Membrane potential-generating malate (MleP) and citrate (CitP) transporters of lactic acid bacteria are homologous proteins. Substrate specificity of the 2-hydroxycarboxylate transporter family.
Membrane potential generation via malate/lactate exchange catalyzed by the malate carrier (MleP) of Lactococcus lactis, together with the generation of a pH gradient via decarboxylation of malate to lactate in the cytoplasm, is a typical example of a secondary proton motive force-generating system. The mleP gene was cloned, sequenced, and expressed in a malolactic fermentation-deficient L. lactis strain. Functional analysis revealed the same properties as observed in membrane vesicles of a malolactic fermentation-positive strain. MleP belongs to a family of secondary transporters in which the citrate carriers from Leuconostoc mesenteroides (CitP) and Klebsiella pneumoniae (CitS) are found also. CitP, but not CitS, is also involved in membrane potential generation via electrogenic citrate/lactate exchange. MleP, CitP, and CitS were analyzed for their substrate specificity. The 2-hydroxycarboxylate motif R1R2COHCOOH, common to the physiological substrates, was found to be essential for transport although some 2-oxocarboxylates could be transported to a lesser extent. Clear differences in substrate specificity among the transporters were observed because of different tolerances toward the R substituents at the C2 atom. Both MleP and CitP transport a broad range of 2-hydroxycarboxylates with R substituents ranging in size from two hydrogen atoms (glycolate) to acetyl and methyl groups (citromalate) for MleP and two acetyl groups (citrate) for CitP. CitS was much less tolerant and transported only citrate and at a low rate citromalate. The substrate specificities are discussed in the context of the physiological function of the transporters.


Modulation instability of finite energy Airy pulse in optical fiber.
We have investigated and analyzed the modulation instability (MI) of finite energy Airy pulse (FEAP) in an optical fiber in order to reveal the impact of truncation coefficient on the nonlinear propagation dynamics of FEAP with or without amplitude perturbation. We have also characterized the difference between the propagation process of smooth FEAP and that of modulated FEAP. It is shown that, for a smooth FEAP, the side lobes prior to the main lobe first undergo compression and then break up into multiple sub-pulses during propagation in the case of small truncation coefficient; while the opposite occurs in the case of large truncation coefficient. For a FEAP with amplitude modulation, the breakup of the main lobe induced by MI precedes that of side lobes for arbitrary values of truncation coefficients; but the evolution of secondary lobes is made by a transition from splitting process to a simple compression process with increasing truncation coefficient. The propagation dynamics of secondary lobes with number symbol larger 2, marked the secondary lobes starting number 1 from near to far according the distance between itself and the main lobe, is insensitive to the truncation coefficients variation in both cases. Finally, the MI gain spectra of FEAP with different truncation coefficients are obtained by numerically solving the nonlinear Schrödinger equation and the results have been compared with the theoretical predictions.


Allogeneic lymphocytes persist and traffic in feral MHC-matched mauritian cynomolgus macaques.
Thus far, live attenuated SIV has been the most successful method for vaccinating macaques against pathogenic SIV challenge; however, it is not clear what mechanisms are responsible for this protection. Adoptive transfer studies in mice have been integral to understanding live attenuated vaccine protection in models like Friend virus. Previous adoptive transfers in primates have failed as transferred cells are typically cleared within hours after transfer. Here we describe adoptive transfer studies in Mauritian origin cynomolgus macaques (MCM), a non-human primate model with limited MHC diversity. Cells transferred between unrelated MHC-matched macaques persist for at least fourteen days but are rejected within 36 hours in MHC-mismatched macaques. Cells trafficked from the blood to peripheral lymphoid tissues within 12 hours of transfer. MHC-matched MCM provide the first viable primate model for adoptive transfer studies. Because macaques infected with SIV are the best model for HIV/AIDS pathogenesis, we can now directly study the correlates of protective immune responses to AIDS viruses. For example, plasma viral loads following pathogenic SIV challenge are reduced by several orders of magnitude in macaques previously immunized with attenuated SIV. Adoptive transfer of lymphocyte subpopulations from vaccinated donors into SIV-naïve animals may define the immune mechanisms responsible for protection and guide future vaccine development.


Proteolytic cleavage of apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of the genetic risk factors identified, the 34 kDa protein, apolipoprotein (apo) E4, is of significant importance as APOE4 carriers account for 65%-80% of all AD cases. Although apoE4 plays a normal role in lipoprotein transport, how it contributes to AD pathogenesis is currently unknown. One potential mechanism by which apoE4 contributes to disease risk is its propensity to undergo proteolytic cleavage generating N- and C-terminal fragments. The purpose of this review will be to examine the mechanisms by which apoE4 contributes to AD pathogenesis focusing on the potential loss or gain of function that may occur following cleavage of the full-length protein. In this context, a discussion of whether targeting apoE4 therapeutically is a rationale approach to treating this disease will be assessed.


Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker.
Missense mutations in the skeletal muscle Na+ channel alpha subunit occur in several heritable forms of myotonia and periodic paralysis. Distinct phenotypes arise from mutations at two sites within the III-IV cytoplasmic loop: myotonia without weakness due to substitutions at glycine 1306, and myotonia plus weakness caused by a mutation at threonine 1313. Heterologous expression in HEK cells showed that substitutions at either site disrupted inactivation, as reflected by slower inactivation rates, shifts in steady-state inactivation, and larger persistent Na+ currents. For T1313M, however, the changes were an order of magnitude larger than any of three substitutions at G1306, and recovery from inactivation was hastened as well. Model simulations demonstrate that these functional difference have distinct phenotypic consequences. In particular, a large persistent Na+ current predisposes to paralysis due to depolarization-induced block of action potential generation.


Brain/MINDS beyond human brain MRI project: A protocol for multi-level harmonization across brain disorders throughout the lifespan.
Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (BMB-HBM, FY2018 ~ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. A high-quality scanning protocol, Harmonization Protocol (HARP), was established for five high-quality 3 T scanners to obtain multimodal brain images including T1 and T2-weighted, resting-state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, suggesting sensitivity to subject-specific connectome. A total of 75 TS and more than two thousand patients with various psychiatric and neurological disorders are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a prospective, multi-level harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.


Characterization of Urinary Phthalate Metabolites Among Custodians.
Phthalates, a ubiquitous class of chemicals found in consumer, personal care, and cleaning products, have been linked to adverse health effects. Our goal was to characterize urinary phthalate metabolite concentrations and to identify work and nonwork sources among custodians using traditional cleaning chemicals and 'green' or environmentally preferable products (EPP). Sixty-eight custodians provided four urine samples on a workday (first void, before shift, end of shift, and before bedtime) and trained observers recorded cleaning tasks and types of products used (traditional, EPP, or disinfectant) hourly over the work shifts. Questionnaires were used to assess personal care product use. Four different phthalate metabolites [monoethyl phthalate (MEP), monomethyl phthalate (MMP), mono (2-ethylhexyl) phthalate (MEHP), and monobenzyl phthalate (MBzP)] were quantified using liquid chromatography mass spectrometry. Geometric means (GM) and 95% confidence intervals (95% CI) were calculated for creatinine-adjusted urinary phthalate concentrations. Mixed effects univariate and multivariate modeling, using a random intercept for each individual, was performed to identify predictors of phthalate metabolites including demographics, workplace factors, and personal care product use. Creatinine-adjusted urinary concentrations [GM (95% CI)] of MEP, MMP, MEHP, and MBzP were 107 (91.0-126), 2.69 (2.18-3.30), 6.93 (6.00-7.99), 8.79 (7.84-9.86) µg g(-1), respectively. An increasing trend in phthalate concentrations from before to after shift was not observed. Creatinine-adjusted urinary MEP was significantly associated with frequency of traditional cleaning chemical intensity in the multivariate model after adjusting for potential confounding by demographics, workplace factors, and personal care product use. While numerous demographics, workplace factors, and personal care products were statistically significant univariate predictors of MMP, MEHP, and MBzP, few associations persisted in multivariate models. In summary, among this population of custodians, we identified both occupational and nonoccupational predictors of phthalate exposures. Identification of phthalates as ingredients in cleaning chemicals and consumer products would allow workers and consumers to avoid phthalate exposure.


Reversibly contractile nuclear matrix. Its isolation, structure, and composition.
From Tetrahymena macronuclei we have isolated a reversibly contractile nucleo-skeleton, i.e., an "expanded" nuclear matrix which reversibly contracts when the total concentration of the bivalent cations, Ca and Mg (3:2), is decreased to 5 mM or increased to 125 mM. During contraction the average diameter of the expanded matrix becomes reduced by about 24%; this corresponds to a volume contraction of about 55%. The reversible contraction of the nuclear matrix does not depend on ATP and cannot be inhibited by salygran. The expanded matrix is obtained by removing carefully from the macronuclei 89.7% of the phospholipid, 99.6% of the DNA, 98.5% of the RNA, and 74.8% of the protein by treatment with Triton X-100 and digestion with DNase and RNase followed by an extraction with 2 M NaCl. Electron microscopy reveals, within the expanded matrix, residual equivalents to the structures characteristic for macronuclei: (a) a residual nuclear envelope with nuclear pore complexes; (b) residual nucleoli at the periphery; (c) a fibrillar internal network. The expanded matrix is essentially composed of proteins (96.2%) and traces of DNA (0.8%), RNA (0.5%), phospholipid (1.6%), and carbohydrates (0.9%). The last, which have been determined by gas chromatography, contain glucose, mannose, and an unidentified sugar in the ratio 1:5.4:5.7. The ratio of acidic to basic amino acids of the expanded matrix is 1.55. Sodium dodecyl sulfate (SDS) gel electrophoresis reveals a predominant protein with a mol wt of 18,000 which is apparently involved in the reversible contractile process. The mechanism of this reversible contraction of the expanded matrix remains to be elucidated, but it differs both from actin-myosin contraction systems and from the contractile spasmoneme system in vorticellids.


