helical CT can be used safely as the primary diagnostic test to evaluate PE. Negative Simplify D-dimer assay and low pretest clinical probability exclude CTPA-detectable PE, and a CTPA is unnecessary in this cohort of patients.


Novel population-based study finding higher than reported hepatocellular carcinoma incidence suggests an updated approach is needed.
Hepatocellular carcinoma (HCC) incidence is rising rapidly in many developed countries. Primary epidemiological data have invariably been derived from cancer registries that are heterogeneous in data quality and registration methodology; many registries have not adopted current clinical diagnostic criteria for HCC and still rely on histology for classification. We performed the first population-based study in Australia using current diagnostic criteria, hypothesizing that HCC incidence may be higher than reported. Incident cases of HCC (defined by American Association for the Study of Liver Diseases diagnostic criteria or histology) were prospectively identified over a 12-month period (2012-2013) from the population of Melbourne, Australia. Cases were captured from multiple sources: admissions to any of Melbourne's seven tertiary hospitals; attendances at outpatients; and radiology, pathology, and pharmacy services. Our cohort was compared to the Victorian Cancer Registry (VCR) cohort (mandatory notified cases) for the same population and period, and incidence rates were compared for both cohorts. There were 272 incident cases (79% male; median age: 65 years) identified. Cirrhosis was present in 83% of patients, with hepatitis C virus infection (41%), alcohol (39%), and hepatitis B virus infection (22%) the commonest etiologies present. Age-standardized HCC incidence (per 100,000, Australian Standard Population) was 10.3 (95% confidence interval [CI]: 9.0-11.7) for males and 2.3 (95% CI: 1.8 to 3.0) for females. The VCR reported significantly lower rates of HCC: 5.3 (95% CI: 4.4 to 6.4) and 1.0 (95% CI: 0.7 to 1.5) per 100,000 males and females respectively (P < 0.0001). HCC incidence in Melbourne is 2-fold higher than reported by cancer registry data owing to under-reporting of clinical diagnoses. Adoption of current diagnostic criteria and additional capture sources will improve registry completeness. Chronic viral hepatitis and alcohol remain leading causes of cirrhosis and HCC.


Sleep-disordered breathing and the menopausal transition among participants in the Sleep in Midlife Women Study.
Menopause is widely believed to be an established cause of sleep disorders, but evidence for this theory is inconclusive. Attributing any sleep problem to normal processes of menopause may lead to underdiagnosis of treatable sleep disorders in midlife women. This study uses detailed longitudinal data on sleep and menopausal health from participants in the Sleep in Midlife Women Study to investigate whether risk and severity of sleep-disordered breathing increase with progression through menopause, accounting for changes in age and body habitus. A total of 219 women aged 38 to 62 years were recruited from participants in the Wisconsin Sleep Cohort Study. Menopause status was determined from daily diaries in which participants reported menstrual flow, hot flashes, and use of hormonal medications. Each participant underwent in-home polysomnography studies every 6 months, to measure the apnea-hypopnea index (AHI) (N = 1,667 studies). Linear models with empirical standard errors were fit for logarithm of AHI on menopause status and years in menopause, adjusting for age, body mass index, waist girth, and neck girth. Compared with women in premenopause, AHI was 21% higher among participants in perimenopause (95% CI, -4 to 54), 31% higher among participants in postmenopause (95% CI, 2-68), and 41% higher among participants whose menopausal stage could not be distinguished between peri- and postmenopause (95% CI, 8-82). Among women who had begun perimenopause, each additional year in menopause was associated with 4% greater AHI (95% CI, 2-6). Progression through menopause is associated with greater sleep-disordered breathing severity. This association is independent of aging and changes in body habitus.


Characterization of Lawsonia intracellularis gen. nov., sp. nov., the obligately intracellular bacterium of porcine proliferative enteropathy.
A novel obligately intracellular bacterium, ileal symbiont intracellularis, which was obtained from the intestines of pigs with proliferative enteropathy disease, was grown in pure cocultures with tissue cultures of rat cells. An examination of the 16S ribosomal DNA gene sequence revealed that the isolates which we obtained are members of the delta subdivision of the Proteobacteria and that the sequences of these organisms exhibit a level of similarly of 91% with the sequence of Desulfovibrio desulfuricans ATCC 27774. These isolates were homogeneous and differed in cellular morphology, acid fastness, phenotype, electrophoretic protein profile, and habitat from Desulfovibrio species. On the basis of the results of an integrated study of the phenotype and genotype of a consistent morphological entity found in particular porcine cells and associated with a well-defined clinical condition, we concluded that these bacteria belong to a previously undescribed genus and species, for which we propose the name Lawsonia intracellularis gen. nov., sp. nov. A species-specific recombinant DNA probe was cloned previously, and this probe was used to identify the bacterium in tissue culture cells and in the ileal epithelia of pigs with proliferative enteropathy disease. Coculture of the organism with a rat enterocyte cell line allowed us to designate strain NCTC 12656 the type strain and to describe the new genus and species. The organism which we cultured is pathogenic for pigs and causes proliferative enteropathy lesions in their ilea and colons, and Koch's postulates were fulfilled for this organism.


Adaptation aftereffects in single neurons of cat visual cortex: response timing is retarded by adapting.
Extracellular single-unit recordings were made from simple cells in area 17 of anesthetized cats. Cells were tested with drifting gratings under control and adapted conditions. Response amplitude and phase were measured as a function of either contrast or temporal frequency. Adapting not only reduces amplitude, but also retards phase. Adaptation alters the responses of simple cells in a particular way: the onset of the response to each cycle of a sinusoidally modulate stimulus is delayed. Once cells start to respond during each cycle, however, they generally recover to control levels, and the offset of the response is unaffected by adapting. The timing aftereffects are independent of the amplitude aftereffects. Timing aftereffects are tuned around the adapting temporal frequency, with a bias toward lower temporal frequencies. Adaptation thus modifies cortical responses even more specifically then previously thought. Firing rates are depressed primarily at response onset, even after several stimulus cycles have occurred following the end of adapting. Because all cells appear to adapt in this way, the data offer an opportunity to theorize about cortical connectivity. One implication is that inhibition onto a simple cell arises from other simple cells with similar response properties that fire a half-cycle out of phase with the target cell.


Interoceptive Pavlovian conditioning with nicotine as the conditional stimulus varies as a function of the number of conditioning trials and unpaired sucrose deliveries.
In rats, the pharmacological (interoceptive) effects of nicotine can serve as a signal (conditional stimulus) in a Pavlovian (classical) conditioning task. In this task, nicotine administration (0.4 mg base/kg, subcutaneous) is typically paired with intermittent access to a liquid sucrose unconditional stimulus; sucrose is withheld on saline sessions. An increase in sucrose receptacle entries (goal tracking) on nicotine sessions indicates conditioning. Given our limited understanding of the functional relationships controlling conditioned responding to a nicotine conditional stimulus, the present research examined nicotine's sensitivity to several manipulations shown to affect the conditioned responding in more widely studied Pavlovian conditioning tasks that use exteroceptive conditional stimuli: number of nicotine conditional stimulus-sucrose unconditional stimulus pairings per session (0, 3, 9, 18, or 36) and the impact of sucrose deliveries in saline sessions. Differential goal tracking developed in fewer sessions and asymptotic conditioned responding magnitude was greater with more nicotine-sucrose pairings. Further, goal tracking was more resistant to extinction (unconditional stimulus withheld) with more conditional-unconditional stimulus pairings during the acquisition phase. The discrimination was not acquired when sucrose presentations (9 or 18) also occurred during saline sessions. Furthermore, expression of the discrimination was disrupted when sucrose was presented in saline sessions; this disruption resulted from goal tracking in saline sessions. These results are consistent with the notion that nicotine-evoked goal tracking results from interoceptive conditioning processes.


