Targeting Vesicular Glutamate Transporter Machinery: Implications on Metabotropic Glutamate Receptor 5 Signaling and Behavior.
Cross talk between both pre- and postsynaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions, including synaptic plasticity and motor planning. Metabotropic glutamate receptor (mGluR) 5 exhibits promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders as a consequence of its modulatory control over diverse neuronal networks required for memory, motor coordination, neuronal survival, and differentiation. Given these crucial roles, mGluR5 signaling is under the tight control of glutamate release machinery mediated through vesicular glutamate transporters (VGLUTs) that ultimately dictate glutamatergic output. A particular VGLUT isoform, VGLUT3, exhibits an overlapping, but unique, distribution with mGluR5, and the dynamic cross talk between mGluR5 and VGLUT3 is key for the function of specific neuronal networks involved in motor coordination, emotions, and cognition. Thus, aberrant signaling of the VGLUT3-mGluR5 axis is linked to various pathologies including, but not limited to, Parkinson disease, anxiety disorders, and drug addiction. We argue that a comprehensive profiling of how coordinated VGLUT3-mGluR5 signaling influences overall glutamatergic neurotransmission is warranted. SIGNIFICANCE STATEMENT: Vesicular glutamate receptor (VGLUT) 3 machinery orchestrates glutamate release, and its distribution overlaps with metabotropic glutamate receptor (mGluR) 5 in regional brain circuitries, including striatum, hippocampus, and raphe nucleus. Therefore, VGLUT3-mGluR5 cross talk can significantly influence both physiologic and pathophysiologic glutamatergic neurotransmission. Pathological signaling of the VGLUT3-mGluR5 axis is linked to Parkinson disease, anxiety disorders, and drug addiction. However, it is also predicted to contribute to other motor and cognitive disorders.


Olfactory cue mediated neonatal recognition in sheep, Ovis aries.
The strong bond between ewe and lamb formed shortly after parturition is an important factor in lamb survival. Evidence exists that a ewe can distinguish her lamb by its unique smell, but the constituents of such a putative olfactory cue have not yet been identified. We have now identified 133 volatile organic compounds associated with the wool of Döhne Merino lambs that we presume may be involved in neonatal recognition. Quantitative analysis and comparison of odor profiles of the twins of 16 ewes (9.69% sample group) of a flock of 165 twin-bearing ewes revealed that the wool volatiles of twins are qualitatively and quantitatively similar, but differ from those of other twins or non-twin lambs in the flock. The 88 constituents present in at least 20% of the analyzed wool samples were considered as variables for multivariate analysis. A P-value < 0.001 was calculated, indicating that the pairing of twins according to the qualitative and quantitative composition of the wool was significant. Bioassays carried out during the lambing seasons of 2009 and 2010 confirmed the previously established role of lamb odor in ewe-lamb recognition. However, when alien lambs were dressed in jackets sprayed with synthetic mixtures formulated to match the chemical composition of the effluvia of the ewes' own lambs, ewes rejected the aliens. This is possibly because the VOCs were not released in quantitative ratios sufficiently accurate to emulate the odor of the ewes' own lambs.


Macrophysiology for a changing world.
The Millennium Ecosystem Assessment (MA) has identified climate change, habitat destruction, invasive species, overexploitation and pollution as the major drivers of biodiversity loss and sources of concern for human well-being. Understanding how these drivers operate and interact and how they might be mitigated are among the most pressing questions facing humanity. Here, we show how macrophysiology--the investigation of variation in physiological traits over large geographical, temporal and phylogenetic scales--can contribute significantly to answering these questions. We do so by demonstrating, for each of the MA drivers, how a macrophysiological approach can or has helped elucidate the impacts of these drivers and their interactions. Moreover, we illustrate that a large-scale physiological perspective can provide insights into previously unrecognized threats to diversity, such as the erosion of physiological variation and stress tolerance, which are a consequence of the removal of large species and individuals from the biosphere. In so doing we demonstrate that environmental physiologists have much to offer the scientific quest to resolve major environmental problems.


Apical sorting of beta-secretase limits amyloid beta-peptide production.
Polarized cells such as neurons and endothelial cells appear to be involved in two invariant pathological features of Alzheimer's disease pathology, namely the formation of senile plaques and cerebral amyloid angiopathy. This implicates polarized sorting mechanisms in the production and accumulation of amyloid beta-peptide (Abeta). We have now studied polarized sorting of beta-secretase (BACE) in Madin-Darby canine kidney (MDCK) cells. The majority of BACE is sorted to the apical surface of MDCK cells where very little beta-amyloid precursor protein (betaAPP) is observed, because betaAPP undergoes basolateral sorting. Consistent with the usage of similar mechanisms for polarized sorting, BACE was also found to be targeted to axons of hippocampal neurons. The remaining basolaterally sorted BACE competes with the highly polarized basolateral alpha-secretase activity. Therefore, substantial amounts of BACE are targeted away from betaAPP to a non-amyloidogenic compartment, a cellular mechanism that limits Abeta generation. In addition, no alpha-secretase activity was observed on the apical side whereas gamma-secretase activity is observed on the basolateral and the apical side. Consistent with this finding, substantial amounts of Abeta can be produced apically upon missorting of betaAPP to the apical surface. These data demonstrate that Abeta production is limited in polarized cells by differential targeting of BACE and its substrate betaAPP. Moreover, our findings suggest that betaAPP may not be a major physiological substrate of BACE.


Image-based carotid flow reconstruction: a comparison between MRI and ultrasound.
Atherosclerosis is a major cause of morbidity and mortality. Its apparent link with wall shear stress (WSS) has led to considerable interest in the in vivo estimation of WSS. Determining WSS by combining medical images with computational fluid dynamics (CFD) simulations can be performed both with magnetic resonance imaging (MRI) and three-dimensional ultrasound (3DUS). This study compares predicted 3D flow patterns based on black blood MRI and 3DUS. Velocity fields in the carotid arteries of nine subjects have been reconstructed, and the haemodynamic wall parameters WSS, oscillatory shear index (OSI), WSS gradients (WSSG) and angle gradients (WSSAG) were compared between the two imaging techniques. There was a good qualitative agreement between results derived from MRI and 3DUS (average correlation strength above 0.60). The root mean square error between haemodynamic wall parameters was comparable to the range of the expected variability of each imaging technique (WSS: 0.411 N m(-2); OSI: 0.048; temporal WSSG: 150 N s(-1) m(-2); spatial WSSG: 2.29 N m(-3); WSSAG: 87.6 rad m(-1)). In conclusion, MRI and 3DUS are capable of providing haemodynamic parameters when combined with CFD, and the predictions are in most cases qualitatively and quantitatively similar. The relatively high cost of MRI and continuing improvement in ultrasound favour US to MRI for future haemodynamic studies of superficial arteries.


Unique microbial communities persist in individual cystic fibrosis patients throughout a clinical exacerbation.
Cystic fibrosis (CF) is caused by inherited mutations in the cystic fibrosis transmembrane conductance regulator gene and results in a lung environment that is highly conducive to polymicrobial infection. Over a lifetime, decreasing bacterial diversity and the presence of Pseudomonas aeruginosa in the lung are correlated with worsening lung disease. However, to date, no change in community diversity, overall microbial load or individual microbes has been shown to correlate with the onset of an acute exacerbation in CF patients. We followed 17 adult CF patients throughout the course of clinical exacerbation, treatment and recovery, using deep sequencing and quantitative PCR to characterize spontaneously expectorated sputum samples We identified approximately 170 bacterial genera, 12 of which accounted for over 90% of the total bacterial load across all patient samples. Genera abundant in any single patient sample tended to be detectable in most samples. We found that clinical stages could not be distinguished by absolute Pseudomonas aeruginosa load, absolute total bacterial load or the relative abundance of any individual genus detected, or community diversity. Instead, we found that the microbial structure of each patient's sputum microbiome was distinct and resilient to exacerbation and antibiotic treatment. Consistent with previously reported sputum microbiome studies we found that total and relative abundance of genera at the population level were remarkably stable for individual patients regardless of clinical status. Patient-by-patient analysis of diversity and relative abundance of each individual genus revealed a complex microbial landscape and highlighted the difficulty of identifying a universal microbial signature of exacerbation. Overall, at the genus level, we find no evidence of a microbial signature of clinical stage.


Tumor angiogenesis and p53 mutations: prognosis in head and neck cancer.
To assess how p53 gene mutations and microvessel density (MVD) may be used as prognostic markers for the study and management of head and neck squamous cell carcinomas and to investigate putative associations between p53 gene mutations and MVD and the relationship of these factors to tumor response to radiotherapy and/or chemotherapy at 6 weeks. Thirty-nine patients with squamous cell carcinoma of the head and neck, stages I to IV, who were examined at Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill, and its affiliated hospitals between 1993 and 1995 were monitored. Mutations in the p53 gene were identified by microdissection of tumor cells on frozen sections, followed by single-strand conformation polymorphism analysis of the products of polymerase chain reaction amplification of exons 5 to 9. The microvessels were immunostained with monoclonal antibodies to factor VIII and/or CD31. Microvessel counts were done by 2 investigators blinded to each other's counts and to the p53 gene status. Intratumoral or peritumoral microvascular "hot spots" were assessed and counts were done with an ocular grid in 3 x 200 fields of hot spots by each investigator. The mean of the highest values was considered. Statistical analysis was done with the Wilcoxon rank sum test, the log-rank test, and proportional hazard models. Of the 39 patients, 13 had mutations in exons 5 to 9. Mutations in the p53 gene were associated with unfavorable overall (P=.003) and disease-free (P=.02) survival. A strong inverse relationship was seen between MVD and p53 mutations (P=.01). No statistically significant relationship was seen between mean MVD and overall and disease-free survival. The response to therapy differed significantly (P=.03) by p53 mutations, whereas there was no statistical significance with MVD counts. In this study a strong inverse relationship was seen between MVD and p53 mutations. p53 Mutations in exons 5 through 9 were associated with unfavorable survival, whereas MVD showed no association with survival.