Forensic analysis of P2P derived amphetamine synthesis impurities: identification and characterization of indene by-products.
1-Phenyl-2-propanone (P2P) is an internationally monitored precursor that has become increasingly difficult for illicit amphetamine producers to source, which means that alternative routes to its preparation have become increasingly important. One such approach includes the hydrolysis of alpha-phenylacetoacetonitrile (APAAN) with sulfuric acid. Previously, we reported the identification of 4,6-dimethyl-3,5-diphenylpryid-2-one following implementation of hydrolysis conditions and it was proposed that this compound might serve as one route specific by-product in the APAAN to P2P conversion. This study continued to explore the presence of impurities formed during this conversion and expanded also into a second route of P2P synthesis starting from alpha-methylstyrene (AMS). All P2P products underwent the Leuckart procedure to probe the presence of P2P-related impurities that might have carried through to the final product. Two by-products associated with the APAAN hydrolysis route to P2P were identified as 2,3-diacetyl-2,3-diphenylsuccinonitrile (1) and 2-methyl-1-phenyl-1,3-dicarbonitrile-1H-indene (2), respectively. Two by-products associated with the AMS route to P2P and subsequent Leuckart reaction were 1,1,3-trimethyl-3-phenyl-2,3-dihydro-1H-indene (3) and 1-phenyl-N-(phenylethyl)propan-2-amine (4), respectively. The two indenes (2 and 3) identified in synthesized amphetamine originating from P2P suggested that it might be possible to differentiate between the two synthetic routes regarding the use of APAAN and AMS. Furthermore, the association of these compounds with amphetamine production appears to have been reported for the first time. The presence of compounds 1 - 4 in seized amphetamine samples and waste products could facilitate the suggestion whether APAAN or AMS were employed in the synthesis route to the P2P. Copyright © 2016 John Wiley & Sons, Ltd.


In Vivo Biotinylation of the Toxoplasma Parasitophorous Vacuole Reveals Novel Dense Granule Proteins Important for Parasite Growth and Pathogenesis.
Toxoplasma gondii is an obligate intracellular parasite that invades host cells and replicates within a unique parasitophorous vacuole. To maintain this intracellular niche, the parasite secretes an array of dense granule proteins (GRAs) into the nascent parasitophorous vacuole. These GRAs are believed to play key roles in vacuolar remodeling, nutrient uptake, and immune evasion while the parasite is replicating within the host cell. Despite the central role of GRAs in the Toxoplasma life cycle, only a subset of these proteins have been identified, and many of their roles have not been fully elucidated. In this report, we utilize the promiscuous biotin ligase BirA* to biotinylate GRA proteins secreted into the vacuole and then identify those proteins by affinity purification and mass spectrometry. Using GRA-BirA* fusion proteins as bait, we have identified a large number of known and candidate GRAs and verified localization of 13 novel GRA proteins by endogenous gene tagging. We proceeded to functionally characterize three related GRAs from this group (GRA38, GRA39, and GRA40) by gene knockout. While Δgra38 and Δgra40 parasites showed no altered phenotype, disruption of GRA39 results in slow-growing parasites that contain striking lipid deposits in the parasitophorous vacuole, suggesting a role in lipid regulation that is important for parasite growth. In addition, parasites lacking GRA39 showed dramatically reduced virulence and a lower tissue cyst burden in vivo Together, the findings from this work reveal a partial vacuolar proteome of T. gondii and identify a novel GRA that plays a key role in parasite replication and pathogenesis. Most intracellular pathogens reside inside a membrane-bound vacuole within their host cell that is extensively modified by the pathogen to optimize intracellular growth and avoid host defenses. In Toxoplasma, this vacuole is modified by a host of secretory GRA proteins, many of which remain unidentified. Here we demonstrate that in vivo biotinylation of proximal and interacting proteins using the promiscuous biotin ligase BirA* is a powerful approach to rapidly identify vacuolar GRA proteins. We further demonstrate that one factor identified by this approach, GRA39, plays an important role in the ability of the parasite to replicate within its host cell and cause disease.


Global field synchronization reveals rapid eye movement sleep as most synchronized brain state in the human EEG.
Sleep is characterized by a loss of consciousness, which has been attributed to a breakdown of functional connectivity between brain regions. Global field synchronization (GFS) can estimate functional connectivity of brain processes. GFS is a frequency-dependent measure of global synchronicity of multi-channel EEG data. Our aim was to explore and extend the hypothesis of disconnection during sleep by comparing GFS spectra of different vigilance states. The analysis was performed on eight healthy adult male subjects. EEG was recorded during a baseline night, a recovery night after 40 h of sustained wakefulness and at 3 h intervals during the 40 h of wakefulness. Compared to non-rapid eye movement (NREM) sleep, REM sleep showed larger GFS values in all frequencies except in the spindle and theta bands, where NREM sleep showed a peak in GFS. Sleep deprivation did not affect GFS spectra in REM and NREM sleep. Waking GFS values were lower compared with REM and NREM sleep except for the alpha band. Waking alpha GFS decreased following sleep deprivation in the eyes closed condition only. Our surprising finding of higher synchrony during REM sleep challenges the view of REM sleep as a desynchronized brain state and may provide insight into the function of REM sleep.


The Cognitive Failures Questionnaire (CFQ) and its correlates.
This paper describes a questionnaire measure of self-reported failures in perception, memory, and motor function. Responses to all questions tend to be positively correlated, and the whole questionnaire correlates with other recent measures of self-reported deficit in memory, absent-mindedness, or slips of action. The questionnaire is however only weakly correlated with indices of social desirability set or of neuroticism. It is significantly correlated with ratings of the respondent by his or her spouse, and accordingly does have some external significance rather than purely private opinion of the self. The score is reasonably stable over long periods, to about the same extent as traditional measures of trait rather than state. Furthermore, it has not thus far been found to change in persons exposed to life-stresses. However, it does frequently correlate with the number of current psychiatric symptoms reported by the same person on the MHQ; and in one study it has been found that CFQ predicts subsequent MHQ in persons who work at a stressful job in the interval. It does not do so in those who work in a less stressful environment. The most plausible view is that cognitive failure makes a person vulnerable to showing bad effects of stress, rather than itself resulting from stress.


Changes in bronchial inflammation during acute exacerbations of chronic bronchitis.
There are little data describing noncellular changes in bronchial inflammation during exacerbations of chronic bronchitis. The relationship between sputum colour and airway inflammation at presentation has been assessed during an exacerbation in patients with chronic bronchitis and a primary care diagnosis of chronic obstructive pulmonary disease. Sputum myeloperoxidase, neutrophil elastase, leukotriene B4 (LTB4), interleukin-8 (IL-8), sol:serum albumin ratio and serum C-reactive protein were measured in patients presenting with an exacerbation and mucoid (n = 27) or purulent sputum (n = 42). Mucoid exacerbations were associated with little bronchial or systemic inflammation at presentation, and sputum bacteriology was similar to that obtained in the stable state. Purulent exacerbations were associated with marked bronchial and systemic inflammation (p < 0.025 for all features) and positive sputum cultures (90%). Resolution was related to a significant reduction in LTB4 (p < 0.01), but no change in IL-8, suggesting that LTB4 may be more important in neutrophil recruitment in these mild, purulent exacerbations. In the stable state, IL-8 remained higher in patients who had experienced a purulent exacerbation (2p < 0.02). The presented results indicate that exacerbations of chronic bronchitis, defined by sputum colour, differ in the degree of bronchial and systemic inflammation. Purulent exacerbations are related to bacterial infection, and are associated with increased neutrophilic inflammation and increased leukotriene B4 concentrations.


[Elucidation of the energy absorption spectra of the (11)C beam in a plastic scintillator.].
Heavy ion therapy using the energetic (12)C beam is successfully under way at HIMAC, Japan. The method is more advantageous than traditional radiation therapy in dose concentration owing to the Bragg peak and high relative biological effectiveness. A research study using the (11)C beam for heavy ion therapy in the future has been carried out in order to develop the capability of monitoring the dose distribution. Our group has examined the total energy absorption spectrum of the (11)C beam in a plastic scintillator. We could clearly observe the total absorption peak of (11)C in the energy spectrum and, in addition, we found a broad bump structure was associated with the peak. The bump area occupies 37% of the total spectrum and it probably affects the dose calculation for an accurate treatment planning. We elucidated the mechanism that leads to the structure of the total energy absorption spectra given by (11)C and (12)C in a block of plastic scintillator. This paper describes the method in detail and gives experimental analysis results which deal with the bump structure. We could explain the bump structure using the energy spectra caused by the fragmentation reactions.


IRSOM, a reliable identifier of ncRNAs based on supervised self-organizing maps with rejection.
Non-coding RNAs (ncRNAs) play important roles in many biological processes and are involved in many diseases. Their identification is an important task, and many tools exist in the literature for this purpose. However, almost all of them are focused on the discrimination of coding and ncRNAs without giving more biological insight. In this paper, we propose a new reliable method called IRSOM, based on a supervised Self-Organizing Map (SOM) with a rejection option, that overcomes these limitations. The rejection option in IRSOM improves the accuracy of the method and also allows identifing the ambiguous transcripts. Furthermore, with the visualization of the SOM, we analyze the rejected predictions and highlight the ambiguity of the transcripts. IRSOM was tested on datasets of several species from different reigns, and shown better results compared to state-of-art. The accuracy of IRSOM is always greater than 0.95 for all the species with an average specificity of 0.98 and an average sensitivity of 0.99. Besides, IRSOM is fast (it takes around 254 s to analyze a dataset of 147 000 transcripts) and is able to handle very large datasets. IRSOM is implemented in Python and C++. It is available on our software platform EvryRNA (http://EvryRNA.ibisc.univ-evry.fr).