Molecular Engineering of Pyrido[3,4-b]pyrazine-Based Donor-Acceptor-π-Acceptor Organic Sensitizers: Effect of Auxiliary Acceptor in Cobalt- and Iodine-Based Electrolytes.
Due to the ease of tuning its redox potential, the cobalt-based redox couple has been extensively applied for highly efficient dye-sensitized solar cells (DSSCs) with extraordinarily high photovoltages. However, a cobalt electrolyte needs particular structural changes in the organic dye components to obtain such high photovoltages. To achieve high device performance, specific requirements in the molecular tailoring of organic sensitizers still need to be met. Besides the need for large electron donors, studies of the auxiliary acceptor segment of donor-acceptor-π-acceptor (D-A-π-A) organic sensitizers are still rare in molecular optimization in the context of cobalt electrolytes. In this work, two novel organic D-A-π-A-type sensitizers (IQ13 and IQ17) have been developed and exploited in cobalt- and iodine-based redox electrolyte DSSCs, specifically to provide insight into the effect of π-bridge modification in different electrolytes. The investigation has been focused on the additional electron-withdrawing acceptor capability with grafted long alkoxy chains. Optoelectronic transient measurements have indicated that IQ17 containing a pyrido[3,4-b]pyrazine moiety bearing long alkoxyphenyl chains is more suitable for application in cobalt-based DSSCs.


Hofstadter Topology: Noncrystalline Topological Materials at High Flux.
The Hofstadter problem is the lattice analog of the quantum Hall effect and is the paradigmatic example of topology induced by an applied magnetic field. Conventionally, the Hofstadter problem involves adding ∼10^{4} T magnetic fields to a trivial band structure. In this Letter, we show that when a magnetic field is added to an initially topological band structure, a wealth of possible phases emerges. Remarkably, we find topological phases that cannot be realized in any crystalline insulators. We prove that threading magnetic flux through a Hamiltonian with a nonzero Chern number or mirror Chern number enforces a phase transition at fixed filling and that a 2D Hamiltonian with a nontrivial Kane-Mele invariant can be classified as a 3D topological insulator (TI) or 3D weak TI phase in periodic flux. We then study fragile topology protected by the product of twofold rotation and time reversal and show that there exists a higher order TI phase where corner modes are pumped by flux. We show that a model of twisted bilayer graphene realizes this phase. Our results rely primarily on the magnetic translation group that exists at rational values of the flux. The advent of Moiré lattices renders our work relevant experimentally. Due to the enlarged Moiré unit cell, it is possible for laboratory-strength fields to reach one flux per plaquette and allow access to our proposed Hofstadter topological phase.


Does presoaking synthetic mesh in antibiotic solution reduce mesh infections? An experimental study.
Prosthetic mesh infection is one of the most challenging complications after hernia repair. We evaluate the efficacy of soaking mesh in antibiotics to prevent prosthetic infection in an animal model of clean-contaminated ventral hernia repair (VHR). Rats underwent an acute VHR with one of four synthetic meshes (composite multifilament polyester (Parietex PCO), multifilament polyester (Parietex TET), composite monofilament polypropylene (Ventralight), or monofilament polypropylene (SoftMesh)). Prior to implantation, mesh was soaked in saline or 10 mg/ml of vancomycin for 15 min. Following implantation, meshes were contaminated with 10(4) CFU of methicillin-resistant Staphylococcus aureus (MRSA) bacteria. Thirty days after implantation, mesh samples were cultured and evaluated under scanning electron microscope for biofilm formation. Presoaking meshes significantly improves bacterial clearance in composite meshes and multifilament polyester mesh. MRSA clearance was as follows for all meshes (saline-soaked vs. vanco-soaked): Parietex PCO (0 vs. 56 %, p = 0.006), Parietex TET (0 vs. 50 %, p = 0.01), Ventralight (20 vs. 78 %, p = 0.012), and SoftMesh (70 vs. 80 %, p = 0.6). MRSA biofilm formation was consistent with bacterial growth. Presoaking multifilament and composite mesh in vancomycin solution reduces MRSA bacterial growth. Its implementation may reduce the risk of mesh infection in clean-contaminated cases, although further investigation with human trials should be performed.


Measurement of blood flow before and after embolization with use of fluorescent microspheres in an animal model.
Catheter-directed embolization has become a widespread technique for the treatment of benign and malignant neoplasms. The mechanism whereby embolization leads to selective atrophy of these neoplasms is largely speculative. As a potential model for the large regional perfusion differences between normal and neoplastic tissues, renal perfusion was studied before and after catheter-directed embolization. The working hypothesis was that embolization would create measurable changes in blood flow in the renal cortex and medulla. Microspheres (l0 microm in diameter) containing a series of different fluorophores were injected into the arterial system before and after the renal arteries were embolized with a series of larger (100-300 microm) particulate embolic agents. The distribution of the microspheres in the renal cortex, renal medulla, and liver was analyzed by fluorescence microscopy as well as by extraction of the fluorophores. The distribution of the fluorescent microspheres was readily assessed by fluorescence microscopy or extraction of the fluorophores. Before embolization, the renal cortex received approximately three times more flow than the medulla. After embolization, perfusion of the renal cortex and medulla decreased in parallel. Fluorescent microspheres are a powerful tool for measuring the changes in flow that occur after catheter-directed embolization. The fact that parallel decreases in flow were found in the renal cortex and medulla indicates that the distribution of each embolic agent was flow-directed. These results might provide insight into the mechanism of tumor atrophy after uterine artery embolization or hepatic chemoembolization.


PIRIN2 stabilizes cysteine protease XCP2 and increases susceptibility to the vascular pathogen Ralstonia solanacearum in Arabidopsis.
PIRIN (PRN) is a member of the functionally diverse cupin protein superfamily. There are four members of the Arabidopsis thaliana PRN family, but the roles of these proteins are largely unknown. Here we describe a function of the Arabidopsis PIRIN2 (PRN2) that is related to susceptibility to the bacterial plant pathogen Ralstonia solanacearum. Two prn2 mutant alleles displayed decreased disease development and bacterial growth in response to R. solanacearum infection. We elucidated the underlying molecular mechanism by analyzing PRN2 interactions with the papain-like cysteine proteases (PLCPs) XCP2, RD21A, and RD21B, all of which bound to PRN2 in yeast two-hybrid assays and in Arabidopsis protoplast co-immunoprecipitation assays. We show that XCP2 is stabilized by PRN2 through inhibition of its autolysis on the basis of PLCP activity profiling assays and enzymatic assays with recombinant protein. The stabilization of XCP2 by PRN2 was also confirmed in planta. Like prn2 mutants, an xcp2 single knockout mutant and xcp2 prn2 double knockout mutant displayed decreased susceptibility to R. solanacearum, suggesting that stabilization of XCP2 by PRN2 underlies susceptibility to R. solanacearum in Arabidopsis.


[The effect of parboiled rice on glycemia in Wistar rats].
Starch is an important energy source and can represent more than 60% of the calories of the human diet. The starch fraction resistant to enzymatic digestion is called resistant starch. When rice is parboiled, the starch retrogrades with the formation of type 3-resistant starch (retrograded), which presents beneficial effects on the health, since it acts as a prebiotic. In the present study three types of rice were selected, with high, medium and low amylose contents, with the objective of evaluating the effects of conventional and parboiled rice on glycemia in Wistar rats. The samples with high and medium amylose contents were soaked for 6 h at 65 degrees C, and the low amylose sample for 7 h at 70 degrees C. The samples were subsequently autoclaved for 10 minutes at 0.7kgf x cm(-2). Six male Wistar rats were used for each treatment. Seven experimental diets were elaborated, formulated according to AIN-93M, the control diet and diets substituting the carbohydrate source with conventional or parboiled rice. Resistant starch was determined in the diets and glycemia monitored using glucose paper strips, the sample being blood obtained from the distal part of the rat's tail. For the glycemic curve, glycemia was measured in the fasting state and during 90 minutes post-prandial. The results indicated there were no significant differences between the diets formulated with high, medium and low amylose, parboiled or conventionally prepared, with respect to fasting or post-prandial glycemia in Wistar rats.


Face exploration dynamics differentiate men and women.
The human face is central to our everyday social interactions. Recent studies have shown that while gazing at faces, each one of us has a particular eye-scanning pattern, highly stable across time. Although variables such as culture or personality have been shown to modulate gaze behavior, we still don't know what shapes these idiosyncrasies. Moreover, most previous observations rely on static analyses of small-sized eye-position data sets averaged across time. Here, we probe the temporal dynamics of gaze to explore what information can be extracted about the observers and what is being observed. Controlling for any stimuli effect, we demonstrate that among many individual characteristics, the gender of both the participant (gazer) and the person being observed (actor) are the factors that most influence gaze patterns during face exploration. We record and exploit the largest set of eye-tracking data (405 participants, 58 nationalities) from participants watching videos of another person. Using novel data-mining techniques, we show that female gazers follow a much more exploratory scanning strategy than males. Moreover, female gazers watching female actresses look more at the eye on the left side. These results have strong implications in every field using gaze-based models from computer vision to clinical psychology.


