A rare case report: bilateral occipital artery arising from the vertebral artery.
Variations of the origin of the occipital artery (OA) can be considered as congenital anomalies that are often asymptomatic and detected incidentally on angiography or during cadaver dissection. While OA normally originates from the posterior aspect of the external carotid artery (ECA), recent evidence also reflects that OA may infrequently originate from the internal carotid artery (ICA); however, OA originating from the vertebral artery (VA) is a highly rare phenomenon. In a 54-year-old female patient with the complaint of left hemiparesis, computed tomography (CT) angiography revealed nonstenotic calcified plaques at the beginning of right ICA where common carotid artery (CCA) bifurcates. We also incidentally observed that bilateral OA originated from the VA using maximum intensity projection (MIP) technique. In addition to this rare variation, CT angiography showed the osseous anomaly termed as high-riding VA (HRVA) in the C1/2 vertebral space of the V3 segment of the VA. To the best of our knowledge, a case of bilateral OA originating from the VA has not been reported to date. We believe that recognition of this rare variation may contribute to the relevant literature and it is of importance to consider this variation in radiological imaging and surgical procedures involving this region.


Marine tubeworm metamorphosis induced by arrays of bacterial phage tail-like structures.
Many benthic marine animal populations are established and maintained by free-swimming larvae that recognize cues from surface-bound bacteria to settle and metamorphose. Larvae of the tubeworm Hydroides elegans, an important biofouling agent, require contact with surface-bound bacteria to undergo metamorphosis; however, the mechanisms that underpin this microbially mediated developmental transition have been enigmatic. Here, we show that a marine bacterium, Pseudoalteromonas luteoviolacea, produces arrays of phage tail-like structures that trigger metamorphosis of H. elegans. These arrays comprise about 100 contractile structures with outward-facing baseplates, linked by tail fibers and a dynamic hexagonal net. Not only do these arrays suggest a novel form of bacterium-animal interaction, they provide an entry point to understanding how marine biofilms can trigger animal development.


Effects of host plant on life-history traits in the polyphagous spider mite Tetranychus urticae.
Studying antagonistic coevolution between host plants and herbivores is particularly relevant for polyphagous species that can experience a great diversity of host plants with a large range of defenses. Here, we performed experimental evolution with the polyphagous spider mite Tetranychus urticae to detect how mites can exploit host plants. We thus compared on a same host the performance of replicated populations from an ancestral one reared for hundreds of generations on cucumber plants that were shifted to either tomato or cucumber plants. We controlled for maternal effects by rearing females from all replicated populations on either tomato or cucumber leaves, crossing this factor with the host plant in a factorial design. About 24 generations after the host shift and for all individual mites, we measured the following fitness components on tomato leaf fragments: survival at all stages, acceptance of the host plant by juvenile and adult mites, longevity, and female fecundity. The host plant on which mite populations had evolved did not affect the performance of the mites, but only affected their sex ratio. Females that lived on tomato plants for circa 24 generations produced a higher proportion of daughters than did females that lived on cucumber plants. In contrast, maternal effects influenced juvenile survival, acceptance of the host plant by adult mites and female fecundity. Independently of the host plant species on which their population had evolved, females reared on the tomato maternal environment produced offspring that survived better on tomato as juveniles, but accepted less this host plant as adults and had a lower fecundity than did females reared on the cucumber maternal environment. We also found that temporal blocks affected mite dispersal and both female longevity and fecundity. Taken together, our results show that the host plant species can affect critical parameters of population dynamics, and most importantly that maternal and environmental conditions can facilitate colonization and exploitation of a novel host in the polyphagous T. urticae, by affecting dispersal behavior (host acceptance) and female fecundity.


Phosphodiesterase 6β Expression In Developing Mouse Retina.
The rd1 mouse is a well-studied model of retinitis pigmentosa (RP), an inherited retinal degenerative disease affecting approximately 1 in 4000 people. It is characterized by a mutation in the Pde6b gene that codes for Phosphodiesterase 6β (PDE6β), a downstream effector of phototransduction. Pde6b gene expression occurs embryonically in mouse retina, whereas other proteins involved in phototransduction are expressed around postnatal day 5 (P5). The primary aim of this study is to investigate the temporal and spatial expression pattern of PDE6β protein during photoreceptor development. Using Western blots with wild type and rd1 mouse retinas from P2 - P21 we demonstrated that PDE6β protein is expressed in wild type retinas by P2 and is not detected in rd1 retinas. The earliest detection of PDE6β in wild type retinas by immunohistochemistry was at P6, where it was confined to the apical region of the photoreceptor layer. The expression of PDE6β protein prior to differentiation of photoreceptor cells and prior to expression of other phototransduction proteins is consistent with the hypothesis that PDE6β may play a role during photoreceptor development distinct from its role in phototransduction. Our lab previously showed that Prenylated Rab Acceptor 1 (PRA1), a vesicular trafficking protein, is downregulated in the developing rd1 retina, although its function in the retina is unknown. The second aim of this study was to explore the relationship between PRA1 and PDE6β. We used immunohistochemistry to determine whether the two proteins are co-localized during the postnatal differentiation period. However, no co-localization between PDE6β and PRA1 was detected. The function of PRA1 in developing retina remains to be elucidated.


Race Disparities and Decreasing Birth Weight: Are All Babies Getting Smaller?
The mean infant birth weight in the United States increased for decades, but it might now be decreasing. Given race disparities in fetal growth, we explored race-specific trends in birth weight at Magee-Womens Hospital, Pittsburgh, Pennsylvania, from 1997 to 2011. Among singleton births delivered at 37-41 weeks (n = 70,607), we evaluated the proportions who were small for gestational age and large for gestational age and changes in mean birth weights over time. Results were stratified by maternal race/ethnicity. Since 1997, the number of infants born small for their gestational ages increased (8.7%-9.9%), whereas the number born large for their gestational ages decreased (8.9%-7.7%). After adjustment for gestational week at birth, maternal characteristics, and pregnancy conditions, birth weight decreased by 2.20 g per year (P < 0.0001). Decreases were greater for spontaneous births. Reductions were significantly greater in infants born to African-American women than in those born to white women (-3.78 vs. -1.88 per year; P for interaction = 0.010). Quantile regression models indicated that birth weight decreased across the entire distribution, but reductions among infants born to African-American women were limited to those in the upper quartile after accounting for maternal factors. Limiting the analysis to low-risk women eliminated birth weight reductions. Birth weight has decreased in recent years, and reductions were greater in infants born to African-American women. These trends might be explained by accumulation of risk factors such as hypertension and prepregnancy obesity that disproportionately affect African-American women. Our results raise the possibility of worsening race disparities in fetal growth.


Seasonality in mortality and its relationship to temperature among the older population in Hanoi, Vietnam.
Several studies have established a relationship between temperature and mortality. In particular, older populations have been shown to be vulnerable to temperature effects. However, little information exists on the temperature-mortality relationship in Vietnam. This article aims to examine the monthly temperature-mortality relationship among older people in Hanoi, Vietnam, over the period between 2005 and 2010, and estimate seasonal patterns in mortality. We employed Generalized Additive Models, including smooth functions, to model the temperature-mortality relationships. A quasi-Poisson distribution was used to model overdispersion of death counts. Temporal trends, seasonality, and population size were adjusted for while estimating changes in monthly mortality over the study period. A cold month was defined as a month with a mean temperature below 19°C. This study found that the high peak of mortality coincided with low temperatures in the month of February 2008, during which the mean temperature was the lowest in the whole study period. There was a significant relationship between mean monthly temperature and mortality among the older people (p<0.01). Overall, there was a significant decrease in the number of deaths in the year 2009 during the study period. There was a 21% increase in the number of deaths during the cold season compared to the warm season. The increase in mortality during the cold period was higher among females compared to males (female: IRR [incidence relative risk] =1.23; male: IRR=1.18). Cold temperatures substantially increased mortality among the older population in Hanoi, Vietnam, and there were gender differences. Necessary preventive measures are required to mitigate temperature effects with greater attention to vulnerable groups.


Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis.
Severe bacterial sepsis often leads to a systemic procoagulant and proinflammatory condition that can manifest as disseminated intravascular coagulation, septic shock, and multiple organ failure. Because activation of the contact proteases factor XII (FXII), prekallikrein, and factor XI (FXI) can trigger coagulation and inflammatory responses, the contact factors have been considered potential targets for the treatment of sepsis. However, the pathogenic role of contact activation in severe infections has not been well defined. We therefore investigated whether an anticoagulant antibody (14E11) that selectively inhibits prothrombotic FXI activation by activated FXII (FXIIa) modifies the course of bowel perforation-induced peritoneal sepsis in mice. Early anticoagulation with 14E11 suppressed systemic thrombin- antithrombin complex formation, IL-6, and TNF-α levels, and reduced platelet consumption in the circulation and deposition in the blood vessels. Treatment with 14E11 within 12 hours after bowel perforation significantly improved survival compared with vehicle treatment, and the saturating dose did not increase tail bleeding. These data suggest that severe polymicrobial abdominal infection induces prothrombotic FXI activation, to the detriment of the host. Systemic anticoagulation by inhibiting FXI activation or FXIIa procoagulant activity during sepsis may therefore limit the development of disseminated intravascular coagulation without increasing bleeding risks.