Demographic transition and factors associated with remaining in place after the 2011 Fukushima nuclear disaster and related evacuation orders.
Demographic changes as a result of evacuation in the acute phase of the 2011 Fukushima nuclear disaster are not well evaluated. We estimated post-disaster demographic transitions in Minamisoma City-located 14-38 km north of the nuclear plant-in the first month of the disaster; and identified demographic factors associated with the population remaining in the affected areas. We extracted data from the evacuation behavior survey administered to participants in the city between July 11, 2011 and April 30, 2013. Using mathematical models, we estimated the total population in the city after the disaster according to sex, age group, and administrative divisions of the city. To investigate factors associated with the population remaining in place after the disaster, a probit regression model was employed, taking into account sex, age, pre-disaster dwelling area, and household composition. The overall population decline in Minamisoma City peaked 11 days after the disaster, when the population reached 7,107 people-11% of the pre-disaster level. The remaining population levels differed by area: 1.1% for mandatory evacuation zone, 12.5% for indoor sheltering zone, and 12.6% for other areas of the city. Based on multiple regression analyses, higher odds for remaining in place were observed among men (odds ratio 1.72 [95% confidence intervals 1.64-1.85]) than women; among people aged 40-64 years (1.40 [1.24-1.58]) than those aged 75 years or older; and among those living with the elderly, aged 70 years or older (1.18 [1.09-1.27]) or those living alone (1.71 [1.50-1.94]) than among those who were not. Despite the evacuation order, some residents of mandatory evacuation zones remained in place, signaling the need for preparation to respond to their post-disaster needs. Indoor sheltering instructions may have accelerated voluntary evacuation, and this demonstrates the need for preventing potentially disorganized evacuation in future nuclear events.


Codes, classifications, terminologies and nomenclatures: definition, development and application in practice.
The Primary Care Informatics Working Group of EFMI is working to help develop the core theory of primary care informatics (PCI). Codes, classifications, terminologies and nomenclatures form an important part of the science of PCI, as they allow clinical information to be readily stored and processed in information systems. This article provides definitions and a history of the International Classification for Primary Care (ICPC), and of the Read code and the Systematized Nomenclature for Medicine (SNOMED). The Working Group wishes to encourage shared definitions and an understanding of the practical application of structured data to improve quality in clinical practice.


Cardioprotective effect of aqueous extract of Embelia ribes Burm fruits against isoproterenol-induced myocardial infarction in albino rats.
In the present study, cardioprotective effect of aqueous extract of fruits of Embelia ribes Burm (ER) was evaluated in a rat model having acute myocardial infarction, induced by isoproterenol (5.25 and 8.5 mg/kg, sc, for two consecutive days). Aqueous ER extract (100 mg/kg) pretreatment orally for 40 days in isoproterenol (ISO)-treated rats significantly decreased the heart rate, systolic blood pressure, increased levels of serum lactate dehydrogenase, serum creatine kinase and myocardial lipid peroxides and significantly increased the myocardial endogenous antioxidants (glutathione, superoxide dismutase and catalase) levels. The results of biochemical observations in serum and heart tissues were supplemented by histopathological examination of rat's heart sections to confirm the myocardial injury. The results were comparable to that of gliclazide treated group. The present results provide evidence for the first time, that aqueous ER extract pretreatment ameliorated myocardial injury and enhanced the antioxidant defense against ISO-induced myocardial infarction in rats and exhibited cardioprotective property.


Influence of ions on genome packaging and ejection: a molecular dynamics study.
We, theoretically, investigate the effect of ions on the packing and ejection dynamics of flexible and semiflexible polymers from spherical viral capsids. We find that when the polymer charge is less screened, or the Debye length increases (corresponding to a buffer with low concentration of a monovalent salt, such as Na(+)), the packing becomes more difficult and it may stop midway. Ejection, instead, proceeds more easily if the electrostatic screening is small. On the other hand, more screening (corresponding, for example, to the addition of divalent ions such as Mg(2+)) results in easier packing and slower ejection. We interpret this as resulting from electrostatic forces among the various polymer sections, which can be tuned with the type of salt present in the solution. We also discuss how the DNA structure inside the capsid changes due to screened electrostatic interactions.


Computing organic stereoselectivity - from concepts to quantitative calculations and predictions.
Advances in theory and processing power have established computation as a valuable interpretative and predictive tool in the discovery of new asymmetric catalysts. This tutorial review outlines the theory and practice of modeling stereoselective reactions. Recent examples illustrate how an understanding of the fundamental principles and the application of state-of-the-art computational methods may be used to gain mechanistic insight into organic and organometallic reactions. We highlight the emerging potential of this computational tool-box in providing meaningful predictions for the rational design of asymmetric catalysts. We present an accessible account of the field to encourage future synergy between computation and experiment.


The Challenges of Afghanistan and Iraq Veterans' Transition from Military to Civilian Life and Approaches to Reconnection.
Afghanistan and Iraq veterans experienced traumas during deployment, and disrupted connections with friends and family. In this context, it is critical to understand the nature of veterans' transition to civilian life, the challenges navigated, and approaches to reconnection. We investigated these issues in a qualitative study, framed by homecoming theory, that comprised in-depth interviews with 24 veterans. Using an inductive thematic analysis approach, we developed three overarching themes. Military as family explored how many veterans experienced the military environment as a "family" that took care of them and provided structure. Normal is alien encompassed many veterans experiences of disconnection from people at home, lack of support from institutions, lack of structure, and loss of purpose upon return to civilian life. Searching for a new normal included strategies and supports veterans found to reconnect in the face of these challenges. A veteran who had successfully transitioned and provided support and advice as a peer navigator was frequently discussed as a key resource. A minority of respondents-those who were mistreated by the military system, women veterans, and veterans recovering from substance abuse problems-were less able to access peer support. Other reconnection strategies included becoming an ambassador to the military experience, and knowing transition challenges would ease with time. Results were consistent with and are discussed in the context of homecoming theory and social climate theory. Social support is known to be protective for veterans, but our findings add the nuance of substantial obstacles veterans face in locating and accessing support, due to disconnection and unsupportive institutions. Larger scale work is needed to better understand how to foster peer connection, build reconnection with family, and engage the broader community to understand and support veterans; interventions to support reconnection for veterans should be developed.


[Clonogenic capacity of proliferating and resting populations of NKLy/LL tumor cells].
On tumor NKLy/LL the author have studied the efficiency of cloning, the fraction of proliferating and resting cells and the rate of DNA synthesis in peripheral and central tumor sites. It was shown that the more far from the periphery the less fraction of labelled cells and the rate of DNA synthesis but the greater are differences in the content of proliferating cells in some sites. The efficiency of cloning in peripheral and central tumor sites does not differ, the fraction of clonogenic cells being larger than that of proliferating ones. Following persistent administration of 3H-thymidine in animals, it was found that the number of colonies produced by proliferating cells is considerably less than the general efficiency of cloning. It is concluded that resting cells can divide infinitely and are clonogenic ones.


Response of type B atrial vagal receptors to changes in wall tension during atrial filling.
In anesthetized curarized cats with their chests open, we recorded the activity of type B right atrial vagal stretch receptors, right atrial pressure, and instantaneous dimensional changes of the right atrium. The nervous activity was analyzed during alterations in atrial dynamics produced by acute volume loading of the right atrium under control conditions and during sympathetic and vagal stimulations. Our results demonstrated that the mean frequency of discharge in the burst was dependent on the absolute tension and the rate of change in tension developed in atrial muscles during filling. The responses of different receptors to changes in atrial dynamics were qualitatively similar but characteristic for each receptor studied. In some experiments nervous activity was recorded after the cats had been killed: static and dynamic changes in atrial tension were then produced by injecting blood into the right atrium. Under these conditions dynamic stimuli always activated the receptors at tensions below the threshold for static stimuli. During dynamic stimuli the instantaneous firing rate was always higher than it was during static stimuli applied at the same level of tension. This study indicates that the nervous activity of type B atrial vagal receptors is closely dependent on static and dynamic changes in atrial wall tension.


Relationship between exposure, clinical malaria, and age in an area of changing transmission intensity.
The relationship between malaria transmission intensity and clinical disease is important for predicting the outcome of control measures that reduce transmission. Comparisons of hospital data between areas of differing transmission intensity suggest that the mean age of hospitalized clinical malaria is higher under relatively lower transmission, but the total number of episodes is similar until transmission drops below a threshold, where the risks of hospitalized malaria decline. These observations have rarely been examined longitudinally in a single community where transmission declines over time. We reconstructed 16 years (1991-2006) of pediatric hospital surveillance data and infection prevalence surveys from a circumscribed geographic area on the Kenyan coast. The incidence of clinical malaria remained high, despite sustained reductions in exposure to infection. However, the age group experiencing the clinical attacks of malaria increased steadily as exposure declined and may precede changes in the number of episodes in an area with declining transmission.