Spirituality and/or religious faith: A means for coping with the effects of amyotrophic lateral sclerosis/motor neuron disease?
The notion of spirituality/religious belief is recognized internationally as a domain within end-of-life care and is important in patients' and carers' quality-of-life. When faced with incurable illness, patients often become more philosophical about their life; many seek comfort in spiritual or religious philosophies. Our intention was to understand how personal spirituality and religious faith might help those living with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) cope with their impending death. Unsolicited narratives (internet and print-published) written by individuals diagnosed with the terminal condition of ALS/MND were analyzed thematically. Narratives from 161 individuals diagnosed with ALS/MND written over a period of 37 years (from 1968 to 2005) were included. Our findings reveal that religious faith sustains and helps people to avoid despair, and personal spirituality helps them make sense of what is happening to them. The use of personal narratives by people with ALS/MND has provided a vehicle for sharing their deepest spiritual and religious thoughts with others. The place of spirituality and religious faith within ALS/MND care should not be underestimated. Assessment of religious or spiritual needs should become a routine part of practice and is the responsibility of all members of the multidisciplinary team.


Characterization of the cell type-specific determinant in the genome of minute virus of mice.
Two strains of minute virus of mice (MVM) show different host cell specificities. The prototype strain MVM(p) grows in fibroblasts, whereas the immunosuppressive variant MVM(i) grows in T lymphocytes. In this study, we have mapped on the viral genome a cell type-specific determinant: it is located between 69 and 85 map units in a region coding for the viral capsid proteins. The DNA of MVM(p) does not replicate in lymphocytes. MVM(i) cannot help MVM(p) grow in lymphocytes; thus the determinant acts in a cis fashion. We did not detect viral mRNA during a restrictive infection of lymphocytes with MVM(p). However, when the same cells were transfected with cloned DNA, both MVM(p) and MVM(i) DNAs were transcribed with the same efficiency from both promoters and the RNA was processed normally. Therefore, the specificity determinant is not a cell type-specific enhancer.


Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial.
Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations. Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been conducted. To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations, antibiotic use for exacerbations and quality of life (QOL) (St George's Respiratory Questionnaire, SGRQ). Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and ≥2 pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18-85 years of age, baseline FEV1 ≥40% and ≤85% predicted and a baseline SGRQ score ≥30. 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol (rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022). SGRQ score was improved on mannitol compared with low-dose mannitol control (-2.4 units, p=0.046). Adverse events were similar between groups. Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated. NCT00669331.


Methicillin-Resistant Macrococcus bohemicus Encoding a Divergent SCCmecB Element.
A methicillin-resistant Macrococcus isolate from canine otitis, H889678/16/1, was whole-genome sequenced using HiSeq technology to identify the species, antimicrobial resistance determinates and their genomic context. H889678/16/1 belonged to the newly described species Macrococcus bohemicus. It encoded mecB within a novel SCCmec element most similar to that of Macrococcus canis KM45013T. This SCCmecH889678/16/1 element also encoded blaZm and fusC, but no other resistance determinates were found in the H889678/16/1 genome. The ccrA and ccrB recombinase genes within SCCmecH889678/16/1 were distinct from those previously described in staphylococci and macrococci and therefore designated here as ccrAm3 and ccrBm3. Our study represents, to the best of our knowledge, the first description of mecB being encoded by M. bohemicus and of methicillin resistance in this species. Furthermore, the SCCmec described here is highly dissimilar to other such elements and encodes novel ccr genes. Our report demonstrates a wider distribution of mecB among Macrococcus species and expands the genomic context in which mecB may be found. The potential for dissemination of mec genes from Macrococcus to related but more pathogenic Staphylococcus species highlights the need to understand the epidemiology of these genes in macrococci.


Shape-memory-actuated change in scaffold fiber alignment directs stem cell morphology.
Tissue engineering scaffolds have traditionally been static physical structures poorly suited to mimicking the complex dynamic behavior of in vivo microenvironments. Here we present a thermoresponsive scaffold that can be programmed to change macroscopic shape and microscopic architecture during cell culture. The scaffold, which was prepared by electrospinning a shape memory polymer (SMP), was used to test the hypothesis that a shape-memory-actuated change in scaffold fiber alignment could be used to control the behavior of attached and viable cells. To test this hypothesis, we stretched an SMP scaffold of randomly oriented fibers and fixed the scaffold in a temporary but stable elongated shape in which fibers were aligned by the strain. Following seeding and culture of human adipose-derived stem cells on the strain-aligned scaffold, the scaffold was triggered to transition back to its initial shape and random fiber orientation via shape memory actuation using a cytocompatible temperature increase. We found that cells preferentially aligned along the fiber direction of the strain-aligned scaffold before shape memory actuation. After shape memory actuation, cells remained attached and viable but lost preferential alignment. These results demonstrate that shape-memory-actuated changes in scaffold fiber alignment can be achieved with attached and viable cells and can control cell morphological behavior. The incorporation of shape memory into cytocompatible scaffolds is anticipated to facilitate the development, delivery and functionality of tissue engineering scaffolds and the in vitro and in vivo study and application of mechanobiology.


The anatomy of the extended peroneal venous system.
The fibula has deservedly become a workhorse flap for vascularized bone grafts. As with most flaps, much is known regarding idiosyncrasies of its arterial supply, and the corresponding venous system has generally been assumed to be comparable. Because this donor site has become increasingly versatile, a detailed anatomic study that would verify this latter assertion should be important. Therefore, venous mapping specifically of the peroneal venae comitantes was completed in 29 fresh lower limbs. In every specimen, paired venae comitantes of large caliber indeed paralleled the course of the peroneal artery. All were of quality satisfactory for microanastomoses, which should provide reassurance that preoperative evaluation of the peroneal venous system is not routinely indicated. However, anatomic variations proved to be the norm. The two venae comitantes did not necessarily coalesce into a single common peroneal vein [6 of 29 (21 percent)]. Usually, the lateral peroneal vein was the larger and continued proximally either alone (17 percent) or as the common peroneal vein (66 percent) to form the lateral tibioperoneal vena comitans. Thus, the venous pedicle of a fibula flap could be lengthened up to its confluence with the popliteal vein, a maneuver that potentially could obviate the need for a vein graft at least on the venous side. Although anomalies of the peroneal artery could preclude use of the fibula altogether, there appeared to be no such contraindications from a venous standpoint, despite the fact that the venous anatomy was unique in every individual. Some important similarities in patterns, though, do exist. For example, a common peroneal vein was formed by the juncture of the lateral peroneal vein and some combination of branches joining the lateral posterior tibial vein and medial peroneal vein in 63 percent of all limbs. Because exceptions are the rule, the choice of donor vein and venous pedicle length best remains an intraoperative decision dependent on the presenting anatomy.


Anti-Inflammatory and Anti-Nociceptive Activities of Stem-Bark Extracts and Fractions of Carpolobia Lutea (Polygalaceae).
In Niger Delta, ethnomedicine hydroalcoholic extract of Carpolobia lutea (CL) (Polygalaceae) is used to relieve inflammatory pains. The purpose of this study is to evaluate the anti-inflammatory and antinociceptive effects of ethanolic stem extract (ESE) and to fractionate the ESE for the elucidation of bioactive molecules. The antinociceptive effects for ESE were tested against two noxious stimuli; chemical (acetic acid-induced writhing and formalin-induced pain) and thermal (hot plate) stimuli. The effects of paracetamol (130 mg/kg), indomethacin (10 mg/kg), and morphine (5 mg/kg) pretreatment were investigated. To isolate the bioactive compounds with anti-inflammatory effect, two doses (86.6 and 173.2 mg/kg) of four fractions (methanol fraction MTF, ethyl acetate fraction EAF, chloroform fraction CHF, and n-hexane fraction n-HF) obtained from fractionating ESE were utilized. Carrageenan, egg albumin, and capsaicin-induced edema of the hind paw of the rats were the models adopted. Paw volume was measured by a digital vernier caliper from 0 to 6 h after injection. This was compared to standard drugs. The results were subjected to statistical analysis. The ESE decreased significantly (P < 0.001) the writhing of acetic acid-induced abdominal contractions and licking of formalin-induced pains but does not have any effects on the hot plate test. Of the four fractions obtained, the EAFs demonstrated a significant (P < 0.001) inflammatory inhibition of 98.97% and 41.91% at 86.6 and 173.2 mg/kg, respectively, compared to 65.75% inhibition demonstrated by the reference drug, acetylsalicylic acid (100 mg/kg) on the carrageenan model while 36.36% and 29.87% inhibition of inflammation at 86.6 and 173.2 mg/kg, respectively, on the egg albumin models; there was no significant effect on the capsaicin model. The isolation of quercetin and kaemferol from CL gave credence to its anti-inflammatory and antinociceptive effects.


