BDNF Depresses Excitability of Parvalbumin-Positive Interneurons through an M-Like Current in Rat Dentate Gyrus.
In addition to their classical roles in neuronal growth, survival and differentiation, neurotrophins are also rapid regulators of excitability, synaptic transmission and activity-dependent synaptic plasticity. We have recently shown that mature BDNF (Brain Derived Neurotrophic Factor), but not proBDNF, modulates the excitability of interneurons in dentate gyrus within minutes. Here, we used brain slice patch-clamp recordings to study the mechanisms through which BDNF modulates the firing of interneurons in rat dentate gyrus by binding to TrkB receptors. Bath application of BDNF (15 ng/ml) under current-clamp decreased the firing frequency (by 80%) and input resistance, blocking the delayed firing observed at near-threshold voltage ranges, with no changes in resting membrane potential or action potential waveform. Using TEA (tetraethylammonium), or XE991(a Kv7/KCNQ channel antagonist), the effect of BDNF was abolished, whereas application of retigabine (a Kv7/KCNQ channel opener) mimicked the effect of BDNF, suggesting that the M-current could be implicated in the modulation of the firing. In voltage-clamp experiments, BDNF increased the M-like current amplitude with no change in holding current. This effect was again blocked by XE991 and mimicked by retigabine, the latter accompanied with a change in holding current. In agreement with the electrophysiology, parvalbumin-positive interneurons co-expressed TrkB receptors and Kv7.2/KCNQ2 channels. In conclusion, BDNF depresses the excitability of interneurons by activating an M-like current and possibly blocking Kv1 channels, thereby controlling interneuron resting membrane potential and excitability.


[Mechanism Analysis and Prevention of Pathogenesis of Nonalcoholic Steatohepatitis].
Nonalcoholic fatty liver disease (NAFLD) is a common disease in humans having a broad spectrum of liver histology from simple fatty liver to mixed inflammatory cell infiltration and fibrosis (nonalcoholic steatohepatitis, NASH), which is a more severe and progressing form. NASH/NAFLD is significantly associated with lifestyle such as diet and exercise, obesity, insulin resistance, type 2 diabetes, dyslipidemia and hypertension. Age and gender are also associated with the development. On the other hand, NAFLD has been found in a high percentage of nonobese individuals in the Asia-Pacific area. Some characteristic animal models of NAFLD/NASH have been developed to clarify the pathogenesis of human NAFLD/NASH. We have recently developed a novel NASH rat model (stroke-prone spontaneously hypertensive rats, SHRSP5/Dmcr), which showed hepatic steatosis and inflammation at 2 weeks, ballooning, macrovesicular steatosis and fibrosis at 8 weeks, and bridging fibrosis at 14 weeks by feeding of high-fat and -cholesterol (HFC) diet alone. This animal model does not have obesity, insulin resistance or diabetes. Therefore, this may be an excellent animal model of human NASH/NAFLD without obesity and diabetes. Sex and strain differences observed in fibrogenesis by the HFC diet in SHRSP5/Dmcr may be associated with the sensitivity to detoxification enzymes in the liver, because the levels of UGP-glucuronosyltransferase and sulfotransferase and their regulating nuclear receptors only decreased in male SHRSP5/Dmcr rats, but not in female and SHRSP rats. This suggests the importance of phase II reactions of drug-metabolizing enzymes in NASH progression. Importantly, SHRSP5/Dmcr rats are spontaneously hypertensive; therefore, when we use the original strain Wistar Kyoto, which has normal blood pressure, the involvement of blood pressure in the development of human NASH/NAFLD may also be clarified.


Local access to care programs (LACPs): new developments in the access to care for the uninsured.
New, locally based health care access programs are emerging in response to the growing number of uninsured, providing an alternative to health insurance and traditional safety net providers. Although these programs have been largely overlooked in health services research and health policy, they are becoming an important local supplement to the historically overburdened safety net. This article is based on a literature review, Internet search, and key actor interviews to document programs in the United States, using a typology to classify the programs and document key characteristics. Local access to care programs (LACPs) fall outside traditional private and publicly subsidized insurance programs. They have a formal enrollment process, eligibility determination, and enrollment fees that give enrollees access to a network of providers that have agreed to offer free or reduced-price health care services. The forty-seven LACPs documented in this article were categorized into four general models: three-share programs, national-provider networks, county-based indigent care, and local provider-based programs. New, locally based health access programs are being developed to meet the health care needs of the growing number of uninsured adults. These programs offer an alternative to traditional health insurance and build on the tradition of county-based care for the indigent. It is important that these locally based, alternative paths to health care services be documented and monitored, as the number of uninsured adults is continuing to grow and these programs are becoming a larger component of the U.S. health care safety net.


Chromatic adaptation of photosynthetic membranes.
Many biological membranes adapt in response to environmental conditions. We investigated how the composition and architecture of photosynthetic membranes of a bacterium change in response to light, using atomic force microscopy. Despite large modifications in the membrane composition, the local environment of core complexes remained unaltered, whereas specialized paracrystalline light-harvesting antenna domains grew under low-light conditions. Thus, the protein mixture in the membrane shows eutectic behavior and can be mimicked by a simple model. Such structural adaptation ensures efficient photon capture under low-light conditions and prevents photodamage under high-light conditions.


Two processes for recognition memory in children of early school age: an event-related potential study.
We examined the ERP correlates of familiarity and recollection and their development in 8- to 10-year-old children and a control group of young adults. Capitalizing on the different temporal dynamics of familiarity and recollection, we tested recognition memory in both groups with a speeded and nonspeeded response condition. Consistent with the view that familiarity is available earlier than recollection and by this more relevant for speeded recognition judgments, adults and children showed an early frontal old/new effect, the putative ERP correlate of familiarity in the speeded response condition. No parietal old/new effect, the putative ERP correlate of recollection was obtained in the speeded condition in neither group. Conversely, in the nonspeeded condition, both groups showed the parietal old/new effect, and a frontal effect was additionally observed for adults. In light of the generally lower memory accuracy of the children, these data suggested that children use a weaker and less matured version of the same explicit memory network used by adults in which familiarity and recollection differentially contribute to speeded and nonspeeded recognition memory judgments.


Access to human, animal, and environmental journals is still limited for the One Health community.
"One Health" is an interdisciplinary approach to evaluating and managing the health and well-being of humans, animals, and the environments they share that relies on knowledge from the domains of human health, animal health, and the environmental sciences. The authors' objective was to evaluate the extent of open access (OA) to journal articles in a sample of literature from these domains. We hypothesized that OA to articles in human health or environmental journals was greater than access to animal health literature. A One Health seminar series provided fifteen topics. One librarian translated each topic into a search strategy and searched four databases for articles from 2011 to 2012. Two independent investigators assigned each article to human health, the environment, animal health, all, other, or combined categories. Article and journal-level OA were determined. Each journal was also assigned a subject category and its indexing evaluated. Searches retrieved 2,651 unique articles from 1,138 journals; 1,919 (72%) articles came from 406 journals that contributed more than 1 article. Seventy-seven (7%) journals dealt with all 3 One Health domains; the remaining journals represented human health 487 (43%), environment 172 (15%), animal health 141 (12%), and other/combined categories 261 (23%). The proportion of OA journals in animal health (40%) differed significantly from journals categorized as human (28%), environment (28%), and more than 1 category (29%). The proportion of OA for articles by subject categories ranged from 25%-34%; only the difference between human (34%) and environment (25%) was significant. OA to human health literature is more comparable to animal health than hypothesized. Environmental journals had less OA than anticipated.


Disease associations depend on visit type: results from a visit-wide association study.
Widespread adoption of Electronic Health Records (EHR) increased the number of reported disease association studies, or Phenome-Wide Association Studies (PheWAS). Traditional PheWAS studies ignore visit type (i.e., department/service conducting the visit). In this study, we investigate the role of visit type on disease association results in the first Visit-Wide Association Study or 'VisitWAS'. We studied this visit type effect on association results using EHR data from the University of Pennsylvania. Penn EHR data comes from 1,048 different departments and clinics. We analyzed differences between cancer and obstetrics/gynecologist (Ob/Gyn) visits. Some findings were expected (i.e., increase of neoplasm diagnoses among cancer visits), but others were surprising, including an increase in infectious disease conditions among those visiting the Ob/Gyn. We conclude that assessing visit type is important for EHR studies because different medical centers have different visit type distributions. To increase reproducibility among EHR data mining algorithms, we recommend that researchers report visit type in studies.


Evidence for a high mutation rate at rapidly evolving yeast centromeres.
Although their role in cell division is essential, centromeres evolve rapidly in animals, plants and yeasts. Unlike the complex centromeres of plants and aminals, the point centromeres of Saccharomcyes yeasts can be readily sequenced to distinguish amongst the possible explanations for fast centromere evolution. Using DNA sequences of all 16 centromeres from 34 strains of Saccharomyces cerevisiae and population genomic data from Saccharomyces paradoxus, I show that centromeres in both species evolve 3 times more rapidly even than selectively unconstrained DNA. Exceptionally high levels of polymorphism seen in multiple yeast populations suggest that rapid centromere evolution does not result from the repeated selective sweeps expected under meiotic drive. I further show that there is little evidence for crossing-over or gene conversion within centromeres, although there is clear evidence for recombination in their immediate vicinity. Finally I show that the mutation spectrum at centromeres is consistent with the pattern of spontaneous mutation elsewhere in the genome. These results indicate that rapid centromere evolution is a common phenomenon in yeast species. Furthermore, these results suggest that rapid centromere evolution does not result from the mutagenic effect of gene conversion, but from a generalised increase in the mutation rate, perhaps arising from the unusual chromatin structure at centromeres in yeast and other eukaryotes.