Can pretreatment screening for dhps and dhfr point mutations in Plasmodium falciparum infections be used to predict sulfadoxine-pyrimethamine treatment failure?
This study examines the relationship between malaria treatment failure after sulfadoxine-pyrimethamine (S-P) chemotherapy and presence of mutations in the Plasmodium falciparum dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) genes (associated with resistance in vitro to S and P) before treatment. In Kenya, 38 malaria patients in a holoendemic area, and 21 in an epidemic area, participated in the trial in 1997-98. In the 2 areas, drug failure occurred in 76% and 75% of cases where any mutation in dhfr was seen (positive predictive values 76% and 75%: P = 0.003 and 0.008) and an identical association was seen with dhfr Asn-108. In the holoendemic area all occurrences of > or = 2 mutations in dhfr predicted drug failure. Only 3 instances were seen in the epidemic focus, but treatment failed in all. Only in the epidemic focus, 7 (88%) of 8 occurrences of > or = 1 mutations in dhps, and all occurrences of the Gly-437 allele of dhps, predicted failure. Association between mutations in dhps and mutations in dhfr was noted in the combined sites, irrespective of outcome. Although this makes the relationship of combined dhfr and dhps mutations to failure more difficult to interpret, it nevertheless supports S-P selection acting on both genes. In the holoendemic site, treatment success increased with age. In this location, acquired immunity may mask the impact of mutations in dhps, since sulfadoxine is a less effective treatment than pyrimethamine.


Use of randomization testing to detect multiple epistatic QTLs.
Here, we describe a randomization testing strategy for mapping interacting quantitative trait loci (QTLs). In a forward selection strategy, non-interacting QTLs and simultaneously mapped interacting QTL pairs are added to a total genetic model. Simultaneous mapping of epistatic QTLs increases the power of the mapping strategy by allowing detection of interacting QTL pairs where none of the QTL can be detected by their marginal additive and dominance effects. Randomization testing is used to derive empirical significance thresholds for every model selection step in the procedure. A simulation study was used to evaluate the statistical properties of the proposed randomization tests and for which types of epistasis simultaneous mapping of epistatic QTLs adds power. Least squares regression was used for QTL parameter estimation but any other QTL mapping method can be used. A genetic algorithm was used to search for interacting QTL pairs, which makes the proposed strategy feasible for single processor computers. We believe that this method will facilitate the evaluation of the importance at epistatic interaction among QTLs controlling multifactorial traits and disorders.


[Chronic granulomatous disease. Update and review].
Chronic granulomatous disease (CGD) is a primary immunodeficiency syndrome which is characterized by increased susceptibility to severe fungal and bacterial infections. CGD is the result of the lack of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme in the patient's phagocytes to produce superoxide. It is characterized by recurrent infections with a narrow spectrum of bacteria and fungi, as well as a common set of inflammatory complications, including inflammatory bowel disease. The most frequently found pathogens are Staphylococcus aureus, species of Aspergillus, species of Klebsiella, Burkholderia cepacia, Serratia marcescens and species of Salmonella. Long term antibiotic prophylaxis has helped fight infections associated with chronic granulomatous disease, while the steady progress in bone marrow transplants and the possibility of gene therapy are defined as permanent treatment options.


Correlation of serum adiponectin levels and hepatic steatosis in hepatitis C virus genotype 1 infection.
Steatosis is an important cofactor in hepatitis C virus (HCV) because it is associated with fibrosis and reduces early and sustained virologic response. Recent studies suggest that HCV genotype 1 is not steatogenic if additional risk factors are not present. Because hypoadiponectinemia was found to be a feature of nonalcoholic steatohepatitis (NASH) independent of insulin resistance, its level in patients with hepatitis C genotype can reveal the optimal therapeutic strategy. This study was conducted to determine the role of the relationship between steatosis and serum adiponectin levels in the progression of liver damage in HCV genotype 1 without known risk factors for NASH. Patients (n=50) with biopsy-proven chronic hepatitis C (CHC), positive HCV RNA, and raised alanine aminotransferase were enrolled. They were carefully selected to rule out possible confounding factors for the presence of steatosis and additional systemic or liver disease. Associations between serum adiponectin levels and grade of steatosis, histologic activity index (HAI), fibrosis grade of liver biopsies, patient age, HCV viral load, and serum transaminase activities were studied. Also, adiponectin levels were compared with those of a control group of 30 healthy volunteers with normal ultrasound findings of the upper abdomen who had no known NASH risk factors. The investigators found that adiponectin levels in patients with CHC genotype 1 were similar to those in healthy subjects. No significant association was found between adiponectin levels and severity of steatosis, HCV RNA levels, HAI, transaminases, and fibrosis. Steatosis was present in 41 patients (82%) with CHC. Multivariate analysis of data on 50 patients revealed that severity of steatosis was independently related to age alone (P=.03). A correlation between HCV RNA load and HAI was observed (P=.02; r=0.712). HAI also was associated with stage of fibrosis (P=.00; r= 0.612). In cases of chronic HCV genotype 1 hepatitis, steatosis is a common histologic feature, although no risk factors are known. Results presented here cannot establish an association between adiponectin and severity of steatosis when risk factors for steatosis are unknown. Additional studies are needed to discover a metabolic treatment that would seek to improve the progression of hepatic steatosis in CHC infection.


Genetic behaviour of physiological traits conferring cytosolic K+/Na+ homeostasis in wheat.
A plant's ability to maintain an optimal cytosolic K(+)/Na(+) ratio has long been cited as a key feature of salinity tolerance. As traditional whole-leaf nutrient analysis does not account for tissue and organelle-specific ion sequestration, the predictive value of this index at the whole-plant level is not always satisfactory. Consequently, suitable in situ methods for functionally assessing the activity of the key membrane transporters contributing to this trait at the cellular level need to be developed. The aim of this work was to investigate the extent to which plasma membrane transporter-mediated Na(+) exclusion and KOR-mediated K(+) retention traits, measured with the microelectrode ion flux measuring (MIFE) technique, are inheritable in wheat, and whether the MIFE technique has the potential to be used in combination with molecular markers to determine QTLs for these transporter proteins. Experiments involved two bread (Triticum aestivum) and two durum (Triticum turgidum) wheat lines contrasting in their salinity tolerance. Net Na(+), K(+) and H(+) fluxes were measured from 6-day-old roots of parental lines and their F(1) hybrids upon addition and removal of NaCl. These results were complemented by assessment of whole-plant physiological and agronomic characteristics. We show evidence for a strong heritability of plasma membrane transporter-mediated Na(+) exclusion and K(+) retention traits in wheat at the cellular level. This opens the prospect of using the MIFE technique to map the position of these transporters on particular loci of wheat chromosomes. The next obvious step would be to pyramid these traits in one ideotype with superior salinity tolerance.


Suicide-related behaviors in older patients with new anti-epileptic drug use: data from the VA hospital system.
The U.S. Food and Drug Administration (FDA) recently linked antiepileptic drug (AED) exposure to suicide-related behaviors based on meta-analysis of randomized clinical trials. We examined the relationship between suicide-related behaviors and different AEDs in older veterans receiving new AED monotherapy from the Veterans Health Administration (VA), controlling for potential confounders. VA and Medicare databases were used to identify veterans 66 years and older, who received a) care from the VA between 1999 and 2004, and b) an incident AED (monotherapy) prescription. Previously validated ICD-9-CM codes were used to identify suicidal ideation or behavior (suicide-related behaviors cases), epilepsy, and other conditions previously associated with suicide-related behaviors. Each case was matched to controls based on prior history of suicide-related behaviors, year of AED prescription, and epilepsy status. The strongest predictor of suicide-related behaviors (N = 64; Controls N = 768) based on conditional logistic regression analysis was affective disorder (depression, anxiety, or post-traumatic stress disorder (PTSD); Odds Ratio 4.42, 95% CI 2.30 to 8.49) diagnosed before AED treatment. Increased suicide-related behaviors were not associated with individual AEDs, including the most commonly prescribed AED in the US - phenytoin. Our extensive diagnostic and treatment data demonstrated that the strongest predictor of suicide-related behaviors for older patients newly treated with AED monotherapy was a previous diagnosis of affective disorder. Additional, research using a larger sample is needed to clearly determine the risk of suicide-related behaviors among less commonly used AEDs.


Changing epidemiology of gastroesophageal reflux disease in the Asian-Pacific region: an overview.
Gastroesophageal reflux disease (GERD) is a common disease in the West, which now appears to be also increasing in prevalence in the Asian Pacific region. The reasons for this changing epidemiology are two-fold: an increased awareness among doctors and patients, and/or a true increase in the prevalence of the disease. Prevalence rates of reflux esophagitis (RE) of up to 16% and prevalence of GERD symptoms of up to 9% have been reported in the Asian population. However, the frequency of strictures and Barrett's esophagus remain very low. Non-erosive reflux disease (NERD) appears to be the most common form of GERD among Asian patients accounting for 50-70% of cases with GERD. Among Asian patients differences can also be discerned among different ethnic groups. For example, in Malaysia where a multiracial society exists, RE is significantly more common among Indians compared to Chinese and Malays whereas NERD is more frequently seen in the Indian and Malays compared to the Chinese. The reasons for these differences are not known but may indicate both genetic factors and environmental factors peculiar to the particular racial group. GERD has also been increasing in the region demonstrating a time-lag phenomenon compared to the West. Differing predisposition to GERD among different ethnic groups would mean that such an increase would be more prominent among certain racial groups.


Lineage relationships, homeostasis, and recall capacities of central- and effector-memory CD8 T cells in vivo.
The lineage relationships of central-memory T cells (T(CM)) cells and effector-memory T cells (T(EM)), as well as their homeostasis and recall capacities, are still controversial. We investigated these issues in a murine model using two complementary approaches: T cell receptor repertoire analysis and adoptive transfer experiments of purified H-Y-specific T(CM) and T(EM) populations. Repertoire studies showed that approximately two thirds of T(CM) and T(EM) clones derived from a common naive precursor, whereas the other third was distinct. Both approaches highlighted that T(CM) and T(EM) had drastically distinct behaviors in vivo, both in the absence of antigen or upon restimulation. T(CM) clones were stable in the absence of restimulation and mounted a potent and sustained recall response upon secondary challenge, giving rise to both T(CM) and T(EM), although only a fraction of T(CM) generated T(EM). In contrast, T(EM) persisted for only a short time in the absence of antigen and, although a fraction of them were able to express CD62L, they were unable to mount a proliferative response upon secondary challenge in this model.


