Presidents Test performance in varieties of diffuse and unilateral cerebral disease.
Two studies addressed issues concerning the validity of the Presidents Test. The results of Study 1 substantiated that generalized impairment for recent presidents occurs frequently in the context of multifocal and diffuse cerebral disease. Performances of normal elderly (n = 31) on all four Presidents subtests were superior to those of patients with confusional states (n = 7), uncomplicated dementia (n = 24), and dementia with confusion (n = 20). Overall, 88% of the combined sample was correctly classified (control v. diffuse cerebral disease). In Study 2, generalized memory impairment for recent presidents was found to be rare among samples of patients with unilateral right- and left-hemisphere lesions (n = 40 each). A selective impairment in temporal sequencing was preferentially associated with right-hemisphere disease, whereas verbal deficit patterns were more common in patients with left-sided lesions. These findings further document the validity of the Presidents Test as an efficient, objective method for assessing recent memory impairment due to widespread cerebral disease and suggest that qualitative analysis of performance patterns may be useful for detecting certain nonmnemonic cognitive defects in patients with focal brain disease.


Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins.
HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1α) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX(-/-)/BAK(-/-) murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease.


Overexpression of the transcription factor Foxo4 is associated with rapid glucose clearance.
Leptin treatment ameliorates lipoatrophic diabetes in animal models and humans. Transgenic mice overexpressing leptin (LepTg) are lipoatrophic but not diabetic and thus represent a model for elucidating mechanisms of leptin-mediated glucose homeostasis. In this communication, we show that LepTg mice overexpress the forkhead transcription factor foxo4 in their remnant adipose tissue. To further characterize the role of foxo4 in adipose tissue, we generated transgenic mice overexpressing a constitutive active form of foxo4 (A3foxo4) under the control of the aP2 promoter/enhancer. aP2-A3foxo4 mice are not lipoatrophic but are able to clear glucose rapidly similar to LepTg mice. In addition, both LepTg and A3foxo4 mice show in their adipocytes increased AMP-activated protein kinase (AMPK) phosphorylation, suggesting a link between AMPK, glucose clearance, foxo4 and the leptin axis. These studies shed new light on mechanisms by which leptin treatment improves glucose disposal.


Design, synthesis and biological studies of novel tubulin inhibitors.
A series of compounds originally derived from the vascular endothelial growth factor receptor tyrosine kinase inhibitor, SU5416, were synthesized and evaluated. The most potent compound in this series, compound 3, which structurally resembles the potent anti-microtubule agent combretastatin A-4, inhibited tubulin polymerization and showed potent growth inhibitory activities on both prostate and breast cancer lines with IC50 values in the low nanomolar range.


Biosocial studies of antisocial and violent behavior in children and adults: a review.
Despite increasing knowledge of social and biological risk factors for antisocial and violent behavior, we know surprisingly little about how these two sets of risk factors interact. This paper documents 39 empirical examples of biosocial interaction effects for antisocial behavior from the areas of genetics, psychophysiology, obstetrics, brain imaging, neuropsychology, neurology, hormones, neurotransmitters, and environmental toxins. Two main themes emerge. First, when biological and social factors are grouping variables and when antisocial behavior is the outcome, then the presence of both risk factors exponentially increases the rates of antisocial and violent behavior. Second, when social and antisocial variables are grouping variables and biological functioning is the outcome, then the social variable invariably moderates the antisocial-biology relationship such that these relationships are strongest in those from benign home backgrounds. It is argued that further biosocial research is critical for establishing a new generation of more successful intervention and prevention research.


Chylous ascites secondary to hyperlipidemic pancreatitis with normal serum amylase and lipase.
A 54-year old man with a family history of hyperlipidemia was admitted with a 12 h history of severe generalized abdominal pain associated with nausea, vomiting and abdominal distension. Examination of the abdomen revealed tenderness in the periumblical area with shifting dullness. Serum pancreatic amylase was 29 IU/L and lipase 44 IU/L, triglyceride 36.28 mmol/L. Ultrasound showed ascites. CT of the abdomen with contrast showed inflammatory changes surrounding the pancreas consistent with acute pancreatitis. Ultrasound (US) guided abdomen paracentesis yielded a milky fluid with high triglyceride content consistent with chylous ascites. The patient was kept fasting and intravenous fluid hydration was provided. Meperidine was administered for pain relief. On the following days the patient's condition improved and he was gradually restarted on a low-fat diet, and fat lowering agent (gemfibrozil) was begun, 600 mg twice a day. On d 14, abdomen US was repeated and showed fluid free peritoneal cavity. The patient was discharged after 18 d of hospitalization with 600 mg gemfibrozil twice a day. At the time of discharge, the fasting triglyceride was 4.2 mmol/L. After four weeks the patient was seen in the clinic, he was well.


Small intestinal MUC2 synthesis in human preterm infants.
Mucin 2 (MUC2) is the structural component of the intestinal protective mucus layer, which contains high amounts of threonine in its peptide backbone. MUC2 synthesis rate might be a potential parameter for intestinal barrier function. In this study, we aimed to determine whether systemic threonine was used for small intestinal MUC2 synthesis and to calculate the MUC2 fractional synthetic rate (FSR) in human preterm infants. Seven preterm infants with an enterostomy following bowel resection for necrotizing enterocolitis received intravenous infusion of [U-(13)C]threonine to determine incorporation of systemic threonine into secreted MUC2 in intestinal outflow fluid. Small intestinal MUC2 was isolated using cesium chloride gradient ultracentrifugation and gravity gel filtration chromatography. MUC2-containing fractions were identified by SDS-PAGE/periodic acid-Schiff staining and Western blot analysis and were subsequently pooled. Isotopic enrichment of threonine, measured in MUC2 using gas chromatography isotopic ratio mass spectrometry, was used to calculate the FSR of MUC2. Systemically derived threonine was indeed incorporated into small intestinal MUC2. Median FSR of small intestinal MUC2 was 67.2 (44.3-103.9)% per day. Systemic threonine is rapidly incorporated into MUC2 in the small intestine of preterm infants, and thereby MUC2 has a very high synthesis rate.


Vitamin D metabolism and therapy in elderly subjects.
Serum 25-hydroxyvitamin D declines in elderly subjects. This decrease reflects, in part, a lower vitamin D intake. But changes in serum 25-hydroxyvitamin D are more marked in the northern latitudes of the world because less vitamin D synthesis occurs n the skin as a result of a reduced amount of ultraviolet light. Consequently, vitamin D deficiency leading to osteomalacia is more common in thr northern latitudes, particularly among the elderly. The Recommended Daily Allowance of 200 IU of vitamin D in the elderly may be insufficient, since higher doses of 800 IU/day have been shown to reduce the incidence of osteoporotic fractures. The use of more potent analogues of vitamin D, such as calcitriol (Rocaltrol), should be reserved only for those patients who have established vertebral osteoporosis and who generally have more pronounced malabsorption of calcium.


Zebrafish homolog of the leukemia gene CBFB: its expression during embryogenesis and its relationship to scl and gata-1 in hematopoiesis.
Mammalian CBFB encodes a transcription factor (CBF beta) that in combination with CBF alpha 2 binds to specific DNA sequences and regulates expression of a number of hematopoietic genes. CBFB is associated with human leukemias through a chromosome 16 inversion and is essential for definitive hematopoiesis during mouse embryo development. We have isolated a zebrafish cbfb complementary DNA (cDNA) clone from a zebrafish kidney cDNA library. This cbfb is highly homologous to human and mouse CBFB/Cbfb genes at both the DNA and protein level. In biochemical analyses, cbfbeta binds to human CBF alpha 2 and enhances its DNA binding. During zebrafish development, cbfb is expressed in the lateral plate mesoderm at tail bud stage and in the intermediate cell mass (ICM, the location of embryonic hematopoiesis) between the 21- to 26-somite stages. The cbfb is also expressed in Rohon-Beard cells, cranial nerve ganglia, hindbrain, retina, branchial arches, jaw, and fin buds. Expression of cbfb is decreased or absent in the ICM and Rohon-Beard cells in some hematopoietic mutants and is unaffected in others. We have also analyzed the expression of scl and gata-1 in the same hematopoietic mutants to ascertain the relative order of these transcription factors to cbfb in zebrafish hematopoiesis. Our results indicate that cbfb is expressed in early hematopoietic progenitors and that its expression pattern in the hematopoietic mutants is similar to that of scl. (Blood. 2000;96:4178-4184)


Fractionating nonword repetition: The contributions of short-term memory and oromotor praxis are different.
The ability to reproduce novel words is a sensitive marker of language impairment across a variety of developmental disorders. Nonword repetition tasks are thought to reflect phonological short-term memory skills. Yet, when children hear and then utter a word for the first time, they must transform a novel speech signal into a series of coordinated, precisely timed oral movements. Little is known about how children's oromotor speed, planning and co-ordination abilities might influence their ability to repeat novel nonwords, beyond the influence of higher-level cognitive and linguistic skills. In the present study, we tested 35 typically developing children between the ages of 5-8 years on measures of nonword repetition, digit span, memory for non-verbal sequences, reading fluency, oromotor praxis, and oral diadochokinesis. We found that oromotor praxis uniquely predicted nonword repetition ability in school-age children, and that the variance it accounted for was additional to that of digit span, memory for non-verbal sequences, articulatory rate (measured by oral diadochokinesis) as well as reading fluency. We conclude that the ability to compute and execute novel sensorimotor transformations affects the production of novel words. These results have important implications for understanding motor/language relations in neurodevelopmental disorders.