Power and predictive accuracy of polygenic risk scores.
Polygenic scores have recently been used to summarise genetic effects among an ensemble of markers that do not individually achieve significance in a large-scale association study. Markers are selected using an initial training sample and used to construct a score in an independent replication sample by forming the weighted sum of associated alleles within each subject. Association between a trait and this composite score implies that a genetic signal is present among the selected markers, and the score can then be used for prediction of individual trait values. This approach has been used to obtain evidence of a genetic effect when no single markers are significant, to establish a common genetic basis for related disorders, and to construct risk prediction models. In some cases, however, the desired association or prediction has not been achieved. Here, the power and predictive accuracy of a polygenic score are derived from a quantitative genetics model as a function of the sizes of the two samples, explained genetic variance, selection thresholds for including a marker in the score, and methods for weighting effect sizes in the score. Expressions are derived for quantitative and discrete traits, the latter allowing for case/control sampling. A novel approach to estimating the variance explained by a marker panel is also proposed. It is shown that published studies with significant association of polygenic scores have been well powered, whereas those with negative results can be explained by low sample size. It is also shown that useful levels of prediction may only be approached when predictors are estimated from very large samples, up to an order of magnitude greater than currently available. Therefore, polygenic scores currently have more utility for association testing than predicting complex traits, but prediction will become more feasible as sample sizes continue to grow.


Synthesis of methanol from CO2 hydrogenation promoted by dissociative adsorption of hydrogen on a Ga3Ni5(221) surface.
Catalytic carbon dioxide (CO2) hydrogenation to liquid fuels including methanol (CH3OH) has attracted great attention in recent years. In this work, density functional theory (DFT) calculations have been employed to study the reaction mechanisms of CO2 hydrogenation to CH3OH on Ga3Ni5(221) surfaces. The results show that all intermediates except for the O atom prefer to adsorb on Ni sites, and dissociative adsorption of hydrogen (H2) on the Ga3Ni5(221) surface is almost barrierless and highly exothermic, favoring CO2 hydrogenation. Moreover, the presence of Ga indeed enhances the dissociative adsorption of H2, and this is verified by the projected density of states (PDOS) analysis. Importantly, three possible reaction pathways based on formate (HCOO) and hydrocarboxyl (COOH) formations and reverse water gas shift (rWGS) with carbon monoxide (CO) hydrogenation have been discussed. It is found that CO2 reduction to CH3OH in these pathways prefers to occur entirely via the Langmuir-Hinshelwood (L-H) mechanism. COOH generation is the most favorable pathway because the HCOO and rWGS with CO hydrogenation pathways have high energy barriers and the resulting HCOOH intermediate in the HCOO pathway is unstable. In the COOH reaction pathway, CO2 is firstly hydrogenated to trans-COOH, followed by the formation of COH via three isomers of COHOH, its hydrogenation to trans-HCOH, and then the production of CH3OH via a CH2OH intermediate.


Oral Motor and Gesture Abilities Independently Associated With Preschool Language Skill: Longitudinal and Concurrent Relationships at 21 Months and 3-4 Years.
Purpose Early motor abilities (gesture, oral motor, and gross/fine skills) are related to language abilities, and this is not due to an association with cognitive or symbolic abilities: Oral motor skills are uniquely associated with language abilities at 21 months of age. It is important to determine whether this motor-language relationship continues beyond the earliest stage of language development to understand language acquisition better and better predict which children may have lasting language difficulties. Method In this longitudinal study, we assessed language comprehension and production, oral motor skill, gross/fine motor skill, and meaningless manual gesture at ages 3 years (N = 89) and 4 years (N = 71), comparing the contribution of motor skill and earlier (at 21 months of age) language ability. We also examined covariates: nonverbal cognitive ability, socioeconomic status, and stimulation in the home as measured on the Home Screening Questionnaire. Results Motor abilities continue to have a significant relationship with language abilities independent of other factors in the preschool years. Meaningless manual gesture ability, gross/fine motor skill, and oral motor skill were still associated with language skill at 3 years of age; these relationships are not explained by the contribution of cognitive abilities or earlier language abilities. Conclusions Relationships between early motor skill and language development persist into preschool years and are not explained by other cognitive or home factors, nor by a relationship with earlier language ability. This finding should lead to a better understanding of the origins of language abilities.


Incidence and severity of neck injury in Rugby Union: a systematic review.
Objectives. To collate and appraise incidence and severity data for neck injury in Rugby Union. To report risk factors for neck injury in Rugby Union that are supported by incidence and severity data. Design. Systematic review. Methods. Original journal articles were retrieved from electronic searches of AusportMed, AUSPORT, Scopus, Medline (Ovid), CINAHL, Mantis, and Pubmed databases and relevant bibliographic hand searches. Selection criteria were restricted to: (a) prospective study designs including cohort, case-control, and intervention methodologies; (b) populations of Rugby Union players, either male or female of any age; (c) studies must report on neck injury incidence and/or severity specifically; (d) articles with republished neck injury data were excluded. The STROBE Statement was adapted for the quality assessment of included studies and categorised as either poor, moderate or good. Results. Thirty-three original articles met the selection criteria. Wide variation of injury and exposure definitions and population sampling was identified in the included articles. Neck injury incidence ranged between 0.26 (CI: 0.08, 0.93) and 9.17 (CI: 1.89, 26.81) per 1000 player hours for mixed populations that adopted an all inclusive sports injury definition. There is a paucity of severity data and analytical data which evaluates causal roles of risk factors for neck injury in Rugby Union. Conclusions. Meaningful understanding of neck injury incidence and severity in Rugby Union is restricted to a few studies which adopt comparable methodological construct. This paper provides an index for future neck injury studies in Rugby Union.


Multi-institutional validation of the predictive value of Ki-67 labeling index in patients with urinary bladder cancer.
Several small single-center studies have reported a prognostic role for Ki-67 labeling index in advanced urothelial carcinoma of the urinary bladder. To investigate whether Ki-67 was a useful biomarker of oncological outcome after radical cystectomy for urothelial carcinoma, we assessed its expression in tumor tissue from 713 patients treated with radical cystectomy and bilateral lymphadenectomy at six centers. A high Ki-67 labeling index was independently associated with established features of aggressive urothelial carcinoma, disease recurrence, and cancer-specific survival. Addition of Ki-67 labeling index improved the accuracy of standard multivariate outcome prediction models, as measured by Harrell concordance index, by 2.9% for disease recurrence and 2.4% for bladder cancer-specific survival (P < .001, two-sided Mantel-Haenszel) -- a statistically and potentially clinically significant margin. In conclusion, routine assessment of Ki-67 expression status along with assessment of other established predictors of urothelial carcinoma outcome has the potential to improve identification of patients who are at increased risk for disease progression after radical cystectomy and thus may benefit from perioperative systemic chemotherapy.


Characterization of SV-40 Tag rats as a model to study prostate cancer.
Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat. The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits. Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats. The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical trials and aids in the rational design of chemoprevention, intervention, regression, and therapeutic studies using prostate cancer rodent models.


Asymmetric loss of parietal activity causes spatial bias in prodromal and mild Alzheimer's disease.
In Alzheimer's disease (AD), loss of effective neuronal activity is reflected by cortical glucose hypometabolism. Hypometabolism in the posterior parietal cortex (PPC) is among the first in vivo signs of AD; however, its functional impact on large-scale brain mechanisms and behavior is poorly understood. The lateral PPC contributes to spatial attention constituting a basic function of the human brain. We hypothesized 1) that lateral PPC hypometabolism is associated with impaired spatial attention in very early AD and 2) that impaired competition of effective neuronal activity across hemispheres might underlie this deficit in terms of brain mechanisms. A model-based imaging approach was applied to assess patients with prodromal (n = 28) and mild (n = 7) AD. Quantitative attention parameters, derived from performance on simple psychophysical tasks and analyzed by Bundesen's computational theory of visual attention, were related to brain metabolism, measured by (18)F-fluorodeoxyglucose positron emission tomography. Patients' left and right lateral PPC metabolism was reduced. Nine patients had significant spatial attentional bias on the left side and two patients on the right. Direction and degree of spatial bias was correlated with direction and degree of an interhemispheric metabolism bias in the inferior parietal lobe and temporoparietal junction. Our data provide evidence that in very early AD, asymmetric hypometabolism of the lateral PPC causes spatial attentional bias. Results are broadly consistent with the model that asymmetrically impaired effective neuronal PPC activity in AD biases the competition of visual objects for cortical representation and access to awareness to one side.


Multiple routes of drug administration and HIV risk among injecting drug users.
This study assesses relationships between drug administration routes and HIV serostatus, drug use, and sexual behaviors among current injecting drug users (IDUs) in Tallinn, Estonia. We recruited 350 IDUs for a cross-sectional risk behavior survey. Adjusted odds ratios (AORs) were calculated to explore injection risk behavior, sexual behavior, and HIV serostatus associated with multiple route use. Focus groups explored reasons why injectors might use non-injecting routes of administration. Those reporting multiple drug administration routes were less likely to be HIV seropositive (AOR = 0.49, 95% confidence interval [CI] = 0.25-0.97) and had almost twice the odds of having more than one sexual partner (AOR = 1.90, 95% CI = 1.01-3.60) and of reporting having sexually transmitted diseases (AOR = 2.38, 95% CI = 1.02-5.59). IDUs who engage in noninjecting drug use may be reducing their risk of acquiring HIV though sharing injection equipment, but if infected may be a critical group for sexual transmission of HIV to people who do not inject drugs.