Removal of bone plates in patients with maxillofacial trauma: a retrospective study.
The aim of this retrospective study was to assess the incidence of and indication for the removal of bone plates over a 5-year period in patients with maxillofacial trauma who had received treatment at the Oral and Maxillofacial Surgery Unit, Al-Nahda Hospital, Muscat, Oman. The medical records of all patients who underwent removal of bone plates after facial bone trauma were reviewed over a 5-year period (2000 to 2004). Data concerning age and gender distribution, cause of trauma, year of removal, time between insertion and removal, indication for removal, site of removal, and general medical factors were evaluated for each patient. Facial bone fractures in 1,177 cases were diagnosed during the study period, of which 465 cases underwent open reduction and internal fixation using bone plates and screws. In 109 cases bone plates were removed (79 males and 30 females), with an overall removal rate of 23.4%. The most common indication for removal was young age (53.4%) followed by infection (25%). The mandible was the most common site of removal (80%). Most of the plates (86%) that required removal in adults were removed within the first year after insertion. Based on this study, the incidence of bone plate removal was relatively low, and the most common indications for plate removal were young age followed by infection.


Life cycle assessment of introducing an anaerobic digester in a municipal wastewater treatment plant in Spain.
Anaerobic digestion (AD) is being established as a standard technology to recover some of the energy contained in the sludge in wastewater treatment plants (WWTPs) as biogas, allowing an economy in electricity and heating and a decrease in climate gas emission. The purpose of this study was to quantify the contributions to the total environmental impact of the plant using life cycle assessment methodology. In this work, data from real operation during 2012 of a municipal WWTP were utilized as the basis to determine the impact of including AD in the process. The climate change human health was the most important impact category when AD was included in the treatment (Scenario 1), especially due to fossil carbon dioxide emissions. Without AD (Scenario 2), increased emissions of greenhouse gases, mostly derived from the use of electricity, provoked a rise in the climate change categories. Biogas utilization was able to provide 47% of the energy required in the WWTP in Scenario 1. Results obtained make Scenario 1 the better environmental choice by far, mainly due to the use of the digested sludge as fertilizer.


Functions of primate amygdala neurons in economic decisions and social decision simulation.
Long implicated in aversive processing, the amygdala is now recognized as a key component of the brain systems that process rewards. Beyond reward valuation, recent findings from single-neuron recordings in monkeys indicate that primate amygdala neurons also play an important role in decision-making. The reward value signals encoded by amygdala neurons constitute suitable inputs to economic decision processes by being sensitive to reward contingency, relative reward quantity and temporal reward structure. During reward-based decisions, individual amygdala neurons encode both the value inputs and corresponding choice outputs of economic decision processes. The presence of such value-to-choice transitions in single amygdala neurons, together with other well-defined signatures of decision computation, indicate that a decision mechanism may be implemented locally within the primate amygdala. During social observation, specific amygdala neurons spontaneously encode these decision signatures to predict the choices of social partners, suggesting neural simulation of the partner's decision-making. The activity of these 'simulation neurons' could arise naturally from convergence between value neurons and social, self-other discriminating neurons. These findings identify single-neuron building blocks and computational architectures for decision-making and social behavior in the primate amygdala. An emerging understanding of the decision function of primate amygdala neurons can help identify potential vulnerabilities for amygdala dysfunction in human conditions afflicting social cognition and mental health.


Relation between social network and psychological distress among middle-aged adults in Japan: Evidence from a national longitudinal survey.
It is widely documented that psychological distress is negatively associated with social networks involvement. However, despite the theoretical postulations that social networks are crucial for alleviating psychological distress, no study has yet empirically confirmed the causality of this relationship. Thus, we used the random-effects generalized least squares method to investigate the effect of one- and two-year lagged values for involvement in social networks on psychological distress. Nine years of longitudinal data were extracted from a nationally representative survey in Japan ("The Longitudinal Survey of Middle-aged and Older Persons"). We utilized the Kessler 6 (K6) score to measure psychological distress among 15,242 respondents aged 50-59 years in the baseline year (2005), and stratified participants into three layers of social networks: inner (well-established friendship ties and participating in hobby activates), intermediary (neighborly ties), and outer (involvement in community activities). We found highly significant and negative associations between all three layers and K6 scores, with the strongest association being for the inner layer. We further observed that one-year lagged involvement in the inner and intermediary layers led to significantly lower K6 scores. However, the protective influences of social networks generally diminished over time. In addition, the protective influences of social network involvement on psychological distress were stronger for women than for men. Furthermore, involvement in social networks was especially important for improving mental health among people with psychological distress. These findings would be important for policymaking to prevent mental health deterioration among middle-aged adults in Japan.


A large-scale validation study of the Medication Adherence Rating Scale (MARS).
Adherence to medication is an important predictor of illness course and outcome in psychosis. The Medication Adherence Rating Scale (MARS) is a ten-item self-report measure of medication adherence in psychosis [Thompson, K., Kulkarni, J., Sergejew, A.A., 2000. Reliability and validity of a new Medication Adherence Rating Scale (MARS) for the psychoses. Schizophrenia Research. 42. 241-247]. Although initial results suggested that the scale has good reliability and validity, the development sample was small. The current study aimed to establish the psychometric properties of the MARS in a sample over four times larger. The scale was administered to 277 individuals with psychosis, along with measures of insight and psychopathology. Medication adherence was independently rated by each individual's keyworker. Results showed the internal consistency of the MARS to be lower than in the original sample, though adequate. MARS total score correlated weakly with keyworker-rated adherence, hence concurrent validity of the scale appeared only moderate to weak. The three factor structure of the MARS was replicated. Examination of the factor scores suggested that the factor 1 total score, which corresponds to the Medication Adherence Questionnaire [Morisky,D.E., Green,L.W. and Levine,D.M., 1986. Concurrent and predictive validity of a self-reported measure of medication adherence. Medical Care. 24, 67-74] may be a preferable measure of medication adherence behaviour to the total scale score.


Role of two-photon absorption in Ta2O5 thin films in nanosecond laser-induced damage.
Laser-induced damage in the nanosecond domain has been connected to the heating and breakdown of local defects within the thin film and the various interfaces. Within the femtosecond regime, the damaging events can be traced back to multiphoton-based excitation into the conduction band. When critical electron density is exceeded, an optical breakdown will occur. In this Letter we report on evidence that two-photon absorption also significantly triggers laser-induced damage in Ta(2)O(5) thin films at 532 nm and 8 ns pulse duration. For experimental verification, single layers of Ta(2)O(5)/SiO(2) mixtures have been analyzed.


Lymphoepithelial Sialadenitis Involving HIV-Infected and Sjogren Syndrome Patients: A Cytologic Study.
Lymphoepithelial salivary gland cysts are rarely seen in autoimmune diseases particularly Sjogren syndrome as well as in HIV for which medical management is advocated. To study the morphology of these cysts, correlate with the disease process and assess the final outcome. Case series. Fine needle aspiration clinic. HIV-infected and autoimmune disease patients with lymphoepithelial cysts. Antiretroviral therapy for HIV-patients and anti-inflammatory drugs for Sjogren syndrome. Three HIV-infected patients (two children and one adult) and three middle aged female patients presented with parotid and submandibular cysts, two of which were bilateral along with submandibular (one each in the HIV and the autoimmune group). In the adult HIV-patient, the cyst was found at the inception of the disease while the other pediatric HIV-patients just crossed a decade. Of the other three cases of Sjogren syndrome, two were primary and one, secondary to rheumatoid arthritis. All the cysts regressed completely with treatment of the respective diseases which was confirmed by ultrasonograms. Lymphoepithelial cysts are produced by release of serous secretion by the acinar and ductal cells within the epithelial islands in the process of their destruction. Possibly, antibody mediated increased secretion in the initial stages also plays a role. Lymphoepithelial cysts of HIV patients may occur in the course of treatment, not necessarily in the beginning, though it resolves spontaneously. Lymphoepithelial cysts of primary or secondary Sjogren syndrome may be repressed sufficiently by anti-inflammatory/immunosuppressant treatment.


Intraspecific differences in long-term drought tolerance in perennial ryegrass.
Lolium perenne L. (perennial ryegrass) is the most important pasture grass species in temperate regions of the world. However, its growth is restricted in summer dry environments. Germplasm screening can be used to identify accessions or individual plants for incorporation into breeding programs for drought tolerance. We selected nine perennial ryegrass accessions from different global origins and from a range of climatic and environmental conditions. In addition, the perennial ryegrass cultivar 'Grasslands Impact' was chosen as a reference. The accessions were grown for 360 days in a controlled environment through six consecutive drought stress and recovery cycles. We observed intraspecific differences in drought stress responsiveness for shoot biomass and survival from the third stress cycle. An accession from Norway had 50% more shoot dry matter than the next best-performing accession after six drought cycles. Compared with the reference cultivar 'Grasslands Impact', shoot dry matter of the accession from Norway was more than seven times higher after six drought cycles, indicating superior performance of this ecotype under drought stress. Drought tolerance was characterized by osmotic adjustment and higher relative leaf water content at low soil moisture levels. Furthermore, the findings of this study identify solute potential as an early predictor of drought stress tolerance. These intraspecific differences can be used in breeding programs for the development of drought-tolerant perennial ryegrass cultivars.


Fluorescent chemosensors for Zn(2+).
In the past decade, fluorescent chemosensors for zinc ion (Zn(2+)) have attracted great attention because of the biological significance of zinc combined with the simplicity and high sensitivity of fluorescence assays. Chemosensors can be divided into a fluorophore, a spacer and a receptor unit; the receptor is the central processing unit (CPU) of a chemosensor. This tutorial review will classify zinc chemosensors based on receptor types.