Water quality modelling: microbial risks associated with manure on pasture and arable land.
While agricultural activities, such as the application of manure on arable land and animal grazing on pastures, provide economic and environmental benefits, they may also pose microbial risks to water sources. The aim of this paper was to study the microbial fate and transport in an agricultural catchment and recipient water source through further development of the hydrological model HYPE. Hydrological modelling was combined with hydrodynamic modelling to simulate the fate and transport of Salmonella spp., verotoxin-producing Escherichia coli O157:H7 (VTEC) and Cryptosporidium parvum in an agricultural catchment of a drinking water source, Lake Vombsjön, in Sweden. This approach was useful to study the influence of different processes on the pathogen fate and transport, and to interpret the relative changes in the simulated concentrations. Sensitivity analysis indicated that the largest uncertainties in the model were associated with the estimation of pathogen loads, parameterisation of the pathogen processes, and simulation of partitioning between surface runoff and infiltration. The proposed modelling approach is valuable for assessing the relative effect of different risk-reducing interventions.


Discrepancy between readiness to change, insight and motivation in alcohol-dependent inpatients.
Poland, Czech Republic, and the Slovak Republic are countries with high alcohol consumption, and alcohol-induced disorders are in the ten leading causes of Years Lost due to Disability. Therefore it is necessary to study factors as insight, motivation, and readiness to change for the better understanding the variables which are in probably connected with therapeutic effectiveness. The purpose of the study was to examine the state of readiness to change at the beginning and the end of inpatient short (six weeks) and long (12 weeks) therapeutic program in the Slovak Republic, Poland, and the Czech Republic, and look for the relationship between readiness to change, insight, and motivation in alcohol-dependent persons. We studied a sample of 380 alcohol-dependent inpatients (282 men and 98 women) by Alcohol Use Disorders Identification Test (AUDIT), The Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES), Readiness to Change Questionnaire (RCQ), and Demographic Questionnaire. The unmarried patients declare a higher severity of alcohol dependence than married or divorced ones in AUDIT questionnaire. At the beginning of the treatment, the majority of patients declared Action (68.5%) or Preparation (26.3%) motivation stage according to RCQ questionnaire. At the end of the treatment, married patients showed higher readiness to change in domain Taking steps of SOCRATES questionnaire. The unmarried patients displayed the decrease of domain Ambivalence. The duration of the completed therapeutic program may not be crucial for improvement in preparedness to change. The intention and motivation to alcohol dependence treatment seem to be high at the beginning of the treatment, but recognition of the alcohol problems were low in highly dependent patients. Marital status was connected with an increased active component for readiness to change. The passive component (decreasing the ambivalence) was observed in the unmarried patients.


Acupuncture treatment and the risk of urinary tract infection in stroke patients: a nationwide matched cohort study.
The association between acupuncture treatment and post-stroke urinary tract infection (UTI) remains incompletely understood. To compare the long-term risks of UTI among stroke patients treated with or without acupuncture treatment. This retrospective cohort study was based on data from the National Health Insurance Research Database in Taiwan that included hospitalized stroke patients. We identified 19,286 patients aged 30 years and older who were hospitalized for newly diagnosed stroke between 1 January 2000 and 31 December 2004. Considering immortal time bias, we compared the incidence of UTI during the follow-up period until the end of 2009 in patients with stroke who did and did not receive acupuncture. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of UTI associated with acupuncture were calculated using multivariate Cox proportional hazard regression analysis. Stroke patients who received acupuncture treatment experienced a lower incidence of UTI than those who were not treated with acupuncture (95.4 vs 110.0 per 1000 person-years) with an HR of 0.76 (95% CI: 0.73-0.80). The association between acupuncture treatment and UTI was significant for both sexes and for patients older than 40 years of age, particularly for patients who had no history of medical conditions. In this nationwide retrospective cohort study, we raised the possibility that acupuncture treatment may be associated with a reduced risk of UTI among stroke patients. However, the protective effect associated with acupuncture treatment requires further validation using randomized clinical trials.


What's behind a P600? Integration operations during irony processing.
The combined knowledge of word meanings and grammatical rules does not allow a listener to grasp the intended meaning of a speaker's utterance. Pragmatic inferences on the part of the listener are also required. The present work focuses on the processing of ironic utterances (imagine a slow day being described as "really productive") because these clearly require the listener to go beyond the linguistic code. Such utterances are advantageous experimentally because they can serve as their own controls in the form of literal sentences (now imagine an active day being described as "really productive") as we employ techniques from electrophysiology (EEG). Importantly, the results confirm previous ERP findings showing that irony processing elicits an enhancement of the P600 component (Regel et al., 2011). More original are the findings drawn from Time Frequency Analysis (TFA) and especially the increase of power in the gamma band in the 280-400 time-window, which points to an integration among different streams of information relatively early in the comprehension of an irony. This represents a departure from traditional accounts of language processing which generally view pragmatic inferences as late-arriving. We propose that these results indicate that unification operations between the linguistic code and contextual information play a critical role throughout the course of irony processing and earlier than previously thought.


The need for large-scale randomized evidence.
The reliable detection of moderate differences in major health outcomes that arise as a result of treatment requires large-scale randomized evidence (and the appropriate interpretation of this evidence once it has been generated). This may take the form of a single mega-trial or, exceptionally, a meta-analysis of many smaller randomized trials may provide worthwhile information. Small or non-randomized studies cannot generally be trusted to distinguish reliably between a moderate benefit, a moderate hazard, and a negligible difference in major outcomes. Simple design, streamlined data collection, and use of the "uncertainty principle' to guide eligibility would all encourage the recruitment of larger samples in randomized trials. Future trials need to adopt these methods in order to detect any moderate improvements in major outcomes that may await discovery.


Koch's postulates and autoimmunity: an opposing viewpoint.
Autoimmunity is characterized as a state of abnormal specific humoral and cell-mediated responses against constituents of body tissues. One time-honored approach to explaining the pathogenesis of autoimmunity has been application of the Koch's postulates, on loan from the field of microbiology suggesting that autoantibodies and/or autoreactive T cells are the presumed "pathogens" of autoimmunity, and that passive transfer of these autoimmune factors to susceptible animals will result in the induction of the autoimmune disease. We suggest that autoimmunity is not in many cases due to the presence of factors leading to the autoimmune response in those susceptible. Instead, it is the lack of a factor which leads to the development of autoimmunity, a factor (cytokine, protein, gene, etc.) which is present in the healthy individual and normally protects in from disordered immune regulation. We propose to direct more research into therapeutic modulation of autoimmunity by administration of putative "protective factors", rather than by attempts to depress or remove autoreactive cells and antibodies from the autoimmune.


Using Phenomenological Models to Characterize Transmissibility and Forecast Patterns and Final Burden of Zika Epidemics.
The World Health Organization declared the ongoing Zika virus (ZIKV) epidemic in the Americas a Public Health Emergency of International Concern on February 1, 2016. ZIKV disease in humans is characterized by a "dengue-like" syndrome including febrile illness and rash. However, ZIKV infection in early pregnancy has been associated with severe birth defects, including microcephaly and other developmental issues. Mechanistic models of disease transmission can be used to forecast trajectories and likely disease burden but are currently hampered by substantial uncertainty on the epidemiology of the disease (e.g., the role of asymptomatic transmission, generation interval, incubation period, and key drivers). When insight is limited, phenomenological models provide a starting point for estimation of key transmission parameters, such as the reproduction number, and forecasts of epidemic impact. We obtained daily counts of suspected Zika cases by date of symptoms onset from the Secretary of Health of Antioquia, Colombia during January-April 2016. We calibrated the generalized Richards model, a phenomenological model that accommodates a variety of early exponential and sub-exponential growth kinetics, against the early epidemic trajectory and generated predictions of epidemic size. The reproduction number was estimated by applying the renewal equation to incident cases simulated from the fitted generalized-growth model and assuming gamma or exponentially-distributed generation intervals derived from the literature. We estimated the reproduction number for an increasing duration of the epidemic growth phase. The reproduction number rapidly declined from 10.3 (95% CI: 8.3, 12.4) in the first disease generation to 2.2 (95% CI: 1.9, 2.8) in the second disease generation, assuming a gamma-distributed generation interval with the mean of 14 days and standard deviation of 2 days. The generalized-Richards model outperformed the logistic growth model and provided forecasts within 22% of the actual epidemic size based on an assessment 30 days into the epidemic, with the epidemic peaking on day 36. Phenomenological models represent promising tools to generate early forecasts of epidemic impact particularly in the context of substantial uncertainty in epidemiological parameters. Our findings underscore the need to treat the reproduction number as a dynamic quantity even during the early growth phase, and emphasize the sensitivity of reproduction number estimates to assumptions on the generation interval distribution.


Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.
The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration. To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets. Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990. Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action. Bill & Melinda Gates Foundation.


Exciton drift in semiconductors under uniform strain gradients: application to bent ZnO microwires.
Optimizing the electronic structures and carrier dynamics in semiconductors at atomic scale is an essential issue for innovative device applications. Besides the traditional chemical doping and the use of homo/heterostructures, elastic strain has been proposed as a promising possibility. Here, we report on the direct observation of the dynamics of exciton transport in a ZnO microwire under pure elastic bending deformation, by using cathodoluminescence with high temporal, spatial, and energy resolutions. We demonstrate that excitons can be effectively drifted by the strain gradient in inhomogeneous strain fields. Our observations are well reproduced by a drift-diffusion model taking into account the strain gradient and allow us to deduce an exciton mobility of 1400 ± 100 cm(2)/(eV s) in the ZnO wire. These results propose a way to tune the exciton dynamics in semiconductors and imply the possible role of strain gradient in optoelectronic and sensing nano/microdevices.