Daptomycin versus vancomycin plus gentamicin for treatment of bacteraemia and endocarditis due to Staphylococcus aureus: subset analysis of patients infected with methicillin-resistant isolates.
In a prospective, randomized trial, daptomycin was non-inferior to standard therapy for Staphylococcus aureus bacteraemia and right-sided endocarditis. Since rates of infection due to methicillin-resistant S. aureus (MRSA) infection are increasing and treatment outcomes for bacteraemia caused by MRSA are generally worse than those observed with methicillin-susceptible S. aureus bacteraemia, clinical characteristics and treatment results in the trial's pre-specified subset of patients with MRSA were analysed. Clinical characteristics and outcomes of patients receiving daptomycin were compared with those receiving vancomycin plus low-dose gentamicin. Success was defined as clinical improvement with clearance of bacteraemia among patients who completed adequate therapy, received no potentially effective non-study antibiotics and had negative blood cultures 6 weeks after end of therapy. Twenty of the 45 (44.4%) daptomycin patients and 14 of the 43 (32.6%) vancomycin/gentamicin patients were successfully treated (difference 11.9%; confidence interval -8.3 to 32.1). Success rates for daptomycin versus vancomycin/gentamicin were 45% versus 27% in complicated bacteraemia, 60% versus 45% in uncomplicated bacteraemia and 50% versus 50% in right-sided MRSA endocarditis. Cure rates in patients with septic emboli and in patients who received pre-enrolment vancomycin were similar between treatment groups. However, in both treatment groups, success rates were lower in the elderly (>/=75 years). Persisting or relapsing bacteraemia occurred in 27% of daptomycin and 21% of vancomycin/gentamicin patients; among these patients, MICs of >/=2 mg/L occurred in five daptomycin and four vancomycin/gentamicin patients. The clinical course of several patients may have been influenced by lack of surgical intervention. Daptomycin was an effective alternative to vancomycin/gentamicin for MRSA bacteraemia or right-sided endocarditis.


Relation between cognitive dysfunction and pseudobulbar palsy in amyotrophic lateral sclerosis.
To examine the relation between cognitive dysfunction and pseudobulbar features in patients with amyotrophic lateral sclerosis (ALS). The performance of two patient groups, ALS with pseudobulbar palsy (n = 24) and ALS without pseudobulbar palsy (n = 28), was compared with 28 healthy age matched controls on an extensive neuropsychological battery. Tests used were the national adult reading test, short form of the WAIS-R, recognition memory test, Kendrick object learning test, paired associate learning, Wisconsin card sorting test, verbal fluency, Stroop and negative priming tests, a random movement joystick test, and a computerised Tower of Hanoi test. Tests of executive function showed a pronounced deficit on written verbal fluency in both ALS groups in comparison to controls, which tended to be more prominent in patients with ALS with pseudobulbar palsy. The random movement joystick test (a non-verbal test of intrinsic movement generation) showed an impairment in the generation of random sequences in patients with pseudobulbar palsy only. The computerised Tower of Hanoi showed a subtle planning impairment (shorter planning times) in all the patients with ALS compared with controls on trials requiring more complex solutions. In addition the pseudobulbar patients displayed shorter planning times on complex trials, and tended to solve these trials less accurately. There was also evidence of a deficit for all patients with ALS in comparison with controls on total errors and number of categories achieved on the Wisconsin card sorting test and a strong tendency towards an impairment on a task of selective attention and cognitive inhibition (negative priming). A word recognition memory deficit was showed across both ALS groups. This study elicited cognitive deficits (involving predominantly executive processes, with some evidence of memory impairment) in patients with ALS and further strengthened the link between ALS and frontal lobe dysfunction, this being more prominent in patients with pseudobulbar palsy. However, cognitive impairments suggestive of extramotor cortical involvement were not exclusive to this subgroup.


Are gene polymorphisms related to treatment outcomes of methotrexate in patients with rheumatoid arthritis? A systematic review and meta-analysis.
Identifying the predictors of responsiveness and adverse events in methotrexate (MTX) treated patients with rheumatoid arthritis (RA) has been the focus of most concern, but still without consistent consensus. PubMed and OVID EMBASE were searched to collect relevant studies that addressed correlations between gene polymorphisms and efficacy and/or toxicity in MTX-treated RA patients. Allelic, recessive, dominant and over-dominant model were applied. A total of 68 studies were included. For associations with efficacy, AMPD1 34C>T polymorphism was related to responsiveness in dominant model (odds ratio [OR]: 1.77; 95% CI: 1.19-2.63) and over-dominant model (OR: 1.59; 95% CI: 1.04-2.45). ATIC T675C polymorphism had association with responsiveness in recessive model (OR: 2.54; 95% CI: 1.23-5.26). For associations with toxicity, polymorphisms in TYMS 1494 del6 and FPGS rs10106 were correlated to absenting overall adverse events in recessive model (OR: 0.68; 95% CI: 0.49-0.95) and dominant model (OR: 0.54; 95% CI: 0.35-0.83) respectively while MTHFR C677T was associated with presenting overall adverse events in allelic model (OR: 1.29; 95% CI: 1.02-1.63), recessive model (OR: 1.38; 95% CI: 1.00-1.89) and dominant model (OR: 1.41; 95% CI: 1.02-1.94). Polymorphisms in AMPD1 34C>T and ATIC T675C predict responsiveness. The absence of TYMS 1494 del6 and FPGS rs10106 and presence of MTHFR C677T predict adverse events in RA patients treated with MTX. Moreover, variations of the associations were found between Caucasians and non-Caucasians.


Metabolic impact of education in NIDDM.
To evaluate the impact of a model program of diabetes education and weight reduction on diabetes control and weight loss in obese individuals with non-insulin-dependent diabetes mellitus (NIDDM). Eighty-two obese diabetic subjects were randomized to three levels of educational intensity: 1) a single individual session, 2) a 12-wk behavior-oriented diabetes education and weight control group intervention, or 3) group intervention plus six individual follow-up sessions. Repeated measures of weight, fasting blood glucose, and HbA1c were collected. Measures of diabetes knowledge, skills, and attitudes were also obtained. By 6 mo, all three intervention groups had a significant weight loss (P less than 0.01). The mean weight loss of approximately 10 lb was independent of treatment group and was maintained over the duration of the study. However, significant improvement in metabolic control was associated with participation in the diabetes education-weight reduction intervention. The findings of this study indicate that a cognitive behavioral group intervention of diabetes knowledge and weight reduction training can produce weight loss and improvements in diabetes control. The addition of individual counseling as a follow-up maintenance strategy does not appear to have any advantage.


Ligand-receptor co-evolution shaped the jasmonate pathway in land plants.
The phytohormone jasmonoyl-isoleucine (JA-Ile) regulates defense, growth and developmental responses in vascular plants. Bryophytes have conserved sequences for all JA-Ile signaling pathway components but lack JA-Ile. We show that, in spite of 450 million years of independent evolution, the JA-Ile receptor COI1 is functionally conserved between the bryophyte Marchantia polymorpha and the eudicot Arabidopsis thaliana but COI1 responds to different ligands in each species. We identified the ligand of Marchantia MpCOI1 as two isomeric forms of the JA-Ile precursor dinor-OPDA (dinor-cis-OPDA and dinor-iso-OPDA). We demonstrate that AtCOI1 functionally complements Mpcoi1 mutation and confers JA-Ile responsiveness and that a single-residue substitution in MpCOI1 is responsible for the evolutionary switch in ligand specificity. Our results identify the ancestral bioactive jasmonate and clarify its biosynthetic pathway, demonstrate the functional conservation of its signaling pathway, and show that JA-Ile and COI1 emergence in vascular plants required co-evolution of hormone biosynthetic complexity and receptor specificity.