B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice.
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antinuclear autoantibodies. Antinuclear autoantibody development is recognized as one of the initial stages of disease that often results in systemic inflammation, kidney disease, and death. The etiology is complex, but it is clear that innate pathways may play an important role in disease progression. Recent data have highlighted an important role for the TLR family, particularly TLR7, in both human disease and murine models. In this study, we have presented a low copy conditional TLR7 transgenic (Tg7) mouse strain that does not develop spontaneous autoimmunity. When we combine Tg7 with the Sle1 lupus susceptibility locus, the mice develop severe disease. Using the CD19(Cre) recombinase system, we normalized expression of TLR7 solely within the B cells. Using this method we demonstrated that overexpression of TLR7 within the B cell compartment reduces the marginal zone B cell compartment and increases B and T cell activation but not T follicular helper cell development. Moreover, this enhanced B cell TLR7 expression permits the specific development of Abs to RNA/protein complexes and exacerbates SLE disease.


Pure fruit juice and fruit consumption and the risk of CVD: the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) study.
Dietary guidelines for pure fruit juice consumption differ between countries, regarding the question whether pure fruit juice is an acceptable alternative for fruit. Currently, little is known about pure fruit juice consumption and the risk of CVD. In this prospective cohort study, we studied the association of pure fruit juice and fruit consumption with the incidence of fatal and non-fatal CVD, CHD and stroke and investigated the differences in association with pure fruit juice consumption between low and high fruit consumers. A validated FFQ was used to estimate dietary intake of 34 560 participants (26·0 % men and 74·0 % women) aged 20-69 years from the European Prospective Investigation into Cancer and Nutrition-Netherlands study. Adjusted hazard ratios (HR) were estimated using Cox regression after average follow-up of 14·6 years. Compared with no consumption, pure fruit juice consumption up to 7 glasses/week - but not consumption of ≥8 glasses - was significantly associated with reduced risk of CVD and CHD, with HR from 0·83 (95 % CI 0·73, 0·95) to 0·88 (95 % CI 0·80, 0·97). Consumption of 1-4 and 4-8 glasses/week was significantly associated with lower risk of stroke with HR of 0·80 (95 % CI 0·64, 0·99) and 0·76 (95 % CI 0·61, 0·94), respectively. Associations did not differ considerably between low and high fruit consumers. The highest three quintiles of fruit consumption (≥121 g/d) were significantly associated with lower incidence of CVD, with HR of 0·87 (95 % CI 0·78, 0·97) and 0·88 (95 % CI 0·80, 0·98). In conclusion, although we observed favourable associations of moderate pure fruit juice consumption with CVD, for now consumption of whole fruit should be preferred because the evidence of the health benefits of fruit is more conclusive.


Structurally divergent human T cell receptor gamma proteins encoded by distinct C gamma genes.
The human T cell receptor (TCR) gamma polypeptide occurs in structurally distinct forms on certain peripheral blood T lymphocytes. Complementary DNA clones representing the transcripts of functionally rearranged TCR gamma genes in these cells have been analyzed. The expression of a disulfide-linked and a nondisulfide-linked form of TCR gamma correlates with the use of the C gamma 1 and C gamma 2 constant-region gene segments, respectively. Variability in TCR gamma polypeptide size and disulfide linkage is determined by the number of copies and the sequence of a repeated segment of the constant region. Thus C gamma 1 and C gamma 2 are used to generate structurally distinct, yet functional, T3-associated receptor complexes on peripheral blood lymphocytes. Tryptic peptide mapping suggests that the T3-associated TCR gamma and delta peptides in the nondisulfide-linked form are distinct.


Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.
Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.


ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma.
Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040-56. ©2017 AACR.


Early hematopoiesis inhibition under chronic radiation exposure in humans.
The major goal of this study was to identify and quantitatively describe the association between the characteristics of chronic (low-dose rate) exposure to (low LET) ionizing radiation and cellularity of peripheral blood cell lines. About 3,200 hemograms (i.e., spectra of blood counts) obtained over the years of maximal exposure to ionizing radiation (1950-1956) for inhabitants of the Techa River were used in analyses. The mean cumulative red bone marrow dose (with standard errors), calculated using Techa River Dosimetry System-2000, was 333.6 +/- 4.6 mGy (SD = 259.9 mGy, max = 1151 mGy) to the year 1956. The statistical approach included both empirical methods for estimating frequencies of cytopenic states of the investigated blood cell lines (e.g. neutrophile, platelets, erythrocyte, etc.), and regression methods, including generalized linear models and logistic regressions which allowed taking into account confounding factors (e.g., attained age, age at maximal exposure, presence of concomitant diseases, and demographic characteristics). The results of the analyses demonstrated hematopoiesis inhibition manifested by a decrease in peripheral blood cellularity and an increase in the frequency of cytopenia in all blood cell lines (leukocytes, including lymphocytes, monocytes, neutrophiles, as well as platelets and erythrocytes). The intensity of hematopoiesis inhibition in the period of maximal exposures is determined by the combined influence of the dose rate and cumulative dose. The contribution of specific confounding factors was quantified and shown to be much less important than dose characteristics. The best predictor among dose characteristics was identified for each blood cell line. A 2-fold increase in dose rate is assumed to be a characteristic of radiosensitivity and a quantitative characteristic of the effect.


Stationarity of the inter-event power-law distributions.
A number of human activities exhibit a bursty pattern, namely periods of very high activity that are followed by rest periods. Records of these processes generate time series of events whose inter-event times follow a probability distribution that displays a fat tail. The grounds for such phenomenon are not yet clearly understood. In the present work we use the freely available Wikipedia's editing records to unravel some features of this phenomenon. We show that even though the probability to start editing is conditioned by the circadian 24 hour cycle, the conditional probability for the time interval between successive edits at a given time of the day is independent from the latter. We confirm our findings with the activity of posting on the social network Twitter. Our results suggest that there is an intrinsic humankind scheduling pattern: after overcoming the encumbrance of starting an activity, there is a robust distribution of new related actions, which does not depend on the time of day at which the activity started.


The genome of model malaria parasites, and comparative genomics.
The field of comparative genomics of malaria parasites has recently come of age with the completion of the whole genome sequences of the human malaria parasite Plasmodium falciparum and a rodent malaria model, Plasmodium yoelii yoelii. With several other genome sequencing projects of different model and human malaria parasite species underway, comparing genomes from multiple species has necessitated the development of improved informatics tools and analyses. Results from initial comparative analyses reveal striking conservation of gene synteny between malaria species within conserved chromosome cores, in contrast to reduced homology within subtelomeric regions, in line with previous findings on a smaller scale. Genes that elicit a host immune response are frequently found to be species-specific, although a large variant multigene family is common to many rodent malaria species and Plasmodium vivax. Sequence alignment of syntenic regions from multiple species has revealed the similarity between species in coding regions to be high relative to non-coding regions, and phylogenetic footprinting studies promise to reveal conserved motifs in the latter. Comparison of non-synonymous substitution rates between orthologous genes is proving a powerful technique for identifying genes under selection pressure, and may be useful for vaccine design. This is a stimulating time for comparative genomics of model and human malaria parasites, which promises to produce useful results for the development of antimalarial drugs and vaccines.


Role of Smad proteins in the regulation of NF-kappaB by TGF-beta in colon cancer cells.
Nuclear factor kappa B (NF-kappaB) has been implicated in cancer cell survival. We explored the role of the TGF-beta pathway in the regulation of NF-kappaB in colon cancer cells. TGF-beta-1 treatment of the colon adenocarcinoma cell line FET-1, results in an early increase in IkappaB-alpha phosphorylation that precedes NF-kappaB nuclear translocation and DNA binding activity. Activation of the TGF-beta type I receptor is required for the TGF-beta-mediated activation of NF-kappaB. No activation of NF-kappaB is observed in a Smad4 null cell line, SW480, even though TGF-beta does result in IkappaB-alpha phosphorylation in these cells. Smad4 restores the TGF-beta-1-mediated NF-kappaB activation in SW480 cells. TGF-beta-1 treatment fails to activate NF-kappaB or phosphorylate IkappaB-alpha in FET-1 cells expressing the inhibitory Smad, Smad7. Taken together, these results suggest a role for Smad4 in the transcriptional activation of NF-kappaB, and a direct effect of Smad 7 inhibiting IkappaB-alpha phosphorylation rather than through the well-established inhibition of Smad2/3 phosphorylation with subsequent inhibition of the TGF-beta pathway.