Can Subclinical Infestation by Paralyzing Dermacentor andersoni (Acari: Ixodidae) Induce Immunity to Tick Paralysis in Sheep?
Cattle and sheep can develop immunity to paralysis caused by Dermacentor andersoni Stiles; however, this has been reported only in animals that were initially challenged with a high dose of ticks and exhibited clear symptoms of paralysis. Paralysis in sheep occurs in a dose-dependent fashion, with no paralysis occurring in sheep exposed to <0.2 ticks per kilogram sheep weight, and 100% paralysis in sheep exposed to >0.8 ticks per kilogram. This experiment was conducted to determine if sheep exposed to a low dose of ticks would also develop immunity to paralysis. Sheep were exposed to either a low (0.2 ticks per kilogram) or high dose of ticks (0.8 ticks per kilogram), then re-exposed to a second challenge of a paralyzing dose of ticks. All naïve sheep (eight of the eight) were paralyzed, while paralysis occurred in only four of the eight sheep previously exposed to a low dose, and one of the eight sheep previously exposed to a high dose. Results indicate that immunity can develop when sheep are exposed to a subclinical dose of paralyzing ticks, but in a smaller percentage of animals than those exposed to a high dose of ticks. Vaccine development perhaps remains the best option for nonacaricidal control of tick paralysis.


Prediction of Psychiatric Hospitalization, Diagnoses, Arrests, and Violent Behavior Through Scored Drawings and Associations.
The article presents a completely empirical approach to using drawings and associations as a supplemental tool in forensic psychological assessment. The present system represents a modern alternative to prior theory-driven "projective technique" approaches that have failed to pass scientific scrutiny. Using an archival sample of 252 forensic cases, House-Tree-Person drawing protocols were scored according to preliminary test items developed from published handbooks, academic courses, and workshops on the use of drawings and related associations for assessment. Intermediate test items were selected according to their being significantly correlated with at least one external psychometric, behavioral, or clinical variable. Psychometric and editorial considerations guided the development of a final set of 66 test items. A "flagged for pathology" approach demonstrated modest convergent and discriminant validity for the final set of test items against clinical criteria on an independent sample of 150 cases of the same type used in the preliminary item development phase. Included are sample items and discussion of psychometric issues in working with this class of data.


Occasion setting by drug states: Functional equivalence following similar training history.
Three experiments examined whether a drug state serving as a positive feature for pairings between a discrete conditional stimulus (CS, 15-s light or 15-s noise) and sucrose could transfer facilitative control to a CS with which it had never been presented. To do so, a CS was paired with a sucrose reward in the nicotine (0.4 mg/kg), amphetamine (AMP, 1mg/kg), or chlordiazepoxide (CDP, 5mg/kg) drug state; in separate saline sessions the CS was presented but was not followed by any reward. All three drug states facilitated responding to a discrete CS; previous studies found that this facilitation did not depend on direct associations between the drug state and sucrose. When a second discrimination was trained (e.g., CDP: light-sucrose and nicotine: noise-sucrose) the drug states facilitated responding to the CS trained in that state (nicotine: noise) as well as the CS normally presented in the other drug state (e.g., nicotine: light). A novel drug state (e.g., amphetamine) did not affect responding to either CS, indicating that the originally trained drug states had acquired functional similarity based on learning history. Also, a novel or ambiguous CS did not evoke responding in the previously trained drug state, indicating that both the features (drug states) and target conditional stimuli had to be trained in discriminations before transfer could occur.


All-Cause Mortality and Progression Risks to Hepatic Decompensation and Hepatocellular Carcinoma in Patients Infected With Hepatitis C Virus.
A key question in care of patients with chronic hepatitis C virus (HCV) infection is beginning treatment immediately vs delaying treatment. Risks of mortality and disease progression in "real world" settings are important to assess the implications of delaying HCV treatment. This was a cohort study of HCV patients identified from 4 integrated health systems in the United States who had liver biopsies during 2001-2012. The probabilities of death and progression to hepatocellular carcinoma, hepatic decompensation (hepatic encephalopathy, esophageal varices, ascites, or portal hypertension) or liver transplant were estimated over 1, 2, or 5 years by fibrosis stage (Metavir F0-F4) determined by biopsy at beginning of observation. Among 2799 HCV-monoinfected patients who had a qualifying liver biopsy, the mean age at the time of biopsy was 50.7 years. The majority were male (58.9%) and non-Hispanic white (66.9%). Over a mean observation of 5.0 years, 261 (9.3%) patients died and 34 (1.2%) received liver transplants. At 5 years after biopsy, the estimated risk of progression to hepatic decompensation or hepatocellular carcinoma was 37.2% in stage F4, 19.6% in F3, 4.7% in F2, and 2.3% in F0-F1 patients. Baseline biopsy stage F3 or F4 and platelet count below normal were the strongest predictors of progression to hepatic decompensation or hepatocellular carcinoma. The risks of death and progression to liver failure varied greatly by fibrosis stage. Clinicians and policy makers could use these progression risk data in prioritization and in determining the timing of treatment for patients in early stages of liver disease.


A registry of HLA-typed donors for production of virus-specific CD4 and CD8 T lymphocytes for adoptive reconstitution of immune-compromised patients.
Virus-specific CD4 and CD8 T lymphocytes from HLA-matched donors are effective for treatment and prophylaxis of viral infections in immune-compromised recipients of hematopoietic stem cell transplant recipients. Adoptive immune reconstitution is based on selection of specific T cells or on generation of specific T-cell lines from the graft donor. Unfortunately, the graft donor is not always immune to the relevant pathogen or the graft donor may not be available (registry-derived or cord blood donors). Since the possibility of using T cells from a third-party subject is now established, we screened potential donors for T-cell responses against cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus, the viruses most frequently targeted by adoptive immune reconstitution. Specific T-cell responses against viral antigens were analyzed in 111 donors using a miniaturized interferon-γ release assay. Responders to CMV were 64%, to EBV 40%, and to adenovirus 51%. Simultaneous responders to the three viruses were 49%. CMV-specific CD4 and CD8 T-cell lines could be generated from 11 of 12 donors defined as positive responders according to the T-cell assay. These data demonstrate that a large fraction of volunteers can be recruited in a donor registry for selection or expansion of virus specific T cells and that our T-cell assay predicts the donors' ability to give rise to established T-cell lines endowed with proliferative potential and effector function for adoptive immune reconstitution.


The Secure Anonymised Information Linkage databank Dementia e-cohort (SAIL-DeC).
The rising burden of dementia is a global concern, and there is a need to study its causes, natural history and outcomes. The Secure Anonymised Information Linkage (SAIL) Databank contains anonymised, routinely-collected healthcare data for the population of Wales, UK. It has potential to be a valuable resource for dementia research owing to its size, long follow-up time and prospective collection of data during clinical care. We aimed to apply reproducible methods to create the SAIL dementia e-cohort (SAIL-DeC). We created SAIL-DeC with a view to maximising its utility for a broad range of research questions whilst minimising duplication of effort for researchers. SAIL contains individual-level, linked primary care, hospital admission, mortality and demographic data. Data are currently available until 2018 and future updates will extend participant follow-up time. We included participants who were born between 1st January 1900 and 1st January 1958 and for whom primary care data were available. We applied algorithms consisting of International Classification of Diseases (versions 9 and 10) and Read (version 2) codes to identify participants with and without all-cause dementia and dementia subtypes. We also created derived variables for comorbidities and risk factors. From 4.4 million unique participants in SAIL, 1.2 million met the cohort inclusion criteria, resulting in 18.8 million person-years of follow-up. Of these, 129,650 (10%) developed all-cause dementia, with 77,978 (60%) having dementia subtype codes. Alzheimer's disease was the most common subtype diagnosis (62%). Among the dementia cases, the median duration of observation time was 14 years. We have created a generalisable, national dementia e-cohort, aimed at facilitating epidemiological dementia research.


Kinetic energy densities based on the fourth order gradient expansion: performance in different classes of materials and improvement via machine learning.
We study the performance of fourth-order gradient expansions of the kinetic energy density (KED) in semi-local kinetic energy functionals depending on the density-dependent variables. The formal fourth-order expansion is convergent for periodic systems and small molecules but does not improve over the second-order expansion (the Thomas-Fermi term plus one-ninth of the von Weizsäcker term). Linear fitting of the expansion coefficients somewhat improves on the formal expansion. The tuning of the fourth order expansion coefficients allows for better reproducibility of the Kohn-Sham kinetic energy density than the tuning of the second-order expansion coefficients alone. The possibility of a much more accurate match with the Kohn-Sham kinetic energy density by using neural networks (NN) trained using the terms of the 4th order expansion as density-dependent variables is demonstrated. We obtain ultra-low fitting errors without overfitting of NN parameters. Small single hidden layer neural networks can provide good accuracy in separate KED fits of each compound, while for joint fitting of KEDs of multiple compounds multiple hidden layers were required to achieve good fit quality. The critical issue of data distribution is highlighted. We also show the critical role of pseudopotentials in the performance of the expansion, where in the case of a too rapid decay of the valence density at the nucleus with some pseudopotentials, numeric instabilities can arise.


The comparison of mouse full metallothionein-1 versus alpha and beta domains and metallothionein-1-to-3 mutation following traumatic brain injury reveals different biological motifs.
Traumatic injury to the brain is one of the leading causes of injury-related death or disability, but current therapies are limited. Previously it has been shown that the antioxidant proteins metallothioneins (MTs) are potent neuroprotective factors in animal models of brain injury. The exogenous administration of MTs causes effects consistent with the roles proposed from studies in knock-out mice. We herewith report the results comparing full mouse MT-1 with the independent alpha and beta domains, alone or together, in a cryoinjury model. The lesion of the cortex caused the mice to perform worse in the horizontal ladder beam and the rota-rod tests; all the proteins showed a modest effect in the former test, while only full MT-1 improved the performance of animals in the rota-rod, and the alpha domain showed a rather detrimental effect. Gene expression analysis by RNA protection assay demonstrated that all proteins may alter the expression of host-response genes such as GFAP, Mac1 and ICAM, in some cases being the beta domain more effective than the alpha domain or even the full MT-1. A MT-1-to-MT-3 mutation blunted some but not all the effects caused by the normal MT-1, and in some cases increased its potency. Thus, splitting the two MT-1 domains do not seem to eliminate all MT functions but certainly modifies them, and different motifs seem to be present in the protein underlying such functions.