Identification and characterization of antidepressant-sensitive serotonin transporter proteins using site-specific antibodies.
Serotonin (5HT) transporters (SERTs) are responsible for clearance of synaptic and plasma 5HT and are molecular targets for multiple therapeutic and addictive compounds. Recently brain and peripheral SERT cDNAs have been cloned and characterized functionally in transfected cells. Antipeptide (S365) and anti-fusion protein (CT-2) antibodies, directed at epitopes poorly conserved among other Na+/Cl- cotransporters, have been prepared to facilitate the identification and characterization of SERT proteins in native and transfected cells. Immunoprecipitations and immunoblots of rat/human SERT-transfected HeLa cells reveal specific SERT-immunoreactive glycoproteins absent from extracts of vector-transfected cells and absent when incubations were conducted using peptide- or fusion protein-absorbed antibody. In SDS-PAGE of membranes prepared from rat midbrain and cortex, SERTs migrate as single 76 kDa polypeptides with a relative abundance consistent with the known distribution of 5HT neurons and axonal projections. SERT-immunoreactive proteins are also detectable in platelet and pulmonary membranes, sites of peripheral 5HT uptake, but not in liver. Our studies also indicate that brain and platelet SERTs are formed from identical polypeptides differing significantly in their extent of N-linked glycosylation. Immunocytochemistry performed on rat brain sections with CT-2 antibody revealed SERT expression associated with brainstem raphe nuclei in a pattern virtually identical to that obtained by labeling adjacent sections with 5HT antisera. SERT-immunoreactive fibers were found to be widely distributed throughout the rodent brain, with highest density in forebrain regions known to receive a dense serotonergic innervation. In a similar manner, CT-2 antibody also detects endogenous expression of human SERT proteins, providing an opportunity for future studies on the modulation of transporter protein expression in neurologic and psychiatric disorders.


Nanoparticle flotation collectors II: the role of nanoparticle hydrophobicity.
The ability of polystyrene nanoparticles to facilitate the froth flotation of glass beads was correlated to the hydrophobicity of the nanoparticles. Contact angle measurements were used to probe the hydrophobicity of hydrophilic glass surfaces decorated with hydrophobic nanoparticles. Both sessile water drop advancing angles, θ(a), and attached air bubble receding angle measurements, θ(r), were performed. For glass surfaces saturated with adsorbed nanoparticles, flotation recovery, a measure of flotation efficiency, increased with increasing values of each type of contact angle. As expected, the advancing water contact angle on nanoparticle-decorated, dry glass surfaces increased with surface coverage, the area fraction of glass covered with nanoparticles. However, the nanoparticles were far more effective at raising the contact angle than the Cassie-Baxter prediction, suggesting that with higher nanoparticle coverages the water did not completely wet the glass surfaces between the nanoparticles. A series of polystyrene nanoparticles was prepared to cover a range of surface energies. Water contact angle measurements, θ(np), on smooth polymer films formed from organic solutions of dissolved nanoparticles were used to rank the nanoparticles in terms of hydrophobicity. Glass spheres were saturated with adsorbed nanoparticles and were isolated by flotation. The minimum nanoparticle water contact angle to give high flotation recovery was in the range of 51° < θ(np(min)) ≤ 85°.


Primary pericardial extragastrointestinal stromal tumor: A case report and literature review.
Gastrointestinal stromal tumors (GISTs) are the most prevalent mesenchymal tumors of the gastrointestinal tract. GISTs are considered to originate from the interstitial cells of Cajal, the pacemakers of the peristaltic activity of the gastrointestinal tract. More than 95% of GISTs express KIT protein and discovered on GIST-1. GISTs may also be encountered in locations outside the gastrointestinal tract, in which case they are referred to as extra-GISTs (EGISTs) and often behave more aggressively. This is the case report of a primary pericardial EGIST in a 53-year-old male patient, confirmed by immunohistochemistry. To the best of our knowledge, this is the third case of EGIST diagnosed above the diaphragm, without being associated with the esophageal wall. Two cases of primary EGIST arising from the pleura were reported previously. In addition, this is the first reported case of an EGIST originating from the pericardium.


SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.
Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.


Synthetic biology: insights into biological computation.
Organisms have evolved a broad array of complex signaling mechanisms that allow them to survive in a wide range of environmental conditions. They are able to sense external inputs and produce an output response by computing the information. Synthetic biology attempts to rationally engineer biological systems in order to perform desired functions. Our increasing understanding of biological systems guides this rational design, while the huge background in electronics for building circuits defines the methodology. In this context, biocomputation is the branch of synthetic biology aimed at implementing artificial computational devices using engineered biological motifs as building blocks. Biocomputational devices are defined as biological systems that are able to integrate inputs and return outputs following pre-determined rules. Over the last decade the number of available synthetic engineered devices has increased exponentially; simple and complex circuits have been built in bacteria, yeast and mammalian cells. These devices can manage and store information, take decisions based on past and present inputs, and even convert a transient signal into a sustained response. The field is experiencing a fast growth and every day it is easier to implement more complex biological functions. This is mainly due to advances in in vitro DNA synthesis, new genome editing tools, novel molecular cloning techniques, continuously growing part libraries as well as other technological advances. This allows that digital computation can now be engineered and implemented in biological systems. Simple logic gates can be implemented and connected to perform novel desired functions or to better understand and redesign biological processes. Synthetic biological digital circuits could lead to new therapeutic approaches, as well as new and efficient ways to produce complex molecules such as antibiotics, bioplastics or biofuels. Biological computation not only provides possible biomedical and biotechnological applications, but also affords a greater understanding of biological systems.


Electronic cigarettes for smoking cessation.
Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e-liquid. People who smoke report using ECs to stop or reduce smoking, but some organisations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This review is an update of a review first published in 2014. To evaluate the effect and safety of using electronic cigarettes (ECs) to help people who smoke achieve long-term smoking abstinence. We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO for relevant records to January 2020, together with reference-checking and contact with study authors. We included randomized controlled trials (RCTs) and randomized cross-over trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. To be included, studies had to report abstinence from cigarettes at six months or longer and/or data on adverse events (AEs) or other markers of safety at one week or longer. We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, AEs, and serious adverse events (SAEs). Secondary outcomes included changes in carbon monoxide, blood pressure, heart rate, blood oxygen saturation, lung function, and levels of known carcinogens/toxicants. We used a fixed-effect Mantel-Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data from these studies in meta-analyses. We include 50 completed studies, representing 12,430 participants, of which 26 are RCTs. Thirty-five of the 50 included studies are new to this review update. Of the included studies, we rated four (all which contribute to our main comparisons) at low risk of bias overall, 37 at high risk overall (including the 24 non-randomized studies), and the remainder at unclear risk. There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.25 to 2.27; I2 = 0%; 3 studies, 1498 participants). In absolute terms, this might translate to an additional four successful quitters per 100 (95% CI 2 to 8). There was low-certainty evidence (limited by very serious imprecision) of no difference in the rate of adverse events (AEs) (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs occurred rarely, with no evidence that their frequency differed between nicotine EC and NRT, but very serious imprecision led to low certainty in this finding (RR 1.37, 95% CI 0.77 to 2.41: I2 = n/a; 2 studies, 727 participants). There was moderate-certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.71, 95% CI 1.00 to 2.92; I2 = 0%; 3 studies, 802 participants). In absolute terms, this might again lead to an additional four successful quitters per 100 (95% CI 0 to 12). These trials used EC with relatively low nicotine delivery. There was low-certainty evidence, limited by very serious imprecision, that there was no difference in the rate of AEs between these groups (RR 1.00, 95% CI 0.73 to 1.36; I2 = 0%; 2 studies, 346 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 0.25, 95% CI 0.03 to 2.19; I2 = n/a; 4 studies, 494 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.50, 95% CI 1.24 to 5.04; I2 = 0%; 4 studies, 2312 participants). In absolute terms this represents an increase of six per 100 (95% CI 1 to 14). However, this finding was very low-certainty, due to issues with imprecision and risk of bias. There was no evidence that the rate of SAEs varied, but some evidence that non-serious AEs were more common in people randomized to nicotine EC (AEs: RR 1.17, 95% CI 1.04 to 1.31; I2 = 28%; 3 studies, 516 participants; SAEs: RR 1.33, 95% CI 0.25 to 6.96; I2 = 17%; 5 studies, 842 participants). Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate over time with continued use. Very few studies reported data on other outcomes or comparisons and hence evidence for these is limited, with confidence intervals often encompassing clinically significant harm and benefit. There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to ECs without nicotine and compared to NRT. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the degree of effect, particularly when using modern EC products. Confidence intervals were wide for data on AEs, SAEs and other safety markers. Overall incidence of SAEs was low across all study arms. We did not detect any clear evidence of harm from nicotine EC, but longest follow-up was two years and the overall number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up-to-date information for decision-makers, this review is now a living systematic review. We will run searches monthly from December 2020, with the review updated as relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.