Expression of the genome of defective interfering pseudorabies virions in the presence or absence of helper functions provided by standard virus.
The synthesis of virus RNA and proteins in cells infected with two populations of defective virions [Pr(1)53 and Pr(2)53] which vary in the overall composition of their DNA, but which share some structural and biological characteristics, have been examined. The experiments were done under two sets of conditions: (1) at high multiplicity of infection. In this case, practically all the cells in the cultures were co-infected with defective and infectious virions; (2) at low multiplicity of infection. In this case, 75% of the cells in the cultures were infected with defective virions only and 25% were co-infected with defective and infectious virions. The relative abundance of RNA classes complementary to different regions of the virus genomes that were synthesized under various conditions of infection were determined by the Southern (1975) technique; the synthesis of virus proteins was determined by polyacrylamide gel electrophoresis (PAGE). In cells co-infected with standard and defective virions, RNA complementary to the regions that are reiterated in the defective genomes is present in larger amounts than in cells infected with standard virions alone, indicating that the genomes of the defective virions are transcribed. Furthermore, the transcriptional controls that operate normally in the infected cells also operate in cells co-infected with standard and defective virions. The over-abundant accumulation of transcripts of some regions of the virus genome in cells co-infected with defective virions is not necessarily accompanied by an overproduction of some virus proteins. No difference in the PAGE profiles of the proteins synthesized was detected in cells co-infected with PR(1)53 and standard virions. However, cells co-infected with standard and Pr(2)53 overproduced three polypeptides. Transcription of the virus genome is detectable in cells infected with Pr(2)53 alone but not in cells infected with Pr(2)53 alone. Virus protein synthesis is also detectable under these conditions in Pr(2)-, but not in Pr(1)-infected cells. Thus, despite the similarities in the biological characteristics of the two populations of defective virions described previously, similarities with respect to the expression of their genomes were not found.


Mental disorders and communication of intent to die in indigenous suicide cases, Queensland, Australia.
In comparing Indigenous to non-Indigenous suicide in Australia, this study focussed on the frequency of the association between some psychiatric conditions, such as depression and alcohol abuse, and some aspect of suicidality, in particular communication of suicide intent. Logistic regression was implemented to analyze cases of Indigenous (n = 471) versus non-Indigenous suicides (n = 6,655), using the Queensland Suicide Register as a data source. Compared to non-Indigenous suicides, Indigenous cases had lower odds of being diagnosed with unipolar depression, seeking treatment for psychiatric conditions or leaving a suicide note. Indigenous suicides had greater odds of verbally communicating suicide intent and having a history of alcohol and substance use. The magnitude of these differences is remarkable, underscoring the need for culturally sensitive suicide prevention efforts.


Involutional entropion repair with fornix sutures and lateral tarsal strip procedure.
To evaluate the long-terrm effectiveness of fornix suture placement combined with a lateral tarsal strip procedure in correcting involutional entropion. Published reports regarding various surgical techniques and results are reviewed. This retrospective study reviewed 119 patients with involutional lower eyelid entropion who underwent surgical repair between January 1987 and May 1999 at the Bascom Palmer Eye Institute. Exclusion criteria included follow-up duration of less than 6 months, previous lower eyelid blepharoplasty, previous conjunctival surgery other than chalazion removal, or cicatricial entropion. The three surgical subsets were (1) combined lateral tarsal strip and fornix sutures: (2) fornix sutures alone; and (3) lateral tarsal strip procedure alone. The chart review was complemented by a telephone questionnaire to assess the long-term clinical outcome, complications, and patient satisfaction. One hundred fifty-two eyelids in 119 patients were included. One hundred twenty-five eyelids had combined surgery (lateral tarsal strip with fornix sutures), 9 eyelids had only fornix suture repair, and 18 eyelids had repair with only the lateral tarsal strip procedure. The recurrence rate in these three surgical subsets was 1.6%, 33%, and 22%, respectively, with average follow-up of 36 months. One case of incisional cellulitis was encountered. Postoperative ectropion was not seen in the group having the combined lateral tarsal strip and fornix suture procedure. Suture advancement of the lower eyelid retractors in conjunction with a lateral tarsal strip procedure is a simple, quick, physiologic, and effective approach in achieving long-lasting correction for involutional entropion.


Hair Proteome Variation at Different Body Locations on Genetically Variant Peptide Detection for Protein-Based Human Identification.
Human hair contains minimal intact nuclear DNA for human identification in forensic and archaeological applications. In contrast, proteins offer a pathway to exploit hair evidence for human identification owing to their persistence, abundance, and derivation from DNA. Individualizing single nucleotide polymorphisms (SNPs) are often conserved as single amino acid polymorphisms in genetically variant peptides (GVPs). Detection of GVP markers in the hair proteome via high-resolution tandem mass spectrometry permits inference of SNPs with known statistical probabilities. To adopt this approach for forensic investigations, hair proteomic variation and its effects on GVP identification must first be characterized. This research aimed to assess variation in single-inch head, arm, and pubic hair, and discover body location-invariant GVP markers to distinguish individuals. Comparison of protein profiles revealed greater body location-specific variation in keratin-associated proteins and intracellular proteins, allowing body location differentiation. However, robust GVP markers derive primarily from keratins that do not exhibit body location-specific differential expression, supporting GVP identification independence from hair proteomic variation at the various body locations. Further, pairwise comparisons of GVP profiles with 8 SNPs demonstrated greatest interindividual variation and high intraindividual consistency, enabling similar differentiative potential of individuals using single hairs irrespective of body location origin.


Temperature distribution simulation of the human eye exposed to laser radiation.
Human eye is a sensitive part of human body with no direct protection and due to its lack of protection against the external heat waves, studying the temperature distribution of heat waves on the human eye is of utmost importance. Various lasers are widely used in medical applications such as eye surgeries. The most significant issue in the eye surgeries with laser is estimation of temperature distribution and its increase in eye tissues due to the laser radiation intensity. Experimental and invasive methods to measure the eye temperature usually have high risks. In this paper, human eye has been modeled through studying the temperature distribution of three different laser radiations, using the finite element method. We simulated human eye under 1064 nm Neodymium-Doped Yttrium Aluminium Garnet (Nd: YAG) laser, 193 nm argon fluoride (ArF) excimer laser, and 1340 nm Neodymium doped Yttrium Aluminum Perovskite (Nd: YAP) laser radiation. The results show that these radiations cause temperature rise in retina, lens and cornea region, which will in turn causes serious damages to the eye tissues. This simulation can be a useful tool to study and predict the temperature distribution in laser radiation on the human eye and evaluate the risk involved in using laser to perform surgery.


Recent planktonic foraminifera: dominance and diversity in north atlantic surface sediments.
Foraminferal dominance values above 50 percent and associated diversity minimums in surface sediments of the North Atlantic coincide with past extremes of temperature, productivity, or salinity in overlying surface waters. These parameters delimit a cold PolarSubpolar water mass and an impoverished, saline Southern Sargasso Central water mass for the late Recent. Anticipated pole-to-equator diversity and dominance gradients in the open ocean are virtually eliminated by the stronger trends of the vigorous subtropical North Atlantic gyre.


Neural correlates of object indeterminacy in art compositions.
Indeterminate art invokes a perceptual dilemma in which apparently detailed and vivid images resist identification. We used event-related fMRI to study visual perception of representational, indeterminate and abstract paintings. We hypothesized increased activation along a gradient of posterior-to-anterior ventral visual areas with increased object resolution, and postulated that object resolution would be associated with visual imagery. Behaviorally, subjects were faster to recognize familiar objects in representational than in both indeterminate and abstract paintings. We found activation within a distributed cortical network that includes visual, parietal, limbic and prefrontal regions. Representational paintings, which depict scenes cluttered with familiar objects, evoked stronger activation than indeterminate and abstract paintings in higher-tier visual areas. Perception of scrambled paintings was associated with imagery-related activation in the precuneus and prefrontal cortex. Finally, representational paintings evoked stronger activation than indeterminate paintings in the temporoparietal junction. Our results suggest that perception of familiar content in art works is mediated by object recognition, memory recall and mental imagery, cognitive processes that evoke activation within a distributed cortical network.


TGF beta 1 inhibits proliferation and has a chemotropic effect on mouse primordial germ cells in culture.
Primordial germ cells are the stem cells that provide the functional gametes of adult animals. In many animal groups they are set aside at the earliest stages of development, and migrate from their sites of first appearance to the sites where the gonad will form, the genital ridges. During this migration they proliferate. In the mouse embryo their numbers increase from less than one hundred to approximately four thousand during the period of their migration. In a previous paper we showed that both the proliferation and the direction of migration of mouse PGCs in culture were influenced by soluble factors released from their target tissue, the genital ridges. Studies on other stem cell populations have shown that complex combinations of growth factors control their proliferation, migration and differentiation. In this paper, we show that TGF beta 1 inhibits proliferation of PGCs taken from 8.5 day old embryos and cultured on embryonic fibroblast feeder layers. We also show that the previously reported chemotropic effect of genital ridges in this culture system is mediated by TGF beta 1, or a closely related molecule, released from the genital ridges.


Information content of point radiance measurements in turbid media: implications for interstitial optical property quantification.
Motivated by a recent report by Dickey et al. [Phys. Med. Biol. 46, 2359 (2001)], who demonstrated optical property retrieval by using relative radiance measurements at a single position, we investigate the uniqueness of relative radiance measurements for quantifying the optical properties of turbid media by studying the solutions of the diffusion and P3 approximations of the Boltzmann transfer equation for a point source. Using the P3 approximation, we investigate the potential of radiance measurements for optical property recovery by examining the optical property response surface for point radiance information. We further derive first-order similarity relations for relative point radiance measurements and use these expressions to examine analytically the effects of noise on optical property retrieval over a wide range of optical properties typical of biological tissue. Finally, optimal experimental configurations are studied and explicit conditions for uniqueness derived that suggest potential strategies for improving optical property recovery. It is expected that point radiance measurements will prove valuable for both on-line treatment planning of minimally invasive laser therapies and optical characterization of tissues.


Framework of barrier reefs threatened by ocean acidification.
To date, studies of ocean acidification (OA) on coral reefs have focused on organisms rather than communities, and the few community effects that have been addressed have focused on shallow back reef habitats. The effects of OA on outer barrier reefs, which are the most striking of coral reef habitats and are functionally and physically different from back reefs, are unknown. Using 5-m long outdoor flumes to create treatment conditions, we constructed coral reef communities comprised of calcified algae, corals, and reef pavement that were assembled to match the community structure at 17 m depth on the outer barrier reef of Moorea, French Polynesia. Communities were maintained under ambient and 1200 μatm pCO2 for 7 weeks, and net calcification rates were measured at different flow speeds. Community net calcification was significantly affected by OA, especially at night when net calcification was depressed ~78% compared to ambient pCO2 . Flow speed (2-14 cm s(-1) ) enhanced net calcification only at night under elevated pCO2 . Reef pavement also was affected by OA, with dissolution ~86% higher under elevated pCO2 compared to ambient pCO2 . These results suggest that net accretion of outer barrier reef communities will decline under OA conditions predicted within the next 100 years, largely because of increased dissolution of reef pavement. Such extensive dissolution poses a threat to the carbonate foundation of barrier reef communities.