Development of an international Core Outcome Set (COS) for best care for the dying person: study protocol.
In contrast to typical measures employed to assess outcomes in healthcare such as mortality or recovery rates, it is difficult to define which specific outcomes of care are the most important in caring for dying individuals. Despite a variety of tools employed to assess different dimensions of palliative care, there is no consensus on a set of core outcomes to be measured in the last days of life. In order to optimise decision making in clinical practice and comparability of interventional studies, we aim to identify and propose a set of core outcomes for the care of the dying person. Following the COMET initiative approach, the proposed study will proceed through four stages to develop a set of core outcomes: In stage 1, a systematic review of the literature will identify outcomes measured in existing peer reviewed literature, as well as outcomes derived through qualitative studies. Grey literature, will also be included. Stage 2 will allow for the identification and determination of patient and proxy defined outcomes of care at the end of life via quantitative and qualitative methods at an international level. In stage 3, from a list of salient outcomes identified through stages 1 and 2, international experts, family members, patients, and patient advocates will be asked to score the importance of the preselected outcomes through a Delphi process. Stage 4 consists of a face-to-face consensus meeting of international experts and patient/family representatives in order to define, endorse, and propose the final Core Outcomes Set. Core Outcome Sets aim at promoting uniform assessment of care outcomes in clinical practice as well as research. If consistently employed, a robust set of core outcomes for the end of life, and specifically for the dying phase, defined by relevant stakeholders, can ultimately be translated into best care for the dying person. Patient care will be improved by allowing clinicians to choose effective and meaningful treatments, and research impact will be improved by employing internationally agreed clinically relevant endpoints and enabling accurate comparison between studies in systematic reviews and/or in meta-analyses.


The impact of recipient cytokine genotype on acute rejection after renal transplantation.
Acute allograft rejection remains an important cause of morbidity after kidney transplantation, and has been shown to be a crucial determinant of long-term graft function. As cytokines are major regulators of the immune system, genetic variation in cytokine production or activity may influence susceptibility to acute rejection. This study sought to determine the impact of recipient cytokine and cytokine receptor polymorphisms on acute rejection after renal transplantation. A total of 209 cadaveric renal transplant recipients were selected for analysis according to the presence or absence of graft rejection in the first 30 days after transplantation. DNA was genotyped for 22 polymorphisms in 11 cytokine and cytokine receptor genes using the polymerase chain reaction with sequence specific primers. Results were stratified by incidence and severity of rejection, and by HLA-DR mismatching. No association between any polymorphism and the incidence or severity of acute rejection was detected. In particular, no association was seen with tumor necrosis factor or interleukin-10 genotype, either alone or in combination. We have failed to demonstrate any association between recipient cytokine genotype and acute rejection after cadaveric renal transplantation. Although more extensive studies may disprove these findings, it would seem premature to use recipient cytokine genotyping to predict transplant outcome, or to guide immunosuppressive therapy after transplantation.


Inhibition of focal adhesion kinase increases myofibril viscosity in cardiac myocytes.
The coordinated generation of mechanical forces by cardiac myocytes is required for proper heart function. Myofibrils are the functional contractile units of force production within individual cardiac myocytes. At the molecular level, myosin motors form cross-bridges with actin filaments and use ATP to convert chemical energy into mechanical forces. The energetic efficiency of the cross-bridge cycle is influenced by the viscous damping of myofibril contraction. The viscoelastic response of myofibrils is an emergent property of their individual mechanical components. Previous studies have implicated titin-actin interactions, cell-ECM adhesion, and microtubules as regulators of the viscoelastic response of myofibrils. Here we probed the viscoelastic response of myofibrils using laser-assisted dissection. As a proof-of-concept, we found actomyosin contractility was required to endow myofibrils with their viscoelastic response, with blebbistatin treatment resulting in decreased myofibril tension and viscous damping. Focal adhesion kinase (FAK) is a key regulator of cell-ECM adhesion, microtubule stability, and myofibril assembly. We found inhibition of FAK signaling altered the viscoelastic properties of myofibrils. Specifically, inhibition of FAK resulted in increased viscous damping of myofibril retraction following laser ablation. This damping was not associated with acute changes in the electrophysiological properties of cardiac myocytes. These results implicate FAK as a regulator of mechanical properties of myofibrils.


Conformational instability governed by disulfide bonds partitions the dominant from subdominant helper T-cell responses specific for HIV-1 envelope glycoprotein gp120.
Most individuals infected with human immunodeficiency virus type 1 (HIV-1) generate a CD4(+) T-cell response that is dominated by a few epitopes. Immunodominance may be counterproductive because a broad CD4(+) T-cell response is associated with reduced viral load. Previous studies indicated that antigen three-dimensional structure controls antigen processing and presentation and therefore CD4(+) T-cell epitope dominance. Dominant epitopes occur adjacent to the V1-V2, V3, and V4 loops because proteolytic antigen processing in the loops promotes presentation of adjacent sequences. In this study, three gp120 (strain JR-FL) variants were constructed, in which deletions of single outer-domain disulfide bonds were expected to introduce local conformational flexibility and promote presentation of additional CD4(+) T-cell epitopes. Following mucosal immunization of C57BL/6 mice with wild-type or variant gp120 lacking the V3-flanking disulfide bond, the typical pattern of dominant epitopes was observed, suggesting that the disulfide bond posed no barrier to antigen presentation. In mice that lacked gamma interferon-inducible lysosomal thioreductase (GILT), proliferative responses to the typically dominant epitopes of gp120 were selectively depressed, and the dominance pattern was rearranged. Deletion of the V3-flanking disulfide bond or one of the V4-flanking disulfide bonds partially restored highly proliferative responses to the typically dominant epitopes. These results reveal an acute dependence of dominant CD4(+) T-cell responses on the native gp120 conformation.


Antibody-recruiting protein-catalyzed capture agents to combat antibiotic-resistant bacteria.
Antibiotic resistant infections are projected to cause over 10 million deaths by 2050, yet the development of new antibiotics has slowed. This points to an urgent need for methodologies for the rapid development of antibiotics against emerging drug resistant pathogens. We report on a generalizable combined computational and synthetic approach, called antibody-recruiting protein-catalyzed capture agents (AR-PCCs), to address this challenge. We applied the combinatorial protein catalyzed capture agent (PCC) technology to identify macrocyclic peptide ligands against highly conserved surface protein epitopes of carbapenem-resistant Klebsiella pneumoniae, an opportunistic Gram-negative pathogen with drug resistant strains. Multi-omic data combined with bioinformatic analyses identified epitopes of the highly expressed MrkA surface protein of K. pneumoniae for targeting in PCC screens. The top-performing ligand exhibited high-affinity (EC50 ∼50 nM) to full-length MrkA, and selectively bound to MrkA-expressing K. pneumoniae, but not to other pathogenic bacterial species. AR-PCCs that bear a hapten moiety promoted antibody recruitment to K. pneumoniae, leading to enhanced phagocytosis and phagocytic killing by macrophages. The rapid development of this highly targeted antibiotic implies that the integrated computational and synthetic toolkit described here can be used for the accelerated production of antibiotics against drug resistant bacteria.


Fusion FISH imaging: single-molecule detection of gene fusion transcripts in situ.
Double-stranded DNA breaks occur on a regular basis in the human genome as a consequence of genotoxic stress and errors during replication. Usually these breaks are rapidly and faithfully repaired, but occasionally different chromosomes, or different regions of the same chromosome, are fused to each other. Some of these aberrant chromosomal translocations yield functional recombinant genes, which have been implicated as the cause of a number of lymphomas, leukemias, sarcomas, and solid tumors. Reliable methods are needed for the in situ detection of the transcripts encoded by these recombinant genes. We have developed just such a method, utilizing single-molecule fluorescence in situ hybridization (sm-FISH), in which approximately 50 short fluorescent probes bind to adjacent sites on the same mRNA molecule, rendering each target mRNA molecule visible as a diffraction-limited spot in a fluorescence microscope. Utilizing this method, gene fusion transcripts are detected with two differently colored probe sets, each specific for one of the two recombinant segments of a target mRNA; enabling the fusion transcripts to be seen in the microscope as distinct spots that fluoresce in both colors. We demonstrate this method by detecting the BCR-ABL fusion transcripts that occur in chronic myeloid leukemia cells, and by detecting the EWSR1-FLI1 fusion transcripts that occur in Ewing's sarcoma cells. This technology should pave the way for accurate in situ typing of many cancers that are associated with, or caused by, fusion transcripts.