Community REACH: An Implementation of an Evidence-Based Caregiver Program.
Family caregivers (CGs) are critical to the provision of long-term services and support for older adults. Numerous intervention programs to alleviate CG distress have been developed and evaluated yet few have been implemented in community settings. This paper describes and presents outcomes from Community REACH, a community implementation of the evidence-based Resources for Enhancing Alzheimer's Caregiver Health (REACH) II program. Community REACH involved a partnership between REACH II investigators and United HomeCare Services (UHCS), a nonprofit home health organization that provides home health, personal care, companion, and respite services. The intervention program, an adapted version of an evidence-based program, was a 6-month multicomponent psychosocial intervention, which involved six individual face-to-face and six individual telephone sessions, and telephone support groups. One hundred and forty-six CGs who were primarily female (76%) and Latino, and providing care for an individual with Alzheimer's disease (AD) were enrolled. Program effectiveness was assessed by examining changes in perceived social support, burden, and depression, and CG self-efficacy. At 6 months, CGs reported significant decreases in depression, burden, being and bothered by the care recipient's memory problems. There was also a significant decline in the number of CGs at risk for clinical depression. These improvements were maintained at 12 months and there was an increase in feelings of social support. The findings indicate that evidence-based CG programs can be successfully implemented in community settings and benefit CGs of AD patients. A continued partnership between the program developers and community partners is key to implementation success.


Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment.
Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3% to 5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMP-activated protein kinase (AMPK)-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of COX-1/COX-2 and modulation of the NFκB or STAT3 pathway. In addition, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β-catenin, and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer.


Spectroscopic approaches to resolving ambiguities of hyper-polarized NMR signals from different reaction cascades.
The influx of exogenous substrates into cellular reaction cascades on the seconds time scale is directly observable by NMR spectroscopy when using nuclear spin polarization enhancement. Conventional NMR assignment spectra for the identification of reaction intermediates are not applicable in these experiments due to the non-equilibrium nature of the nuclear spin polarization enhancement. We show that ambiguities in the intracellular identification of transient reaction intermediates can be resolved by experimental schemes using site-specific isotope labelling, optimised referencing and response to external perturbations.


Double-negative metamaterial from conducting spheres with a high-permittivity shell.
A three-dimensional, isotropic metamaterial with double-negative behavior is proposed. The material comprises metallic spheres coated in a high-permittivity shell and dispersed in a host medium. In stark contrast to other Mie resonance-based metamaterial designs, ours relies on the metallic phase behaving as a near-perfect electric conductor, rather than a plasmonic. As such, by tuning the particle dimensions, double-negative behavior can be achieved at any frequency where one can find high-conductivity and high-permittivity materials.


Roughness perception: A multisensory/crossmodal perspective.
Roughness is a perceptual attribute typically associated with certain stimuli that are presented in one of the spatial senses. In auditory research, the term is typically used to describe the harsh effects that are induced by particular sound qualities (i.e., dissonance) and human/animal vocalizations (e.g., screams, distress cries). In the tactile domain, roughness is a crucial factor determining the perceptual features of a surface. The same feature can also be ascertained visually, by means of the extraction of pattern features that determine the haptic quality of surfaces, such as grain size and density. By contrast, the term roughness has rarely been applied to the description of those stimuli perceived via the chemical senses. In this review, we take a critical look at the putative meaning(s) of the term roughness, when used in both unisensory and multisensory contexts, in an attempt to answer two key questions: (1) Is the use of the term 'roughness' the same in each modality when considered individually? and (2) Do crossmodal correspondences involving roughness match distinct perceptual features or (at least on certain occasions) do they merely pick-up on an amodal property? We start by examining the use of the term in the auditory domain. Next, we summarize the ways in which the term roughness has been used in the literature on tactile and visual perception, and in the domain of olfaction and gustation. Then, we move on to the crossmodal context, reviewing the literature on the perception of roughness in the audiovisual, audiotactile, and auditory-gustatory/olfactory domains. Finally, we highlight some limitations of the reviewed literature and we outline a number of key directions for future empirical research in roughness perception.


Clinical Features of Lysosomal Acid Lipase Deficiency.
The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults. Investigators reviewed medical records of LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset. A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ∼1.15 multiples of normal (MN) and median spleen volume was ∼2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years). This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.


Economic reasoning and artificial intelligence.
The field of artificial intelligence (AI) strives to build rational agents capable of perceiving the world around them and taking actions to advance specified goals. Put another way, AI researchers aim to construct a synthetic homo economicus, the mythical perfectly rational agent of neoclassical economics. We review progress toward creating this new species of machine, machina economicus, and discuss some challenges in designing AIs that can reason effectively in economic contexts. Supposing that AI succeeds in this quest, or at least comes close enough that it is useful to think about AIs in rationalistic terms, we ask how to design the rules of interaction in multi-agent systems that come to represent an economy of AIs. Theories of normative design from economics may prove more relevant for artificial agents than human agents, with AIs that better respect idealized assumptions of rationality than people, interacting through novel rules and incentive systems quite distinct from those tailored for people.


Trajectories of suicide ideation and nonsuicidal self-injury among adolescents in mainland China: Peer predictors, joint development, and risk for suicide attempts.
This study expanded knowledge about the development of suicide ideation and nonsuicidal self-injury (NSSI) among adolescents by investigating (a) peer experiences as predictors of trajectories of suicide ideation and NSSI, (b) the joint development of suicide ideation and NSSI, and (c) the risk for suicide attempts (SA) across joint trajectories of suicide ideation and NSSI. At baseline, 565 tenth-grade Chinese adolescents (48.3% males) reported depressive symptoms and friend support. Moreover, peer victimization and friendships were assessed using a sociometric procedure. After baseline, participants completed measures of suicide ideation, NSSI, and SA every 3 months for 2 years. Three similar trajectories of suicide ideation and NSSI were identified. After accounting for depressive symptoms, peer victimization differentiated adolescents in the high trajectory of suicide ideation and NSSI from those in the low and moderate trajectories of suicide ideation and NSSI, respectively. Friend support and friendlessness distinguished between the high and low and the moderate and low NSSI trajectories, respectively. Joint trajectory models revealed a strong overlap between the course of suicide ideation and NSSI: Adolescents in the chronically high suicide ideation trajectory were at the highest risk to follow a chronically high NSSI trajectory and vice versa. Finally, adolescents in the joint chronically high trajectory were approximately 5 times more likely to report SA than were their peers, above and beyond prior SA. Findings highlight the role of negative peer experiences as risk factors for NSSI and suicide ideation, which, in turn, can potentially increase risk for SA. (PsycINFO Database Record


Universal Design in Architectural Education - Community Liaison on 'Live Projects'.
The infusion of Universal Design principles into existing courses in architecture should become evident in any project work undertaken. 'Live project' is a term used to describe projects that engage the academic world with real-world groups/organizations. CCAE sees such projects as valuable exercises in a student's education, particularly, the practical experience of interaction with 'user-experts.' In 2016 Cork County Council approached CCAE with a proposal to promote age-friendly housing as part of their age-friendly initiative. CCAE developed this into a 'live project' for Year 2 architecture students, continuing the integration of UD into the curriculum. This helps students to identify the negative disabling aspects of ageing and show UD principles can be seen as commonplace. For their part, the County Council were able to expand their own thinking, availing of the less constrained ideas that students brought to their schemes. An approach to achieving the adoption of UD is to consider the Vitruvian definition of architecture as having 'commodity, firmness and delight'. From this, the aesthetic integration of features to benefit users of limited ability can be achieved without stigmatising anyone as being old or disabled. Now in its second year the project is being run in West Cork. The chosen site in Bantry town centre, has interesting challenges for the students to incorporate UD principles. This paper will present imaginative but viable projects as examples of student' responses to the challenges of designing housing solutions and will report on their ability to integrate age-friendly features at different scales.


Polarization control of defect modes in three-dimensional woodpile photonic crystals.
The symmetry of a Fabry-Perot-like planar cavity embedded within a three-dimensional (3D) woodpile photonic crystal prevents the observation of polarization effects. In this letter we propose a geometry to break the degeneracy of the Fabry-Perot-like cavity modes by introducing asymmetry. The introduction of a one-dimensional (1D) lattice to the centre of a planar cavity allows for distinct modes parallel (TE) and perpendicular (TM) to the layer. This hybrid 3D-1D-3D lattice structure exhibits a pronounced increase in the quality-factor, and in particular shows an increase of up to 50% more than that of a planar cavity for TM modes.


RESOLFT Nanoscopy of Fixed Cells Using a Z-Domain Based Fusion Protein for Labelling.
RESOLFT super-resolution microscopy allows subdiffraction resolution imaging of living cells using low intensities of light. It relies on the light-driven switching of reversible switchable fluorescent proteins (RSFPs). So far, RESOLFT imaging was restricted to living cells, because chemical fixation typically affects the switching characteristics of RSFPs. In this study we created a fusion construct (FLASR) consisting of the RSFP rsEGFP2 and the divalent form of the antibody binding Z domain from protein A. FLASR can be used analogous to secondary antibodies in conventional immunochemistry, facilitating simple and robust sample preparation. We demonstrate RESOLFT super-resolution microscopy on chemically fixed mammalian cells. The approach may be extended to other super-resolution approaches requiring fluorescent proteins in an aqueous environment.