Condom negotiation: findings and future directions.
The aim of this review was to summarize factors associated with condom negotiation among heterosexual men. Literature searches were conducted using multiple databases spanning several disciplines. Studies examining psychological, demographic, relational, communication, and environmental factors related to condom negotiation are described, and a three-dimensional framework of condom negotiation is proposed. This framework of condom negotiation may aid researchers in operationalizing this construct, organizing this literature, and facilitating measurement development. We used this three-dimensional framework to articulate the influence of gender, ethnicity, relationship type, partner characteristics, trauma history, post-traumatic stress, and alcohol use on condom negotiation. Areas for future research are outlined. More research is needed to understand how these factors interact to influence condom negotiation, as well as the interaction between gender and the identified factors.


Lophotrochozoan mitochondrial genomes.
Progress in both molecular techniques and phylogenetic methods has challenged many of the interpretations of traditional taxonomy. One example is in the recognition of the animal superphylum Lophotrochozoa (annelids, mollusks, echiurans, platyhelminthes, brachiopods, and other phyla), although the relationships within this group and the inclusion of some phyla remain uncertain. While much of this progress in phylogenetic reconstruction has been based on comparing single gene sequences, there are also higher order features of genomes, such as the relative order of genes, that have contributed, and this seems likely to be even more fruitful in the future. Even though tremendous progress is being made on the sequence determination of whole nuclear genomes, the dataset of choice for genome-level characters for many animals across a broad taxonomic range remains mitochondrial genomes. We review here what is known about mitochondrial genomes of the lophotrochozoans and how comparisons of some of these features may be useful in discerning the phylogeny of this group.


Optical aberrations described by an alternative series expansion.
Aberrations of optical systems are usually analyzed by decomposing the wavefront aberration at a pupil into a series of terms. The Seidel and Zernike series are two common examples, each with its own strengths and weaknesses. A new aberration series is proposed that combines some of the strengths of each. The new series is consistent with the traditional system of aberration types but enables the straightforward characterization and comparison of different optical systems, independent of pupil size or shape. Expressions for the conversion between the new and common aberration series are given, and the physical interpretations of the different aberrations are discussed.


Estimating risk in Medicare patients with THA: an electronic risk calculator for periprosthetic joint infection and mortality.
Although risk factors for periprosthetic joint infection (PJI) and mortality after total hip arthroplasty (THA) have been identified, interactions between specific patient risk factors are poorly understood. Therefore, it is difficult for surgeons to counsel patients on their individual risk of PJI or mortality after THA. We evaluated the interaction between patient clinical and demographic factors on the risk of PJI and mortality after THA and developed an electronic risk calculator for estimating the patient-specific risk of PJI and mortality in Medicare patients with THA. We used the Medicare 5% sample claims database to calculate the risk of PJI within 2 years and mortality within 90 days after THA in 53,252 Medicare patients with primary THAs between 1998 and 2009. Logistic regression using 29 comorbid conditions, age, sex, race, and socioeconomic status were used as inputs to develop an electronic risk calculator to estimate patient-specific risk of PJI and mortality after THA. The overall 2-year risk of PJI and 90-day risk of mortality after primary THA were 2.07% and 1.30%, respectively. White women aged 70 to 74 years with alcohol abuse, depression, electrolyte disorder, peptic ulcer disease, urinary tract infection, rheumatologic disease, preoperative anemia, cardiopulmonary (cardiac arrhythmia, congestive heart failure, ischemic heart disease, chronic pulmonary disease) comorbidities, and peripheral vascular disease were at highest risk for PJI. White women aged 65 to 69 years with electrolyte disorder, hemiplegia/paraplegia, hypertension, hypothyroidism, metastatic tumor, preoperative anemia, coagulopathy, cardiopulmonary (congestive heart failure, chronic pulmonary disease) and psychiatric (psychoses, depression) comorbidities, malignancies, and peripheral vascular disease were at highest risk for mortality. An electronic risk calculator was developed to estimate the risk of PJI and mortality in Medicare patients with THA. This electronic risk calculator can be used to counsel Medicare patients regarding their patient-specific risks of PJI and mortality after THA. Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.


Progesterone increases the release of brain-derived neurotrophic factor from glia via progesterone receptor membrane component 1 (Pgrmc1)-dependent ERK5 signaling.
Progesterone (P4) is cytoprotective in various experimental models, but our understanding of the mechanisms involved is still incomplete. Our laboratory has implicated brain-derived neurotrophic factor (BDNF) signaling as an important mediator of P4's protective actions. We have shown that P4 increases the expression of BDNF, an effect mediated by the classical P4 receptor (PR), and that the protective effects of P4 were abolished using inhibitors of Trk receptor signaling. In an effort to extend our understanding of the interrelationship between P4 and BDNF signaling, we determined whether P4 influenced BDNF release and examined the role of the classical PR and a putative membrane PR, progesterone receptor membrane component-1 (Pgrmc1), as mediators of this response. Given recent data from our laboratory that supported the role of ERK5 in BDNF release, we also tested whether P4-induced BDNF release was mediated by ERK5. In this study, we found that P4 and the membrane-impermeable P4 (P4-BSA) both induced BDNF release from cultured C6 glial cells and primary astrocytes. Both these cells lack the classical nuclear/intracellular PR but express high levels of membrane-associated PR, including Pgrmc1. Using RNA interference-mediated knockdown of Pgrmc1 expression, we determined that P4-induced BDNF release was dependent on the expression of Pgrmc1, although pharmacological inhibition of the PR failed to alter the effects of P4. Furthermore, the BDNF release elicited by P4 was mediated by ERK5, and not ERK1/2. Collectively, our data describe that P4 elicits an increase in BDNF release from glia via a Pgrmc1-induced ERK5 signaling mechanism and identify Pgrmc1 as a potential therapeutic target for future hormone-based drug development for the treatment of such degenerative diseases as Alzheimer's disease as well as other diseases wherein neurotrophin dysregulation is noted.


Application of colloid probe atomic force microscopy to the adhesion of thin films of viscous and viscoelastic silicone fluids.
The adhesive characteristics of thin films (0.2-2 μm) of linear poly(dimethylsiloxane) (PDMS) liquids with a wide range of molecular weights have been measured using an atomic force microscope with a colloid probe (diameters 5 and 12 μm) for different separation velocities. The data were consistent with a residual film in the contact region having a thickness of ∼6 nm following an extended dwell time before separation of the probe. It was possible to estimate the maximum adhesive force as a function of the capillary number, Ca, by applying existing theoretical models based on capillary interactions and viscous flow except at large values of Ca in the case of viscoelastic fluids, for which it was necessary to develop a nonlinear viscoelastic model. The compliance of the atomic force microscope colloid beam was an important factor in governing the retraction velocity of the probe and therefore the value of the adhesive force, but the inertia of the beam and viscoelastic stress overshoot effects were not significant in the range of separation velocities investigated.