Residential racial segregation and mortality among black, white, and Hispanic urban breast cancer patients in Texas, 1995 to 2009.
The authors investigated whether residential segregation (the degree to which racial/ethnic groups live separately from one another in a geographic area) 1) was associated with mortality among urban women with breast cancer, 2) explained racial/ethnic disparities in mortality, and 3) whether its association with mortality varied by race/ethnicity. Using Texas Cancer Registry data, all-cause mortality and breast-cancer mortality were examined among 109,749 urban black, Hispanic, and white women aged ≥50 years who were diagnosed with breast cancer from 1995 to 2009. Racial (black) segregation and ethnic (Hispanic) segregation of patient's neighborhoods were measured and were compared with the larger metropolitan statistical area using the location quotient measure. Shared frailty Cox proportional hazard models were used to nest patients within residential neighborhoods (census tract) and were controlled for race/ethnicity, age, diagnosis year, tumor stage, grade, histology, neighborhood poverty, and county-level mammography availability. Greater black segregation and Hispanic segregation were adversely associated with cause-specific mortality and all-cause mortality. For example, in adjusted models, Hispanic segregation was associated with cause-specific mortality (adjusted hazard ratio, 1.24; 95% confidence interval, 1.05-1.46). Compared with whites, blacks had higher mortality for both outcomes, whereas Hispanics demonstrated equivalent (cause-specific) or lower (all-cause) mortality. Segregation did not explain racial/ethnic disparities in mortality. Within each race/ethnicity strata, segregation was either adversely associated with mortality or was not significant. Among urban women with breast cancer in Texas, segregation has an independent, adverse association with mortality, and the effect of segregation varies by patient race/ethnicity. The novel application of a small-area measure of relative racial segregation should be examined in other cancer types with documented racial/ethnic disparities across varied geographic areas.


The expression of retinal cell markers in human retinal pigment epithelial cells and their augmentation by the synthetic retinoid fenretinide.
In several species the retinal pigment epithelium (RPE) has the potential to transdifferentiate into retinal cells to regenerate functional retinal tissue after injury. However, this capacity for regeneration is lost in mammals. The synthetic retinoic acid derivative, fenretinide [N(4-hydroxyphenyl) retinamide], induces a neuronal-like phenotype in the human adult retinal pigment epithelial cell line (ARPE-19). These changes are characterized by the appearance of neural-like processes and the expression of neuronal markers not normally associated with RPE cells. Here we assess whether fenretinide can induce a neuroretinal cell phenotype in ARPE-19 cells, by examining retinal cell marker expression. ARPE-19 cells were treated daily with culture medium containing either 3 μM fenretinide or dimethyl sulfoxide as a control for 7 days. Cells were processed for immunocytochemistry, western blotting, and for analysis by PCR to examine the expression of a panel of RPE, neural, and retinal-associated cellular markers, including classical and non-canonical opsins. Treatment with fenretinide for 7 days induced the formation of neuronal-like processes in ARPE-19 cells. Fenretinide induced the expression of the cone long wavelength sensitive opsin (OPN1lw) but not rhodopsin (RHO), while decreasing the expression of RPE cell markers. Many of the neuronal and retinal specific markers examined were expressed in both control and fenretinide treated cells, including those involved in photoreceptor cell development and the multipotency of neural retinal progenitor cells. Interestingly, ARPE-19 cells also expressed both photoreceptor specific and non-specific canonical opsins. The expression of retinal-associated markers and loss of RPE cell markers in control ARPE-19 cells suggests that these cells might have dedifferentiated from an RPE cell phenotype under standard culture conditions. The expression of molecules, such as the transcription factors paired box 6 gene (PAX6), sex determining region Y-box 2 (SOX2), cone-rod homeobox (CRX), and neural retina leucine zipper (NRL), further implies that in culture these cells are predisposed toward a retinal progenitor-like state. The fenretinide-induced increase in photoreceptor cell markers, accompanied by a decrease in RPE cell markers, suggests that retinoids may play a role in the transdifferentiation of RPE cells. Importantly, our data show for the first time the expression of a vertebrate ciliary opsin (OPN1lw) and rhabdomeric-like opsin, opsin 4 (OPN4 also known as melanopsin) in a clonal cell line. Together these data suggest that ARPE-19 cells are primed for and possess the capacity to differentiate toward a retinal cell-like lineage.


Oligosaccharides from Gracilaria lemaneiformis better attenuated high fat diet-induced metabolic syndrome by promoting the Bacteroidales proliferation.
Polysaccharides from Gracilaria lemaneiformis (GLPs) were shown to reduce high fat diet (HFD)-induced metabolic syndrome (MS), but its high molecular weight (MW) causes lots of barriers to its application in foods as a functional ingredient. In this study, oligosaccharides derived from GLPs (D-GLPs) were prepared, and its effect on HFD-induced MS and inflammation was evaluated in mice. It revealed that D-GLPs reduced fat accumulation, lipid disorders and inflammation in HFD-fed mice accompanied by an improvement of the gut microbiota. D-GLPs reversed HFD-induced gut microbiota dysbiosis characterized by the increased ratio of Bacteroidetes to Firmicutes and the abundance of the Bacteroidales. Spearman correlation analysis showed that some members of the Bacteroidales were positively correlated with reduced fat accumulation, inflammation and lipid disorders. Compared to GLPs, D-GLPs had a better inhibition effect on MS-related parameters, which may be attributed to higher abundance of some Bacteroidales members owing to their prioritization strategy to D-GLPs. The anti-obesity effect was transmissible through fecal transfer from D-GLPs-fed mice to HFD-fed mice, implying that the effect was associated with the gut microbiota. It indicated that D-GLPs can be used as a potential prebiotic agent to MS therapy.


Regeneration of lesioned corticospinal tract fibers in the adult rat spinal cord under experimental conditions.
The absence of fiber regrowth in the injured spinal cord and brain is influenced by several different factors and mechanisms. Among these are factors which inhibit neurite growth which are found on the surface of oligodendrocytes and central myelin. Their neutralization by a specific antibody allowed regeneration of transected corticospinal tract fibers in the adult rat spinal cord. Using a recently introduced novel neuroanatomical tracer, biotin-dextran-amine, we demonstrate the extensive regenerative sprouting of lesioned corticospinal fibers in the lesioned adult spinal cord. In the presence of the antibody against the myelin-associated neurite growth inhibitors, some of these fibers grew over remaining tissue bridges into the caudal spinal cord. They branched extensively in the lumbar spinal cord segments. These branches were decorated with synapse-like boutons. This neuroanatomical configuration probably contributes importantly to the functional recovery observed earlier in these antibody-treated animals.


Multi-Parameter Relief Map from High-Resolution DEMs: A Case Study of Mudstone Badland.
Topographic parameters of high-resolution digital elevation models (DEMs) with meter to sub-meter spatial resolution, such as slope, curvature, openness, and wetness index, show the spatial properties and surface characterizations of terrains. The multi-parameter relief map, including two-parameter (2P) or three-parameter (3P) information, can visualize the topographic slope and terrain concavities and convexities in the hue, saturation, and value (HSV) color system. Various combinations of the topographic parameters can be used in the relief map, for instance, using wetness index for upstream representation. In particular, 3P relief maps are integrated from three critical topographic parameters including wetness or aspect, slope, and openness data. This study offers an effective way to explore the combination of topographic parameters in visualizing terrain features using multi-parameter relief maps in badlands and in showing the effects of smoothing and parameter selection. The multi-parameter relief images of high-resolution DEMs clearly show micro-topographic features, e.g., popcorn-like morphology and rill.


Historical evidence that electrification caused the 20th century epidemic of "diseases of civilization".
The slow spread of residential electrification in the US in the first half of the 20th century from urban to rural areas resulted by 1940 in two large populations; urban populations, with nearly complete electrification and rural populations exposed to varying levels of electrification depending on the progress of electrification in their state. It took until 1956 for US farms to reach urban and rural non-farm electrification levels. Both populations were covered by the US vital registration system. US vital statistics tabulations and census records for 1920-1960, and historical US vital statistics documents were examined. Residential electrification data was available in the US census of population for 1930, 1940 and 1950. Crude urban and rural death rates were calculated, and death rates by state were correlated with electrification rates by state for urban and rural areas for 1940 white resident deaths. Urban death rates were much higher than rural rates for cardiovascular diseases, malignant diseases, diabetes and suicide in 1940. Rural death rates were significantly correlated with level of residential electric service by state for most causes examined. I hypothesize that the 20th century epidemic of the so called diseases of civilization including cardiovascular disease, cancer and diabetes and suicide was caused by electrification not by lifestyle. A large proportion of these diseases may therefore be preventable.


The full-length Saccharomyces cerevisiae Sgs1 protein is a vigorous DNA helicase that preferentially unwinds holliday junctions.
The highly conserved RecQ family of DNA helicases has multiple roles in the maintenance of genome stability. Sgs1, the single RecQ homologue in Saccharomyces cerevisiae, acts both early and late during homologous recombination. Here we present the expression, purification, and biochemical analysis of full-length Sgs1. Unlike the truncated form of Sgs1 characterized previously, full-length Sgs1 binds diverse single-stranded and double-stranded DNA substrates, including DNA duplexes with 5'- and 3'-single-stranded DNA overhangs. Similarly, Sgs1 unwinds a variety of DNA substrates, including blunt-ended duplex DNA. Significantly, a substrate containing a Holliday junction is unwound most efficiently. DNA unwinding is catalytic, requires ATP, and is stimulated by replication protein A. Unlike RecQ homologues from multicellular organisms, Sgs1 is remarkably active at picomolar concentrations and can efficiently unwind duplex DNA molecules as long as 23,000 base pairs. Our analysis shows that Sgs1 resembles Escherichia coli RecQ protein more than any of the human RecQ homologues with regard to its helicase activity. The full-length recombinant protein will be invaluable for further investigation of Sgs1 biochemistry.