Replacement of posttranscriptional regulation in SIVmac239 generated a Rev-independent infectious virus able to propagate in rhesus peripheral blood mononuclear cells.
Lentiviruses control virion production via posttranscriptional regulation mediated by the viral Rev protein. In this study, we demonstrate that the Rev regulation of SIVmac239 can be replaced by the presence of the cis-acting transport element (CTE) of the type D simian retroviruses 1 (SRV-1). To avoid the possibility of generating revertants, the Rev-Independent SIV clones have both rev and the Rev responsive element (RRE) destroyed by multiple point mutations that do not affect the overlapping tat and env open reading frames. Virus stocks generated from these Rev-independent SIV molecular clones can infect and can be propagated in rhesus peripheral blood mononuclear cells (PBMCs). Therefore, the Rev/RRE system of SIVmac239 can be replaced by the SRV-1 CTE as previously shown for HIV-1. In both rhesus and human primary cells, the replicative capacity of the Rev-independent SIV is 10- to 20-fold lower than that of the wild-type virus. Rhesus PBMC-derived virus stocks of the Rev-independent SIV have lower infectivity. Interestingly, in CEM x 174 cells, no difference in replicative capacity between wild-type and Rev-independent SIV has been observed. The Rev-independent SIV has a stable genotype after several passages in primary cells. The availability of such Rev-Independent viruses will allow the study of the role of Rev in pathogenesis and the potential generation of attenuated SIV strains.


Clubfoot in Malawi: local theories of causation.
This paper examines local theories of the causation of clubfoot expressed by the guardians of children undergoing treatment at clinics run by the Malawi National Clubfoot Programme (MNCP). Core data was collected and analysed using qualitative methodologies of critical medical anthropology. Sixty detailed case studies were completed, each based on an extended open-ended interview with patient guardians. Five main theories of causation were put forward: God; the devil; witchcraft or curses; biological reasons; and inherited condition. Each was elaborated in a variety of ways. There is growing international recognition of the importance of examining the relationship between culture and disability. This study is the first attempt to do so for clubfoot in Malawi. It provides a platform on which to build future qualitative research that can be harnessed by the MNCP and similar initiatives to develop their knowledge base and service provision, both in Malawi and the wider African context.


Novel brain permeant mTORC1/2 inhibitors are as efficacious as rapamycin or everolimus in mouse models of acquired partial epilepsy and tuberous sclerosis complex.
Mechanistic target of rapamycin (mTOR) regulates cell proliferation, growth and survival, and is activated in cancer and neurological disorders, including epilepsy. The rapamycin derivative ("rapalog") everolimus, which allosterically inhibits the mTOR pathway, is approved for the treatment of partial epilepsy with spontaneous recurrent seizures (SRS) in individuals with tuberous sclerosis complex (TSC). In contrast to the efficacy in TSC, the efficacy of rapalogs on SRS in other types of epilepsy is equivocal. Furthermore, rapalogs only poorly penetrate into the brain and are associated with peripheral adverse effects, which may compromise their therapeutic efficacy. Here we compare the antiseizure efficacy of two novel, brain-permeable ATP-competitive and selective mTORC1/2 inhibitors, PQR620 and PQR626, and the selective dual pan-PI3K/mTORC1/2 inhibitor PQR530 in two mouse models of chronic epilepsy with SRS, the intrahippocampal kainate (IHK) mouse model of acquired temporal lobe epilepsy and Tsc1GFAP CKO mice, a well-characterized mouse model of epilepsy in TSC. During prolonged treatment of IHK mice with rapamycin, everolimus, PQR620, PQR626, or PQR530; only PQR620 exerted a transient antiseizure effect on SRS, at well tolerated doses whereas the other compounds were ineffective. In contrast, all of the examined compounds markedly suppressed SRS in Tsc1GFAP CKO mice during chronic treatment at well tolerated doses. Thus, against our expectation, no clear differences in antiseizure efficacy were found across the three classes of mTOR inhibitors examined in mouse models of genetic and acquired epilepsies. The main advantage of the novel 1,3,5-triazine derivatives is their excellent tolerability compared to rapalogs, which would favor their development as new therapies for TORopathies such as TSC.


Rethinking cortical organization: moving away from discrete areas arranged in hierarchies.
One way to understand the topography of the cerebral cortex is that "like attracts like." The cortex is organized to maximize nearest neighbor similarity. This principle can explain the separation of the cortex into discrete areas that emphasize different information domains. It can also explain the maps that form within cortical areas. However, because the cortex is two-dimensional, when a parameter space of much higher dimensionality is reduced onto the cortical sheet while optimizing nearest neighbor relationships, the result may lack an obvious global ordering into separate areas. Instead, the topography may consist of partial gradients, fractures, swirls, regions that resemble separate areas in some ways but not others, and in not a lack of topographic maps but an excess of maps overlaid on each other, no one of which seems to be entirely correct. Like a canvas in a gallery of modern art that no two observers interpret the same way, this lack of obvious ordering of high-dimensional spaces onto the cortex might then result in some scientific controversy over the true organization. In this review, the authors suggest that at least some sectors of the cortex do not have a simple global ordering and are better understood as a result of a reduction of a high-dimensional space onto the cortical sheet. The cortical motor system may be an example of this phenomenon. The authors discuss a model of the lateral motor cortex in which a reduction of many parameters onto a simulated cortical sheet results in a complex topographic pattern that matches the actual monkey motor cortex in surprising detail. Some of the ambiguities of topography and areal boundaries that have plagued the attempt to systematize the lateral motor cortex are explained by the model.


The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy.
The gene for myotonic dystrophy (DM) has recently been isolated and amplification of an unstable CTG trinucleotide repeat, located within the DM gene, has been identified in virtually all patients studied to date. A high proportion of DM families who are studied show a progressively earlier age of onset with succeeding generations and, in the few pedigrees reported so far, an increasing degree of amplification of the CTG repeat has been noted to parallel this trend. It has been implicit in several of the original reports on the nature of the changes in the DM gene that knowledge of CTG amplification status at the DM locus of a person will provide useful information concerning prognosis. However, no studies of genotype-phenotype correlation have been reported and there are no specific data on which to base such counsel. In this paper we report the correlation between the degree of CTG amplification and age of onset in 109 DM gene carriers from 17 families. Included are parent-child and sib-sib comparisons which provide a framework in which to incorporate DNA diagnostic studies when counselling subjects and families at risk for DM.


PerCEN: a cluster randomized controlled trial of person-centered residential care and environment for people with dementia.
There is good evidence of the positive effects of person-centered care (PCC) on agitation in dementia. We hypothesized that a person-centered environment (PCE) would achieve similar outcomes by focusing on positive environmental stimuli, and that there would be enhanced outcomes by combining PCC and PCE. 38 Australian residential aged care homes with scope for improvement in both PCC and PCE were stratified, then randomized to one of four intervention groups: (1) PCC; (2) PCE; (3) PCC +PCE; (4) no intervention. People with dementia, over 60 years of age and consented were eligible. Co-outcomes assessed pre and four months post-intervention and at 8 months follow-up were resident agitation, emotional responses in care, quality of life and depression, and care interaction quality. From 38 homes randomized, 601 people with dementia were recruited. At follow-up the mean change for quality of life and agitation was significantly different for PCE (p = 0.02, p = 0.05, respectively) and PCC (p = 0.0003, p = 0.002 respectively), compared with the non-intervention group (p = 0.48, p = 0.93 respectively). Quality of life improved non-significantly for PCC+PCE (p = 0.08), but not for agitation (p = 0.37). Improvements in care interaction quality (p = 0.006) and in emotional responses to care (p = 0.01) in PCC+PCE were not observed in the other groups. Depression scores did not change in any of the groups. Intervention compliance for PCC was 59%, for PCE 54% and for PCC+PCE 66%. The hypothesis that PCC+PCE would improve quality of life and agitation even further was not supported, even though there were improvements in the quality of care interactions and resident emotional responses to care for some of this group. The Australian New Zealand Clinical Trials Registry Number is ACTRN 12608000095369.


Detection of infectious salmon anaemia virus by real-time RT-PCR.
A one-tube real-time reverse transcription-polymerase chain reaction (RT-PCR) using LightCycler technology and SYBR Green chemistry that quantitatively detects infectious salmon anaemia virus (ISAV) in biological samples is described. The assay utilized primers targeting ISAV RNA segment 8, with ISAV isolate U5575-1 as template. The entire optimized assay, including one cycle of reverse transcription, 50 cycles of complementary DNA amplification, and data acquisition and analysis took only 80min. The melting curve and gel electrophoresis analyses of real-time RT-PCR showed harmony with each other as a virus-specific single melting peak and a product of the expected size of 211 bp were obtained. A regression line between the mean threshold cycle (Ct) values and viral template concentrations over a 1:10(5) dilution range with an r(2) value of 0.962 and a slope of -3.771 indicated that the assay was highly reproducible. This assay was 100 times more sensitive than the conventional one-tube RT-PCR assay when compared on the same sample. Analysis of different tissues from fish that survived an ISAV experimental infection further confirmed that real-time RT-PCR was more sensitive than regular RT-PCR for detection of ISAV nucleic acids. Temporal analysis of ISAV-infected TO cell cultures showed that the amount of the specific viral RNA increased more than 100-fold within 32 h post-inoculation (p.i.) and over 1200-fold by 144 h p.i. The melting curve analysis throughout the duration of the infection sampled had a single melting peak suggesting that the virus population was uniform in the targeted region. Quantitative analysis of CHSE-214 cell cultures infected with different ISAV isolates indicated that ISAV isolates, based on their ability to replicate and cause cytopathic effects in CHSE-214 cells, may be differentiated into three CHSE phenotypes: replicating cytopathic, replicating non-cytopathic, and non-replicating. Thus, the SYBR Green real-time RT-PCR is a sensitive, rapid, and highly reproducible assay that can be used to quantitate ISAV in biological samples.