Rhesus negative males have an enhanced IFNγ-mediated immune response to influenza A virus.
The Rhesus D antigen (RhD) has been associated with susceptibility to several viral infections. Reports suggest that RhD-negative individuals are better protected against infectious diseases and have overall better health. However, potential mechanisms contributing to these associations have not yet been defined. Here, we used transcriptomic and genomic data from the Milieu Interieur cohort of 1000 healthy individuals to explore the effect of Rhesus status on the immune response. We used the rs590787 SNP in the RHD gene to classify the 1000 donors as either RhD-positive or -negative. Whole blood was stimulated with LPS, polyIC, and the live influenza A virus and the NanoString human immunology panel of 560 genes used to assess donor immune response and to investigate sex-specific effects. Using regression analysis, we observed no significant differences in responses to polyIC or LPS between RhD-positive and -negative individuals. However, upon sex-specific analysis, we observed over 40 differentially expressed genes (DEGs) between RhD-positive (n = 384) and RhD-negative males (n = 75) after influenza virus stimulation. Interestingly these Rhesus-associated differences were not seen in females. Further investigation, using gene set enrichment analysis, revealed enhanced IFNγ signalling in RhD-negative males. This amplified IFNγ signalling axis may explain the increased viral resistance previously described in RhD-negative individuals.


Healthcare and disease burden among refugees in long-stay refugee camps at Lesbos, Greece.
To assess current medical problems at two Greek refugee sites at Lesbos island (Camp Moria and Caritas hotel), to explore which care is needed and to assess how the provided healthcare can be improved. In this dynamic cohort study all consecutive patients who visited doctors from the Boat Refugee Foundation were included. Treatment Rates (TR) with 95% Confidence Intervals (95% CI) were calculated for all major health issues. Additionally, the provided health care was evaluated using the SPHERE project standards. During the observation period of 30 March 2016 to 15 May 2016, 2291 persons were followed for a total of 289 person years (py). The median age of patients was 23.0 (IQR 8-38) years, 30.0% was aged <18. The healthcare demand was high with 3.6 patient visits per py. Upper respiratory tract infections were most commonly diagnosed with a TR of 89.6/100py (95% CI 78.7-10.1) followed by dental problems (TR 18.0/100py, 95% CI 13.1-22.9). The rate of suicide attempts was high at TR 1.4/100py (95% CI 0.03-2.8), and many psychological problems were diagnosed, TR 19.4/100py (95% CI 14.3-24.4). Major health care threats are the lack of a vaccination program, inadequate sanitation and hygiene, and severe overcrowding. This study can help policy makers and Non-Governmental Organizations decide which health care is needed most in the current European refugee crisis. There is an urgent need for mental and dental healthcare. Furthermore, it is crucial that vaccination programs are initiated and "hotspot" camps should transform in camps designed for long-stay situations.


Chemoselective Wittig and Michael ligations of unprotected peptidyl phosphoranes in water furnish potent inhibitors of caspase-3.
Unprotected peptidyl phosphoranes 1 with sequence Ac-L-aspartyl-L-glutamyl-L-valinyl-L-aspartyl are released from polymer support and react with aliphatic and aromatic aldehydes in aqueous medium in a Wittig ligation. Obtained vinyl ketones 6-12 are potent inhibitors of caspase-3. Vinyl ketone 6, derived from formaldehyde, undergoes Michael ligations with thiol nucleophiles furnishing products 14-16, also in aqueous medium. The demonstrated ligation reactions enable the modification of complex functionalized peptides in water providing bioactive protein ligands without side-chain protection.


Identification of determinants of the utilisation of acupuncture treatment using Andersen's behavioural model.
The utilisation of healthcare services is the result of a complex decision-making process with different determinants. This study aims to identify the determinants of the utilisation of acupuncture treatment using Andersen's behavioural model and quality of life. In this study we reviewed Korean Health Panel data, a nationally representative set of data, and analysed the utilisation of outpatient acupuncture services during 2011. A two-part model, which included predisposing, enabling and need factors of Andersen's behavioural model in model 1 and the additional factor of health-related quality of life (HRQOL, EQ-5D Korean index) in model 2, was analysed by logistic analysis to identify determinants of acupuncture service usage among subjects who visited traditional Korean medical clinics. The higher frequency of acupuncture service usage among patients who visited traditional Korean medical clinics was associated with gender, age, number of chronic diseases, physical disabilities and HRQOL of the subjects. This study shows that the important determinants of the frequency of acupuncture treatment utilisation are gender, age, number of chronic diseases and the presence of physical disabilities. Our findings contribute to understanding the characteristics of patients who use acupuncture treatment and may be used as a basic resource for related policy making by government officials and medical professionals.


Young calcareous soil chronosequences as a model for ecological restoration on alkaline mine tailings.
Tailings are artificial soil-forming substrates that have not been created by the natural processes of soil formation and weathering. The extreme pH environment and corresponding low availability of some macro- and micronutrients in alkaline tailings, coupled with hostile physical and geochemical conditions, present a challenging environment to native biota. Some significant nutritional constraints to ecosystem reconstruction on alkaline tailings include i) predominant or complete absence of combined nitrogen (N) and poor soil N retention; ii) the limited bioavailability of some micronutrients at high soil pH (e.g., Mn, Fe, Zn and Cu); and iii) potentially toxic levels of biologically available soil phosphorus (P) for P-sensitive plants. The short regulatory time frames (years) for mine closure on tailings landforms are at odds with the long time required for natural pedogenic processes to ameliorate these factors (thousands of years). However, there are similarities between the chemical composition and nutrient status of alkaline tailings and the poorly-developed, very young calcareous soils of biodiverse regions such as south-western Australia. We propose that basic knowledge of chronosequences that start with calcareous soils may provide an informative model for understanding the pedogenic processes required to accelerate soil formation on tailings. Development of a functional, stable root zone is crucial to successful ecological restoration on tailings, and three major processes should be facilitated as early as possible during processing or in the early stages of restoration to accelerate soil development on alkaline tailings: i) acidification of the upper tailings profile; ii) establishment of appropriate and resilient microbial communities; and iii) the early development of appropriate pioneer vegetation. Achieving successful ecological restoration outcomes on tailings landforms is likely one of the greatest challenges faced by restoration ecologists and the mining industry, and successful restoration on alkaline tailings likely depends upon careful management of substrate chemical conditions by targeted amendments.


Sub-crestal positioning of implants results in higher bony crest resorption: an experimental study in dogs.
To compare peri-implant soft- and hard-tissue integration at implants installed juxta- or sub-crestally. Furthermore, differences in the hard and soft peri-implant tissue dimensions at sites prepared with drills or sonic instruments were to be evaluated. Three months after tooth extraction in six dogs, recipient sites were prepared in both sides of the mandible using conventional drills or a sonic device (Sonosurgery(®)). Two implants with a 1.7-mm high-polished neck were installed, one with the rough/smooth surface interface placed at the level of the buccal bony crest (control) and the second placed 1.3 mm deeper (test). After 8 weeks of non-submerged healing, biopsies were harvested and ground sections prepared for histological evaluation. The buccal distances between the abutment/fixture junction (AF) and the most coronal level of osseointegration (B) were 1.6 ± 0.6 and 2.4 ± 0.4 mm; between AF and the top of the bony crest (C), they were 1.4 ± 0.4 and 2.2 ± 0.2 mm at the test and control sites, respectively. The top of the peri-implant mucosa (PM) was located more coronally at the test (1.2 ± 0.6 mm) compared to the control sites (0.6 ± 0.5 mm). However, when the original position of the bony crest was taken into account, a higher bone loss and a more apical position of the peri-implant mucosa resulted at the test sites. The placement of implants into a sub-crestal location resulted in a higher vertical buccal bone resorption and a more apical position of the peri-implant mucosa in relation to the level of the bony crest at implant installation. Moreover, peri-implant hard-tissue dimensions were similar at sites prepared with either drills or Sonosurgery(®).


Host restriction of Salmonella enterica serotype Typhi is not caused by functional alteration of SipA, SopB, or SopD.
Salmonella enterica serotype Typhi is a strictly human adapted pathogen that does not cause disease in nonprimate vertebrate hosts, while Salmonella enterica serotype Typhimurium is a broad-host-range pathogen. Serotype Typhi lacks some of the proteins (effectors) exported by the invasion-associated type III secretion system that are required by serotype Typhimurium for eliciting fluid secretion and inflammation in bovine ligated ileal loops. We investigated whether the remaining serotype Typhi effectors implicated in enteropathogenicity (SipA, SopB, and SopD) are functionally exchangeable with their serotype Typhimurium homologues. Serotype Typhi elicited fluid accumulation in bovine ligated ileal loops at levels similar to those elicited by a noninvasive serotype Typhimurium strain (the sipA sopABDE2 mutant) or by sterile culture medium. However, introduction of the cloned serotype Typhi sipA, sopB, and sopD genes complemented the ability of a serotype Typhimurium sipA sopABDE2 mutant to elicit fluid secretion in bovine ligated ileal loops. Introduction of the cloned serotype Typhi sipA, sopB, and sopD genes increased the invasiveness of a serotype Typhimurium sipA sopABDE2 mutant for human colon carcinoma epithelial (HT-29 and T84) cells and bovine kidney (MDBK) cells. Translational fusions between the mature TEM-1 beta-lactamase reporter and SipA or SopD demonstrated that serotype Typhi translocates these effectors into host cells. We conclude that the inability of serotype Typhi to cause fluid accumulation in bovine ligated ileal loops is not caused by a functional alteration of its SipA, SopB, and SopD effector proteins with respect to their serotype Typhimurium homologues.