Long-term antecedents of constraints and mastery: Findings from the Health and Retirement Study.
Whereas it is well established that having a sense of control over one's life circumstances facilitates positive aging-related outcomes across adulthood and old age, far less is known about what factors contribute to perceived control and whether these factors differ across the adult life span. We used longitudinal data from the Health and Retirement Study (N = 7,624, M age at 2006 = 67.50 years, range 50-104, 59% women) to examine whether level of, and time-related change in, episodic memory, depressive symptoms, and health (functional limitations, self-rated health) predict levels of 2 distinct components of perceived control: constraints and mastery. We found that lower levels of memory, more depressive symptoms, and less positive self-rated health were each associated with higher levels of constraints. Increases in depressive symptoms and functional limitations were also associated with higher levels of constraints, whereas stability in memory was related to lower levels of constraints. Conversely, lower levels of, and declines in, depressive symptoms and functional limitations as well as higher self-rated health were associated with self-reported higher levels of mastery. We found some evidence to suggest that these effects differ across the adult life span. Our findings show that, across adulthood and old age, constraints and mastery are shaped by level of, and time-related changes in, key domains of functioning. These findings provide impetus for future research to target mechanisms and moderators of such associations. (PsycINFO Database Record


Blood stage merozoite surface protein conjugated to nanoparticles induce potent parasite inhibitory antibodies.
In this proof-of-concept study we report the use of <15 nm, water soluble, inorganic nanoparticles as a vaccine delivery system for a blood stage malaria vaccine. The recombinant malarial antigen, Merozoite Surface Protein 1 (rMSP1) of Plasmodium falciparum served as the model vaccine. The rMSP1 was covalently conjugated to polymer-coated quantum dot CdSe/ZnS nanoparticles (QDs) via surface carboxyl groups, forming rMSP1-QDs. Anti-MSP1 antibody responses induced by rMSP1-QDs were found to have 2-3 log higher titers than those obtained with rMSP1 administered with the conventional adjuvants, Montanide ISA51 and CFA. Moreover, the immune responsiveness and the induction of parasite inhibitory antibodies were significantly superior in mice injected with rMSP1-QDs. The rMSP1-QDs delivered via intra-peritoneal (i.p.), intra-muscular (i.m.), and subcutaneous (s.c.) routes were equally efficacious. The high level of immunogenicity exhibited by the rMSP1-QDs was achieved without further addition of other adjuvant components. Bone marrow derived dendritic cells were shown to efficiently take up the nanoparticles leading to their activation and the expression/secretion of key cytokines, suggesting that this may be a mode of action for the enhanced immunogenicity. This study provides promising results for the use of water soluble, inorganic nanoparticles (<15 nm) as potent vehicles/platforms to enhance the immunogenicity of polypeptide antigens in adjuvant-free immunizations.


Association of diabetes with amnestic and nonamnestic mild cognitive impairment.
Type 2 diabetes may increase the risk of amnestic mild cognitive impairment (aMCI) through Alzheimer's disease (AD)-related and vascular pathology and may also increase the risk of nonamnestic MCI (naMCI) through vascular disease mechanisms. We examined the association of type 2 diabetes with mild cognitive impairment (MCI) and MCI subtype (aMCI and naMCI) overall and by sex. Participants were Olmsted County, Minnesota residents (70 years and older) enrolled in a prospective, population-based study. At baseline and every 15 months thereafter, participants were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of normal cognition, MCI, and dementia by a consensus panel. Type 2 diabetes was ascertained from the medical records of participants at baseline. Over a median 4.0 years of follow-up, 348 of 1450 subjects developed MCI. Type 2 diabetes was associated (hazard ratio [95% confidence interval]) with MCI (1.39 [1.08-1.79]), aMCI (1.58 [1.17-2.15]; multiple domain: 1.58 [1.01-2.47]; single domain: 1.49 [1.09-2.05]), and the hazard ratio for naMCI was elevated (1.37 [0.84-2.24]). Diabetes was strongly associated with multiple-domain aMCI in men (2.42 [1.31-4.48]) and an elevated risk of multiple domain naMCI in men (2.11 [0.70-6.33]), and with single domain naMCI in women (2.32 [1.04-5.20]). Diabetes was associated with an increased risk of MCI in elderly persons. The association of diabetes with MCI may vary with subtype, number of domains, and sex. Prevention and control of diabetes may reduce the risk of MCI and Alzheimer's disease.


Green Synthesis of Zr-Based Metal-Organic Framework Hydrogel Composites and Their Enhanced Adsorptive Properties.
Metal-organic frameworks (MOFs) have emerged as promising candidates for a wide range of applications due to their high surface area and customizable structures, however, the minimal external hydrophilicity of MOFs has limited their biomedical implementations. Structuring of MOFs within polymer frameworks is an approach used to create hybrid materials that retain many of the MOF characteristics (e.g. high adsorption capacity) but expand the range of mechanical and surface properties as well as form factors accessible. Using this approach, hybridizing MOFs with hydrophilic hydrogels can give rise to materials with improved hydrophilicity and biocompatibility. Here, we describe the synthesis of the first Zr-based MOF-hydrogel hybrid material (composite 3) using a green chemistry approach, in which only water was used as the solvent and relatively low temperature (50 °C) was applied. Using methylene blue (MB) as a probe molecule, composite 3 exhibited greater adsorption capacity than the MOF or the hydrogel alone in aqueous solution at most tested pH values (all except pH 13). At an initial MB concentration of 0.0096 mg/mL (30.014uM) and neutral pH conditions, this new hybrid presented the highest loading of MB among similar materials (MB adsorbed = 4.361 ± 0.092 mg MB/g Zr, partition coefficient = 0.172 ± 0.004 mg/g/uM) and largely retained its adsorption capacity under varied conditions (pH 1-13 and 0.2-1.0M NaCl), rendering possible applications in drug delivery and the removal of tumor contrast agent/dye with minimal leakage due to its broad chemical stability.


Mapping and modeling the biogeochemical cycling of turf grasses in the United States.
Turf grasses are ubiquitous in the urban landscape of the United States and are often associated with various types of environmental impacts, especially on water resources, yet there have been limited efforts to quantify their total surface and ecosystem functioning, such as their total impact on the continental water budget and potential net ecosystem exchange (NEE). In this study, relating turf grass area to an estimate of fractional impervious surface area, it was calculated that potentially 163,800 km2 (+/- 35,850 km2) of land are cultivated with turf grasses in the continental United States, an area three times larger than that of any irrigated crop. Using the Biome-BGC ecosystem process model, the growth of warm-season and cool-season turf grasses was modeled at a number of sites across the 48 conterminous states under different management scenarios, simulating potential carbon and water fluxes as if the entire turf surface was to be managed like a well-maintained lawn. The results indicate that well-watered and fertilized turf grasses act as a carbon sink. The potential NEE that could derive from the total surface potentially under turf (up to 17 Tg C/yr with the simulated scenarios) would require up to 695 to 900 liters of water per person per day, depending on the modeled water irrigation practices, suggesting that outdoor water conservation practices such as xeriscaping and irrigation with recycled waste-water may need to be extended as many municipalities continue to face increasing pressures on freshwater.


Patient-specific modeling and quantification of the aortic and mitral valves from 4-D cardiac CT and TEE.
As decisions in cardiology increasingly rely on noninvasive methods, fast and precise image processing tools have become a crucial component of the analysis workflow. To the best of our knowledge, we propose the first automatic system for patient-specific modeling and quantification of the left heart valves, which operates on cardiac computed tomography (CT) and transesophageal echocardiogram (TEE) data. Robust algorithms, based on recent advances in discriminative learning, are used to estimate patient-specific parameters from sequences of volumes covering an entire cardiac cycle. A novel physiological model of the aortic and mitral valves is introduced, which captures complex morphologic, dynamic, and pathologic variations. This holistic representation is hierarchically defined on three abstraction levels: global location and rigid motion model, nonrigid landmark motion model, and comprehensive aortic-mitral model. First we compute the rough location and cardiac motion applying marginal space learning. The rapid and complex motion of the valves, represented by anatomical landmarks, is estimated using a novel trajectory spectrum learning algorithm. The obtained landmark model guides the fitting of the full physiological valve model, which is locally refined through learned boundary detectors. Measurements efficiently computed from the aortic-mitral representation support an effective morphological and functional clinical evaluation. Extensive experiments on a heterogeneous data set, cumulated to 1516 TEE volumes from 65 4-D TEE sequences and 690 cardiac CT volumes from 69 4-D CT sequences, demonstrated a speed of 4.8 seconds per volume and average accuracy of 1.45 mm with respect to expert defined ground-truth. Additional clinical validations prove the quantification precision to be in the range of inter-user variability. To the best of our knowledge this is the first time a patient-specific model of the aortic and mitral valves is automatically estimated from volumetric sequences.


Factors Predictive of Severe Multiple Sclerosis Disease Reactivation After Fingolimod Cessation.
Fingolimod withdrawal may trigger the return of pretreatment disease activity. It is difficult to identify patients at risk of disease reactivation. We compared the demographic and clinical features of patients experiencing severe disease reactivation (SDR) after fingolimod cessation with those of patients who did not. All patients who commenced fingolimod and who continued therapy for at least 6 months were included. The demographic and clinical features of the 2 groups (SDR vs. no SDR) were assessed. Forty-four of 303 patients discontinued fingolimod for various reasons. Among these, 31 fulfilled our inclusion criteria and 8 (25.8%) exhibited SDR after drug cessation. The mean time for SDR was 2.6 months (range, 2 to 3 mo). The annualized relapse rate before fingolimod therapy was higher in the SDR than in the non-SDR group (1.59 vs. 0.81) (P=0.018). Although statistical significance was not attained, the mean Expanded Disability Status Scale score at the time of fingolimod cessation was higher in the non-SDR than in the SDR group (2.5 vs. 1.12) (P=0.074). SDR may develop within the first 3 months after cessation of fingolimod. Patients with higher annualized relapse rates and lower Expanded Disability Status Scale scores before commencing fingolimod treatment were more likely to exhibit SDR.