Allyl Isothiocyanate Inhibits Actin-Dependent Intracellular Transport in Arabidopsis thaliana.
Volatile allyl isothiocyanate (AITC) derives from the biodegradation of the glucosinolate sinigrin and has been associated with growth inhibition in several plants, including the model plant Arabidopsis thaliana. However, the underlying cellular mechanisms of this feature remain scarcely investigated in plants. In this study, we present evidence of an AITC-induced inhibition of actin-dependent intracellular transport in A. thaliana. A transgenic line of A. thaliana expressing yellow fluorescent protein (YFP)-tagged actin filaments was used to show attenuation of actin filament movement by AITC. This appeared gradually in a time- and dose-dependent manner and resulted in actin filaments appearing close to static. Further, we employed four transgenic lines with YFP-fusion proteins labeling the Golgi apparatus, endoplasmic reticulum (ER), vacuoles and peroxisomes to demonstrate an AITC-induced inhibition of actin-dependent intracellular transport of or, in these structures, consistent with the decline in actin filament movement. Furthermore, the morphologies of actin filaments, ER and vacuoles appeared aberrant following AITC-exposure. However, AITC-treated seedlings of all transgenic lines tested displayed morphologies and intracellular movements similar to that of the corresponding untreated and control-treated plants, following overnight incubation in an AITC-absent environment, indicating that AITC-induced decline in actin-related movements is a reversible process. These findings provide novel insights into the cellular events in plant cells following exposure to AITC, which may further expose clues to the physiological significance of the glucosinolate-myrosinase system.


Vapour phase polymerisation of conducting and non-conducting polymers: a review.
Vapour phase polymerisation (VPP) is a well established technique in which the monomer is introduced to an oxidant-coated substrate in vapour form. Polymerisation then takes place at the oxidant vapour interface. VPP is a technique that could be used to immobilise materials to the modified electrode surface. This review article concentrates on the VPP of conducting polymers such as Polypyrrole (PPy) polythiophen (PT) and polyaniline (PANi). VPP of conducting polymers and other non-conducting polymers have extensively been investigated. This review article is divided into three main parts as given in Table of contents related to the VPP process of some important conducting polymers such as PPy, PT, PANi and Poly(3,4-ethylenedioxythiophene). A total of 181 references are cited in this review article and it attempts to look into VPP from inception of the method till present day.


Probing the interplay between the two steps of group I intron splicing: competition of exogenous guanosine with omega G.
One largely unexplored question about group I intron splicing is how the cleavage and ligation steps of the reaction are coordinated. We describe a simple in vitro trans-splicing model system in which both steps take place, including the exchange of ligands in the guanosine-binding site that must occur between the two steps. Using this model system, we show that the switch is accomplished by modulating the relative affinity of the binding site for the two ligands. While the terminal guanosine of the intron (omegaG) and exogenous guanosine compete for binding during the first step of splicing, no competition is apparent during the second step, when omegaG is bound tightly. These results help explain how the ribozyme orchestrates progression through the splicing reaction. In addition to providing a new tool to ask basic questions about RNA catalysis, the trans-splicing model system will also facilitate the development of therapeutically useful group I ribozymes that can repair mutant mRNAs.


Canopy leaf area constrains [CO2]-induced enhancement of productivity and partitioning among aboveground carbon pools.
Net primary productivity (NPP) is enhanced under future atmospheric [CO2] in temperate forests representing a broad range of productivity. Yet questions remain in regard to how elevated [CO2]-induced NPP enhancement may be affected by climatic variations and limiting nutrient resources, as well as how this additional production is distributed among carbon (C) pools of different longevities. Using 10 years of data from the Duke free-air CO2 enrichment (Duke FACE) site, we show that spatially, the major control of NPP was nitrogen (N) availability, through its control on canopy leaf area index (L). Elevated CO2 levels resulted in greater L, and thus greater NPP. After canopy closure had occurred, elevated [CO2] did not enhance NPP at a given L, regardless of soil water availability. Additionally, using published data from three other forest FACE sites and replacing L with leaf area duration (LD) to account for differences in growing season length, we show that aboveground NPP responded to [CO2] only through the enhancement of LD. For broadleaf forests, the fraction of aboveground NPP partitioned to wood biomass saturated with increasing LD and was not enhanced by [CO2], whereas it linearly decreased for the conifer forest but was enhanced by [CO2]. These results underscore the importance of resolving [CO2] effects on L to assess the response of NPP and C allocation. Further study is necessary to elucidate the mechanisms that control the differential allocation of C among aboveground pools in different forest types.


To what extent do food preferences explain the trophic position of heterotrophic and mixotrophic microbial consumers in a Sphagnum peatland?
Although microorganisms are the primary drivers of biogeochemical cycles, the structure and functioning of microbial food webs are poorly studied. This is the case in Sphagnum peatlands, where microbial communities play a key role in the global carbon cycle. Here, we explored the structure of the microbial food web from a Sphagnum peatland by analyzing (1) the density and biomass of different microbial functional groups, (2) the natural stable isotope (δ(13)C and δ(15)N) signatures of key microbial consumers (testate amoebae), and (3) the digestive vacuole contents of Hyalosphenia papilio, the dominant testate amoeba species in our system. Our results showed that the feeding type of testate amoeba species (bacterivory, algivory, or both) translates into their trophic position as assessed by isotopic signatures. Our study further demonstrates, for H. papilio, the energetic benefits of mixotrophy when the density of its preferential prey is low. Overall, our results show that testate amoebae occupy different trophic levels within the microbial food web, depending on their feeding behavior, the density of their food resources, and their metabolism (i.e., mixotrophy vs. heterotrophy). Combined analyses of predation, community structure, and stable isotopes now allow the structure of microbial food webs to be more completely described, which should lead to improved models of microbial community function.


The humanistic and economic burden of chronic wounds: a protocol for a systematic review.
Chronic non-healing wounds present a substantial economic burden to healthcare system; significant reductions in quality of life for those affected, and precede often serious events such as limp amputations or even premature deaths. This burden is also likely to increase with a larger proportion of elderly and increasing prevalence of life-style diseases such as obesity and diabetes. Reviews of the evidence on the burden of illness associated with chronic wounds have not been comprehensive in scope and have not provided an assessment of the distribution of the health care costs across categories of resource use. This study is a systematic review of multiple databases for studies on adult patients with chronic wounds and with the primary objective to assess the impact on health-related quality of life by category of ulcers, and associated direct and indirect costs. Eligible studies will primary be empirical studies evaluating, describing or comparing measurement of quality of life and economic impact. Two reviewers will independently screen titles and abstracts and select studies involving adults with chronic wounds. These investigators will also independently extract data using a pre-designed data extraction form. Differences in applied methodologies and uncertainties will clearly be accounted for. Conservative valuations of costs and impact on health-related quality of life will be prioritised. Variations that may depend on age distribution, the categorisation of ulcer, healthcare system etc. will be described clearly. The proposed systematic review will yield a comprehensive assessment of the humanistic and economic burden of chronic wounds in an adult population. A better understanding of the humanistic and economic burden of chronic wounds is essential for policy and planning purposes, to monitor trends in disease burden and not at least in order to estimate the real-world cost-effectiveness of new treatments and therapies. PROSPERO CRD42016037496.


Synthesis, physical properties, multitemperature crystal structure, and 20 K synchrotron X-ray charge density of a magnetic metal organic framework structure, Mn3(C8O4H4)3(C5H11ON)2.
A new magnetic metal organic framework material has been synthesized, Mn3(C8O4H4)3(C5H11ON)2, 1. Magnetic susceptibility measurements from 2 to 400 K reveal anti-ferromagnetic ordering at approximately 4 K and a total magnetic moment of 6.0 micro(B). The magnetic phase transition is confirmed by heat capacity data (2-300 K). The crystal structure is studied by conventional single-crystal X-ray diffraction data at 300, 275, 250, 225, 200, 175, 150, 125, and 100 K, and synchrotron data at 20 K. There is a phase transition between 100 and 20 K due to ordering of the diethylformamide molecules. The X-ray charge density is determined based on multipole modeling of a second 20 K single-crystal synchrotron radiation data set. The electron distributions around the two unique Mn centers are different, and both have substantial anisotropy. Orbital population analysis reveals large electron donation (1.7 e) to each Mn atom and the maximum possible number of unpaired electrons is 3.2 for both Mn sites. Thus, there is a considerable orbital component to the magnetic moment. Bader topological analysis shows an absence of Mn-Mn bonding, and the magnetic ordering is via super-exchange through the oxygen bridges. Formal electron counting suggests Mn2+ sites, but this is not supported by the Bader atomic charges, Mn1 = +0.11 e, Mn2 = +0.17 e. The topological measures show the dominant metal-ligand interactions to be electrostatic, and a simple exponential correlation is derived between Mn-O bond lengths and the values of nabla2rho at the bond critical points.