Effects of Concussion in Adolescent Students: Perceptions and Performance.
The purpose of this study was to compare adolescent students with and without concussion on a battery of academic, neurocognitive, and socioemotional measures and assess the aftereffects of concussion across domains of functioning. Twenty-four adolescents (ages 13-17) reporting postconcussion symptoms were compared to 24 controls matched for age and gender across a battery of tests and surveys. After correcting for multiple comparisons, there were no significant differences on any neuropsychological measures. Similarly, there were no significant group differences on academic measures of vocabulary, word recognition, or reading comprehension. Self-reported concussion symptoms were much greater for students with concussion, as were self-reports of anxiety, depression, and somatization symptoms. Parents also rated those with concussion as having greater depression and somatization symptoms, but not to a degree that survived Bonferroni correction. Lastly, those with concussion reported a significantly greater number of school problems and academic concerns. Results indicated that adolescents who reported postconcussion symptoms do not perform differently from peers on most neurocognitive and academic tasks, yet they showed considerably more worry, somatization, academic concerns, and feelings of inadequacy than matched controls. The findings suggest that interventions to address psychological and academic stress may be indicated for adolescents symptomatic from concussion.


The economics of upper gastrointestinal bleeding in a US managed-care setting: a retrospective, claims-based analysis.
To assess 12-month healthcare resource utilization and costs associated with upper gastrointestinal (UGI) bleeding events. Patients hospitalized with a UGI bleeding event were identified in US national health-plan claims data (1999-2003) and propensity matched to control patients without UGI bleeding in the same health plan. Matching criteria included age, gender, index date, Charlson Comorbidity Index score, geographic region, and prior medical utilization. A total of 9,033 UGI-bleed patients and 579,018 control patients met the inclusion criteria, yielding 4,651 matched pairs. After matching, differences between the UGI bleed and general population cohorts remained for office visits, ER visits, and ER costs during the 6-month baseline period prior to the index date. During the 12 months following the index date, both UGI-related healthcare utilization and total healthcare, medical, and pharmacy costs incurred by the UGI-bleed cohort were significantly greater (p< 0.0001) than those incurred by the general population cohort (mean of $20,405 vs. 3,652), even after excluding the initial hospitalization costs (mean of $11,228 vs. 3,652). Costs were primarily due to inpatient hospitalizations (mean of $13,059 for the UGI-bleed cohort vs. $729 for the general population cohort) and ambulatory services (mean of $4,037 for the UGI-bleed cohort vs. $1,537 for the general population cohort). Sixteen percent of the UGI-bleed cohort had a GI-related hospitalization, and about 40% of total costs occurred after the initial hospitalization. Patients with UGI bleeds experienced significantly higher (p< 0.0001) 12-month health-resource utilization and costs than patients without UGI bleeds. This study provides empirical evidence of the long-term economic burden associated with UGI bleeding. Interpretation of the results should take into account the lack of available information in claims data that could have an effect on study outcomes, such as particular clinical and disease-specific parameters that are not mitigated by propensity score and comorbidity index matching. In addition, this study is limited by the intensive demographic matching that was done between the two cohorts, which may have eliminated the sickest UGI patients and the healthiest general health-plan population patients.


CHANGES IN THE MEMBRANE PERMEABILITY OF FROG'S SARTORIUS MUSCLE FIBERS IN CA-FREE EDTA SOLUTION.
The changes in the membrane permeability to sodium, potassium, and chloride ions as well as the changes in the intracellular concentration of these ions were studied on frog sartorius muscles in Ca-free EDTA solution. It was found that the rate constants for potassium and chloride efflux became almost constant within 10 minutes in the absence of external calcium ions, that for potassium increasing to 1.5 to 2 times normal and that for chloride decreasing about one-half. The sodium influx in Ca-free EDTA solution, between 30 and 40 minutes, was about 4 times that in Ringer's solution. The intracellular sodium and potassium contents did not change appreciably but the intracellular chloride content had increased to about 4 times normal after 40 minutes. By applying the constant field theory to these results, it was concluded that (a) P(Cl) did not change appreciably whereas P(K) decreased to a level that, in the interval between 10 and 40 minutes, was about one-half normal, (b) P(Na) increased until between 30 and 40 minutes it was about 8 times normal. The low value of the membrane potential between 30 and 40 minutes was explained in terms of the changes in the membrane permeability and the intracellular ion concentrations. The mechanism for membrane depolarization in this solution was briefly discussed.


E protein transcription factors are required for the development of CD4(+) lineage T cells.
The double-positive (DP) to single-positive (SP) transition during T cell development is initiated by downregulation of the E protein transcription factors HEB and E2A. Here, we have demonstrated that in addition to regulating the onset of this transition, HEB and E2A also play a separate role in CD4(+) lineage choice. Deletion of HEB and E2A in DP thymocytes specifically blocked the development of CD4(+) lineage T cells. Furthermore, deletion of the E protein inhibitors Id2 and Id3 allowed CD4(+) T cell development but blocked CD8(+) lineage development. Analysis of the CD4(+) lineage transcriptional regulators ThPOK and Gata3 placed HEB and E2A upstream of CD4(+) lineage specification. These studies identify an important role for E proteins in the activation of CD4(+) lineage differentiation as thymocytes undergo the DP to SP transition.


Clinical Dutch-English Lambert-Eaton Myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS.
Approximately one half of patients with Lambert-Eaton myasthenic syndrome (LEMS) have small-cell lung carcinomas (SCLC), aggressive tumors with poor prognosis. In view of its profound impact on therapy and survival, we developed and validated a score to identify the presence of SCLC early in the course of LEMS. We derived a prediction score for SCLC in LEMS in a nationwide cohort of 107 Dutch patients, and validated it in a similar cohort of 112 British patients. A Dutch-English LEMS Tumor Association Prediction (DELTA-P) score was developed based on multivariate logistic regression. Age at onset, smoking behavior, weight loss, Karnofsky performance status, bulbar involvement, male sexual impotence, and the presence of Sry-like high-mobility group box protein 1 serum antibodies were independent predictors for SCLC in LEMS. A DELTA-P score was derived allocating 1 point for the presence of each of the following items at or within 3 months from onset: age at onset ≥ 50 years, smoking at diagnosis, weight loss ≥ 5%, bulbar involvement, erectile dysfunction, and Karnofsky performance status lower than 70. The area under the curve of the receiver operating curve was 94.4% in the derivation cohort and 94.6% in the validation set. A DELTA-P score of 0 or 1 corresponded to a 0% to 2.6% chance of SCLC, whereas scores of 4, 5, and 6 corresponded to chances of SCLC of 93.5%, 96.6%, and 100%, respectively. The simple clinical DELTA-P score discriminated patients with LEMS with and without SCLC with high accuracy early in the course of LEMS.


Temporal kinetics of Marek's disease herpesvirus: integration occurs early after infection in both B and T cells.
Marek's disease virus (MDV) is an oncogenic α-herpesvirus that induces Marek's disease characterized by fatal lymphomas in chickens. Here, we explored the timing during pathogenesis when the virus integrates into the host genome, the cell type involved, the role of viral integration on cellular transformation, and tumor clonality. Three immune organs of chicken (thymus, bursa, and spleen) were extracted following infection with either an oncogenic or a non-oncogenic strain of MDV. Using molecular cytogenetics, cells were investigated for viral integration at key time points throughout pathogenesis. Integration profiling of tumors (early to late stage) was conducted. Virus integration was widespread in B and T lymphocytes based on their abundance in bursa and thymus, respectively. Viral replication was detected early after infection as was viral integration into the host genome. Integration is a natural part of the MDV herpesvirus life cycle. In addition, our data using a non-oncogenic virus establish that although integration is a hallmark of tumor cell populations, integration alone is not sufficient for cellular transformation. Our results provide evidence for progression of lineage clonality within tumors. Understanding the features of integration provides insight into the mechanisms of herpesvirus pathology which could lead to disease mitigation strategies.


Voxelotor: A Hemoglobin S Polymerization Inhibitor for the Treatment of Sickle Cell Disease.
Sickle cell disease (SCD) affects millions of people throughout the world. Hemoglobin S (HbS) polymerization is the fundamental cause of SCD pathophysiology, which leads to hemolysis, increased viscosity, and acute vaso-occlusive episodes. Novel agents have been developed to target the pathophysiology of SCD and decrease the frequency of SCD complications. Voxelotor (Oxbryta) is an HbS polymerization inhibitor that is approved by the U.S. Food & Drug Administration for the treatment of SCD in adults and pediatric patients 12 years and older.


Climatic correlates of tree mortality in water- and energy-limited forests.
Recent increases in tree mortality rates across the western USA are correlated with increasing temperatures, but mechanisms remain unresolved. Specifically, increasing mortality could predominantly be a consequence of temperature-induced increases in either (1) drought stress, or (2) the effectiveness of tree-killing insects and pathogens. Using long-term data from California's Sierra Nevada mountain range, we found that in water-limited (low-elevation) forests mortality was unambiguously best modeled by climatic water deficit, consistent with the first mechanism. In energy-limited (high-elevation) forests deficit models were only equivocally better than temperature models, suggesting that the second mechanism is increasingly important in these forests. We could not distinguish between models predicting mortality using absolute versus relative changes in water deficit, and these two model types led to different forecasts of mortality vulnerability under future climate scenarios. Our results provide evidence for differing climatic controls of tree mortality in water- and energy-limited forests, while highlighting the need for an improved understanding of tree mortality processes.