Reductive alteration of the regulatory function of the CD4(+)CD25(+) T cell fraction in silicosis patients.
Causal links have been documented between silica and rheumatoid arthritis, lupus erythematosus, systemic sclerosis and glomerulonephritis. Two different effects of silica have been suggested, an enhanced inflammatory response in the pulmonary region (e.g. activation of alveolar macrophages) and dysregulation of autoimmunity. Based on our previous reports showing in vitro activation of peripheral T cells by silica and reduced regulatory function of the peripheral CD4(+)CD25(+) fraction in which FoxP(3)+ regulatory T cells (Treg) are located, reconstitution of the CD4(+)CD25(+) fraction in silicosis patients (SILs) was investigated. Since T cells in peripheral CD4(+)CD25(+) and CD4(+)CD25(-) (effector T cells; Teff) fractions from SILs showed higher expression of pd-1 (a marker gene for T cell activation) in comparison to that of healthy donors (HDs), chronic T cell activation was considered to have occurred in SILs. In this study, a higher expression of the CD95/Fas molecule in Treg was recorded from silicosis patients (SILs) compared to healthy donors (HDs), and excess loss of FoxP3(+) Treg in freshly isolated peripheral blood mononuclear cells (PBMCs) from SILs relative to HDs was demonstrated when these cells were cultured with silica ex vivo, whereas CD25(+) cells were not reduced due to contamination of activated Teff in the CD4(+)CD25(+) fraction. The activation of both Teff and Treg results in reconstitution of the peripheral CD4(+)CD25(+) fraction, loss of Treg and contamination of activated Teff, resulting in reduction of the number and function of Treg. These results contribute to our understanding of the development of autoimmune diseases found in SILs.


Circadian variation in gastric vagal afferent mechanosensitivity.
Food intake is coordinated to cellular metabolism by clock gene expression with a master clock in the suprachiasmatic nucleus synchronized by light exposure. Gastric vagal afferents play a role in regulating food intake, but it is unknown whether they exhibit circadian variation in their mechanosensitivity. We aimed to determine whether gastric vagal afferents express clock genes and whether their response to mechanical stimuli oscillates throughout the light/dark cycle. Nodose ganglia were collected from 8-week-old female C57BL/6 mice every 3 h starting at lights off (1800 h) to quantify Bmal1, Per1, Per2, and Nr1d1 mRNA by qRT-PCR. Additionally in vitro single-fiber recordings of gastric vagal mechanoreceptors were taken at all time points. Per1, Per2, Bmal1, and Nr1d1 mRNA is expressed in the nodose ganglia and levels oscillated over a 24 h period. In mice fed ad libitum, gastric content was 3 times higher at 0000 h and 0300 h than 1200 h. The response of tension receptors to 3 g stretch was reduced by up to 70% at 2100 h, 0000 h, and 0300 h compared with 1200 h. Gastric mucosal receptor response to stroking with a 50 mg von Frey hair was 3 times greater at 1200 h and 1500 h than the response at 0000 h. Similar findings were obtained in mice fasted for 6 h or maintained in darkness for 3 d before study. Therefore, these changes do not result from food intake or the light/dark cycle. Thus, gastric vagal mechanoreceptors display circadian rhythm, which may act to control food intake differentially at different times of the day.


Killer cell immunoglobulin-like receptor gene diversity in the Tibetan ethnic minority group of China.
The aim of this study was to analyze killer immunoglobulin-like receptor (KIR) gene polymorphisms in the Tibetan ethnic minority of China. To that purpose, we have studied KIR gene frequencies and genotype diversities of 16 KIR genes and three pseudogenes (2DL1, 2DL2, 2DL3, 2DL4, 2DL5A, 2DL5B, 2DS1, 2DS2, 2DS3, 2DS4*001/002, 2DS4*003-007, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1, 2DP1, 3DP1*001/002/004, and 3DP1*003) in a population sample of 102 unrelated healthy individuals of the Tibetan population living in Lhasa city, Tibet Autonomous Region of China. Tibetans mainly live in "the roof of the world," the Qinghai-Tibet Plateau of China and surrounding areas stretching from central Asia in the North and West to Myanmar and mainland China in the East, and India, Nepal, and Bhutan to the south. KIR gene frequencies and statistical parameters of Tibetan ethnic minority were calculated. Fifteen KIR genes were observed in the 102 tested Tibetan individuals with different frequencies. The allelic frequencies of the 15 KIR genes ranged from 0.06 to 0.86. In addition, KIR 2DL1, 2DL4, 3DL2, and 3DL3 were found to be present in every individual. Variable gene content, together with allelic polymorphisms, can result in individualized human KIR genotypes and haplotypes, with the A haplotypes being predominantly observed. The results of tested linkage disequilibrium (LD) among KIR genes demonstrated that KIR genes present a wide range of linkage disequilibrium. Moreover, a comparison of the population data of our study with previously published population data of other ethnic groups or areas was performed. The differences of allelic frequency distribution in KIR2DL2, 2DL3, 2DL5, 3DL1, 2DS1, 2DS2, 2DS3, 3DS1, and 2DP1 were statistically significant among different populations using the statistical method of the standard χ(2) test. In conclusion, the results of the present study can be valuable for enriching the Chinese ethnical gene information resources of the KIR gene pool and for anthological studies, as well as for KIR-related disease research.


Pharmacokinetics, dynamics and toxicity of docetaxel: Why the Japanese dose differs from the Western dose.
Docetaxel (Taxotere(®)) has been one of the most important chemotherapeutic drugs for cancer treatment since 1996. Although a large number of clinical studies have been conducted in various cancer fields, there is a discrepancy in the standard dose between Japan and Western countries. This article reviews the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem. The original recommended dose was 100 mg/m(2) every 3 weeks in US and European populations, while a Japanese phase I study suggested the recommended dose as 60 mg/m(2) every 3 weeks. A prospective population pharmacokinetic analysis of docetaxel conducted in both the USA/Europe and Japan, indicated an absence of ethnic difference in the pharmacokinetics. Both analyses demonstrated that docetaxel clearance is related to α1-acid glycoprotein level, hepatic function, age and body surface area. The relationship was observed between increasing docetaxel dose and increased tumor response rates across the dose range of 60 to 100 mg/m(2). The area under the serum concentration time curve (AUC) of docetaxel at the first cycle was significantly related to time to progression. Hematological toxicities were well correlated with the AUC of docetaxel, and severe hematological toxicities were more frequently observed in Japanese patients treated with 60 mg/m(2), compared to the US/European patients treated with 75-100 mg/m(2) dose. The Japanese population seems more susceptible to the toxicity of docetaxel. A docetaxel dose of 75 mg/m(2) is now standard not only in global trials but also in recent Japanese trials. Although the optimal dose of docetaxel is still unclear, we need to continue to seek the appropriate dose of docetaxel depending on patient status and the goals of chemotherapy.


Isolated pharyngeal swallow exists during normal human feeding.
Swallowing is one of the basic activities in humans. The pharynx functions as an airway and a food channel, and a pharyngeal swallow usually occurs after bolus transport from the oral cavity. However, direct fluid infusion through a catheter into the hypopharynx produces a pharyngeal swallow without the oral stage in experimental situations. The purpose of this study was to examine whether a pharyngeal swallow, which is not accompanied by bolus transport, can occur during normal human feeding. Fifty-three healthy volunteers (25-89 years) were recorded, via videofluoroscopic examination of swallowing, during 3 different swallowing trials: command swallow of 10 ml liquid barium, chew-swallow of corned beef, and chew-swallow of a mixture of corned beef and liquid barium. Subsequently each swallow was classified as being either a consecutive pharyngeal swallow (CPS), following transport, or an isolated pharyngeal swallow (IPS), without immediately prior transport. The location of the bolus at swallow initiation was also noted. Of 307 trials, 681 swallows were identified, which included 43 IPS and 638 CPS. IPS only occurred as the first swallow of a trial, but the frequency of IPS did not differ between 28 younger (< 60 years) and 25 older (≥ 60 years) people. Of the three food types, IPS occurred more frequently with the mixed food than with liquid. These results suggest that IPS may represent an airway protective mechanism. In conclusion, IPS occurs in normal swallowing during a daily eating situation. Swallowing is more complex than a simple reflex.


Testicular cancer in young men: the search for causes of the epidemic increase in the United States.
A case-control study of 271 men with testicular cancer and 259 controls was conducted in the Washington, DC area to evaluate whether suggested risk factors could be responsible for the epidemic increases in testicular cancer in young men. No substantial risks were associated with a history of groin hernia operation, the common childhood diseases, allergies, x rays below the waist, venereal disease, vasectomy, or external means of elevating the temperature of the testis. Excess risks were associated with a history of undescended testis (RR = 3.7, CI = 1.5-9.5), testicular trauma (RR = 2.6, CI = 1.6-4.2), and mumps orchitis (RR = 5.8, CI = 0.7-129.7). It is unlikely, however, that any of these conditions has increased sufficiently over time to markedly affect the testicular cancer incidence patterns. Therefore, while the risk factors identified in this paper are of epidemiological interest, they do not account for the increase in testicular cancer in young men.


Role of the Histone-Like Nucleoid Structuring Protein (H-NS) in the Regulation of Virulence Factor Expression and Stress Response in Vibrio vulnificus.
Temperature is one of the important parameters regulating the expression of virulence factors in bacteria. The global regulator, a histone-like nucleoid structuring protein (H-NS), is known to play a crucial role in this regulation. In the present study, we first clarified the role of H-NS in the temperature-dependent regulation of virulence factor production in Vibrio vulnificus, including that of the cytolytic toxin (V. vulnificus hemolysin: VVH) and the proteolytic enzyme (V. vulnificus protease: VVP). The expression of hns itself was subjected to temperature regulation, where hns was expressed more at 26 ℃ than at 37 ℃. VVH production and the expression of its gene vvhA were increased by disruption of the hns gene. H-NS appeared to affect the vvhA expression by the well-documented transcriptional silencing mechanism. On the other hand, hns disruption resulted in the reduction of VVP production and the expression of its gene vvpE. H-NS was suggested to positively regulate vvpE expression through the increase in the level of the rpoS mRNA. Moreover, H-NS was found to contribute to the survival of V. vulnificus in stressful environments. When compared to the wild type strain, the hns mutant exhibited reduced survival rates when subjected to acidic pH, hyperosmotic and oxidative stress.