Tie line framework to optimize non-enveloped virus recovery in aqueous two-phase systems.
Viral particle purification is a challenge due to the complexity of the broth, the particle size, and the need to maintain virus activity. Aqueous two-phase systems (ATPSs) are a viable alternative for the currently used and expensive downstream processes. This work investigated the purification of two non-enveloped viruses, porcine parvovirus (PPV), and human rhinovirus (HRV) at various ATPS tie lines. A polyethylene glycol (PEG) 12 kDa-citrate system at pH 7 was used to study the behavior of the partitioning on three different thermodynamic tie line lengths (TLLs). It was experimentally determined that increasing the TLL, and therefore increasing the hydrophobic and electrostatic driving forces within the ATPS, facilitated higher virus recoveries in the PEG-rich phase. A maximum of 79% recovery of infectious PPV was found at TLL 36 w/w% and tie line (TL) ratio 0.1. Increased loading of PPV was studied to observe the change in the partitioning behavior and similar trends were observed for all the TLs. Most contaminants remained in the citrate-rich phase at all the chosen TLLs, demonstrating purification of the virus from protein contaminants. Moderate DNA removal was also measured. Net neutral charged HRV was studied to demonstrate the effects of driving forces on neutrally charged viruses. HRV recovery trends remained similar to PPV on each TLL studied, but the values were lower than PPV. Recovery of viral particles in the PEG-rich phase of the PEG-citrate system utilized the difference in the surface hydrophobicity between virus and proteins and showed a direct dependence on the surface charge of each studied virus. The preferential partitioning of the relatively hydrophobic viral particles in the PEG-rich phase supports the hypothesis that both hydrophobic and electrostatic forces govern the purification of viruses in ATPS.


Caveolin-1 expression negatively regulates cell cycle progression by inducing G(0)/G(1) arrest via a p53/p21(WAF1/Cip1)-dependent mechanism.
Caveolin-1 is a principal component of caveolae membranes in vivo. Caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes. Interestingly, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). However, it remains unknown whether caveolin-1 plays any role in regulating cell cycle progression. Here, we directly demonstrate that caveolin-1 expression arrests cells in the G(0)/G(1) phase of the cell cycle. We show that serum starvation induces up-regulation of endogenous caveolin-1 and arrests cells in the G(0)/G(1) phase of the cell cycle. Moreover, targeted down-regulation of caveolin-1 induces cells to exit the G(0)/G(1) phase. Next, we constructed a green fluorescent protein-tagged caveolin-1 (Cav-1-GFP) to examine the effect of caveolin-1 expression on cell cycle regulation. We directly demonstrate that recombinant expression of Cav-1-GFP induces arrest in the G(0)/G(1) phase of the cell cycle. To examine whether caveolin-1 expression is important for modulating cell cycle progression in vivo, we expressed wild-type caveolin-1 as a transgene in mice. Analysis of primary cultures of mouse embryonic fibroblasts from caveolin-1 transgenic mice reveals that caveolin-1 induces 1) cells to exit the S phase of the cell cycle with a concomitant increase in the G(0)/G(1) population, 2) a reduction in cellular proliferation, and 3) a reduction in the DNA replication rate. Finally, we demonstrate that caveolin-1-mediated cell cycle arrest occurs through a p53/p21-dependent pathway. Taken together, our results provide the first evidence that caveolin-1 expression plays a critical role in the modulation of cell cycle progression in vivo.


Maternal hydrocephalus in pregnancy and delivery: a report of two cases.
We present two cases of maternal hydrocephalus in pregnancy. In one case, the patient had no medical problems and had a spontaneous vaginal delivery of a normal neonate at term. In the second case, the patient had an uneventful pregnancy until 36 weeks when she presented to the labour ward with drowsiness and decreasing consciousness. She only recovered after emergency Caesarean section and revision of her ventriculo-peritoneal shunt. Her neonate although preterm had no anomalies and was sent home soon after birth with the mother.


The UK's pandemic influenza research portfolio: a model for future research on emerging infections.
The 2009 influenza A H1N1 pandemic was responsible for considerable global morbidity and mortality. In 2009, several research studies in the UK were rapidly funded and activated for clinical and public health actions. However, some studies were too late for their results to have an early and substantial effect on clinical care, because of the time required to call for research proposals, assess, fund, and set up the projects. In recognition of these inherent delays, a portfolio of projects was funded by the National Institute for Health Research in 2012. These studies have now been set up (ie, with relevant permissions and arrangements made for data collection) and pilot tested where relevant. All studies are now on standby awaiting activation in the event of a pandemic being declared. In this Personal View, we describe the projects that were set up, the challenges of putting these projects into a maintenance-only state, and ongoing activities to maintain readiness for activation, and discuss how to plan research for a range of major incidents.


Health-related quality of life in neuroendocrine neoplasia: a critical review.
Incidence of neuroendocrine neoplasia (NEN) is increasing, as is use of health-related quality of life (HRQoL) measurement in clinical trials. Following development of validated questionnaires, HRQoL is widely used to assess outcomes. This review is intended for healthcare professionals and is based on a selection of data published in the last decade. HRQoL is on par with other clinical endpoints such as performance status. Assessments in clinical trials have been particularly useful for monitoring the symptom burden of NEN, for the effects of treatments on patients' lives, and have provided new data allied to the usual clinical endpoints. QoL expressed as quality-adjusted life years (QALYs) have become the most important primary outcome to establish cost-effectiveness in health economic evaluation. From looking at clinical trials over the last 10 years, we see that the quality of HRQoL evidence reported in published studies has improved and, in general, recent studies are likely to be more methodologically robust. Assessment of HRQoL in clinical trials is likely to become a standard part of clinical practice in NEN, as in other cancers. However, clear methods for calculating the clinical meaningfulness of changes in scores are needed. Other limitations of HRQoL measurement include lack of specificity to certain symptom sets and ease of completion and administration. An international group taking a lead on developing HRQoL research specifically in NEN patients is needed to address limitations of the evidence base. In order for greater weight to be placed on HRQoL data, agreement on optimal, validated scoring systems is needed.


[Risk assessment of violent women: development of the 'Female Additional Manual' (FAM)].
Violence perpetrated by women is a growing problem. Research has shown that the risk factors associated with women differ from those associated with men and that the risk assessments currently in use are not adequate for predicting violence in women. To develop a clinically relevant, useful tool for an accurate, gender-sensitive assessment of risk of violent behaviour in women and to offer guidelines for risk management in women. On the basis of literature research, clinical expertise and the results of a pilot study, we adapted the much-used 'Historical Clinical Risk management-20 (HCR-20) for use with female (forensic) psychiatric patients who have a record of violence towards other people. The 'Female Additional Manual (FAM) supplemented and added value to the HCR-20 for assessing the risk of violent behaviour by women. The fam is a valuable addition to the currently available risk assessment tools in that it provides a more accurate gender-specific risk assessment with regard to female (forensic) psychiatric patients. Future research will have to further demonstrate the value of the FAM.


THE EFFECT OF A HYPNOTIC-BASED ANIMATED VIDEO ON STRESS AND PAIN REDUCTION IN PEDIATRIC SURGERY.
Presurgical stress and its negative influences on postsurgical recovery and pain are well documented in the medical literature. Hence, the reduction of stress is advisable. The present study aimed to reduce stress using a hypnotic-based animated video. Thirty children aged 3 to 16 years hospitalized for ambulatory surgery for undescended testes or umbilical/inguinal hernia were recruited for the study. They watched the video 1 time prior to surgery in the presence of their parents and reported their anxiety and pain pre- and postvideo watching on a visual analogue scale. The results show a statistically significant reduction in both anxiety and pain. The article describes the structuring of the animated video and includes links to English, Hebrew, and Arabic versions of it.


A New Quaternion-Based Encryption Method for DICOM Images.
In this paper, a new quaternion-based lossless encryption technique for digital image and communication on medicine (DICOM) images is proposed. We have scrutinized and slightly modified the concept of the DICOM network to point out the best location for the proposed encryption scheme, which significantly improves speed of DICOM images encryption in comparison with those originally embedded into DICOM advanced encryption standard and triple data encryption standard algorithms. The proposed algorithm decomposes a DICOM image into two 8-bit gray-tone images in order to perform encryption. The algorithm implements Feistel network like the scheme proposed by Sastry and Kumar. It uses special properties of quaternions to perform rotations of data sequences in 3D space for each of the cipher rounds. The images are written as Lipschitz quaternions, and modular arithmetic was implemented for operations with the quaternions. A computer-based analysis has been carried out, and the obtained results are shown at the end of this paper.


Silibinin--a promising new treatment for cancer.
Silymarin and its major constituent, Silibinin, are extracts from the medicinal plant Silybum marianum (milk thistle) and have traditionally been used for the treatment of liver diseases. Recently, these orally active, flavonoid agents have also been shown to exert significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas. The aim of the present review is to examine the pharmacokinetics, mechanisms, effectiveness and adverse effects of silibinin's anti-cancer actions reported to date in pre-clinical and clinical trials. The review will also discuss the results of current research efforts seeking to determine the extent to which the effectiveness of silibinin as an adjunct cancer treatment is influenced by such factors as histologic subtype, hormonal status, stromal interactions and drug metabolising gene polymorphisms. The results of these studies may help to more precisely target and dose silibinin therapy to optimise clinical outcomes for oncology patients.


Use of carboxyhaemoglobin levels to predict the development of diseases associated with cigarette smoking.
Carboxyhaemoglobin (COHb) levels in tobacco smokers vary throughout the day since they are affected by the pattern of tobacco consumption and the rate at which COHb is eliminated. A method is described whereby a single COHb measurement together with a recent smoking history may be used to estimate the average COHb "boost" produced by each cigarette, the total daily carbon monoxide (CO) uptake from smoking, and the mean COHb level throughout the day. These three indices of tobacco smoke absorption were estimated in nine healthy cigarette smokers on different days, each set of three estimations being derived from separate COHb determinations. The indices were reasonably reproducible within the same person, and the differences between people were statistically highly significant (P less than 0-001). For example, the estimates of mean daily COHb level resulting from smoking ranged from 0-7% to 9-3% in smokers who smoked 15 to 40 cigarettes a day. These differences are sufficiently large to distinguish possible differences in the risk of developing diseases such as ischaemic heart disease which may result from the inhalation and absorption of tobacco smoke. The suggested indices also depend less on the time of the blood test and on the daily pattern of smoking than a COHb level alone. The ratio of the COHb boost to the CO yield of a cigarrette may reflect depth of inhalation more accurately than a smoker's self-assessment. Moreover there was little correlation between these two measures of inhalation in the nine subjects studied.