Canopy Temperature and Vegetation Indices from High-Throughput Phenotyping Improve Accuracy of Pedigree and Genomic Selection for Grain Yield in Wheat.
Genomic selection can be applied prior to phenotyping, enabling shorter breeding cycles and greater rates of genetic gain relative to phenotypic selection. Traits measured using high-throughput phenotyping based on proximal or remote sensing could be useful for improving pedigree and genomic prediction model accuracies for traits not yet possible to phenotype directly. We tested if using aerial measurements of canopy temperature, and green and red normalized difference vegetation index as secondary traits in pedigree and genomic best linear unbiased prediction models could increase accuracy for grain yield in wheat, Triticum aestivum L., using 557 lines in five environments. Secondary traits on training and test sets, and grain yield on the training set were modeled as multivariate, and compared to univariate models with grain yield on the training set only. Cross validation accuracies were estimated within and across-environment, with and without replication, and with and without correcting for days to heading. We observed that, within environment, with unreplicated secondary trait data, and without correcting for days to heading, secondary traits increased accuracies for grain yield by 56% in pedigree, and 70% in genomic prediction models, on average. Secondary traits increased accuracy slightly more when replicated, and considerably less when models corrected for days to heading. In across-environment prediction, trends were similar but less consistent. These results show that secondary traits measured in high-throughput could be used in pedigree and genomic prediction to improve accuracy. This approach could improve selection in wheat during early stages if validated in early-generation breeding plots.


Biological and analytical characterization of two extracts from Valeriana officinalis.
The anticoronaryspastic and antibronchospastic activities of ethanolic and aqueous extracts of Valeriana officinalis L. roots were investigated in anaesthetized guinea-pigs and the results were correlated with the qualitative/quantitative chemical composition of the extracts in order to account for some of the common uses of this plant. The protective effects of orally administered ethanolic and aqueous extracts (50, 100 and 200 mg/kg) were evaluated against pitressin-induced coronary spasm and pressor response in guinea-pigs and were compared with those of nifedipine. Furthermore, the protective effects against histamine-induced and Oleaceae antigen challenge-induced bronchospasm were evaluated. Finally, the two valerian extracts were analytically characterized by qualitative and quantitative chromatographic analysis. The results showed that the two valeriana extracts possessed significant anticoronaryspastic, antihypertensive and antibronchospastic properties. These were similar to those exhibited by nifedipine and are due to the structural features of the active principles they contain. This study justifies the traditional use of this plant in the treatment of some respiratory and cardiovascular disorders.


Effects of arsenic trioxide, all-trans-retinoic acid and dexamethasone on NB4 cell line.
Experimental and preclinical observations have indicated that combination therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) may strongly enhance their therapeutic effects in the treatment of acute promyelocytic leukemia (APL). Whilst dexamethasone (Dex) is routinely used for the control of APL- differentiation syndrome, its effect on the pharmacodynamics of ATO is not clear. Therefore, in this study, effects of therapeutic concentrations of ATO, ATRA and Dex and their sequential usages on the proliferation, differentiation and apoptosis in t(15;17)-positive NB4 cells was investigated. Cells were treated with therapeutic concentrations of ATO, ATRA and Dex either as single or in combination and cell proliferation was assessed by XTT assay. Expression of CD11b as an indicator of cell differentiation and the percentage of 7-AAD positive cells as a marker of apoptosis were determined by flow cytometry. ATO, but not ATRA and Dex, decreased proliferation of the cells dose-dependently. Pre-treatment of the cells with any of the drugs did not alter the effects of other drugs on the proliferation. Pre-treatments with Dex blocked the apoptotic effect of ATO (1 µM). No improvement or antagonistic effects was observed with the pretreatment/ combination of the ATO and ATRA on the differentiation and apoptosis of the cells. It is possible that concomitant usage of Dex with apoptotic doses of ATO in APL patients counteract therapeutic effects of ATO.


Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer.
Lymphatic vasculature is crucial for metastasis in triple-negative breast cancer (TNBC); however, cellular and molecular drivers controlling lymphovascular metastasis are poorly understood. We define a macrophage-dependent signaling cascade that facilitates metastasis through lymphovascular remodeling. TNBC cells instigate mRNA changes in macrophages, resulting in β4 integrin-dependent adhesion to the lymphovasculature. β4 integrin retains macrophages proximal to lymphatic endothelial cells (LECs), where release of TGF-β1 drives LEC contraction via RhoA activation. Macrophages promote gross architectural changes to lymphovasculature by increasing dilation, hyperpermeability, and disorganization. TGF-β1 drives β4 integrin clustering at the macrophage plasma membrane, further promoting macrophage adhesion and demonstrating the dual functionality of TGF-β1 signaling in this context. β4 integrin-expressing macrophages were identified in human breast tumors, and a combination of vascular-remodeling macrophage gene signature and TGF-β signaling scores correlates with metastasis. We postulate that future clinical strategies for patients with TNBC should target crosstalk between β4 integrin and TGF-β1.


Fruit and vegetable intake and mortality from ischaemic heart disease: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study.
A higher intake of fruits and vegetables has been associated with a lower risk of ischaemic heart disease (IHD), but there is some uncertainty about the interpretation of this association. The objective was to assess the relation between fruit and vegetable intake and risk of mortality from IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study. After an average of 8.4 years of follow-up, there were 1636 deaths from IHD among 313 074 men and women without previous myocardial infarction or stroke from eight European countries. Participants consuming at least eight portions (80 g each) of fruits and vegetables a day had a 22% lower risk of fatal IHD [relative risk (RR) = 0.78, 95% confidence interval (CI): 0.65-0.95] compared with those consuming fewer than three portions a day. After calibration of fruit and vegetable intake to account for differences in dietary assessment between the participating centres, a one portion (80 g) increment in fruit and vegetable intake was associated with a 4% lower risk of fatal IHD (RR = 0.96, 95% CI: 0.92-1.00, P for trend = 0.033). Results from this large observational study suggest that a higher intake of fruits and vegetables is associated with a reduced risk of IHD mortality. Whether this association is causal and, if so, the biological mechanism(s) by which fruits and vegetables operate to lower IHD risks remains unclear.


Australians' use of surrogacy.
To investigate the characteristics of parents and intended parents and their current and planned behaviour in relation to surrogacy arrangements. Members of two Australian parenting support forums who were considering surrogacy or were currently or previously in a surrogacy arrangement were invited to complete an online survey during July 2013. Sociodemographic characteristics; proportions engaging in domestic uncompensated and overseas compensated arrangements; countries used; costs incurred; and impact on behaviour of state laws criminalising compensated surrogacy. Of 1135 potential participants, 312 (27%) commenced the survey. Of these, 24 did not fulfil inclusion criteria and 29 did not complete the survey. Eighty-nine respondents were considering surrogacy and 170 had commenced or completed surrogacy. Many respondents (53%) considered both overseas and domestic surrogacy. Among those who only considered one option, overseas surrogacy was considered significantly more often than domestic surrogacy (92% v 8%; P < 0.05). Only 22 respondents (8%) commenced with a surrogate in Australia. The most common countries used for compensated surrogacy were India and the United States, and average total estimated costs were $69 212 for India and $172 347 for the US. Barriers discouraging domestic surrogacy included concern that the surrogate might keep the child (75%), belief that it was too long and complicated a process (68%) and having no one of the right age or life stage to ask (61%). Few intended parents (9%) were deterred by state laws criminalising compensated surrogacy. Most Australian intended parents via surrogacy consider or use overseas compensated arrangements. Laws banning compensated surrogacy do not appear to deter those seeking surrogacy arrangements.


Lessons learned in shaping vaccine markets in low-income countries: a review of the vaccine market segment supported by the GAVI Alliance.
The Global Alliance for Vaccines and Immunization (GAVI) anticipated that growing demand for new vaccines could sufficiently impact the vaccines market to allow low-income countries (LICs) to self-finance new vaccines. But the time required to lower vaccine prices was underestimated and the amount that prices would decline overestimated. To better understand how prices in the LIC vaccine market can be impacted, the vaccine market was retrospectively examined. GAVI archives and the published literature on the vaccine markets in LICs were reviewed for the purpose of identifying GAVI's early assumptions for the evolution of vaccine prices, and contrasting these retrospectively with actual outcomes. The prices in Phases I and II of GAVI-supported vaccines failed to decline to a desirable level within a projected 5-year timeframe. GAVI-eligible countries were unable to sustain newly introduced vaccines without prolonged donor support. Two key lessons can be applied to future vaccine market-shaping strategies: (1) accurate demand forecasting together with committed donor funding can increase supply to the LIC vaccines market, but even greater strides can be made to increase the certainty of purchase; and (2) the expected time to lower prices took much longer than 5 years; market competition is inherently linked to the development time for new vaccines--a minimum of 5-10 or more years. Other factors that can lower vaccine prices include: large-scale production or alternate financing mechanisms that can hasten vaccine price maturation. The impacts of competition on vaccine prices in the LIC new-vaccines market occurred after almost 10 years. The time for research and development, acquisition of technological know-how and to scale production must be accounted for to more accurately predict significant declines on vaccine prices. Alternate financing mechanisms and the use of purchase agreements should also be considered for lowering prices when planning new vaccine introductions.