Photoinduced bimolecular electron transfer investigated by femtosecond time-resolved infrared spectroscopy.
Ultrafast infrared transient absorption spectroscopy is used to study the photoinduced bimolecular electron transfer reaction between perylene in the first singlet excited state and 1,4-dicyanobenzene in acetonitrile and dichloromethane. Following vibrational marker modes on both donor and acceptor sides in real time provides direct insight into the structural dynamics during the reaction. A band narrowing on a time scale of a few tens of picoseconds observed on the antisymmetric CN stretching vibration of the dicyanobenzene radical anion indicates that a substantial part of the excess energy is channeled into vibrational modes of the product, despite the fact that the reaction is weakly exergonic. An additional narrowing of the same band on a time scale of several hundreds of picoseconds observed in acetonitrile only is interpreted as a signature of the dissociation of the geminate ion pairs into free ions.


The OMERACT core set of outcome measures for use in clinical trials of ANCA-associated vasculitis.
There has been a marked increase in the past 15 years in the number and quality of clinical trials in the idiopathic inflammatory vasculitides, especially the small-vessel vasculitides known as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis [AAV; granulomatosis, with polyangiitis (Wegener's)]. These trials have been conducted by multicenter, international groups in Europe and the United States with financial support provided by government agencies and biopharmaceutical companies. This increased clinical trial activity in vasculitis has been accompanied by the development and validation of new outcome measures--a challenging process for these complex, multiorgan system diseases. The international OMERACT Vasculitis Working Group has developed and implemented an iterative research agenda that has utilized accumulated experience and datasets from several multicenter clinical trials and large cohort studies. This work has led to the development, evaluation, validation, and endorsement, through the OMERACT consensus and validation processes, of a "core set" of outcome measurements for use in clinical trials of AAV. The core set includes domains of disease activity, damage assessment, patient-reported outcomes, and mortality; there is at least one validated outcome measurement instrument available for each domain. This report reviews the domains of illness in AAV included in the OMERACT core set, describes the instruments validated to measure these domains, and presents the approved core set.


Dietary cholesterol modulates pathogen blocking by Wolbachia.
The bacterial endosymbiont Wolbachia pipientis protects its hosts from a range of pathogens by limiting their ability to form infections inside the insect. This "pathogen blocking" could be explained by innate immune priming by the symbiont, competition for host-derived resources between pathogens and Wolbachia, or the direct modification of the cell or cellular environment by Wolbachia. Recent comparative work in Drosophila and the mosquito Aedes aegypti has shown that an immune response is not required for pathogen blocking, implying that there must be an additional component to the mechanism. Here we have examined the involvement of cholesterol in pathogen blocking using a system of dietary manipulation in Drosophila melanogaster in combination with challenge by Drosophila C virus (DCV), a common fly pathogen. We observed that flies reared on cholesterol-enriched diets infected with the Wolbachia strains wMelPop and wMelCS exhibited reduced pathogen blocking, with viral-induced mortality occurring 2-5 days earlier than flies reared on Standard diet. This shift toward greater virulence in the presence of cholesterol also corresponded to higher viral copy numbers in the host. Interestingly, an increase in dietary cholesterol did not have an effect on Wolbachia density except in one case, but this did not directly affect the strength of pathogen blocking. Our results indicate that host cholesterol levels are involved with the ability of Wolbachia-infected flies to resist DCV infections, suggesting that cholesterol contributes to the underlying mechanism of pathogen blocking.


Bayesian evaluation of constrained hypotheses on variances of multiple independent groups.
Research has shown that independent groups often differ not only in their means, but also in their variances. Comparing and testing variances is therefore of crucial importance to understand the effect of a grouping variable on an outcome variable. Researchers may have specific expectations concerning the relations between the variances of multiple groups. Such expectations can be translated into hypotheses with inequality and/or equality constraints on the group variances. Currently, however, no methods are available for testing (in)equality constrained hypotheses on variances. This article proposes a novel Bayesian approach to this challenging testing problem. Our approach has the following useful properties: First, it can be used to simultaneously test multiple (non)nested hypotheses with equality as well as inequality constraints on the variances. Second, our approach is fully automatic in the sense that no subjective prior specification is needed. Only the hypotheses need to be provided. Third, a user-friendly software application is included that can be used to perform this Bayesian test in an easy manner. (PsycINFO Database Record


Secondary bronchiolitis obliterans organising pneumonia in a patient with carbamazepine-induced hypogammaglobulinaemia.
Here we describe a case of a secondary bronchiolitis obliterans organizing pneumonia (BOOP), which was associated with repeated respiratory infections caused by carbamazepine (CBZ)- induced hypogammaglobulinaemia. A 49-year-old woman had been treated with CBZ (400 mg/day). Two and a half years later, she developed of dyspnea with productive cough and high-grade fever. Chest roentgenogram and computed tomography showed bilateral infiltrates in lower lung fields. Her laboratory findings revealed severe hypogammaglobulinaemia, suggesting that an immune system disorder caused pulmonary infection. Histological examination by trans-bronchial lung biopsy (TBLB) demonstrated that many foamed alveolar macrophages were obstructing the alveolar ducts and adjacent alveoli, suggesting BOOP. After cessation of CBZ, the hypogammaglobulinaemia and chest roentgenogram findings markedly improved. The present case suggests that CBZ may have some adverse effects on the immune system and cause frequent airway infections, and that secondary BOOP could be induced by repeated infections caused by CBZ-induced hypogammaglobulinaemia.


Examiner differences in the mini-CEX.
The objective of this study was to analyze whether faculty ratings of residents, using the mini-CEX oral exam format, differed in stringency or were influenced by the clinical setting. It also sought to learn whether the examiners were satisfied with the format. A mini-CEX encounter consisted of a single faculty member observing a resident conduct a focused history and physical examination in an inpatient, outpatient, or emergency room setting. After asking the resident for a diagnosis and treatment plan, the faculty member rated the resident and provided educational feedback. The encounters were intended to be short and occur as a routine part of the training, so each resident would be evaluated on many occasions by different faculty. Sixty-four attending physicians evaluated residents from five internal medicine training programs; data were analyzed for 355 mini-CEX encounters involving 88 residents. There were not large differences among the examiners in their ratings. Moreover, there were not great differences among the ratings in terms of the training program with which the examiner was associated, the setting of the mini-CEX, or the nature of the patient. The examiners were generally satisfied with the format and their level of satisfaction was correlated with the residents' perceptions of the format. The mini-CEX adapts itself to a broad range of clinical situations, and these results show that it should produce roughly comparable scores over examiners and settings. This makes it a worthwhile device for evaluation at the local level.


Insights into the cell of origin in breast cancer and breast cancer stem cells.
The precise cell types that give rise to tumors and mechanisms that underpin tumor heterogeneity are poorly understood. There is increasing evidence to suggest that diverse solid tumors are hierarchically organized and may be sustained by a distinct subpopulation of cancer stem cells (CSCs). The CSC hypothesis provides an attractive cellular mechanism that can account for the therapeutic refractoriness and dormant behavior exhibited by many tumor types. Breast cancer was the first solid malignancy from which CSCs were identified and isolated. Direct evidence for the CSC hypothesis has also recently emerged from mouse models of mammary tumorigenesis, although alternative models to explain heterogeneity also seem to apply. Our group has found that the luminal epithelial progenitor marker CD61/beta3 integrin identified a CSC population in mammary tumors from MMTV-wnt-1 mice. However, no CSCs could be identified in the more homogeneous MMTV-neu/erbB2 model, suggesting an alternate (clonal evolution or stochastic) model of tumorigenesis. It seems likely that both paradigms of tumor propagation exist in human cancer. From a clinical perspective, the CSC concept has significant implications. Quiescent CSCs are thought to be more resistant to chemotherapy and targeted therapy. Enrichment of putative CSCs has been noted in studies of chemotherapy-treated patients, lending support to the CSC hypothesis and their potential role in chemoresistance. Although many unresolved questions on CSCs remain, ongoing efforts to identify and characterize CSCs continue to be an important area of investigation, with the potential to identify novel tumor targeting strategies.


Multiple sclerosis and nutrition.
Benefits from any particular diet in multiple sclerosis (MS) have not yet been proven. It is, however, frequent that malnutrition may potentially exacerbate the symptoms of MS. There is some evidence that a high intake of saturated fat increases the incidence of MS. Epidemiological studies imply that unsaturated fatty acids may have a positive effect on the course of MS. However, the results of controlled studies are ambiguous. A meta-analysis of three small controlled clinical trials suggests a benefit from linoleic acid. Intake of Vitamin D is associated with a lower incidence of MS. In MS, the risk of osteoporosis is high, and prophylactic vitamin D and calcium should be considered at an early stage. The role of minerals, trace elements, antioxidants, vitamins or fish oil is unclear. The possible relationships between diet and MS have not been subjected to adequate study. It seems possible that in the future, diets or dietary supplements may become recommended forms of treatment for MS.