Widespread correlation patterns of fMRI signal across visual cortex reflect eccentricity organization.
The human visual system can be divided into over two-dozen distinct areas, each of which contains a topographic map of the visual field. A fundamental question in vision neuroscience is how the visual system integrates information from the environment across different areas. Using neuroimaging, we investigated the spatial pattern of correlated BOLD signal across eight visual areas on data collected during rest conditions and during naturalistic movie viewing. The correlation pattern between areas reflected the underlying receptive field organization with higher correlations between cortical sites containing overlapping representations of visual space. In addition, the correlation pattern reflected the underlying widespread eccentricity organization of visual cortex, in which the highest correlations were observed for cortical sites with iso-eccentricity representations including regions with non-overlapping representations of visual space. This eccentricity-based correlation pattern appears to be part of an intrinsic functional architecture that supports the integration of information across functionally specialized visual areas.


Can urologists introduce the concept of "oligometastasis" for metastatic bladder cancer after total cystectomy?
We investigated whether the concept of oligometastasis may be introduced to the clinical management of metastatic bladder cancer patients. Our study population comprised 128 patients diagnosed with metastatic bladder cancer after total cystectomy at our 6 institutions between 2004 and 2014. We extracted independent predictors for identifying a favorable. Occurrence that fulfilled all 4 criteria which were independently associated with cancer-specific death was defined as oligometastasis: a solitary metastatic organ; number of metastatic lesions of 3 or less; the largest diameter of metastatic foci of 5cm or less; and no liver metastasis. We evaluated differences in clinical outcomes between patients with oligometastasis (oligometastasis group) and those without oligometastasis (non-oligometastasis group). Overall, there were 43 patients in the oligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 53.3%, which was significantly higher than that in the non-oligometastasis group (16.1%, p<0.001). A multivariate analysis revealed that non-oligometastasis (p<0.001), not performing salvage chemotherapy (p<0.001), and not performing metastatectomy (p=0.028) were independent risk factors for cancer-specific death. In the subgroup of 83 patients who received salvage chemotherapy, 30 were in the oligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 55.0%, which was significantly higher than that in the non-oligometastasis group (22.0%, p=0.005). Non-oligometastasis (p=0.009) was the only independent risk factor for cancer-specific death. We presented that urothelial carcinoma with oligometastasis had a favorable prognosis and responded to systemic chemotherapy. Oligometastasis may be treated as a separate entity in the field of metastatic urothelial carcinoma.


Controlling your impulses: electrical stimulation of the human supplementary motor complex prevents impulsive errors.
To err is human. However, an inappropriate urge does not always result in error. Impulsive errors thus entail both a motor system capture by an urge to act and a failed inhibition of that impulse. Here we show that neuromodulatory electrical stimulation of the supplementary motor complex in healthy humans leaves action urges unchanged but prevents them from turning into overt errors. Subjects performed a choice reaction-time task known to trigger impulsive responses, leading to fast errors that can be revealed by analyzing accuracy as a function of poststimulus time. Yet, such fast errors are only the tip of the iceberg: electromyography (EMG) revealed fast subthreshold muscle activation in the incorrect response hand in an even larger proportion of overtly correct trials, revealing covert response impulses not discernible in overt behavior. Analyzing both overt and covert response tendencies enables to gauge the ability to prevent these incorrect impulses from turning into overt action errors. Hyperpolarizing the supplementary motor complex using transcranial direct current stimulation (tDCS) preserves action impulses but prevents their behavioral expression. This new combination of detailed behavioral, EMG, and tDCS techniques clarifies the neurophysiology of impulse control, and may point to avenues for improving impulse control deficits in various neurologic and psychiatric disorders.


Assessment of movement quality in robot- assisted upper limb rehabilitation after stroke: a review.
: Studies of stroke patients undergoing robot-assisted rehabilitation have revealed various kinematic parameters describing movement quality of the upper limb. However, due to the different level of stroke impairment and different assessment criteria and interventions, the evaluation of the effectiveness of rehabilitation program is undermined. This paper presents a systematic review of kinematic assessments of movement quality of the upper limb and identifies the suitable parameters describing impairments in stroke patients. A total of 41 different clinical and pilot studies on different phases of stroke recovery utilizing kinematic parameters are evaluated. Kinematic parameters describing movement accuracy are mostly reported for chronic patients with statistically significant outcomes and correlate strongly with clinical assessments. Meanwhile, parameters describing feed-forward sensorimotor control are the most frequently reported in studies on sub-acute patients with significant outcomes albeit without correlation to any clinical assessments. However, lack of measures in coordinated movement and proximal component of upper limb enunciate the difficulties to distinguish the exploitation of joint redundancies exhibited by stroke patients in completing the movement. A further study on overall measures of coordinated movement is recommended.


Differences in Whole Blood Gene Expression Associated with Infection Time-Course and Extent of Fetal Mortality in a Reproductive Model of Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Infection.
Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infection of pregnant females causes fetal death and increased piglet mortality, but there is substantial variation in the extent of reproductive pathology between individual dams. This study used RNA-sequencing to characterize the whole blood transcriptional response to type 2 PRRSV in pregnant gilts during the first week of infection (at 0, 2, and 6 days post-inoculation), and attempted to identify gene expression signatures associated with a low or high level of fetal mortality rates (LFM and HFM; n = 8/group) at necropsy, 21 days post-inoculation. The initial response to infection measured at 2 days post-inoculation saw an upregulation of genes involved in innate immunity, such as interferon-stimulated antiviral genes and inflammatory markers, and apoptosis. A concomitant decrease in expression of protein synthesis and T lymphocyte markers was observed. By day 6 the pattern had reversed, with a drop in innate immune signaling and an increase in the expression of genes involved in cell division and T cell signaling. Differentially expressed genes (DEGs) associated with extremes of litter mortality rate were identified at all three time-points. Among the 15 DEGs upregulated in LFM gilts on all three days were several genes involved in platelet function, including integrins ITGA2B and ITGB3, and the chemokine PF4 (CXCL4). LFM gilts exhibited a higher baseline expression of interferon-stimulated and pro-inflammatory genes prior to infection, and of T cell markers two days post-infection, indicative of a more rapid progression of the immune response to PRRSV. This study has increased our knowledge of the early response to PRRSV in the blood of pregnant gilts, and could ultimately lead to the development of a biomarker panel that can be used to predict PRRSV-associated reproductive pathology.


[Interhemisphere asymmetry of the CSF dynamics and biomechanical properties of the skull].
This investigation shows that both intracranial liquor circulation and skull biomechanical properties evaluated by its pliability (compliance) to intracranial pressure are characterised by marked interhemisphere asymmetry. The interhemisphere differences of cerebrospinal fluid mobility were evaluated by means of asymmetry coefficient (right/left ratio of liquor mobility) which was found to be 1.25-1.45 in healthy middle-age persons. For the skull pliability (compliance) the coefficient of hemispheric asymmetry was 0.75-0.95. These two hemisphere asymmetry coefficients are characterized by reciprocal relationships. These coefficients demonstrated no dominancy related to right/left hemisphere as well as no correlation with neurophysiological parameter. Functional tests (apnoea, hyperventilation, Stookey test) gave rise to significant changes of these coefficient values. At ageing, the magnitudes of these coefficients decreased. The spectral analysis of pulse waves of dopplerogram and rheoencephalogram reveals hemisphere asymmetry, too. It should be suggested that the interhemisphere asymmetry of the CSF dynamics and skull biomechanical properties is a special mechanism which contributes in the process of circulatory-metabolic support of brain activity.