Adverse Childhood Experiences Among Hispanic Children in Immigrant Families Versus US-Native Families.
To examine the prevalence of child and family characteristics associated with adverse childhood experiences (ACEs) in Hispanic children in immigrant families compared with Hispanic children in US-native families. Data were from the nationally representative 2011-2012 National Survey of Children's Health. Parent-reported child ACE exposure was classified as no ACEs (0), low ACEs (1), or high ACEs (≥2). By using multinomial logistic regression, we evaluated the odds of low or high ACE exposure versus no ACE exposure by immigrant family status and child and family characteristics (eg, insurance status, child health status, or household-to-income ratio). The study sample included 12 162 Hispanic children. More children in immigrant families lived ≤200% of the federal poverty level compared with children in US-native families (80% vs 47%, respectively; P < .001). Thirty percent of children in US-native families reported high ACEs compared with only 16% of children in immigrant families (P < .001). The odds of high ACE exposure versus no ACE exposure for children in immigrant families compared with US-native children was 0.46 (95% confidence interval: 0.34-0.61). Child and family characteristics did not explain the difference in odds of ACE exposure by immigrant family status. Children in immigrant families had significantly lower odds of ACE exposure despite higher prevalence of poverty. This may not reflect a true health advantage in this population. There may be unmeasured factors that buffer children in immigrant families from ACE exposure, or ACE questions may not capture the adverse experiences specific to immigrant families.


The intestinal environment in health and disease - recent insights on the potential of intestinal bacteria to influence human health.
The human intestine is colonized by a complex microbial ecosystem, which could be considered as a separate organ within the human host, having a coding capacity which exceeds the liver by a factor 100. On the one hand, this extensive microbiome is closely involved in the first-pass metabolism and bioavailability of food and drug compounds. Understanding to which extent each individual's gut microbiota affects the bioavailability and response to orally administered drugs is therefore a first important challenge towards novel drug development strategies. On the other hand, as our microbiota is directly or indirectly involved in the onset of a number of disease states, a new generation of therapeutics may be developed that affect the structure and functioning of the intestinal microbiota and interfere with their specific cross-talk with the human host. Ultimately, the intestinal microbiota may even be used as a biomarker for impending diseases inside or outside the gastrointestinal tract and for the evaluation of responses to specific therapeutic interventions. This review will therefore highlight the importance of the indigenous microbial community and its enormous metabolic potential, microbe-microbe interactions, mechanisms of host-bacterium cross-talk and will discuss the onset of obesity, a specific disease state in which the role of intestinal bacteria becomes more and more apparent. Understanding the importance of the intestinal ecosystem in these phenomena may open the door for new strategies which target the management of the intestinal microbiome into the desired direction and therefore to a completely new type of nutrition research and pharmaceutical design.


Effects of Strength Training on Running Economy in Highly Trained Runners: A Systematic Review With Meta-Analysis of Controlled Trials.
Balsalobre-Fernández, C, Santos-Concejero, J, and Grivas, GV. Effects of strength training on running economy in highly trained runners: a systematic review with meta-analysis of controlled trials. J Strength Cond Res 30(8): 2361-2368, 2016-The purpose of this study was to perform a systematic review and meta-analysis of controlled trials to determine the effect of strength training programs on the running economy (RE) of high-level middle- and long-distance runners. Four electronic databases were searched in September 2015 (PubMed, SPORTDiscus, MEDLINE, and CINAHL) for original research articles. After analyzing 699 resultant original articles, studies were included if the following criteria were met: (a) participants were competitive middle- or long-distance runners; (b) participants had a V[Combining Dot Above]O2max >60 ml·kg·min; (c) studies were controlled trials published in peer-reviewed journals; (d) studies analyzed the effects of strength training programs with a duration greater than 4 weeks; and (e) RE was measured before and after the strength training intervention. Five studies met the inclusion criteria, resulting in a total sample size of 93 competitive, high-level middle- and long-distance runners. Four of the 5 included studies used low to moderate training intensities (40-70% one repetition maximum), and all of them used low to moderate training volume (2-4 resistance lower-body exercises plus up to 200 jumps and 5-10 short sprints) 2-3 times per week for 8-12 weeks. The meta-analyzed effect of strength training programs on RE in high-level middle- and long-distance runners showed a large, beneficial effect (standardized mean difference [95% confidence interval] = -1.42 [-2.23 to -0.60]). In conclusion, a strength training program including low to high intensity resistance exercises and plyometric exercises performed 2-3 times per week for 8-12 weeks is an appropriate strategy to improve RE in highly trained middle- and long-distance runners.


Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear. Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, the discovery of adaptive natural killer (NK) cell subsets associated with certain viral infections, and compelling links between stress, adrenaline, and cytotoxic lymphocyte function, we reassessed the role of cytotoxic lymphocytes in ME/CFS. Forty-eight patients from two independent cohorts fulfilling the Canada 2003 criteria for ME/CFS were evaluated with respect to cytotoxic lymphocyte phenotype and function. Results were compared to values from matched healthy controls. Reproducible differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, or cytokine production. One patient expressed low levels of perforin, explained by homozygosity for the PRF1 p.A91V variant. However, overall, this variant was present in a heterozygous state at the expected population frequency among ME/CFS patients. No single patient displayed any pathological patterns of cellular responses. Increased expansions of adaptive NK cells or deviant cytotoxic lymphocyte adrenaline-mediated inhibition were not observed. In addition, supervised dimensionality reduction analyses of the full, multidimensional datasets did not reveal any reproducible patient/control discriminators. In summary, employing sensitive assays and analyses for quantification of cytotoxic lymphocyte differentiation and function, cytotoxicity lymphocyte aberrances were not found among ME/CFS patients. These assessments of cytotoxic lymphocytes therefore do not provide useful biomarkers for the diagnosis of ME/CFS.


Simulations of multi-beam sonar echos from schooling individual fish in a quiet environment.
A model is developed and demonstrated for simulating echosounder and sonar observations of fish schools with specified shapes and composed of individuals having specified target strengths and behaviors. The model emulates the performances of actual multi-frequency echosounders and multi-beam echosounders and sonars and generates synthetic echograms of fish schools that can be compared with real echograms. The model enables acoustic observations of large in situ fish schools to be evaluated in terms of individual and aggregated fish behaviors. It also facilitates analyses of the sensitivity of fish biomass estimates to different target strength models and their parameterizations. To demonstrate how this tool may facilitate objective interpretations of acoustically estimated fish biomass and behavior, simulated echograms of fish with different spatial and orientation distributions are compared with real echograms of herring collected with a multi-beam sonar aboard the research vessel "G.O. Sars." Results highlight the important effects of fish-backscatter directivity, particularly when sensing with small acoustic wavelengths relative to the fish length. Results also show that directivity is both a potential obstacle to estimating fish biomass accurately and a potential source of information about fish behavior.


Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.
Voltage-gated sodium channels (Na(V)) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a-/- mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/- mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of Na(V)1.1 did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. The sodium current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/- and Scn1a-/- mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of Na(V)1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/- heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.


Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally.
The synthesis of brain phosphatidylcholine may utilize three circulating precursors: choline; a pyrimidine (e.g., uridine, converted via UTP to brain CTP); and a PUFA (e.g., docosahexaenoic acid); phosphatidylethanolamine may utilize two of these, a pyrimidine and a PUFA. We observe that consuming these precursors can substantially increase membrane phosphatide and synaptic protein levels in gerbil brains. (Pyrimidine metabolism in gerbils, but not rats, resembles that in humans.) Animals received, daily for 4 weeks, a diet containing choline chloride and UMP (a uridine source) and/or DHA by gavage. Brain phosphatidylcholine rose by 13-22% with uridine and choline alone, or DHA alone, or by 45% with the combination, phosphatidylethanolamine and the other phosphatides increasing by 39-74%. Smaller elevations occurred after 1-3 weeks. The combination also increased the vesicular protein Synapsin-1 by 41%, the postsynaptic protein PSD-95 by 38% and the neurite neurofibrillar proteins NF-70 and NF-M by up to 102% and 48%, respectively. However, it had no effect on the cytoskeletal protein beta-tubulin. Hence, the quantity of synaptic membrane probably increased. The precursors act by enhancing the substrate saturation of enzymes that initiate their incorporation into phosphatidylcholine and phosphatidylethanolamine and by UTP-mediated activation of P2Y receptors. Alzheimer's disease brains contain fewer and smaller synapses and reduced levels of synaptic proteins, membrane phosphatides, choline and DHA. The three phosphatide precursors might thus be useful in treating this disease.