Perspectives on contraceptive implant use in women living with HIV in Cape Town, South Africa: a qualitative study among primary healthcare providers and stakeholders.
This study explored primary healthcare provider and HIV/contraception expert stakeholder perspectives on South Africa's public sector provision of contraceptive implants to women living with HIV. We investigated the contraceptive service-impact of official advice against provision of implants to women using the HIV antiretroviral drug, efavirenz, issued by the South African National Department of Health (NDoH) in 2014. Qualitative data was collected in Cape Town in 2017 from primary healthcare contraceptive providers in four clinics that provide implants, as well as from other expert stakeholders selected for expertise in HIV and/or contraception. In-depth interviews and a group discussion explored South Africa's implant introduction and implant provision to women living with HIV. Data was analysed using an inductive thematic analysis approach. Interviews were conducted with 10 providers and 10 stakeholders. None of the four clinics where the providers worked currently offered the implant to women living with HIV. Stakeholders confirmed that this was consistent with patterns of implant provision at primary healthcare facilities across Cape Town. Factors contributing to providers' decisions to suspend provision of the implant to women living with HIV included: inadequate initial and ongoing provider training; interpretation of NDoH communications about implant use with efavirenz; provider unwillingness to risk harming clients and concerns about professional liability; and other pressures related to provider capacity. All South African women, including those living with HIV, should have access to the full range of contraceptive options for which they are medically eligible. Changing guidance should be initiated and communicated in consultation with primary-level providers and service beneficiaries. Guidance issued to providers needs to be clear and fully evidence-informed, and its correct interpretation and implementation facilitated and monitored. Guidance should be accompanied by provider training, as well as counselling messages and tools to support providers. Generalized retraining of providers in rights-based, client-centred family planning, and in particular implant provision for women with HIV, is needed. These recommendations accord with the right of women living with HIV to access the highest possible standard of sexual and reproductive healthcare, including informed contraceptive choice and access to the contraceptive implant.


Packing arrangement of 13C selectively labeled sequence model peptides of Samia cynthia ricini silk fibroin fibers studied by solid-state NMR.
Samia cynthia ricini (S. c. ricini) is one of the wild silkworms. Their silk fibroins have been paid attention as potentially valuable biomedical materials as well as Bombyx mori silk fibroins, but detailed information on the packing arrangement of the fibers is still not currently well understood at a molecular level. In this study, 34 mer model peptides, GGAGGGYGGDGG(A)12GGAGDGYGAG with different 13C labeled positions have been synthesized as a typical sequence of the primary structure of S. c. ricini silk fibroins made up of tandemly repeated sequences of polyalanine as the crystalline region and glycin-rich sequences as the non-crystalline region. The heterogeneous structure was obtained from the determination of the fraction of several conformations depending on the position of the Ala residue by 13C cross polarization/magic angle spinning NMR. The packing arrangement was studied by 13C dipolar assisted rotational resonance NMR and packing in a staggered arrangement rather than a rectangular arrangement of this peptide with an anti-parallel β-sheet structure was clarified, which is in good agreement with our previous report on the packing arrangement of (Ala)7 with an anti-parallel β-sheet structure.


Aldehyde dehydrogenase 2-a potential genetic risk factor for lung function among southern Chinese: evidence from the Guangzhou Biobank Cohort Study.
In Asia, moderate alcohol users have better lung function. Never users have more inactive aldehyde dehydrogenase 2 (ALDH2) alleles (A) potentially generating confounding because inactive alleles may increase acetaldehyde exposure and reduce lung function. We examined the association of ALDH2 genotypes with percentage predicted lung function (forced expiratory volume in 1 second; forced vital capacity) for age, sex, and height among 5641 older Chinese using multivariable linear regression. ALDH2 genotypes were associated with alcohol use and height but not other attributes. Inactive alleles were inversely associated with lung function (percentage predicted forced expiratory volume in 1 second -1.52%, 95% confidence interval [CI], -2.52% to -0.51% for one inactive allele and -2.05%, 95% CI, -3.85% to -0.26% for two inactive alleles compared with two active alleles; and for percentage predicted forced vital capacity -1.25%, 95% CI -2.15% to -0.35% and -1.65%, 95% CI, -3.25% to -0.04%). The association of moderate use with lung function was attenuated after adjusting for ALDH2, in addition to other potential confounders. Previous findings in Chinese may be confounded by ALDH2. High frequency of inactive ALDH2 alleles in East Asia may exacerbate the effect of environmental acetaldehyde exposure on lung function and potentially on chronic obstructive pulmonary disease.


Asymmetry of retinal arteriolar branch widths at junctions affects ability of formulae to predict trunk arteriolar widths.
To describe a revised formula for the estimation of retinal trunk arteriole widths from their respective arteriolar branch widths that improves the summarizing of retinal arteriolar diameters. A group of young, healthy individuals underwent retinal photography and arteriolar and venular branching points were identified. Vessel widths of the vessel trunks and their branches were determined. The relationship between the branching coefficient (BC; quotient of the area of the branch and trunk vessels) and the asymmetry index (AI) of the vessel branches was explored. The result was used to formulate a new BC. To test the new BC, a second group of young, healthy individuals also underwent retinal photography. Arteriolar branching points were identified, and the trunk and branch arteriolar widths were recorded. This "revised" BC was compared against the gold standard of the BC as a constant value (1.28), as well as a theoretical formula for the BC that includes the angle between the two vessel branches. The BC of arterioles (but not venules) related to the AI (R = 0.275, P = 0.0001; BC arterioles = 0.78 +/- 0.63 . AI). In the second group, the mean arteriolar trunk diameter was 15.56 pixels. The linear regression model for the arteriolar BC was superior to the BC constant of 1.28 (mean difference between estimated and calculated trunk vessel width was 2.16 vs. 2.23 pixels, respectively). The model based on the angle between the branch arterioles was the least accurate (3.43 pixels). A revised formula has been devised for the arteriolar BC using a linear regression model that incorporates its relationship to the AI. Further studies using this refined formula to calculate the BC are needed to determine whether it improves the ability to detect smaller associations between the retinal vascular network and cardiovascular disease.


Combining Optical Character Recognition With Paper ECG Digitization.
We propose a MATLAB-based tool to convert electrocardiography (ECG) waveforms from paper-based ECG records into digitized ECG signals that is vendor-agnostic. The tool is packaged as an open source standalone graphical user interface (GUI) based application. To reach this objective we: (1) preprocess the ECG records, which includes skew correction, background grid removal and linear filtering; (2) segment ECG signals using Connected Components Analysis (CCA); (3) implement Optical Character Recognition (OCR) for removal of overlapping ECG lead characters and for interfacing of patients' demographic information with their research records or their electronic medical record (EMR). The ECG digitization results are validated through a reader study where clinically salient features, such as intervals of QRST complex, between the paper ECG records and the digitized ECG records are compared. Comparison of clinically important features between the paper-based ECG records and the digitized ECG signals, reveals intra- and inter-observer correlations of 0.86-0.99 and 0.79-0.94, respectively. The kappa statistic was found to average at 0.86 and 0.72 for intra- and inter-observer correlations, respectively. The clinically salient features of the ECG waveforms such as the intervals of QRST complex, are preserved during the digitization procedure. Clinical and Healthcare Impact: This open-source digitization tool can be used as a research resource to digitize paper ECG records thereby enabling development of new prediction algorithms to risk stratify individuals with cardiovascular disease, and/or allow for development of ECG-based cardiovascular diagnoses relying upon automated digital algorithms.


Sentinel Wraps: Real-Time Monitoring of Food Contamination by Printing DNAzyme Probes on Food Packaging.
Here, we report the development of a transparent, durable, and flexible sensing surface that generates a fluorescence signal in the presence of a specific target bacterium. This material can be used in packaging, and it is capable of monitoring microbial contamination in various types of food products in real time without having to remove the sample or the sensor from the package. The sensor was fabricated by covalently attaching picoliter-sized microarrays of an E. coli-specific RNA-cleaving fluorogenic DNAzyme probe (RFD-EC1) to a thin, flexible, and transparent cyclo-olefin polymer (COP) film. Our experimental results demonstrate that the developed (RFD-EC1)-COP surface is specific, stable for at least 14 days under various pH conditions (pH 3-9), and can detect E. coli in meat and apple juice at concentrations as low as 103 CFU/mL. Furthermore, we demonstrate that our sensor is capable of detecting bacteria while still attached to the food package, which eliminates the need to manipulate the sample. The developed biosensors are stable for at least the shelf life of perishable packaged food products and provide a packaging solution for real-time monitoring of pathogens. These sensors hold the potential to make a significant contribution to the ongoing efforts to mitigate the negative public-health-related impacts of food-borne illnesses.


Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma.
Malignant glioma is the most common central nervous system tumor of adults and is associated with a significant degree of morbidity and mortality. Gliomas are highly invasive and respond poorly to conventional treatments. Gliomas, like other tumor types, arise from a complex and poorly understood sequence of genetic and epigenetic alterations. Epigenetic alterations leading to gene silencing, in the form of aberrant CpG island promoter hypermethylation and histone deacetylation, have not been thoroughly investigated in brain tumors, and elucidating such changes is likely to enhance our understanding of their etiology and provide new treatment options. We used a combined approach of pharmacologic inhibition of DNA methylation and histone deacetylation, coupled with expression microarrays, to identify novel targets of epigenetic silencing in glioma cell lines. From this analysis, we identified >160 genes up-regulated by 5-aza-2'-deoxycytidine and trichostatin A treatment. Further characterization of 10 of these genes, including the putative metastasis suppressor CST6, the apoptosis-inducer BIK, and TSPYL5, whose function is unknown, revealed that they are frequent targets of epigenetic silencing in glioma cell lines and primary tumors and suppress glioma cell growth in culture. Furthermore, we show that other members of the TSPYL gene family are epigenetically silenced in gliomas and dissect the contribution of individual DNA methyltransferases to the aberrant promoter hypermethylation events. These studies, therefore, lay the foundation for a comprehensive understanding of the full extent of epigenetic changes in gliomas and how they may be exploited for therapeutic purposes.


Does case conferencing for people with advanced dementia living in nursing homes improve care outcomes: evidence from an integrative review?
This integrative review aimed to appraise the evidence for case conferencing as an intervention to improve palliative care outcomes for older people living with advanced dementia in nursing homes. An integrative review of English language citations from CINHAL, MEDLINE, PSYCHINFO and CareSearch using a palliative care filter was undertaken. Two reviewers screened 238 titles to find 77 relevant articles which were reviewed in detail to identify nine studies that addressed the specific review questions. The analysis process allowed study characteristics, process and outcome measures along with implementation barriers and facilitators to be identified and the results synthesised. The highest level of evidence (Level II) was generated by two randomised controlled case conferencing trials which demonstrated enhance medication management for people with dementia living in a nursing home. Several pre-post test studies suggest that case conferencing enhances palliative symptom management and care outcomes in nursing homes. Qualitative evidence suggests that case conferencing is feasible and worthwhile if the identified barriers are addressed and the facilitators optimised. Case conferencing provides opportunities to improve care palliative care outcomes for older people with dementia by engaging family and all relevant internal and external health providers in prospective care planning. More evidence is needed to determine the efficacy and cost-effectiveness of case conferencing as a strategy for improving care outcomes for older people living with advanced dementia in nursing homes. The evidence generated by this integrative review will be of interest to policy makers, aged care organisations and clinicians alike, especially as services endeavour to meet the increasingly complex care needs of older people admitted to nursing homes with advanced dementia, and the needs of their families.


Biochemical and nutritional characteristics of buffalo meat and potential implications on human health for a personalized nutrition.
The human consumption of food animal products is the main topic of an important debate among professionals in this sector: dietologists, dietitians and nutritional biologists. The red meat provides all the essential amino acids, bioavailable iron, zinc, calcium, lipids and B-group vitamins. A valid alternative to beef could be the buffalo meat. Italy is the largest European producer of buffalo meat and derivatives. The high nutritional characteristics of buffalo meat make it suitable to be included in the Mediterranean diet to customize it in relation to the needs and conditions of the population. Polyunsaturated/saturated fatty acids ratio can be influenced by diet, breed and type of breeding, but muscle tissue fat percentage is the main factor in determining a favorable fatty acid composition. This review focuses on the biochemical and nutritional characteristics of the buffalo meat (content of fats, cholesterol, amino acids, vitamins and minerals), explaining their variability depending on the different breeds, and the favorable implications on the human health. These results suggest that buffalo meat can be a healthier alternative to beef, not only for healthy people in particular physiological conditions (i.e. pregnancy), but also for persons at risk for cardiovascular and cerebrovascular diseases, thus achieving the goal of a personalized nutrition.


Heterogeneity within human-derived centers for disease control and prevention (CDC) coryneform group ANF-1-like bacteria and description of Corynebacterium auris sp. nov.
Recently, Centers for Disease Control and Prevention coryneform group ANF-1 bacteria were described as Corynebacterium afermentans, and group ANF-1-like bacteria were described as Turicella otitidis. Over a 1.5-year period 10 strains of a previously undescribed, gram-positive, rod-shaped organism that was not partially acid fast and resembled ANF-1-like bacteria were isolated from different pediatric patients with ear infections. These previously undescribed coryneform bacteria exhibited a distinct colony morphology and consistency, had a carbon source utilization pattern distinct from the carbon source utilization patterns of C. afermentans and T. otitidis, had a cell wall based on meso-diaminopimelic acid, contained mycolic acids, and had DNA G+C contents of 68 to 74 mol%. A 16S rRNA gene sequence analysis revealed that these clinical isolates are members of the genus Corynbacterium and that they are distinct from C. afermentans and T. otitidis. On the basis of phenotypic and phylogenetic evidence we propose a new species, Corynebacterium auris, for these Centers for Disease Control and Prevention coryneform group ANF-1-like bacteria. The type strain is strain DSM 44122 (CCUG 33426).


Immunosuppressive compounds exhibit particular effects on functional properties of human anti-Aspergillus Th1 cells.
Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at high risk for invasive aspergillosis. Whereas adoptive immunotherapy transferring donor-derived anti-Aspergillus TH1 cells has been shown to be beneficial for HSCT recipients suffering from invasive aspergillosis, little is known about the impact of commonly used immunosuppressants on the functional properties of anti-Aspergillus TH1 cells. Anti-Aspergillus TH1 cells were coincubated with different concentrations of methylprednisolone, cyclosporine (CsA), mycophenolic acid (MPA), the active component of mycophenolate mofetil, and rapamycin. Immunosuppressants were tested in concentrations reflecting common target levels in serum and in significantly lower and higher concentrations. Apoptosis of anti-Aspergillus TH1 cells, as well as proliferation and production of gamma interferon (IFN-γ) and CD154 upon restimulation, was evaluated in the presence and absence of immunosuppressive compounds. All dosages of CsA, MPA, and methylprednisolone significantly decreased the number of viable anti-Aspergillus TH1 cells in the cell culture, which was due partly to an impaired proliferative capacity of the cells and partly to an increased rate of apoptosis. In addition, CsA significantly decreased the number of IFN-γ-producing cells and had the highest impact of all immunosuppressants on IFN-γ levels in the supernatant. CsA also significantly decreased the expression of CD154 by anti-Aspergillus TH1 cells. Variant dosages of immunosuppressants exhibit particular effects on essential functional properties of anti-Aspergillus TH1 cells. Our findings may have an important impact on the design of clinical trials evaluating the therapeutic benefit of anti-Aspergillus TH1 cells in allogeneic HSCT recipients suffering from invasive aspergillosis.


Hospital CEOs Need Health IT Knowledge and Trust in CIOs: Insights from a Qualitative Study.
IT is getting an increasing importance in hospitals. In this context, major IT decisions are often made by CEOs who are not necessarily IT experts. Therefore, this study aimed at a) exploring different types of IT decision makers at CEO level, b) identifying hypotheses if trust exists between these different types of CEOs and their CIOs and c) building hypotheses on potential consequences regarding risk taking and innovation. To this end, 14 qualitative interviews with German hospital CEOs were conducted to explore the research questions. The study revealed three major types: IT savvy CEOs, IT enthusiastic CEOs and IT indifferent CEOs. Depending on these types, their relationship with the CIO varied in terms of trust and common language. In case of IT indifferent CEOs, a potential vicious circle of lack of IT knowledge, missing trust, low willingness to take risks and low innovation power could be identified. In order to break of this circle, CEOs seem to need more IT knowledge and/or greater trust in their CIO.


Translational infidelity-induced protein stress results from a deficiency in Trm9-catalyzed tRNA modifications.
Correct codon-anticodon pairing promotes translational fidelity, with these interactions greatly facilitated by modified nucleosides found in tRNA. We hypothesized that wobble uridine modifications catalyzed by tRNA methyltransferase 9 (Trm9) are essential for translational fidelity. In support, we have used phenotypic, reporter and protein-based assays to demonstrate increased translational infidelity in trm9Δ Saccharomyces cerevisiae cells. Codon reengineering studies suggest that Trm9-catalyzed tRNA modifications promote fidelity during the translation of specific genes, those rich in arginine and glutamic acid codons from mixed boxes. Using quantitative tRNA modification analysis, we determined that trm9Δ cells are only deficient in 2 of 23 tRNA modifications, with those 2, 5-methoxycarbonylmethyluridine (mcm ( 5) U) and 5-methoxycarbonylmethyl-2-thiouridine (mcm ( 5) s ( 2) U), classified as key determinants of translational fidelity. We also show that in the absence of mcm ( 5) U and mcm ( 5) s ( 2) U, the resulting translational infidelity promotes protein errors and activation of unfolded protein and heat shock responses. These data support a model in which Trm9-catalyzed tRNA modifications promote fidelity during the translation of specific transcripts, with decreased wobble base modification leading to translational infidelity, protein errors and activation of protein stress response pathways.


Breastfeeding peer support: are there additional benefits?
Anecdotal discussion among breastfeeding peer supporters and the infant-feeding co-ordinator suggested that breastfeeding peer support provided by breastfeeding peer supporters may offer benefits to breastfeeding women and their families other than increasing breastfeeding initiation and sustainability. The aim of this research was to determine whether there was evidence to support this. The research team used focus groups to obtain information from 16 local women who had received breastfeeding peer support from breastfeeding peer supporters. The key themes that emerged were--improved mental health, increased self-esteem or confidence, parenting skills, improved family diet, breastfeeding sustainability and poor hospital experience.The findings suggest that breastfeeding peer supporters supporting mothers to breastfeed, with the intention of increasing both breastfeeding rates and sustainability, may have additional benefits in several aspects of families' lives. Breastfeeding peer support may play an important role in helping to attain targets such as reducing obesity and postnatal depression.


Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes.
Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.


Axl-gas6 interaction counteracts E1A-mediated cell growth suppression and proapoptotic activity.
The adenovirus type 5 early region 1A gene (E1A) has previously been known as an immortalization oncogene because E1A is required for transforming oncogenes, such as ras and E1B, to transform cells in primary cultures. However, E1A has also been shown to downregulate the overexpression of the Her-2/neu oncogene, resulting in suppression of transformation and tumorigenesis induced by that oncogene. In addition, E1A is able to promote apoptosis induced by anticancer drugs, irradiation, and serum deprivation. Many tyrosine kinases, such as the epidermal growth factor receptor, Her-2/Neu, Src, and Axl, are known to play a role in oncogenic signals in transformed cells. To study the mechanism underlying the E1A-mediated tumor-suppressing function, we exploited a modified tyrosine kinase profile assay (D. Robinson, F. Lee, T. Pretlow, and H.-J. Kung, Proc. Natl. Acad. Sci. USA 93:5958-5962, 1996) to identify potential tyrosine kinases regulated by E1A. Reverse transcription (RT)-PCR products were synthesized with two degenerate primers derived from the conserved motifs of various tyrosine kinases. A tyrosine kinase downregulated by E1A was identified by analyzing the AluI-digested RT-PCR products. We isolated the DNA fragment of interest and found that E1A negatively regulated the expression of the transforming receptor tyrosine kinase Axl at the transcriptional level. To study whether downregulation of the Axl receptor is involved in E1A-mediated growth suppression, we transfected axl cDNA into E1A-expressing cells (ip1-E1A) to establish cells that overexpressed Axl. The Axl ligand Gas6 triggered a greater mitogenic effect in these ip1-E1A-Axl cells than in ip1-E1A control cells and protected the Axl-expressing cells from serum deprivation-induced apoptosis. These results indicate that downregulation of the Axl receptor by E1A is involved in E1A-mediated growth suppression and E1A-induced apoptosis and thereby contributes to E1A's antitumor activities.


Periplasmic response upon disruption of transmembrane Cu transport in Pseudomonas aeruginosa.
Pseudomonas aeruginosa, an opportunistic pathogen, has two transmembrane Cu(+) transport ATPases, CopA1 and CopA2. Both proteins export cytoplasmic Cu(+) into the periplasm and mutation of either gene leads to attenuation of virulence. CopA1 is required for maintaining cytoplasmic copper levels, while CopA2 provides copper for cytochrome c oxidase assembly. We hypothesized that transported Cu(+) ions would be directed to their destination via specific periplasmic partners and disruption of transport should affect the periplasmic copper homeostasis. Supporting this, mutation of either ATPase gene led to large increments in periplasmic cuproprotein levels. Toward identifying the proteins participating in this cellular response the periplasmic metalloproteome was resolved in non-denaturing bidimensional gel electrophoresis, followed by X-ray fluorescence visualization and identification by mass-spectrometry. A single spot containing the electron shuttle protein azurin was responsible for the observed increments in cuproprotein contents. In agreement, lack of either Cu(+)-ATPase induced an increase in azu transcription. This is associated with an increase in the expression of anr and rpoS oxidative stress response regulators, rather than cueR, a copper sensing regulator. We propose that azurin overexpression and accumulation in the periplasm is part of the cellular response to cytoplasmic oxidative stress in P. aeruginosa.


Therapeutic progestin segesterone acetate promotes neurogenesis: implications for sustaining regeneration in female brain.
Neurogenesis is the principal regenerative mechanism to sustain the plasticity potential in adult brains. Decreased neurogenesis parallels the cognition decline with aging, and has been suggested as a common hallmark in the progression of many neurodegeneration diseases. We previously reported that acute exposure to segesterone acetate (ST-1435; Nestorone), alone or in combination with 17β-estradiol (E2), increased human neural stem cells proliferation and survival both in vitro and in vivo. The present study expanded our previous findings to investigate the more clinical related chronic exposure in combination with E2 on the regenerative capacity of adult brain. To mimic the chronic contraception exposure in women, 3-month old female mice (n = 110) were treated with ST-1435, with or without co-administration of E2, for 4 weeks. Neural cell proliferation and survival, and oligodendrocyte generation were assessed. The involvement of insulin-like growth factor 1 signaling was studied. Our results demonstrated that chronic ST-1435 and E2 alone or in combination increased neurogenesis by a comparable magnitude, with minimum to no antagonistic or additive effects between ST-1435 and E2. In addition, chronic exposure of ST-1435 or ST-1435 + E2 stimulated oligodendrocyte generation, indicating potential elevated myelination. Insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) were also up-regulated after chronic ST-1435 and E2 exposure, suggesting the involvement of IGF-1 signaling as the potential underlined regulatory pathway transducing ST-1435 effect. These findings provide preclinical evidence and mechanistic insights for the development of ST-1435 as a neuroregenerative therapy to promote intrinsic regenerative capacity in female brains against aging and neurodegenerative disorders.


Subacute sclerosing panencephalitis: results of the Canadian Paediatric Surveillance Program and review of the literature.
Subacute Sclerosing Panencephalitis (SSPE) is so rare in developed countries with measles immunization programs that national active surveillance is now needed to capture sufficient number of cases for meaningful analysis of data. Through the Canadian Paediatric Surveillance Program (CPSP), the SSPE study was able to document a national incidence and determine the epidemiology of affected Canadian children. Between 1997 and 2000, the CPSP surveyed monthly 1978 to 2294 Canadian pediatricians and sub-specialists for SSPE cases. The response rate varied from 82-86% over those years. Altogether, four SSPE cases were reported to the CPSP: one case before, two during and one after the study period. The incidence of SSPE in Canadian children was 0.06/million children/year. Of the four cases, diagnosed between ages four and 17 years, three children had measles infection in infancy. All children showed a progressive course of dementia, loss of motor skills and epilepsy. Two children were treated with isoprinosine and intraventricular interferon but died in less than three years from disease onset. One child did not have any treatment and died after seven years of illness. One child received intraventricular ribavirin and remains alive, but markedly impaired, nine years following diagnosis. The CPSP has demonstrated that Canadian paediatricians and paediatric neurologists may encounter cases of SSPE. This report highlights the clinical course of affected Canadian children and provides a review of the disease and its management.


Electron-Phonon Coupling in the Bulk of Anatase TiO2 Measured by Resonant Inelastic X-Ray Spectroscopy.
We investigate the polaronic ground state of anatase TiO2 by bulk-sensitive resonant inelastic x-ray spectroscopy (RIXS) at the Ti L3 edge. We find that the formation of the polaron cloud involves a single 95 meV phonon along the c axis, in addition to the 108 meV ab-plane mode previously identified by photoemission. The coupling strength to both modes is the same within error bars, and it is unaffected by the carrier density. These data establish RIXS as a directional bulk-sensitive probe of electron-phonon coupling in solids.


Partial purification and characterization of dendritic cell differentiation factor.
Previously, we reported that interleukin-2 (IL-2)-stimulated helper T cells produced an unknown soluble factor which induced dendritic cell-like differentiation in primary cultures of monocytic leukemia cells and we referred to this factor as dendritic cell differentiation factor (DCDF). In this study, we attempted to purify and characterize DCDF and investigated its biological effect on normal human monocytes. Gel filtration chromatography indicated that the molecular weight of DCDF is approximately 30-35 kDa. Chromatofocusing indicated that the isoelectric point of DCDF is approximately 5.0. DCDF, partially purified by subsequent gel filtration, chromatofocusing, and hydrophobic chromatography, significantly enhanced the HLA-DR expression of normal human monocytes and a human monocytic leukemia cell line, THP-1. This biological activity was not neutralized by any known antibodies to human cytokines. DCDF significantly amplified the T-cell stimulatory activity of monocytes in the allogeneic mixed leukocyte reaction (MLR). Moreover, DCDF significantly enhanced IL-1 beta and IL-6 production by monocytes in a dose-dependent manner. These results suggest that DCDF is a novel human cytokine which stimulates the accessory cell function of monocytes.


Differential synaptic localization of the glutamate transporter EAAC1 and glutamate receptor subunit GluR2 in the rat hippocampus.
EAAC1, a neuron-specific glutamate transporter, is likely to play an important role in the regulation of glutamate levels in the synaptic cleft. Ultrastructural studies have demonstrated that the glutamate receptor subunit proteins (e.g., GluR2) are frequently preferentially located at the postsynaptic density of asymmetric synapses. While the glutamate/glutamate receptor interaction is likely to be influenced by the activity and location of the transporter molecules, the spatial localization of the transporter molecules relative to the receptor molecules is not well delineated. Thus, we analyzed the cellular, ultrastructural, and synaptic distribution of EAAC1 in the context of the distribution of the AMPA receptor subunit GluR2 in the hippocampus. While GluR2 and EAAC1 are both present in hippocampal projection neurons, their intracellular distribution patterns differ. Both GluR2 and EAAC1 are present in the dendritic membranes and cytoplasm; however EAAC1 has a distinctive punctate distribution in the dendrite compared to the more diffuse labeling reflected by GluR2. Pre-embedding ultrastructural studies also revealed cytoplasmic and membrane-associated pools of EAAC1 within dendritic shafts and spines, as well as in a subset of axonal profiles and terminals. Postembedding double label immunogold localization demonstrated a similar intraneuronal distribution, but in addition showed that membrane-associated EAAC1 is not intermingled with GluR2 within the synaptic complex, but in contrast is primarily located perisynaptically, often immediately outside the synaptic specialization. In addition, there is a significant presynaptic pool of EAAC1, whereas GluR2 is essentially absent from the pre-synaptic profile. Thus, membrane-associated EAAC1 within the synaptic region is ideally situated to restrict the site of action of glutamate with respect to ionotropic receptors to the synaptic cleft, as well as regulate glutamate levels in the perisynaptic and presynaptic domains, the ultrastructural sites that have been associated with metabotropic receptor localization.