Replicating Neuroscience Observations on ML/MF and AM Face Patches by Deep Generative Model.
A recent Cell paper (Chang & Tsao, 2017) reports an interesting discovery. For the face stimuli generated by a pretrained active appearance model (AAM), the responses of neurons in the areas of the primate brain that are responsible for face recognition exhibit a strong linear relationship with the shape variables and appearance variables of the AAM that generates the face stimuli. In this letter, we show that this behavior can be replicated by a deep generative model, the generator network, that assumes that the observed signals are generated by latent random variables via a top-down convolutional neural network. Specifically, we learn the generator network from the face images generated by a pretrained AAM model using a variational autoencoder, and we show that the inferred latent variables of the learned generator network have a strong linear relationship with the shape and appearance variables of the AAM model that generates the face images. Unlike the AAM model, which has an explicit shape model where the shape variables generate the control points or landmarks, the generator network has no such shape model and shape variables. Yet it can learn the shape knowledge in the sense that some of the latent variables of the learned generator network capture the shape variations in the face images generated by AAM.


Structural classification of zinc fingers: survey and summary.
Zinc fingers are small protein domains in which zinc plays a structural role contributing to the stability of the domain. Zinc fingers are structurally diverse and are present among proteins that perform a broad range of functions in various cellular processes, such as replication and repair, transcription and translation, metabolism and signaling, cell proliferation and apoptosis. Zinc fingers typically function as interaction modules and bind to a wide variety of compounds, such as nucleic acids, proteins and small molecules. Here we present a comprehensive classification of zinc finger spatial structures. We find that each available zinc finger structure can be placed into one of eight fold groups that we define based on the structural properties in the vicinity of the zinc-binding site. Three of these fold groups comprise the majority of zinc fingers, namely, C2H2-like finger, treble clef finger and the zinc ribbon. Evolutionary relatedness of proteins within fold groups is not implied, but each group is divided into families of potential homologs. We compare our classification to existing groupings of zinc fingers and find that we define more encompassing fold groups, which bring together proteins whose similarities have previously remained unappreciated. We analyze functional properties of different zinc fingers and overlay them onto our classification. The classification helps in understanding the relationship between the structure, function and evolutionary history of these domains. The results are available as an online database of zinc finger structures.


The long-term management of nuclear emergencies: the principles.
The long-term impact of the Chernobyl accident on the most affected populations in Belarus, Ukraine and the Russian Federation is still evident in terms of a continuing elevated level of thyroid cancer, prominent psychosocial effects, a depressed economy and a low level of well being. Some of these impacts are directly and primarily attributable to exposure to ionising radiation, while others have more complex origins and have evolved over the period since the accident. It is argued that although these latter impacts were largely unpredictable at the time of the accident, they could have been minimised had an appropriate management plan been in force. The principles underlying such a management plan for use in future accidents are enumerated. An essential component in further developing such a plan would be a thorough review of the experience of the Chernobyl accident in order to 'learn the lessons' that accident holds.


A carbon dot-based tandem luminescent solar concentrator.
Luminescent solar concentrators (LSCs) are light-management devices and are used for harvesting and concentrating solar light from a large area to their edges. Being semitransparent devices, LSCs show great promise for future utilization in glass walls of urban buildings as environmentally friendly photovoltaic power plants. The development of cheap and eco-safe materials, the extension of the LSC operation range, and the enhancement of the optical efficiency are the key challenges, which need to be solved in order to transform energetically passive buildings into self-sustainable units. Herein, a large area (64 cm2) tandem LSC fabricated using entirely eco-friendly highly emissive blue, green, and red carbon dots is demonstrated, with an internal optical quantum efficiency of 23.6% and an external optical quantum efficiency of 2.3%, while maintaining a high transparency across the visible spectrum. This opens up a new direction for the application of carbon dots in advanced solar light harvesting technologies.


Effect of prophenoloxidase expression knockout on the melanization of microfilariae in the mosquito Armigeres subalbatus.
Melanization is an effective defence reaction used by mosquito hosts to kill malarial and filarial worm parasites. Although phenoloxidase (PO) has long been considered to be the key enzyme in the biosynthesis of melanotic material in insects, there is no direct evidence verifying its role in parasite melanization. To elucidate the role of PO in the melanization of microfilariae (mf) by mosquitoes, a double subgenomic Sindbis (dsSIN) recombinant virus was used to transduce Armigeres subalbatus mosquitoes with a 600 base antisense RNA targeted to the highly conserved copper-binding region of an Ar. subalbatus PO gene. Compared with controls, haemolymph PO activity in mosquitoes transduced with antisense RNA was significantly reduced. When these mosquitoes were challenged with Dirofilaria immitis mf, the melanization of mf was almost completely inhibited. These data verify that PO is an essential component of the biochemical pathway required for the melanization of parasites, and that the dsSIN expression system represents a useful tool in the functional analysis of endogenous gene expression in mosquitoes.


Phase-plane geometries in coupled enzyme assays.
The determination of a substrate or enzyme activity by coupling one enzymatic reaction with another easily detectable (indicator) reaction is a common practice in the biochemical sciences. Usually, the kinetics of enzyme reactions is simplified with singular perturbation analysis to derive rate or time course expressions valid under the quasi-steady-state and reactant stationary state assumptions. In this paper, the dynamical behavior of coupled enzyme catalyzed reaction mechanisms is studied by analysis of the phase-plane. We analyze two types of time-dependent slow manifolds - Sisyphus and Laelaps manifolds - that occur in the asymptotically autonomous vector fields that arise from enzyme coupled reactions. Projection onto slow manifolds yields various reduced models, and we present a geometric interpretation of the slow/fast dynamics that occur in the phase-planes of these reactions.


Assessment of Osteogenic Exercise Efficacy via Bone Turnover Markers in Premenopausal Women: A Randomized Controlled Trial.
Assessing bone's response to physical activity interventions is challenging. This randomized controlled trial investigates if changes in bone turnover markers can offer an early evaluation of a physical activity intervention's effectiveness in improving bone mineral density (BMD) in premenopausal women. Participants in the intervention group (n = 27, with 24 completing the trial) were instructed to walk at least 10,000 steps every day on a brisk walk and to execute 60 jumps daily, each surpassing 4g of acceleration, using an accelerometer-based wearable device. Meanwhile, the control group (n = 26, with 18 completing the trial) continued with their usual lifestyle. Bone turnover markers, comprising of C-terminal telopeptide of Type I collagen, procollagen Type 1 N-terminal propeptide, and total osteocalcin (carboxylated and undercarboxylated) were measured at baseline and midway through the intervention (3 months). Dual-energy X-ray absorptiometry scans of the hip and lumbar spine were conducted at baseline and the end of the intervention (6 months) to estimate BMD. Analysis of covariance exhibited significant differences between groups in procollagen Type 1 N-terminal propeptide (-6.74 μg/L, p = .023) and C-terminal telopeptide of Type I collagen (-83 ng/L, p = .043) after 3 months, and in femoral neck BMD (+0.024 g/cm2, p = .016), total hip BMD (+0.036 g/cm2, p = .004), and lumbar spine BMD (+0.026 g/cm2, p = .020) after 6 months. A significant correlation (r = -.73; p < .001) was detected between reductions in C-terminal telopeptide of Type I collagen and increases in femoral neck BMD. In conclusion, this intervention improved BMD in premenopausal women, with bone turnover markers potentially useful for early intervention assessment, though further research is needed.


Mechanosensitive gating of atrial ATP-sensitive potassium channels.
Cell-attached and inside-out excised-patch recording techniques were used to search for mechanosensitive ion channels in neonatal and adult rat atrial myocytes. A channel activated by negative pressure applied to the patch, with a single-channel conductance of 52 pS in symmetric potassium solutions, was frequently observed. This channel has been identified as the atrial ATP-sensitive potassium (KATP) channel on the basis of its potassium selectivity, as well as its inhibition by ATP or tolbutamide in the inside-out excised patch. Mechanosensitive modulation of the KATP channel has not previously been reported. In the presence of 1 mM ATP, 10-50 microM pinacidil (a specific KATP channel agonist) does not significantly increase basal KATP channel activity; however, these concentrations of pinacidil potentiated the mechanosensitive modulation of the KATP channel. A hypotonic swelling protocol (a mechanical stimulus) was used in an effort to determine whether mechanosensitive modulation of this channel can generate significant whole-cell currents. Under perforated-patch whole-cell recording conditions, superfusion of atrial myocytes with a 240 mosm/kg solution (control solution, 290 mosm/kg) stimulated whole-cell currents with a magnitude similar to those activated by 10 microM pinacidil. These results demonstrate that the gating of the atrial KATP channel is mechanosensitive and suggest that mechanosensitive modulation may be an additional and significant mechanism, modulating channel activity under both physiological and pathological conditions.


Sulfidic Anion Concentrations on Early Earth for Surficial Origins-of-Life Chemistry.
A key challenge in origin-of-life studies is understanding the environmental conditions on early Earth under which abiogenesis occurred. While some constraints do exist (e.g., zircon evidence for surface liquid water), relatively few constraints exist on the abundances of trace chemical species, which are relevant to assessing the plausibility and guiding the development of postulated prebiotic chemical pathways which depend on these species. In this work, we combine literature photochemistry models with simple equilibrium chemistry calculations to place constraints on the plausible range of concentrations of sulfidic anions (HS-, HSO3-, SO32-) available in surficial aquatic reservoirs on early Earth due to outgassing of SO2 and H2S and their dissolution into small shallow surface water reservoirs like lakes. We find that this mechanism could have supplied prebiotically relevant levels of SO2-derived anions, but not H2S-derived anions. Radiative transfer modeling suggests UV light would have remained abundant on the planet surface for all but the largest volcanic explosions. We apply our results to the case study of the proposed prebiotic reaction network of Patel et al. ( 2015 ) and discuss the implications for improving its prebiotic plausibility. In general, epochs of moderately high volcanism could have been especially conducive to cyanosulfidic prebiotic chemistry. Our work can be similarly applied to assess and improve the prebiotic plausibility of other postulated surficial prebiotic chemistries that are sensitive to sulfidic anions, and our methods adapted to study other atmospherically derived trace species.