Treatment patterns, health state, and health care resource utilization of patients with radioactive iodine refractory differentiated thyroid cancer.
Patients with differentiated thyroid cancer (DTC) often respond well to treatment but some become refractory to radioactive iodine (RAI) treatment, and treatment options are limited. Despite the humanistic and economic burden RAI refractory disease imposes on patients, published research concerning treatment patterns and health care resource utilization is sparse. Data were collected from an online retrospective chart review study in the US and five European Union (EU) countries (France, Germany, Italy, Spain, and UK) with physicians recruited from an online panel. Physicians (N=211) provided demographics, disease history, treatment information, and health care resource utilization for one to four of their patients with radioactive iodine refractory differentiated thyroid cancer (RR-DTC). The majority of the patients with RR-DTC (N=623) were female (56%), and their mean age was 58.2 years. In this sample, 63.2% had papillary thyroid cancer and 57.0% were in Stage IV when deemed RAI refractory. Patients with RR-DTC experienced regional recurrence in the thyroid bed/central neck area (25.3%) and had distant metastatic disease (53.6%). At the time data were collected, 50.7% were receiving systemic treatment. Of those, 78.5% were on first-line treatment and 62.7% were receiving multikinase inhibitors. Regional differences for prescribed treatments were observed; the US was more likely to have patients receiving multikinase inhibitors (79.2%) compared with UK (41.2%) and Italy (17.1%). Additional details regarding treatment patterns and resource utilization are discussed. The current study aimed to obtain a greater understanding of RR-DTC treatment globally. These results can assist in the development and implementation of treatment guidelines and ultimately enhance the care of patients with RR-DTC.


Amphetamines modulate prefrontal γ oscillations during attention processing.
Amphetamine-based medications robustly suppress symptoms of attention-deficit/hyperactivity disorder (ADHD), but their exact mechanisms remain poorly understood. Recent hemodynamic imaging studies have suggested that amphetamines may modulate the prefrontal and anterior cingulate brain regions, although few studies have been published and the results have not been entirely consistent. Meanwhile, several electrophysiological studies have shown that abnormal fast oscillations (in the γ range) may be closely linked to inattention and other cardinal symptoms of ADHD. In this study, we utilized magnetoencephalography to examine how amphetamines modulate high-frequency brain activity in adults with ADHD. Participants performed an auditory attention task, which required sustained attention in one block and passive listening in a separate block. Participants completed the task twice in the on-medication and off-medication states. All data were analyzed using beamforming techniques to resolve cortical regions showing event-related synchronizations and desynchronizations. Our primary findings indicated that oral administration of amphetamine decreased γ-band event-related desynchronization activity significantly in the medial prefrontal area and decreased event-related synchronization in bilateral superior parietal areas, left inferior parietal, and the left inferior frontal gyrus. These results suggest that psychostimulants strongly modulate γ activity in frontal and parietal cortical areas, which are known to be central to the brain's core attentional networks.


p53 prevents entry into mitosis with uncapped telomeres.
Telomeres are protected by capping structures consisting of core protein complexes that bind with sequence specificity to telomeric DNA. In their absence, telomeres trigger a DNA damage response, materialized in accumulation at the telomere of damage response proteins, e.g., phosphorylated histone H2AX (gammaH2AX), into telomere-dysfunction-induced foci. Telomere uncapping occurs transiently in every cell cycle in G2, following DNA replication, but little is known about how protective structures are reassembled or whether this process is controlled by the cell-cycle surveillance machinery. Here, we report that telomere capping is monitored at the G2/M transition by the p53/p21 damage response pathway. Unlike their wild-type counterparts, human and mouse cells lacking p53 or p21 progress into mitosis prematurely with persisting uncapped telomeres. Furthermore, artificially uncapped telomeres delay mitotic entry in a p53- and p21-dependent manner. Uncapped telomeres that persist in mitotic p53-deficient cells are shorter than average and religate to generate end-to-end fusions. These results suggest that a p53-dependent pathway monitors telomere capping after DNA replication and delays G2/M progression in the presence of unprotected telomeres. This mechanism maintains a cell-cycle stage conducive for capping reactions and prevents progression into stages during which uncapped telomeres are prone to deleterious end fusions.


The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans.
Common sequence variants situated between the HBS1L and MYB genes on chromosome 6q23.3 (HMIP) influence the proportion of F cells (erythrocytes that carry measurable amounts of fetal hemoglobin). Since the physiological processes underlying the F-cell variability are thought to be linked to kinetics of erythrocyte maturation and differentiation, we have investigated the influence of the HMIP locus on other hematologic parameters. Here we show a significant impact of HMIP variability on several types of peripheral blood cells: erythrocyte, platelet, and monocyte counts as well as erythrocyte volume and hemoglobin content in healthy individuals of European ancestry. These results support the notion that changes of F-cell abundance can be an indicator of more general shifts in hematopoietic patterns in humans.


Cognitive outcomes after acute coronary syndrome: a population based comparison with transient ischaemic attack and minor stroke.
Acute coronary syndrome (ACS) is associated with increased risk of cognitive decline when compared with controls, but case:control studies are subject to selection bias. We therefore compared cognitive outcomes in ACS with transient ischaemic attack (TIA) and minor stroke, diseases with similar risk factor burden generally considered to be at high risk of cognitive decline. Prospective population based cohort study Oxford Vascular Study (OXVASC) carried out within a defined population of 91 000 in Oxfordshire, UK. 614 in total: 216 ACS, 182 TIA, 216 minor (non-disabling) stroke. Mini-Mental-State-Examination (MMSE), Telephone Interview for Cognitive Status-modified (TICSm), and Montreal Cognitive Assessment (MoCA) at 1 and 5 years. Overall risk factor burden was similar across groups but ACS patients had more smoking (27% vs 14%, p<0.001) and less hypertension (45% vs 53%, p<0.01) and atrial fibrillation (6% vs 14%, p<0.001). Cognitive outcomes were worse at 1 year in ACS versus TIA patients: mean±SD MMSE 26.6±2.7 vs 27.6±2.5, p<0.0001; OR=2.14, 95% CI 1.11 to 4.13 for moderate/severe cognitive impairment (MMSE <24) with a similar trend at 5 years, and ACS outcomes were more similar to minor stroke. Memory and language versus frontal/executive subtests were relatively more impaired in ACS than TIA and minor stroke patients. Risk of cognitive impairment after ACS is similar to minor stroke and higher than TIA with implications for clinical practice including consent and adherence with medication. Differences in cognitive domain performance suggest a greater role for degenerative brain pathology in ACS which may be linked to vascular risk profile and cardiac factors.


The First World War years of Sydney Domville Rowland: an early case of possible laboratory-acquired meningococcal disease.
Sydney Domville Rowland was a bacteriologist and staff member at the Lister Institute of Preventive Medicine when the First World War broke out in 1914. Following a request to the Director of the Lister Institute to staff and equip a mobile field laboratory as quickly as possible, Rowland was appointed to take charge of No. 1 Mobile Laboratory and took up a temporary commission at the rank of Lieutenant in the Royal Army Medical Corps. On 9 October 1914, Rowland set out for the European mainland and was subsequently attached to General Headquarters in Saint-Omer, France (October 1914-June 1915), No. 10 Casualty Clearing Station in Lijssenthoek, Belgium (June 1915-February 1916, during which period he was promoted Major), and No. 26 General Hospital in Étaples, France (February 1916-March 1917). His research focused on gas gangrene, typhoid fever, trench fever, wound infection and cerebrospinal fever. In February of 1917, while engaged in identifying meningococcal carriers, Rowland contracted cerebrospinal meningitis to which he succumbed at age 44 on 6 March 1917. His untimely death might have been caused by laboratory-acquired meningococcal disease, especially since Rowland's work with Neisseria meningitidis isolates had extended beyond routine laboratory techniques and included risk procedures like immunisation of rabbits with pathogenic strains isolated from cerebrospinal fluid. Currently, microbiology laboratory workers who are routinely exposed to N. meningitidis isolates are recognised as a population at increased risk for meningococcal disease, for which reason recommended preventive measures include vaccination and handling of isolates within a class II biosafety cabinet.