Glomerular lesions in dogs infected with Leishmania organisms.
To histologically identify glomerular lesions in dogs infected with Leishmania organisms. 41 dogs (17 sexually intact males and 14 sexually intact and 10 ovariohysterectomized females) that had positive results when tested for leishmaniosis as determined by use of serologic evaluation (indirect fluorescent antibody test, titers of 1:80 to 1:640) and direct microscopic identification of the protozoal organisms. Urine samples were collected by use of cystocentesis and examined by qualitative SDS-agarose gel electrophoresis (AGE). All dogs had non-selective (glomerular) or mixed (glomerular and tubular) proteinemia. Specimens were obtained from each dog during ultrasound-assisted renal biopsy and used for histologic examination. Each specimen was stained with H&E, periodic acid-Schiff, Goldner's trichrome, methenamine silver, and Congo Red stains. Specimens were adequate for evaluation when they contained at least 5 glomeruli/section, except for specimens stained with Congo Red in which 1 glomerulus/section was adequate. Examination of renal biopsy specimens revealed various glomerular lesions in all dogs and interstitial or tubular (or both) lesions in 23 of 41 (55%) dogs. Glomerular lesions that develop in dogs during infection with Leishmania organisms can be classified histologically as mesangial glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and focal segmental glomerulonephritis. Tubulointerstitial histopathologic conditions were not observed as the primary lesion, despite being evident in 23 of 41 (55%) dogs. Use of SDS-AGE for qualitative evaluation of proteinuria and successive collection of specimens during renal biopsies following diagnosis of nonselective glomerular proteinuria provides the possibility for early identification of renal lesions.


Pulmonary hypertension and interstitial lung disease within PHAROS: impact of extent of fibrosis and pulmonary physiology on cardiac haemodynamic parameters.
We sought to examine the relationship between measures of ILD severity and PH in patients with SSc. We identified 55 subjects from 12 PHAROS sites with RHC-proven PH and HRCT evidence of ILD. Subjects with PH due to left heart disease were excluded. Baseline HRCT scans were scored by a standardised system that graded severity of ILD. Summary statistics were generated for baseline characteristics. Spearman correlation and linear regression were used to examine relationships between ILD and PH severity variables. The majority of subjects were white women; nearly half had limited cutaneous SSc. Most subjects were New York Heart Association functional class II or III. Pulmonary function testing revealed moderate restriction (mean FVC 64.3 ± 17.2% predicted) with severe reduction in diffusing capacity (mean DLco 34.2 ± 13.3% predicted). RHC demonstrated mild to moderate PH (mean PAP 35 ± 9 mmHg, mean PVR 5.1 ± 3.7 WU). There was no correlation between severity of ILD (by either HRCT or PFT) and cardiac haemodynamic parameters of PH. No association between severity of ILD and cardiac haemodynamic profiles were identified in this cohort. We believe this underscores the complex nature of PH and ILD in individuals with SSc. We do suspect that some individuals with SSc-ILD will also have concomitant pulmonary vascular disease but simple assessments to grade severity of ILD - by PFT or HRCT estimates of ILD extent - are likely not enough to reliably distinguish between PAH versus PH-ILD. Further research into how to distinguish and manage these subsets is warranted.


Marine conservation: towards a multi-layered network approach.
Valuing, managing and conserving marine biodiversity and a full range of ecosystem services is at the forefront of research and policy agendas. However, biodiversity is being lost at up to a thousand times the average background rate. Traditional disciplinary and siloed conservation approaches are not able to tackle this massive loss of biodiversity because they generally ignore or overlook the interactive and dynamic nature of ecosystems processes, limiting their predictability. To conserve marine biodiversity, we must assess the interactions and impacts among biodiversity and ecosystem services (BD-ES). The scaling up in complexity from single species to entire communities is necessary, albeit challenging, for a deeper understanding of how ecosystem services relate to biodiversity and the roles species have in ecosystem service provision. These interactions are challenging to map, let alone fully assess, but network and system-based approaches provide a powerful way to progress beyond those limitations. Here, we introduce a conceptual multi-layered network approach to understanding how ecosystem services supported by biodiversity drive the total service provision, how different stressors impact BD-ES and where conservation efforts should be placed to optimize the delivery of ecosystem services and protection of biodiversity. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.


Excavation of a chimpanzee stone tool site in the African rainforest.
Chimpanzees from the Tai forest of Côte d'Ivoire produce unintentional flaked stone assemblages at nut-cracking sites, leaving behind a record of tool use and plant consumption that is recoverable with archaeological methods. About 40 kilograms of nutshell and 4 kilograms of stone were excavated at the Panda 100 site. The data unearthed show that chimpanzees transported stones from outcrops and soils to focal points, where they used them as hammers to process foodstuff. The repeated use of activity areas led to refuse accumulation and site formation. The implications of these data for the interpretation of the earliest hominin archaeological record are explored.


Evolutionary Divergence of Plant Borate Exporters and Critical Amino Acid Residues for the Polar Localization and Boron-Dependent Vacuolar Sorting of AtBOR1.
Boron (B) is an essential micronutrient for plants but is toxic when accumulated in excess. The plant BOR family encodes plasma membrane-localized borate exporters (BORs) that control translocation and homeostasis of B under a wide range of conditions. In this study, we examined the evolutionary divergence of BORs among terrestrial plants and showed that the lycophyte Selaginella moellendorffii and angiosperms have evolved two types of BOR (clades I and II). Clade I includes AtBOR1 and homologs previously shown to be involved in efficient transport of B under conditions of limited B availability. AtBOR1 shows polar localization in the plasma membrane and high-B-induced vacuolar sorting, important features for efficient B transport under low-B conditions, and rapid down-regulation to avoid B toxicity. Clade II includes AtBOR4 and barley Bot1 involved in B exclusion for high-B tolerance. We showed, using yeast complementation and B transport assays, that three genes in S. moellendorffii, SmBOR1 in clade I and SmBOR3 and SmBOR4 in clade II, encode functional BORs. Furthermore, amino acid sequence alignments identified an acidic di-leucine motif unique in clade I BORs. Mutational analysis of AtBOR1 revealed that the acidic di-leucine motif is required for the polarity and high-B-induced vacuolar sorting of AtBOR1. Our data clearly indicated that the common ancestor of vascular plants had already acquired two types of BOR for low- and high-B tolerance, and that the BOR family evolved to establish B tolerance in each lineage by adapting to their environments.


An antiviral substance from Penicillium funiculosum. I. Effect upon infection in mice with swine influenza virus and Columbia SK encephalomyelitis virus.
A culture of P. funiculosum isolated on Guam proved capable of elaborating a substance which exerted a favorable therapeutic effect against swine influenza virus infections in white mice. The culture was extremely variable and irregular in its production of the antiviral substance, and during maintenance in the laboratory for several years gradually lost this property. Efforts to restore it were unsuccessful. Subsequently it was found that the mold elaborated a substance, now designated helenine, which is therapeutically effective against Columbia SK encephalomyelitis virus infections in mice. Helenine appears to differ from the substance earlier procured from the mold, which was active against swine influenza virus infections in mice. It is frequently present in greater or lesser amount in the fluid portions of stationary cultures of P. funiculosum but is more regularly obtained and in larger amount, from the cellular components of the pellicles. When liberated from these latter by mechanical bruising and fracturing, it goes into solution in the culture fluids. It is precipitable from aqueous solution by 50 per cent acetone. Infected mice injected with helenine in amounts less than the amount which produces a maximal therapeutic effect exhibit a dosage response. Increasing the dose above the optimum fails to increase the therapeutic effect. Helenine exerts its maximum effect when given within the first 10 hours after viral infection but its influence is apparent even when treatment is delayed for up to 24 hours. It is not effective against massive amounts of virus and gives the best therapeutic results when used in the treatment of animals infected with from 10 to 1000 fatal doses of virus. Treatment of infected mice with helenine delays the entrance of virus into their brains for from 24 to 48 hours. The mechanism by which helenine exerts its therapeutic effect against SK virus is not known but the findings presented suggest either that it causes an inhibition or interruption of multiplication of the virus, slowing down the whole process of infection and spread to the central nervous system, or that in some way it interferes temporarily with the neuroinvasiveness of the virus.


"Inside-out" signaling of sphingosine-1-phosphate: therapeutic targets.
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes including proliferation, survival, and migration, as well as angiogenesis and allergic responses. S1P levels inside cells are tightly regulated by the balance between its synthesis by sphingosine kinases and degradation. S1P is interconvertible with ceramide, which is a critical mediator of apoptosis. It has been postulated that the ratio between S1P and ceramide determines cell fate. Activation of sphingosine kinase by a variety of agonists increases intracellular S1P, which in turn can function intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signaling through S1P receptors in autocrine and/or paracrine manners. Recent studies suggest that this "inside-out" signaling by S1P may play a role in many human diseases, including cancer, atherosclerosis, inflammation, and autoimmune disorders such as multiple sclerosis. In this review we summarize metabolism of S1P, mechanisms of sphingosine kinase activation, and S1P receptors and their downstream signaling pathways and examine relationships to multiple disease processes. In particular, we describe recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod), S1P receptor agonists, sphingosine kinase inhibitors, and anti-S1P monoclonal antibody.