Expression and functional characterization of bluetongue virus VP5 protein: role in cellular permeabilization.
Segment 5 of bluetongue virus (BTV) serotype 10, which encodes the outer capsid protein VP5, was tagged with glutathione S-transferase and expressed by a recombinant baculovirus. The recombinant protein was subsequently purified to homogeneity, and its possible biological role in virus infection was investigated. Purified VP5 was able to bind mammalian cells but was not internalized, which indicates it is not involved in receptor-mediated endocytosis. The purified VP5 protein was shown to be able to permeabilize mammalian and Culicoides insect cells, inducing cytotoxicity. Sequence analysis revealed that VP5 possesses characteristic structural features (including two amino-terminal amphipathic helices) compatible with virus penetration activity. To assess the role of each feature in the observed cytotoxicity, a series of deleted VP5 molecules were generated, and their expression and biological activity was compared with the parental molecule. VP5 derivatives that included the two amphipathic helices exhibited cytotoxicity, while those that omitted these sequences did not. To confirm their role in membrane destabilization two synthetic peptides (amino acids [aa] 1 to 20 and aa 22 to 41) encompassing the two helices and an additional peptide representing the adjacent downstream sequences were also assessed for their effect on the cell membrane. Both helices, but not the downstream VP5 sequence, exhibited cytotoxicity with the most-amino-terminal helix (aa 1 to 20) showing a higher activity than the adjacent peptide (aa 22 to 41). Purified VP5 was shown to readily form trimers in solution, a feature of many proteins involved in membrane penetration. Taken together, these data support a role for VP5 in virus-cell penetration consistent with its revelation in the entry vesicle subsequent to cell binding and endocytosis.


Fourier relationship between angular position and optical orbital angular momentum.
We demonstrate the Fourier relationship between angular position and angular momentum for a light mode. In particular we measure the distribution of orbital angular momentum states of light that has passed through an aperture and verify that the orbital angular momentum distribution is given by the complex Fourier-transform of the aperture function. We use spatial light modulators, configured as diffractive optical components, to define the initial orbital angular momentum state of the beam, set the defining aperture, and measure the angular momentum spread of the resulting beam. These measurements clearly confirm the Fourier relationship between angular momentum and angular position, even at light intensities corresponding to the single photon level.


Resistance to geminivirus infection by virus-induced expression of dianthin in transgenic plants.
Ribosome-inactivating proteins (RIPs) are naturally occurring plant toxins that exhibit antiviral activity against a diverse range of plant and animal viruses. Here, the action of dianthin, a potent RIP isolated from Dianthus caryophyllus, has been exploited to engineer resistance to a plant DNA virus, African cassava mosaic virus (ACMV), in transgenic Nicotiana benthamiana. To achieve this, dianthin has been expressed from the ACMV virion-sense promoter that is transactivated by the product of viral gene AC2. This avoids the need for constitutive expression of the RIP, facilitating the regeneration of phenotypically normal plants, and ensures transgene expression is localized to virus-infected cells. When challenged with ACMV, transgenic plants produce atypical necrotic lesions on inoculated leaves, indicative of dianthin expression, viral DNA accumulation is significantly reduced in these tissues, and plants exhibit attenuated systemic symptoms from which they recover. This phenotype holds for isolates of ACMV but not for other geminiviruses, suggesting that AC2 homologues from the latter are unable to efficiently transactivate the ACMV promoter.


Prenatal exposure to traffic-related air pollution and ultrasound measures of fetal growth in the INMA Sabadell cohort.
Few studies have used longitudinal ultrasound measurements to assess the effect of traffic-related air pollution on fetal growth. We examined the relationship between exposure to nitrogen dioxide (NO2) and aromatic hydrocarbons [benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene (BTEX)] on fetal growth assessed by 1,692 ultrasound measurements among 562 pregnant women from the Sabadell cohort of the Spanish INMA (Environment and Childhood) study. We used temporally adjusted land-use regression models to estimate exposures to NO2 and BTEX. We fitted mixed-effects models to estimate longitudinal growth curves for femur length (FL), head circumference (HC), abdominal circumference (AC), biparietal diameter (BPD), and estimated fetal weight (EFW). Unconditional and conditional SD scores were calculated at 12, 20, and 32 weeks of gestation. Sensitivity analyses were performed considering time-activity patterns during pregnancy. Exposure to BTEX from early pregnancy was negatively associated with growth in BPD during weeks 20-32. None of the other fetal growth parameters were associated with exposure to air pollution during pregnancy. When considering only women who spent < 2 hr/day in nonresidential outdoor locations, effect estimates were stronger and statistically significant for the association between NO2 and growth in HC during weeks 12-20 and growth in AC, BPD, and EFW during weeks 20-32. Our results lend some support to an effect of exposure to traffic-related air pollutants from early pregnancy on fetal growth during mid-pregnancy..


Draining the pond and catching the fish: Uncovering the ecosystem of auditory verbal hallucinations.
The various models proposed for the mediation of auditory verbal hallucinations (AVH) implicate a considerable number of brain areas and mechanisms. To establish which of those mechanisms are actually involved in the mediation of AVH, we developed a novel method to analyze functional MRI data, which allows for the detection of the full network of mutually interacting brain states, and the identification of those states that are relevant to the mediation of AVH, while applying a minimum number of preconceived assumptions. This method is comparable to the draining of a pond to lay bare the full ecosystem that affects the presence of a particular fish species. We used this model to analyze the fMRI data of 85 psychotic patients experiencing AVH. The data were decomposed into 98 independent components (ICs) representing all major functions active in the brain during scanning. ICs involved in mediating AVH were identified by associating their time series with the hallucination time series as provided by subjects within the scanner. Using graph theory, a network of interacting ICs was created, which was clustered into IC modules. We used causal reasoning software to determine the direction of links in this network, and discover the chain of events that leads to the conscious experience of hallucinations. Hallucinatory activity was linked to three of the seven IC clusters and 11 of the 98 ICs. ICs with the most influential roles in producing AVH-related activity were those within the so-called salience network (comprising the anterior cingulate gyrus, right insula, Broca's homologue, premotor cortex, and supramarginal gyrus). Broca's area and the cerebellar regions were significantly, but more distantly involved in the mediation of AVH. These results support the notion that AVH are largely mediated by the salience network. We therefore propose that the mediation of AVH in the context of schizophrenia spectrum disorders involves the attribution of an excess of negative salience by anterior-cingulate areas to linguistic input from Broca's right homologue, followed by subsequent processing errors in areas further 'downstream' the causal chain of events. We provide a detailed account of the origin of AVH for this patient group, and make suggestions for selective interventions directed at the most relevant brain areas.


Obesity induced by neonatal overfeeding worsens airway hyperresponsiveness and inflammation.
Obesity is a risk factor for the development of certain respiratory diseases, and neonatal overfeeding results in an early onset of obesity in adulthood. However, the influence of neonatal overfeeding on respiratory diseases has rarely been studied. Therefore, this paper is aimed at investigating the effect of neonatal overfeeding on airway responsiveness and inflammation. The neonatal overfeeding was induced by reducing litter size to three pups per litter (small litter, SL) in contrast to the normal litter size with ten pups per litter (NL) on postnatal day 3 (P3) in male ICR mice. On P21, mice were weaned to standard chow diet. Airway responsiveness to methacholine was measured either on P21 or P150. Total and classified inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted, lung inflammatory cells were evaluated through staining with hematoxylin & eosin and F4/80 immunohistochemistry; lung fibrosis was evaluated through staining with Masson and α-SAM immunohistochemistry. Leptin levels in serum were measured by RIA; TNF-α levels in serum and BALF were quantified by ELISA; mRNA levels of TNF-α, CTGF and TGF-β1 in lung tissues were measured using real-time PCR. Mice from SL exhibited accelerated body weight gain, impaired glucose tolerance and hyperleptinemia. Enhanced airway responsiveness to methacholine was observed in SL mice on P150, but not on P21. Pulmonary inflammation was evident in SL mice on P150, as reflected by inflammatory cells especially macrophages around bronchi and interstitium. BALF and serum TNF-α levels and lung TNF-α mRNA expression were significantly increased in SL mice on P150. More collagen accumulated surrounding the bronchi on P150; lung mRNA levels of TGF-β1 and CTGF were also increased on P150. In addition to inducing a variety of metabolic defects, neonatal overfeeding enhanced lung inflammation, which may lead to airway remodeling and airway hyperresponsiveness in adulthood.


Transition metal (Fe, Co, Ni) fluoride-based materials for electrochemical energy storage.
The improvement of advanced battery performance has always been a key issue in energy research. Therefore, it is necessary to explore the applications of excellent materials in advanced batteries. Transition-metal (Fe, Co, Ni) fluoride-based materials exhibit excellent chemical tailorability due to their different functional groups, and they have attracted wide research interest for use in next-generation electrochemical energy storage. This review introduces methods to synthesize transition metal (Fe, Co, Ni) fluoride materials and their applications in batteries and supercapacitors. We also present the current challenges and future opportunities of iron fluoride in electrochemistry, including processing techniques, composite properties, and prospective applications. It is believed that in the future, the research and influence of iron fluoride and its composites will be more far-reaching and lasting.