Pretreatment of ferulic acid attenuates inflammation and oxidative stress in a rat model of lipopolysaccharide-induced acute respiratory distress syndrome.
Acute respiratory distress syndrome (ARDS) is a fatal clinical condition that can be caused by pulmonary and non-pulmonary diseases. Oxidative stress and inflammation play key roles in the development of ARDS. In this study, we investigated whether ferulic acid (FA), an anti-oxidant, was beneficial for prophylaxis of ARDS. We established an ARDS rat model using lipopolysaccharide (LPS) administration. Lung injury was assessed by lung wet/dry ratio and broncho-alveolar lavage fluid (BALF) analysis. Hematoxylin and eosin staining was performed to evaluate the histological changes of the lungs. Enzyme-linked immunosorbent assay (ELISA) and immunoblotting were performed to detect proteins in BALF and lung tissue, respectively. Pulmonary function was determined by testing the oxygen level in BALF. FA pretreatment significantly alleviated LPS-induced pulmonary histological changes. FA reversed LPS-induced changes of lung wet/dry ratio, total protein in BALF, P(A-a)O2, and PaO2/FiO2. In addition, LPS dramatically up-regulated the secretion of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-10 in BALF ( P < 0.01). However, pretreatment of FA significantly improved LPS-induced inflammation. We found that FA indeed reduced oxidative stress in the lungs by testing malondialdehyde level, myeloperoxidase level, and total anti-oxidant capacity. We also proved that FA inactivated multiple mitogen-activated protein kinase signaling pathways in the lungs. In conclusion, FA alleviated LPS-induced ARDS through its anti-inflammatory and anti-oxidant activities.


Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human-induced pluripotent stem cells.
Heart failure invariably affects patients with various forms of muscular dystrophy (MD), but the onset and molecular sequelae of altered structure and function resulting from full-length dystrophin (Dp427) deficiency in MD heart tissue are poorly understood. To better understand the role of dystrophin in cardiomyocyte development and the earliest phase of Duchenne muscular dystrophy (DMD) cardiomyopathy, we studied human cardiomyocytes differentiated from induced pluripotent stem cells (hiPSC-CMs) obtained from the urine of a DMD patient. The contractile properties of patient-specific hiPSC-CMs, with no detectable dystrophin (DMD-CMs with a deletion of exon 50), were compared to CMs containing a CRISPR-Cas9 mediated deletion of a single G base at position 263 of the dystrophin gene (c.263delG-CMs) isogenic to the parental line of hiPSC-CMs from a healthy individual. We hypothesized that the absence of a dystrophin-actin linkage would adversely affect myofibril and cardiomyocyte structure and function. Cardiomyocyte maturation was driven by culturing long-term (80-100 days) on a nanopatterned surface, which resulted in hiPSC-CMs with adult-like dimensions and aligned myofibrils. Our data demonstrate that lack of Dp427 results in reduced myofibril contractile tension, slower relaxation kinetics, and to Ca2+ handling abnormalities, similar to DMD cells, suggesting either retarded or altered maturation of cardiomyocyte structures associated with these functions. This study offers new insights into the functional consequences of Dp427 deficiency at an early stage of cardiomyocyte development in both patient-derived and CRISPR-generated models of dystrophin deficiency.


Genome sequence of the thermophilic strain Bacillus coagulans 2-6, an efficient producer of high-optical-purity L-lactic acid.
Bacillus coagulans 2-6 is an efficient producer of lactic acid. The genome of B. coagulans 2-6 has the smallest genome among the members of the genus Bacillus known to date. The frameshift mutation at the start of the d-lactate dehydrogenase sequence might be responsible for the production of high-optical-purity l-lactic acid.


Controlling the pore size in conjugated polymer films via crystallization-driven phase separation.
A wide range of possible applications in sensors and optoelectronic devices have focused considerable attention on porous membranes made of semi-conducting polymers. In this study, porous films of poly(3-hexylthiophene) (P3HT) were conveniently constructed through spin-coating of solutions of a blend of P3HT and polyethylene glycol (PEG). Pores were formed by phase separation driven simultaneously by incompatibility and crystallization. The influence of the polymer concentration (c), molecular weight (Mn) and spin-coating temperature (Tsp) on the pore size and structure was investigated. With increasing c from 0.5 to 5.0 wt%, the pore diameter (d) varied from ≈1.3 μm to ≈38 μm. Similarly, we observed a substantial increase of d with increasing Mn of PEG, while changing Mn of P3HT did not affect d. Micron- and nano-scale pores coexisted in porous P3HT films. While incompatibility of P3HT and PEG caused the formation of nano-pores, micron-scale pores resulted from crystallization in the PEG-rich domains by forcing PEG molecules to diffuse from the surrounding PEG-P3HT blend region to the crystal growth front.


A Comparison of Maize Stalk Rot Occurrence in Bt and Non-Bt Hybrids.
Stalk rots, caused by a complex of fungal species, are among the most widespread and destructive diseases of maize. Larvae of the European corn borer (ECB) (Ostrinia nubilalis) promote stalk rot development by creating entry points for fungi, serving as vectors of pathogens, and causing physiological stress that may predispose plants to stalk decay. Field experiments were conducted in 1998, 1999, and 2000 to determine whether the use of transgenic Bt hybrids expressing insecticidal proteins would influence stalk rot symptoms (pith disintegration, pith discoloration, and lodging). Five hybrids representing different Bt types (or "Bt events") (176, BT11, MON810, DBT418, and CBH351) were paired with their near-isogenic, non-Bt counterparts and subjected to treatments of manual and natural infestation with ECB larvae. Manual infestation resulted in significantly more ECB tunneling than natural infestation in 1998 and 1999 and significantly more lodging in 1998. There were significant linear correlations between ECB injury and stalk rot symptoms in non-Bt hybrids in 1998 and 1999, but not in 2000. A standard foliar insecticide treatment for ECB did not significantly affect stalk rot symptoms. In 1998, Bt hybrids had significantly less ECB tunneling, stalk discoloration, pith disintegration, and lodging compared with non-Bt hybrids, but these effects depended upon the Bt event and the infestation treatment. Similar but less pronounced effects of Bt events were observed in 1999. The 2000 results were more variable; the amount of pith disintegration was significantly lower but discoloration was significantly higher in the BT11 hybrid compared with its non-Bt counterpart, and the amount of lodging was significantly higher in the event 176 hybrid compared with its non-Bt counterpart. The ratio of stalk strength to grain weight did not consistently differ between Bt and non-Bt hybrids. These results indicate that, although specific Bt events in some years may cause reductions in stalk rot, the overall effect of Bt transformation on stalk rot occurrence is highly variable.


Complex architecture of primes and natural numbers.
Natural numbers can be divided in two nonoverlapping infinite sets, primes and composites, with composites factorizing into primes. Despite their apparent simplicity, the elucidation of the architecture of natural numbers with primes as building blocks remains elusive. Here, we propose a new approach to decoding the architecture of natural numbers based on complex networks and stochastic processes theory. We introduce a parameter-free non-Markovian dynamical model that naturally generates random primes and their relation with composite numbers with remarkable accuracy. Our model satisfies the prime number theorem as an emerging property and a refined version of Cramér's conjecture about the statistics of gaps between consecutive primes that seems closer to reality than the original Cramér's version. Regarding composites, the model helps us to derive the prime factors counting function, giving the probability of distinct prime factors for any integer. Probabilistic models like ours can help to get deeper insights about primes and the complex architecture of natural numbers.


SU-E-T-08: Simple Governing Equations for Tumor Growth.
To derive a set of simple differential equations, which can represent temporal growth of typical tumors, by taking into account the effects of the tumor microenvironment on cell proliferation. Cause-effect relationships between cell proliferation and nutrients contained in blood stream, which included oxygen and glucose, were modeled. By formulating a set of rate equations and simplifying those, we finally obtained two differential equations. One equation represents the change of the tumor mass and included time-varying growth rate, which was a solution of another equation relating the growth rate with the blood volume in the tumor. The set of differential equations were numerically solved by varying a parameter, kappa, which represented the growth rate of the blood volume relative to the tumor mass. Through numerical experiments we showed that the tumor volume increased exponentially if the blood volume increased at the same rate as the tumor. However, the blood volume did not increase rapidly enough as the tumor grew, the tumor showed the saturation in the growth when the tumor grew by 1000-fold. Such a retardation of tumor growth was experimentally observed and the function representing the growth curve is called as Gompertz equation. One of solutions also showed that the tumor stopped growing when the blood supply was shut off (or kappa = 0). A solution of simple differential equations derived in this study could reproduce the tumor growth which can be represented by the well known Gompertz equation. Using these equations we were able to theoretically show that the saturation of tumor growth observed often for larger tumors could be explained by a relative lack of blood supply which leads to a decrease in the cell proliferation rate. In a future study the effects of radiation on the tumor growth will be included in the model.


Multi-Domain Touchscreen-Based Cognitive Assessment of C57BL/6J Female Mice Shows Whole-Body Exposure to 56Fe Particle Space Radiation in Maturity Improves Discrimination Learning Yet Impairs Stimulus-Response Rule-Based Habit Learning.
Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Most preclinical studies with mature, "astronaut-aged" rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As there are conflicting results on whether the female rodent brain is preferentially injured by or resistant to charged particle exposure, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to fractionated whole-body 56Fe irradiation (3 × 6.7cGy 56Fe over 5 days, 600 MeV/n) would improve performance vs. Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function [e.g., location discrimination reversal (LDR) and extinction, respectively]. In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal stimulus-response rule-based habit learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASA's risk assessments from being based on a single cognitive domain.