Frail elderly patients with dementia go too fast.
The reason why patients with dementia fall more often and sustain more fractures than patients without dementia remains unclear. Therefore, the relationship between dementia and gait velocity as a marker for mobility and falls in a cohort of frail elderly (mean age of 77.3 years) inpatients was assessed. Patients with dementia were expected to walk slower than patients without dementia. A trend was indeed observed: absolute gait velocity of 0.59 m/s in patients with dementia (n = 63) versus 0.65 m/s in patients without dementia (n = 62; p = 0.19). After adjustment for parkinsonism and walking aids, however, patients with dementia walked 0.44 m/s faster than patients without dementia (p = 0.02). Probable explanations are frontal lobe disinhibition and lack of insight, causing patients with dementia to walk relatively too fast in the context of their frailty. Therefore, the high risk of falls in dementia may be partially explained by the loss of control of gait velocity.


Fimbrial adhesins of Salmonella typhimurium. Role in bacterial interactions with epithelial cells.
S. typhimurium initiates infection of its mammalian host by attachment to mucosal surfaces in the intestine and subsequent invasion of epithelial cells. To date, three S. typhimurium fimbrial operons, fim, lpf and pef, have been characterized. This analysis suggests that fimbrial adhesins fulfill multiple functions during the initial phase of an infection. In addition to their role in colonization of the small intestine, adhesins contribute to the tissue tropism for Peyer's patches, which is characteristic for Salmonella infections. Furthermore, by mediating the initial contact to epithelial cells, fimbrial adhesins appear to be necessary for invasion and possibly for elicitation of an inflammatory response. Thus, fimbriae are important virulence factors of S. typhimurium and their future analysis promises to yield fascinating new insights into host-parasite interactions of this pathogen.


Isolation of a chick cytokeratin cDNA clone indicative of regional specialization in early embryonic ectoderm.
During early vertebrate development, a series of inductive tissue interactions appear to be involved in establishing regional specializations that are eventually elaborated in the basic body plan of the embryo. These early inductive interactions are particularly difficult to study because they often occur in the absence of any associated morphological changes. In the chick embryo, the regional subdivision of the early ectoderm is evidenced by a marked lens-forming bias in the head ectoderm, which is absent from the presumptive dorsal epidermis of the trunk region. This striking divergence in developmental state is present long before any differentiation into lens or epidermal phenotypes can be detected. As a strategy for isolating genes whose differential expression might be a reflection of this regional subdivision, a cDNA library was prepared from early embryos and screened for differential hybridization to radiolabelled probes prepared from head ectoderm and trunk ectoderm. Two related cDNA clones were isolated that hybridize to transcripts present at much higher levels in trunk ectoderm than in head ectoderm. Sequence analysis of one of these clones revealed a high degree of similarity to members of the type II subfamily of intermediate filament cytokeratins. This clone (pCKse1) was used to examine cytokeratin gene expression in ectodermal tissues. A large increase in the level of CKse1 transcripts was found to take place in trunk ectoderm, approximately coordinate with neurulation, contrasting sharply with the much lower levels detected in head ectoderm and neural ectoderm at all stages tested. These results indicate that differential cytokeratin gene expression can occur within a contiguous layer of simple embryonic epithelia, and that this expression pattern coincides closely to the subdivision of the early ectoderm into regions with distinct developmental potencies. This type of regulation has not been described previously for members of the cytokeratin gene family.


Prospective evaluation of the feasibility of sentinel lymph node biopsy in breast cancer patients with negative axillary conversion after neoadjuvant chemotherapy.
Tumor response to neoadjuvant chemotherapy (NAC) may adversely affect the identification and accuracy rate of sentinel lymph node biopsy (SLNB). This study was conducted to evaluate the feasibility of SLNB in node-positive breast cancer patients with negative axillary conversion after NAC. Ninety-six patients with positive nodes at presentation were prospectively enrolled. (18)Fluorodeoxyglucose-positron emission tomography ((18)F-FDG PET) and ultrasonography were performed before and after NAC. A metastatic axillary lymph node was defined as positive if it was positive upon both (18)F-FDG PET and ultrasonography, while it was considered negative if it was negative upon both (18)F-FDG PET and ultrasonography. After NAC, 55 cases (57.3%) became clinically node-negative, while 41 cases (42.7%) remained node-positive. In the entire cohort, the sentinel lymph node (SLN) identification and false-negative rates were 84.3% (81/96) and 18.4% (9/49), respectively. In the negative axillary conversion group, the results of SLNB showed an 85.7% (48/55) identification rate and 16.7% (4/24) false-negative rate. For breast cancer patients with clinically positive nodes at presentation, it is difficult to conclude whether the SLN accurately represents the metastatic status of all axillary lymph nodes, even after clinically negative node conversion following NAC.


Outcome of schizophrenic subtypes defined by four diagnostic systems.
This report examines the short- and long-term outcome of the subtypes of schizophrenia as defined by four diagnostic systems: DSM-III, Research Diagnostic Criteria, Ninth Revision of the International Classification of Diseases, and the Tsuang-Winokur (T-W) criteria. Patients were from the Iowa 500 study and met Washington University criteria for schizophrenia. Subtype diagnosis was based on extensive chart material reviewed by investigators blind to outcome. Short-term outcome, based on chart information, and long-term outcome, based on individual field follow-up, were both better for paranoid than for nonparanoid schizophrenia, the difference being greatest using the T-W criteria. The difference in outcome between paranoid and nonparanoid schizophrenia was greater at long-term than at short-term follow-up, and greater using residential and occupational than psychiatric outcome criteria. Outcome did not differ for the two common forms of nonparanoid schizophrenia: hebephrenic and undifferentiated. The subtyping of schizophrenia has important predictive validity, which was greatest using the T-W criteria.


Comparison of single-molecule sequencing and hybrid approaches for finishing the genome of Clostridium autoethanogenum and analysis of CRISPR systems in industrial relevant Clostridia.
Clostridium autoethanogenum strain JA1-1 (DSM 10061) is an acetogen capable of fermenting CO, CO2 and H2 (e.g. from syngas or waste gases) into biofuel ethanol and commodity chemicals such as 2,3-butanediol. A draft genome sequence consisting of 100 contigs has been published. A closed, high-quality genome sequence for C. autoethanogenum DSM10061 was generated using only the latest single-molecule DNA sequencing technology and without the need for manual finishing. It is assigned to the most complex genome classification based upon genome features such as repeats, prophage, nine copies of the rRNA gene operons. It has a low G + C content of 31.1%. Illumina, 454, Illumina/454 hybrid assemblies were generated and then compared to the draft and PacBio assemblies using summary statistics, CGAL, QUAST and REAPR bioinformatics tools and comparative genomic approaches. Assemblies based upon shorter read DNA technologies were confounded by the large number repeats and their size, which in the case of the rRNA gene operons were ~5 kb. CRISPR (Clustered Regularly Interspaced Short Paloindromic Repeats) systems among biotechnologically relevant Clostridia were classified and related to plasmid content and prophages. Potential associations between plasmid content and CRISPR systems may have implications for historical industrial scale Acetone-Butanol-Ethanol (ABE) fermentation failures and future large scale bacterial fermentations. While C. autoethanogenum contains an active CRISPR system, no such system is present in the closely related Clostridium ljungdahlii DSM 13528. A common prophage inserted into the Arg-tRNA shared between the strains suggests a common ancestor. However, C. ljungdahlii contains several additional putative prophages and it has more than double the amount of prophage DNA compared to C. autoethanogenum. Other differences include important metabolic genes for central metabolism (as an additional hydrogenase and the absence of a phophoenolpyruvate synthase) and substrate utilization pathway (mannose and aromatics utilization) that might explain phenotypic differences between C. autoethanogenum and C. ljungdahlii. Single molecule sequencing will be increasingly used to produce finished microbial genomes. The complete genome will facilitate comparative genomics and functional genomics and support future comparisons between Clostridia and studies that examine the evolution of plasmids, bacteriophage and CRISPR systems.


Affective response to color-slide stimuli in subjects with physical anhedonia: a three-systems analysis.
Emotion-provoking visual stimuli were presented to college undergraduates identified as anhedonic or normal, based on their scores on the Physical Anhedonia Scale (Chapman, Chapman, & Raulin, 1976). The affective stimuli (35 mm color slides) were chosen to elicit a wide range of both positive and negative emotion, with emotional response assessed through affective judgments, viewing time, and monitoring of a variety of physiological systems (heart rate, skin conductance, and facial musculature). The experiment was successful in demonstrating differential emotional response in the two subject groups; anhedonic subjects reported a less positive response than control subjects to positive and neutral stimuli and showed no association between heart rate and the emotion content of the slides. Paradoxically, activity in the muscles of facial expression was greater in anhedonic than control subjects during the presentation of both positive and negative slides. No between-group differences were noted in the viewing-time measure. The results are discussed in the context of Lang's bioinformational theory of human emotion (Lang, 1984, 1985).


Genomic Blocks in Aethionema arabicum Support Arabideae as Next Diverging Clade in Brassicaceae.
The tribe Aethionemeae is sister to all other crucifers, making it a crucial group for unraveling genome evolution and phylogenetic relationships within the crown group Brassicaceae. In this study, we extend the analysis of Brassicaceae genomic blocks (GBs) to Aethionema whereby we identified unique block boundaries shared only with the tribe Arabideae. This was achieved using bioinformatic methods to analyze synteny between the recently updated genome sequence of Aethionema arabicum and other high-quality Brassicaceae genome sequences. We show that compared to the largely conserved genomic structure of most non-polyploid Brassicaceae lineages, GBs are highly rearranged in Aethionema. Furthermore, we detected similarities between the genomes of Aethionema and Arabis alpina, in which also a high number of genomic rearrangements compared to those of other Brassicaceae was found. These similarities suggest that tribe Arabideae, a clade showing conflicting phylogenetic position between studies, may have diverged before diversification of the other major lineages, and highlight the potential of synteny information for phylogenetic inference.