Interaction between anesthetic conditioning and ischemic preconditioning on metabolic function after hepatic ischemia-reperfusion in rabbits.
Both anesthetic-induced and ischemic preconditioning are protective against hepatic ischemia-reperfusion injury. However, the effects of these preventive methods on the metabolic function remain to be elucidated. We investigated the anesthetic conditioning and ischemic preconditioning on the metabolic function of the rabbit model of hepatic ischemia-reperfusion. After approval by the institutional animal care and use committee, 36 Japanese White rabbits underwent partial hepatic ischemia for 90 min either under sevoflurane or propofol anesthesia. All the rabbits underwent 90 min of hepatic ischemia, and half of the rabbits in each group underwent additional 10-min ischemia and 10-min reperfusion before index ischemia. Hepatic microvascular blood flow was intermittently measured during reperfusion period, and galactose clearance, serum aminotransferase activities, and lactate concentrations were determined 180 min after reperfusion. Neither anesthetic conditioning with sevoflurane nor ischemic preconditioning altered hepatic microvascular blood flow during reperfusion and serum transaminase activities after reperfusion. However, galactose clearance of reperfused liver was significantly higher under sevoflurane anesthesia than propofol (0.016 ± 0.005/min vs. 0.011 ± 0.004/min). Statistically significant interaction between anesthetic choice and application of ischemic preconditioning suggests that the ischemic preconditioning is selectively protective under propofol anesthesia. Increase of blood lactate concentration was significantly suppressed under sevoflurane anesthesia compared to propofol (1.5 ± 0.8 vs. 3.9 ± 1.4 mmol/l) without any statistically significant interaction with the application of ischemic preconditioning. Sevoflurane attenuated the decrease of galactose clearance and increase of the blood lactate after reperfusion compared to propofol. Application of ischemic preconditioning was significantly protective under propofol anesthesia.


Preexposure Prophylaxis and Patient Centeredness: A Call for Holistically Protecting and Promoting the Health of Gay Men.
Preexposure prophylaxis has transformed HIV prevention, becoming widespread in communities of gay and bisexual men in the developed world in a short time. There is a broad concern that preexposure prophylaxis will discourage condom use among gay men (i.e., "risk compensation"). This commentary argues for broadening the focus on gay men's health beyond sexual health to address the holistic health and well-being of gay men. Gay men may benefit from being offered candid, nonjudgmental health promotion/HIV prevention messages not requiring condom use for anal sex. Lessons can be drawn from the family planning movement, which has undergone a similar shift in focus. The principle of patient centeredness supports such a shift in gay men's health toward the goal of providing men with the knowledge to evaluate various prevention approaches according to the specifics of their life circumstances and health needs. Bringing more nuance to discussions of sexual risk and sexual pleasure could facilitate more universally healthy attitudes regarding sex among gay men, in turn enabling healthier decisions more compatible with men's own values and preferences.


Tentorial meningiomas: follow-up review.
Tentorial meningiomas comprise 3-5% of the intracranial meningiomas. Different locations and sinus invasion require special surgical skills. This study aimed to analyze factors influencing the outcome of 29 patients (30 tumors) with tentorial meningiomas surgically treated. The study included 22 female and seven male patients, with age of 18-76 years old, and a follow-up of 6-179 months. Eight tumors were located on the inner tentorial ring, 15 on the outer ring, four were falcotentorial, and three attached/invading the torcula. Outcome was analyzed using survival and recurrence-free survival (RFS) curves. Twenty-seven tumors were WHO grade I and three were grades II-III. Total and subtotal resections were reached in 87.5% and 12.5% of tumors. Survival was better for patients with grade I tumors and similar according to sex, location, size, and extent of resection. Recurrence/regrowing rate was 12.5%. RFS curves were better for patients with grade I or with radical resection and similar according to sex, location, and size. There was no operative mortality. Permanent postoperative cranial nerve deficits occurred in 9.7% (all inner ring tumors). Despite being many times large-sized, surgical treatment of tentorial meningiomas gives good results. Prognostic factors for recurrence were histopathologic grade III and subtotal resection. Radical resection allowed better results. Nevertheless, subtotal resection may be acceptable for cases with cranial nerves or sinuses invasions.


Evaluation of non-Gaussian diffusion in cardiac MRI.
The diffusion tensor model assumes Gaussian diffusion and is widely applied in cardiac diffusion MRI. However, diffusion in biological tissue deviates from a Gaussian profile as a result of hindrance and restriction from cell and tissue microstructure, and may be quantified better by non-Gaussian modeling. The aim of this study was to investigate non-Gaussian diffusion in healthy and hypertrophic hearts. Thirteen rat hearts (five healthy, four sham, four hypertrophic) were imaged ex vivo. Diffusion-weighted images were acquired at b-values up to 10,000 s/mm2 . Models of diffusion were fit to the data and ranked based on the Akaike information criterion. The diffusion tensor was ranked best at b-values up to 2000 s/mm2 but reflected the signal poorly in the high b-value regime, in which the best model was a non-Gaussian "beta distribution" model. Although there was considerable overlap in apparent diffusivities between the healthy, sham, and hypertrophic hearts, diffusion kurtosis and skewness in the hypertrophic hearts were more than 20% higher in the sheetlet and sheetlet-normal directions. Non-Gaussian diffusion models have a higher sensitivity for the detection of hypertrophy compared with the Gaussian model. In particular, diffusion kurtosis may serve as a useful biomarker for characterization of disease and remodeling in the heart. Magn Reson Med 78:1174-1186, 2017. © 2016 International Society for Magnetic Resonance in Medicine.


Comparative genome and phenotypic analysis of three Clostridioides difficile strains isolated from a single patient provide insight into multiple infection of C. difficile.
Clostridioides difficile infections (CDI) have emerged over the past decade causing symptoms that range from mild, antibiotic-associated diarrhea (AAD) to life-threatening toxic megacolon. In this study, we describe a multiple and isochronal (mixed) CDI caused by the isolates DSM 27638, DSM 27639 and DSM 27640 that already initially showed different morphotypes on solid media. The three isolates belonging to the ribotypes (RT) 012 (DSM 27639) and 027 (DSM 27638 and DSM 27640) were phenotypically characterized and high quality closed genome sequences were generated. The genomes were compared with seven reference strains including three strains of the RT 027, two of the RT 017, and one of the RT 078 as well as a multi-resistant RT 012 strain. The analysis of horizontal gene transfer events revealed gene acquisition incidents that sort the strains within the time line of the spread of their RTs within Germany. We could show as well that horizontal gene transfer between the members of different RTs occurred within this multiple infection. In addition, acquisition and exchange of virulence-related features including antibiotic resistance genes were observed. Analysis of the two genomes assigned to RT 027 revealed three single nucleotide polymorphisms (SNPs) and apparently a regional genome modification within the flagellar switch that regulates the fli operon. Our findings show that (i) evolutionary events based on horizontal gene transfer occur within an ongoing CDI and contribute to the adaptation of the species by the introduction of new genes into the genomes, (ii) within a multiple infection of a single patient the exchange of genetic material was responsible for a much higher genome variation than the observed SNPs.


Small-bodied humans from Palau, Micronesia.
Newly discovered fossil assemblages of small bodied Homo sapiens from Palau, Micronesia possess characters thought to be taxonomically primitive for the genus Homo. Recent surface collection and test excavation in limestone caves in the rock islands of Palau, Micronesia, has produced a sizeable sample of human skeletal remains dating roughly between 940-2890 cal ybp. Preliminary analysis indicates that this material is important for two reasons. First, individuals from the older time horizons are small in body size even relative to "pygmoid" populations from Southeast Asia and Indonesia, and thus may represent a marked case of human insular dwarfism. Second, while possessing a number of derived features that align them with Homo sapiens, the human remains from Palau also exhibit several skeletal traits that are considered to be primitive for the genus Homo. These features may be previously unrecognized developmental correlates of small body size and, if so, they may have important implications for interpreting the taxonomic affinities of fossil specimens of Homo.


Rural-Urban Variation in COVID-19 Experiences and Impacts among U.S. Working-Age Adults.
This study investigates rural-urban differences in COVID-19 in terms of its impacts on the physical and mental health, social relationships, employment, and financial hardship of U.S. working-age adults (18-64). I use data from the National Wellbeing Survey collected in February and March 2021 (N=3,933). Most respondents (58 percent) reported that COVID-19 has had a negative impact on their lives. Residents of rural counties adjacent to metro areas reported the worst outcomes: they were more likely than residents of large urban counties to report positive tests for coronavirus; to live with someone who tested positive or have a close friend or family member outside of the household test positive; to have a close friend or family member hospitalized; to seek treatment for anxiety or depression; to be late paying rent, mortgage, and other bills; to not be able to afford groceries or other necessities; and to get a loan from family or friends. Recovery policies must consider geographic variation in COVID-19 vulnerability and impacts.


Applications of image-logic algebra: wire routing and numerical data processings.
Image logic algebra (ILA) is a comprehensive language for single-instruction stream multidata stream-type parallel processing, particularly for processing that is based on pattern matching. To demonstrate the usefulness of ILA for application to the computer-aided design of very-large-scale-integrated circuits, we describe a mostly parallel wire-routing algorithm based on Lee's maze algorithm by using ILA; our computer simulation verifies its validity. Another application to numerical data processing algorithms (including addition and multiplication) that is based on Booth's algorithm is also described by using ILA. Furthermore, the computational complexity of the proposed algorithms is evaluated.