The brain as a complex network: assessment of EEG-based functional connectivity patterns in patients with childhood absence epilepsy.
The human brain is increasingly seen as a dynamic neural system, the function of which relies on a diverse set of connections between brain regions. To assess these complex dynamical interactions, formalism of complex networks was suggested as one of the most promising tools to offer new insight into the brain's structural and functional organization, with a potential also for clinical implications. Irrespective of the brain mapping technique, modern network approaches have revealed fundamental aspects of normal brain-network organization, such as small-world and scale-free patterns, hierarchical modularity, and the presence of hubs. Moreover, the utility of these approaches, to gain a better understanding of neurological diseases, is of great interest. In the present contribution, we first describe the basic network measures and how the brain networks are constructed on the basis of brain activity data in order to introduce clinical neurologists to this new theoretical paradigm. We then demonstrate how network formalism can be used to detect changes in EEG-based functional connectivity patterns in six paediatric patients with childhood absence epilepsy. Notably, our results do not only indicate enhanced synchronicity during epileptic episodes but also reveal specific spatial changes in the electrical activity of the brain. We argue that the network-based evaluation of functional brain networks can provide clinicians with more detailed insight into the activity of a pathological brain and can also be regarded as a support for objective diagnosis and treatment for various neurological diseases.


Clinical uses of intravenous immunoglobulins.
To ascertain the activity of intravenous immunoglobulin in a wide range of diseases. English-language literature search using MEDLINE (1982 to 89), review of meeting reports, and extensive hand searching of bibliographies of identified articles. All identified articles. Study quality and specific descriptive information concerning population, intervention, and outcome measurements were assessed. There have been few controlled, randomized trials of intravenous immunoglobulin. Available data suggest efficacy in persons with primary immune deficiency, premature infants at risk for group B streptococcus infection, patients with Kawasaki disease, transplant recipients at risk for cytomegalovirus infection, patients with idiopathic thrombocytopenic purpura, and selected patients with chronic lymphocytic leukemia. Data are also favorable concerning the use of intravenous immunoglobulin in some other autoimmune disorders, but randomized trials are needed. Interesting areas for future study include the acquired immunodeficiency syndrome (AIDS), multiple myeloma, and lymphomas. Risks of intravenous immunoglobulin are minimal. Intravenous immunoglobulin is safe and effective in treating several human diseases. Additional randomized trials are needed.


Predicate-Based Focus-and-Context Visualization for 3D Ultrasound.
Direct volume visualization techniques offer powerful insight into volumetric medical images and are part of the clinical routine for many applications. Up to now, however, their use is mostly limited to tomographic imaging modalities such as CT or MRI. With very few exceptions, such as fetal ultrasound, classic volume rendering using one-dimensional intensity-based transfer functions fails to yield satisfying results in case of ultrasound volumes. This is particularly due its gradient-like nature, a high amount of noise and speckle, and the fact that individual tissue types are rather characterized by a similar texture than by similar intensity values. Therefore, clinicians still prefer to look at 2D slices extracted from the ultrasound volume. In this work, we present an entirely novel approach to the classification and compositing stage of the volume rendering pipeline, specifically designed for use with ultrasonic images. We introduce point predicates as a generic formulation for integrating the evaluation of not only low-level information like local intensity or gradient, but also of high-level information, such as non-local image features or even anatomical models. Thus, we can successfully filter clinically relevant from non-relevant information. In order to effectively reduce the potentially high dimensionality of the predicate configuration space, we propose the predicate histogram as an intuitive user interface. This is augmented by a scribble technique to provide a comfortable metaphor for selecting predicates of interest. Assigning importance factors to the predicates allows for focus-and-context visualization that ensures to always show important (focus) regions of the data while maintaining as much context information as possible. Our method naturally integrates into standard ray casting algorithms and yields superior results in comparison to traditional methods in terms of visualizing a specific target anatomy in ultrasound volumes.


An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer's and Lewy body pathology.
The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies. A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3'UTR SNP rs356165 on the burden of AD and LB pathology were assessed. Neurofibrillary tangles (NFTs) were counted in four brain regions, senile plaques in five and LBs in four. Braak NFT stage, brain weight and presence of vascular pathology were also documented. MAPT H1 associated with lower counts of NFTs in the middle frontal (p<0.001) and inferior parietal (p=0.005) cortices, and also with lower counts of senile plaques in the motor cortex (p=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (p=0.011) and inferior parietal cortex (p=0.033) were observed but were not significant after multiple testing adjustment. The APOE ε4 allele was strongly associated with overall Alzheimer type pathology (all p≤0.001). SNCA rs356165 and the MAPT H1 specific SNP rs242557 did not associate with AD or LB pathology. This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology which could have important implications for the understanding of disease mechanisms and their genetic determinants.


[Secrets of the Mediterranean diet].
Mediterranean diet is a modern nutritional model inspired by the traditional dietary pattern of some of the countries of the Mediterranean basin. At least 16 countries border the Mediterranean Sea. Diets vary between these countries and also between regions within a country. Many differences in culture, ethnic background, religion, economy and agricultural productions result in different diets. But the common Mediterranean dietary pattern has these characteristics: high consumption of fruits, vegetables, bread and other cereals, potatoes, beans, nuts and seeds, olive oil is an important monounsaturated fat source, dairy products, fish and poultry are consumed in low to moderate amounts, and relatively small amounts of red meat is eaten, eggs are consumed zero to four times a week and wine is consumed in low to moderate amounts. A recent study has once again confirmed that people who closely follow 'the Mediterranean Diet' live longer than other Europeans and Americans and the incidence of heart disease in Mediterranean countries is lower than in the United States. But this may not be entirely due only to the diet. Lifestyle factors (such as more physical activity and extended social support systems) may also play a part.


Immune intervention in children with type 1 diabetes.
Not only T cells but also B cells play a role in the autoimmune process. Both monoclonal antiCD3 and antiCD20 antibodies seem efficacious. However, such treatments need to be refined to minimize adverse events. Use of autoantigens to create tolerance is a concept with great potential. GAD65 treatment has shown efficacy without adverse events thus far, and administration of the insulin B chain shows interesting immunologic effects. Other more or less speculative approaches to modulate the immune process need further studies with good design. Risks that are too serious cannot be motivated. In addition, as the beta cells may die even though the autoimmune process is stopped, protective measures may be valuable (eg, active insulin treatment, and perhaps interleukin-1 receptor antagonists to reduce the nonautoimmune inflammation). Combination of immune intervention, protection of the beta cells, and stimulation of regeneration may lead to a milder disease or even a cure in the future, and prevention is no longer unrealistic.


Different Machine Learning and Deep Learning Methods for the Classification of Colorectal Cancer Lymph Node Metastasis Images.
The classification of colorectal cancer (CRC) lymph node metastasis (LNM) is a vital clinical issue related to recurrence and design of treatment plans. However, it remains unclear which method is effective in automatically classifying CRC LNM. Hence, this study compared the performance of existing classification methods, i.e., machine learning, deep learning, and deep transfer learning, to identify the most effective method. A total of 3,364 samples (1,646 positive and 1,718 negative) from Harbin Medical University Cancer Hospital were collected. All patches were manually segmented by experienced radiologists, and the image size was based on the lesion to be intercepted. Two classes of global features and one class of local features were extracted from the patches. These features were used in eight machine learning algorithms, while the other models used raw data. Experiment results showed that deep transfer learning was the most effective method with an accuracy of 0.7583 and an area under the curve of 0.7941. Furthermore, to improve the interpretability of the results from the deep learning and deep transfer learning models, the classification heat-map features were used, which displayed the region of feature extraction by superposing with raw data. The research findings are expected to promote the use of effective methods in CRC LNM detection and hence facilitate the design of proper treatment plans.


Dynamic metabolomics differentiates between carbon and energy starvation in recombinant Saccharomyces cerevisiae fermenting xylose.
The concerted effects of changes in gene expression due to changes in the environment are ultimately reflected in the metabolome. Dynamics of metabolite concentrations under a certain condition can therefore give a description of the cellular state with a high degree of functional information. We used this potential to evaluate the metabolic status of two recombinant strains of Saccharomyces cerevisiae during anaerobic batch fermentation of a glucose/xylose mixture. Two isogenic strains were studied, differing only in the pathways used for xylose assimilation: the oxidoreductive pathway with xylose reductase (XR) and xylitol dehydrogenase (XDH) or the isomerization pathway with xylose isomerase (XI). The isogenic relationship between the two strains ascertains that the observed responses are a result of the particular xylose pathway and not due to unknown changes in regulatory systems. An increased understanding of the physiological state of these strains is important for further development of efficient pentose-utilizing strains for bioethanol production. Using LC-MS/MS we determined the dynamics in the concentrations of intracellular metabolites in central carbon metabolism, nine amino acids, the purine nucleotides and redox cofactors. The general response to the transition from glucose to xylose was increased concentrations of amino acids and TCA-cycle intermediates, and decreased concentrations of sugar phosphates and redox cofactors. The two strains investigated had significantly different uptake rates of xylose which led to an enhanced response in the XI-strain. Despite the difference in xylose uptake rate, the adenylate energy charge remained high and stable around 0.8 in both strains. In contrast to the adenylate pool, large changes were observed in the guanylate pool. The low uptake of xylose by the XI-strain led to several distinguished responses: depletion of key metabolites in glycolysis and NADPH, a reduced GTP/GDP ratio and accumulation of PEP and aromatic amino acids. These changes are strong indicators of carbon starvation. The XR/XDH-strain displayed few such traits. The coexistence of these traits and a stable adenylate charge indicates that xylose supplies energy to the cells but does not suppress a response similar to carbon starvation. Particular signals may play a role in the latter, of which the GTP/GMP ratio could be a candidate as it decreased significantly in both strains.