A microdeletion proximal of the critical deletion region is associated with mild Wolf-Hirschhorn syndrome.
It is generally accepted that the facial phenotype of Wolf-Hirschhorn syndrome is caused by deletions of either Wolf-Hirschhorn critical regions 1 or 2 (WHSCR 1-2). Here, we identify a 432 kb deletion located 600 kb proximal to both WHSCR1-2 in a patient with a WHS facial phenotype. Seven genes are underlying this deletion region including FAM193a, ADD1, NOP14, GRK4, MFSD10, SH3BP2, TNIP2. The clinical diagnosis of WHS facial phenotype was confirmed by 3D facial analysis using dense surface modeling. Our results suggest that the WHSCR1-2 flanking sequence contributes directly or indirectly to the severity of WHS. Sequencing the Wolf-Hirschhorn syndrome candidate 1 and 2 genes did not reveal any mutations. Long range position effects of the deletion that could influence gene expression within the WHSCR were excluded in EBV cell lines derived from patient lymphoblasts. We hypothesize that either (1) this locus harbors regulatory sequences which affect gene expression in the WHSCR1-2 in a defined temporal and spatial developmental window or (2) that this locus is additive to deletions of WHSCR1-2 increasing the phenotypic expression.


Population genetic structure and phylogeographical pattern of a relict tree fern, Alsophila spinulosa (Cyatheaceae), inferred from cpDNA atpB- rbcL intergenic spacers.
Sequences of chloroplast DNA (cpDNA) atpB- rbcL intergenic spacers of individuals of a tree fern species, Alsophila spinulosa, collected from ten relict populations distributed in the Hainan and Guangdong provinces, and the Guangxi Zhuang region in southern China, were determined. Sequence length varied from 724 bp to 731 bp, showing length polymorphism, and base composition was with high A+T content between 63.17% and 63.95%. Sequences were neutral in terms of evolution (Tajima's criterion D=-1.01899, P>0.10 and Fu and Li's test D*=-1.39008, P>0.10; F*=-1.49775, P>0.10). A total of 19 haplotypes were identified based on nucleotide variation. High levels of haplotype diversity (h=0.744) and nucleotide diversity (Dij=0.01130) were detected in A. spinulosa, probably associated with its long evolutionary history, which has allowed the accumulation of genetic variation within lineages. Both the minimum spanning network and neighbor-joining trees generated for haplotypes demonstrated that current populations of A. spinulosa existing in Hainan, Guangdong, and Guangxi were subdivided into two geographical groups. An analysis of molecular variance indicated that most of the genetic variation (93.49%, P<0.001) was partitioned among regions. Wright's isolation by distance model was not supported across extant populations. Reduced gene flow by the Qiongzhou Strait and inbreeding may result in the geographical subdivision between the Hainan and Guangdong + Guangxi populations (FST=0.95, Nm=0.03). Within each region, the star-like pattern of phylogeography of haplotypes implied a population expansion process during evolutionary history. Gene genealogies together with coalescent theory provided significant information for uncovering phylogeography of A. spinulosa.


Burden on family carers and care-related financial strain at the end of life: a cross-national population-based study.
The rising number of deaths from cancer and other life-limiting illnesses is accompanied by a growing number of family carers who provide long-lasting care, including end-of-life care. This population-based epidemiological study aimed to describe and compare in four European countries the prevalence of and factors associated with physical or emotional overburden and difficulties in covering care-related costs among family carers of people at the end of life. A cross-national retrospective study was conducted via nationwide representative sentinel networks of general practitioners (GPs). Using a standardized form, GPs in Belgium, The Netherlands, Italy and Spain recorded information on the last 3 months of life of every deceased adult practice patient (1 January 2009-31 December 2010). Sudden deaths were excluded. We studied 4466 deaths. GPs judged family carers of 28% (Belgium), 30% (The Netherlands), 35% (Spain) and 71% (Italy) of patients as physically/emotionally overburdened (P < 0.001). For 8% (Spain), 14% (Belgium), 36% (The Netherlands) and 43% (Italy) patients, GPs reported difficulties in covering care-related costs (P < 0.001). Patients <85 years of age (Belgium, Italy) had higher odds of having physically/emotionally overburdened family carers and financial burden. Death from non-malignant illness (vs. cancer) (Belgium and Italy) and dying at home compared with other locations (The Netherlands and Italy) were associated with higher odds of difficulties in covering care-related costs. In all countries studied, and particularly in Italy, GPs observed a considerable extent of physical/emotional overburden as well as difficulties in covering care-related costs among family carers of people at the end of life. Implications for health- and social care policies are discussed.


Identification in Xenopus of a structural homologue of the Drosophila gene snail.
We have cloned a Xenopus cDNA that is related to snail, a gene that is required for mesoderm formation in Drosophila. The cDNA encodes a protein that contains five zinc-fingers that closely resemble those of snail. In the non-canonical parts of the DNA-binding loop, there is almost 90% homology between snail and xsna. The corresponding mRNA (xsna) is expressed strongly at the start of zygotic transcription simultaneously with the transcription factor EF1 alpha. In early gastrulae, xsna is equally distributed between the dorsal and ventral halves of the equatorial zone. The possibility that the capacity to synthesise xsna is more localised before the start of zygotic transcription has been investigated by culturing fragments of stage 8 embryos until xsna is synthesised. The capacity to synthesise xsna at stage 8 is located principally in the dorsal half of the equatorial zone. A small amount of maternal xsna is localised in the vegetal hemisphere before zygotic transcription starts. xsna is not present in isolated animal caps but can be induced by the mesoderm-inducing factors XTC-MIF and bFGF. Synthesis of xsna does not occur autonomously in dispersed cells but is restored when cells reaggregate in the presence of calcium and magnesium.


Adverse Childhood Experiences, Mental Health, and Risk Behaviors in Adulthood: Exploring Sex, Racial, and Ethnic Group Differences in a Nationally Representative Sample.
This study examined sex, racial, and ethnic differences in the short- and long-term associations between adverse childhood experiences (ACEs), mental health, and risk behaviors in a nationally representative sample. Analysis was based on the National Longitudinal Study of Adolescent to Adult Health, a longitudinal cohort of U.S. adolescents followed in five waves of data collection from adolescence to adulthood. Analysis included design-based regression models to examine the associations between ACEs and proximal and distal outcomes (i.e., depression, suicidal ideation, number of sexual partners, binge drinking, current smoker) assessed in the transition to adulthood (mean age 21; 2001-2002) and adulthood (mean age 38; 2016-2018). Sex, racial, and ethnic interactions were included in regression models to examine effect modification in the association of ACEs, mental health, and risk behaviors. In this analytical sample (N = 9,690), we identified a graded association between ACEs and depression, suicide ideation, and current smoker status at both time points (i.e., mean age 21 and 38). Sex moderated the relationship between ACEs and depression at mean age 21, while race (i.e., American Indian versus White) moderated the relationship between ACEs and number of sexual partners at mean age 38. A greater number of cumulative traumatic experiences in childhood may amplify adverse health outcomes among women and adults of American Indian descent in particular.


Structure of the Mycobacterium smegmatis α-maltose-1-phosphate synthase GlgM.
Mycobacterium tuberculosis produces glycogen (also known as α-glucan) to help evade human immunity. This pathogen uses the GlgE pathway to generate glycogen rather than the more well known glycogen synthase GlgA pathway, which is absent in this bacterium. Thus, the building block for this glucose polymer is α-maltose-1-phosphate rather than an NDP-glucose donor. One of the routes to α-maltose-1-phosphate is now known to involve the GlgA homologue GlgM, which uses ADP-glucose as a donor and α-glucose-1-phosphate as an acceptor. To help compare GlgA (a GT5 family member) with GlgM enzymes (GT4 family members), the X-ray crystal structure of GlgM from Mycobacterium smegmatis was solved to 1.9 Å resolution. While the enzymes shared a GT-B fold and several residues responsible for binding the donor substrate, they differed in some secondary-structural details, particularly in the N-terminal domain, which would be expected to be largely responsible for their different acceptor-substrate specificities.


Transparency and imaginary colors.
Unlike the Metelli monochrome transparencies, when overlays and their backgrounds have chromatic content, the inferred surface colors may not always be physically realizable, and are in some sense "imaginary." In these cases, the inferred chromatic transmittance or reflectance of the overlay lies outside the RGB spectral boundaries. Using the classical Metelli configuration, we demonstrate this illusion and briefly explore some of its attributes. Some observer differences in perceiving transparencies are also highlighted. These results show that the perception of transparency is much more complex than conventionally envisioned.


Nonlinear temporal dynamics of the cerebral blood flow response.
The linearity of the cerebral perfusion response relative to stimulus duration is an important consideration in the characterization of the relationship between regional cerebral blood flow (CBF), cerebral metabolism, and the blood oxygenation level dependent (BOLD) signal. It is also a critical component in the design and analysis of functional neuroimaging studies. To study the linearity of the CBF response to different duration stimuli, the perfusion response in primary motor and visual cortices was measured during stimulation using an arterial spin labeling technique with magnetic resonance imaging (MRI) that allows simultaneous measurement of CBF and BOLD changes. In each study, the perfusion response was measured for stimuli lasting 2, 6, and 18 sec. The CBF response was found in general to be nonlinearly related to stimulus duration, although the strength of nonlinearity varied between the motor and visual cortices. In contrast, the BOLD response was found to be strongly nonlinear in both regions studied, in agreement with previous findings. The observed nonlinearities are consistent with a model with a nonlinear step from stimulus to neural activity, a linear step from neural activity to CBF change, and a nonlinear step from CBF change to BOLD signal change.


The value of survival gains in myelodysplastic syndromes.
To measure the value of survival gains attributable to the introduction of 3 novel therapies for myelodysplastic syndromes (MDS). Retrospective study of patients diagnosed with MDS in the Surveillance, Epidemiology and End Results Program (SEER) registry, clinical trial evidence for MDS therapies, and claims data. We used multivariate Cox proportional hazards models to estimate the increase in survival associated with the introduction of the 3 new therapies for patients diagnosed with MDS from 2001 to 2011 in the SEER cancer registry. Increases in survival associated with the 3 novel therapies were estimated using retrospective survival analyses and published clinical trial evidence. MDS treatment costs were estimated using Ingenix claims data and used to calculate the share of the value of survival gains retained by patients. We estimated that the introduction of these 3 therapies is associated with a hazard ratio of 0.901 (P <.10), and a 73% increase in median survival from 33 to 57 months. We estimated that for current and future MDS patients, these 3 therapies will generate over $193 billion in cumulative value through extensions in patient survival. This study demonstrates that the value of recently approved innovative therapies in MDS is large and that the value of survival gains in MDS far outweighs their costs.