Prospective participant selection and ranking to maximize actionable pharmacogenetic variants and discovery in the eMERGE Network.
In an effort to return actionable results from variant data to electronic health records (EHRs), participants in the Electronic Medical Records and Genomics (eMERGE) Network are being sequenced with the targeted Pharmacogenomics Research Network sequence platform (PGRNseq). This cost-effective, highly-scalable, and highly-accurate platform was created to explore rare variation in 84 key pharmacogenetic genes with strong drug phenotype associations. To return Clinical Laboratory Improvement Amendments (CLIA) results to our participants at the Group Health Cooperative, we sequenced the DNA of 900 participants (61 % female) with non-CLIA biobanked samples. We then selected 450 of those to be re-consented, to redraw blood, and ultimately to validate CLIA variants in anticipation of returning the results to the participant and EHR. These 450 were selected using an algorithm we designed to harness data from self-reported race, diagnosis and procedure codes, medical notes, laboratory results, and variant-level bioinformatics to ensure selection of an informative sample. We annotated the multi-sample variant call format by a combination of SeattleSeq and SnpEff tools, with additional custom variables including evidence from ClinVar, OMIM, HGMD, and prior clinical associations. We focused our analyses on 27 actionable genes, largely driven by the Clinical Pharmacogenetics Implementation Consortium. We derived a ranking system based on the total number of coding variants per participant (75.2±14.7), and the number of coding variants with high or moderate impact (11.5±3.9). Notably, we identified 11 stop-gained (1 %) and 519 missense (20 %) variants out of a total of 1785 in these 27 genes. Finally, we prioritized variants to be returned to the EHR with prior clinical evidence of pathogenicity or annotated as stop-gain for the following genes: CACNA1S and RYR1 (malignant hyperthermia); SCN5A, KCNH2, and RYR2 (arrhythmia); and LDLR (high cholesterol). The incorporation of genetics into the EHR for clinical decision support is a complex undertaking for many reasons including lack of prior consent for return of results, lack of biospecimens collected in a CLIA environment, and EHR integration. Our study design accounts for these hurdles and is an example of a pilot system that can be utilized before expanding to an entire health system.


Stroke outcomes in a socio-economically disadvantaged urban community.
To determine survival, disability and functional outcomes of stroke patients following their discharge from an acute stroke unit in an urban community with limited rehabilitative resources. Stroke patients were recruited from a district hospital in Cape Town and followed-up for 6 months. Clinical characteristics, demographic and socioeconomic data, and disability and function as measured by modified Rankin Score (mRS), modified Barthel Index (mBI) at recruitment and 3 follow-up visits, were recorded. The study included 196 patients. Median age was 60 (IQR 51-69) years, 135 (68.9%) were female, 57.7% black, 42.3% coloured, and 45 (23%) died within 6 months. At discharge, median mBI score was 7 (IQR 3-12) and median mRS 4 (IQR 3-5). In the multivariate regression models, only function (mBI OR 0.88, 95% confidence interval (CI) 0.79-0.96, p < 0.0001) and disability (mRS OR 2.34, 95%CI 1.20-4.54, p < 0.0001) were independently associated with risk of death. Shack housing was independently associated with moderate or severe disability (odds ratio 3.42, 95% CI 1.22-9.59, p = 0.02). Despite limited rehabilitation resources, 67% of survivors had mild to moderate disability at 6 months. Apart from initial stroke severity, risk factors for poor survival were a severe disability category and the presence of impaired swallowing at discharge. Shack housing was independently associated with poor functional outcomes. These findings should be helpful in allocating home-based care and inpatient rehabilitation resources to high-risk groups to improve outcomes.


Ecosystem sentinels for climate change? Evidence of wetland cover changes over the last 30 years in the tropical Andes.
While the impacts of climate change on individual species and communities have been well documented there is little evidence on climate-mediated changes for entire ecosystems. Pristine alpine environments can provide unique insights into natural, physical and ecological response to climate change yet broad scale and long-term studies on these potential 'ecosystem sentinels' are scarce. We addressed this issue by examining cover changes of 1689 high-elevation wetlands (temporarily or perennial water-saturated grounds) in the Bolivian Cordillera Real, a region that has experienced significant warming and glacier melting over the last 30 years. We combined high spatial resolution satellite images from PLEIADES with the long-term images archive from LANDSAT to 1) examine environmental factors (e.g., glacier cover, wetland and watershed size) that affected wetland cover changes, and 2) identify wetlands' features that affect their vulnerability (using habitat drying as a proxy) in the face of climate change. Over the (1984-2011) period, our data showed an increasing trend in the mean wetland total area and number, mainly related to the appearance of wet grassland patches during the wetter years. Wetland cover also showed high inter-annual variability and their area for a given year was positively correlated to precipitation intensities in the three months prior to the image date. Also, round wetlands located in highly glacierized catchments were less prone to drying, while relatively small wetlands with irregularly shaped contours suffered the highest rates of drying over the last three decades. High Andean wetlands can therefore be considered as ecosystem sentinels for climate change, as they seem sensitive to glacier melting. Beyond the specific focus of this study, our work illustrates how satellite-based monitoring of ecosystem sentinels can help filling the lack of information on the ecological consequences of current and changing climate conditions, a common and crucial issue especially in less-developed countries.


Paleoanthropology. Late Pliocene fossiliferous sedimentary record and the environmental context of early Homo from Afar, Ethiopia.
Sedimentary basins in eastern Africa preserve a record of continental rifting and contain important fossil assemblages for interpreting hominin evolution. However, the record of hominin evolution between 3 and 2.5 million years ago (Ma) is poorly documented in surface outcrops, particularly in Afar, Ethiopia. Here we present the discovery of a 2.84- to 2.58-million-year-old fossil and hominin-bearing sediments in the Ledi-Geraru research area of Afar, Ethiopia, that have produced the earliest record of the genus Homo. Vertebrate fossils record a faunal turnover indicative of more open and probably arid habitats than those reconstructed earlier in this region, which is in broad agreement with hypotheses addressing the role of environmental forcing in hominin evolution at this time. Geological analyses constrain depositional and structural models of Afar and date the LD 350-1 Homo mandible to 2.80 to 2.75 Ma.


Conversion in ASIA impairment scale during the first year after traumatic spinal cord injury.
The neurological severity of a spinal cord injury (SCI) is commonly classified according to the American Spinal Injury Association (ASIA) Impairment Scale (AIS). The aim of this study was to assess the course of the AIS following SCI, and to discern the nature of any changes in the classification that occur. Assessments were performed in a European cohort of SCI patients within 2 weeks and at 1, 3, 6, and 12 months after the initial injury. Overall, about 70% of the patients initially diagnosed as AIS A did not convert, as did 90% of the AIS D patients. When only evaluating patients with complete datasets, 68% did not convert, while the AIS category improved in 30% of patients and deteriorated in 2%. A change in the last sacral segments (40%), motor improvement (31%), sensory improvement (19%), and a change in the neurological level of the SCI (10%) contributed to or accompanied the AIS conversion. When the AIS remained unchanged between successive assessment points, there was no change in the number of muscles graded three or more (NMG3(+)) in 73% of the transitions. An improvement in AIS was associated with a gain in NMG3(+) in 49% of the transitions, while an aggravation in AIS was accompanied by a loss in NMG3(+) in 10% of the transitions. These results, documenting a substantial amount of spontaneous AIS conversions, should be taken into consideration when designing clinical trials to assess the effects of potential new treatments for SCI.


[Evaluation of condylar fractures treatment].
We analysed 40 patients with mandibular condylar process fractures, treated through the closed (intermaxilary fixation or conservatively) or open methods (wire internal fixation,titanium miniplates, bone reduction or articular exploration), from January 1993 to January 1999. We evaluated these patients clinically with pre-determined criteria through the temporomandibular articulation touching (ATM), by observing the mandibular symmetry, dental oclusion, deviation to the mouth opening and maximum interincisal opening, besides the questionnaire about the complaints at ATM, disfunction of the mastication system and satisfaction of the treatment. We found an index of good clinical results of, at least, 70% (in the maximum interincisal opening) in the patients submitted to IMF. In the conservative method, we found an index of, at least, 42.9% and in the patients submitted to wire open reduction, at least, 28.6% (in the ATM touching exam) without significant difference in the clinical exams; the pain index at ATM in the closed method was 3.7% and in the open one was 15.4%; mastication disfunction was 22.2% in the closed method and 15.4% in the open one; we only found 7.1% dissatisfied patients in the closed method. There was no significant difference in the method results. The closed method - with IMF and conservative - and the open reduction - with ORIF - brought good clinical results in an evaluation up to 6 months. We could also conclude that there is no difference in the complaint results after the open or closed treatment according to the patients' opinion.


Forward versus backward walking: transfer of podokinetic adaptation.
We asked whether podokinetic adaptation to walking on a circular treadmill transfers to different forms of locomotion. Subjects were blindfolded and asked to walk straight across the floor, in the forward and backward directions, following podokinetic (PK) stimulation that consisted of 30 min of forward walking-in-place on the perimeter of a disk rotating in the clockwise direction. During both forward and backward walking following forward-walking PK stimulation, subjects involuntarily walked along curved trajectories at angular velocities well above vestibular threshold, although they perceived that they were walking along straight paths. The curved paths of forward and backward walking were indistinguishable from one another. Transfer of PK adaptations acquired during forward walking on the turntable to backward walking trials suggests that the PK system controls general locomotor trajectory. Adaptation of the system thus influences forms of locomotion other than that used during acquisition of the adaptation. This transfer also supports the concept that forward and backward walking are controlled by neural networks that share common elements. An interesting feature of the transfer of PK adaptation is that for both forward and backward walking, subjects turned in a counterclockwise direction. As such, the direction of relative rotation between the trunk and feet was maintained for both forward and backward walking. However, the relationship of the lower extremities to the center of rotation was not preserved. The left limb was the inner leg during PK stimulation and forward walking after adaptation, but the left leg was the outer leg during backward walking. These results suggest that PK adaptation affects general locomotor trajectory via a remodeling of the rotational relationship between the trunk and the feet.