Does mental number line training work? The effects of cognitive training on real-life mathematics, numeracy, and decision making.
We developed and validated intervention aimed at enhancing numeracy (the ability to understand and use the concept of probability and statistical information) and decision making. One hundred and twenty-two participants were randomly assigned to a Mental Number Line Training condition (MNLT) or an Arithmetic Training Active Control condition (ATAC). Response mode (a slider anchored within the current response range vs. a numerical keyboard) was the only, and essential, difference between experimental conditions. After MNLT, participants developed a more precise mapping of numbers onto the mental number line. However, the results regarding the transfer of this effect to performance in other cognitive tasks were mixed. We observed the transfer to an ability to quickly estimate the sum of numerical quantities (measured by the precision of estimates for the total price of everyday products), but we did not find evidence that MNLT, as compared to the control condition, improved performance on numerical competencies measures or decision-making tasks. Interestingly, we found that both MNLT and ATAC resulted in higher subjective numeracy as well as normatively better financial decisions, and valuation of risky prospects. Developing more exact symbolic-number mapping may be a promising direction of future research on improving decision making skills. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Leukocyte toll-like receptor expression in pathergy positive and negative Behçet's disease patients.
To investigate whether the auto-inflammatory nature and the pathergic reaction in Behçet's disease (BD) are driven by a disturbed toll-like receptor (TLR) response. We compared both TLR expression by flow-cytometry and TLR response by stimulation assay in 18 BD patients (both pathergy positive and pathergy negative) with 15 healthy controls. Expression of TLR1 and 2 was significantly elevated in B-lymphocytes of BD patients compared with healthy controls. TLR1, 2 and 4 were significantly more highly expressed in both CD4+ and CD8+ T-lymphocytes of BD patients. Granulocytes of BD patients displayed significantly higher expression of TLR1, 2, 4 and 6. TLR2, 4 and 5 expression was significantly increased on classical monocytes of BD patients. Intermediate monocytes of BD patients showed an increase in expression of TLR2. Furthermore, TLR2 and 5 were significantly more highly expressed in non-classical monocytes of BD patients. In pathergy positive patients, TLR5 was even more highly expressed compared with pathergy negative patients on B- and T-lymphocytes and granulocytes. Furthermore, TLR2 and 5 showed an elevated TNF-α response to stimulation with their cognate ligands. Immune cells of BD patients overexpress TLR1, 2, 4, 5 and 6. Furthermore, after stimulation of TLR2 and 5, BD patients demonstrate a more potent TNF-α response. Although this is a small cohort, in the pathergy positive patients, TLR5 expression is even further augmented, suggesting that a microbial (flagellin) or damage (HMGB1) associated signal may trigger the exaggerated immune response that is characteristic for the pathergy phenomenon in BD. In conclusion, these results point to an exaggerated TLR response in the auto-inflammatory nature of BD.


Feeding Cyprinus carpio with infectious materials mediates cyprinid herpesvirus 3 entry through infection of pharyngeal periodontal mucosa.
Cyprinid herpesvirus 3 (CyHV-3), also known as Koi herpesvirus, is the etiological agent of a mortal disease in common and koi carp. Recently, we investigated the entry of CyHV-3 in carp using bioluminescence imaging and a CyHV-3 recombinant strain expressing luciferase (LUC). We demonstrated that the skin is the major portal of entry after inoculation of carp by immersion in water containing CyHV-3. While this model of infection mimics some natural conditions in which infection takes place, other epidemiological conditions could favour entry of virus through the digestive tract. Here, we investigated whether ingestion of infectious materials mediates CyHV-3 entry through the digestive tract. Carp were fed with materials contaminated with the CyHV-3 LUC recombinant (oral contamination) or immersed in water containing the virus (contamination by immersion). Bioluminescence imaging analyses performed at different times post-infection led to the following observations: (i) the pharyngeal periodontal mucosa is the major portal of entry after oral contamination, while the skin is the major portal of entry after contamination by immersion. (ii) Both modes of inoculation led to the spreading of the infection to the various organs tested. However, the timing and the sequence in which some of the organs turned positive were different between the two modes of inoculation. Finally, we compared the disease induced by the two inoculation modes. They led to comparable clinical signs and mortality rate. The results of the present study suggest that, based on epidemiological conditions, CyHV-3 can enter carp either by skin or periodontal pharyngeal mucosal infection.


Set shifting training with categorization tasks.
The very few cognitive training studies targeting an important executive function, set shifting, have reported performance improvements that also generalized to untrained tasks. The present randomized controlled trial extends set shifting training research by comparing previously used cued training with uncued training. A computerized adaptation of the Wisconsin Card Sorting Test was utilized as the training task in a pretest-posttest experimental design involving three groups of university students. One group received uncued training (n = 14), another received cued training (n = 14) and the control group (n = 14) only participated in pre- and posttests. The uncued training group showed posttraining performance increases on their training task, but neither training group showed statistically significant transfer effects. Nevertheless, comparison of effect sizes for transfer effects indicated that our results did not differ significantly from the previous studies. Our results suggest that the cognitive effects of computerized set shifting training are mostly task-specific, and would preclude any robust generalization effects with this training.


Weakly guiding fibers.
Thin glass fibers imbedded into a glass cladding of slightly lower refractive index represent a promising medium for optical communication. This article presents simple formulas and functions for the fiber parameters as a help for practical design work. It considers the propagation constant, mode delay, the cladding field depth, and the power distribution in the fiber cross section. Plots vs frequency of these parameters are given for 70 modes.


[Treatment of solitary pyogenic liver abscess (author's transl)].
A solitary pyogenic liver abscess usually requires open surgical drainage. Digital exploration of the cavity is important for eliminating any loculations and avoiding complications after the drainage procedure. Chronic liver abscesses which are enclosed by a fibrous capsule and thus may simulate a neoplastic tumor are best treated by atypical liver resection close to the abscess or by a procedure similar to pericystectomy. Early radical operation is indicated for a complicated liver abscess whenever two drainage procedures have failed and the patient's condition is deteriorating. In such a case the development of sepsis and (or) multiple abscesses caused by an internal fistula to the bile duct system are a potential and increasing danger. Anatomical liver resection, though the most radical operation, carries a comparatively low risk as its mortality rate is less than 10%. The prognosis of solitary abscess has improved during the last decade due to an earlier diagnosis and adequate surgical drainage in combination with antibiotics. Anaerobic liver abscesses have the best prognosis.


The hydrophobic cysteine-rich domain of SNAP25 couples with downstream residues to mediate membrane interactions and recognition by DHHC palmitoyl transferases.
SNAP25 is synthesized as a soluble protein but must associate with the plasma membrane to function in exocytosis; however, this membrane-targeting pathway is poorly defined. SNAP25 contains a palmitoylated cysteine-rich domain with four cysteines, and we show that coexpression of specific DHHC palmitoyl transferases is sufficient to promote SNAP25 membrane association in HEK293 cells. siRNA-mediated knockdown of its SNARE partner, syntaxin 1A, does not affect membrane interaction of SNAP25 in PC12 cells, whereas specific cysteine-to-alanine mutations perturb membrane binding, which is restored by leucine substitutions. These results suggest a role for cysteine hydrophobicity in initial membrane interactions of SNAP25, and indeed other hydrophobic residues in the cysteine-rich domain are also important for membrane binding. In addition to the cysteine-rich domain, proline-117 is also essential for SNAP25 membrane binding, and experiments in HEK293 cells revealed that mutation of this residue inhibits membrane binding induced by coexpression with DHHC17, but not DHHC3 or DHHC7. These results suggest a model whereby SNAP25 interacts autonomously with membranes via its hydrophobic cysteine-rich domain, requiring only sufficient expression of partner DHHC proteins for stable membrane binding. The role of proline-117 in SNAP25 palmitoylation is one of the first descriptions of elements within substrate proteins that modulate DHHC specificity.


Event memory: the temporal organization of social action sequences.
We used comparative judgment procedures in two experiments to investigate the cognitive processes that mediate people's reconstruction of the social events they read about. Subjects in Experiment 1 read a passage describing a series of behaviors manifested by a person in three situations. Subsequently, they were given pairs of these actions and were asked to judge either which action occurred sooner or which occurred later. These judgments were (a) faster when the behaviors being compared occurred near the middle of the situation to which they pertained than when they occurred near either the beginning or the end, (b) faster when the three situations were unrelated to one another than when they were thematically related, and (c) faster when the behaviors being compared occurred in different situations than when they occurred in the same situation. Actions were compared more quickly if they were far apart in the overall series presented than if they were close together, replicating the symbolic temporal distance effects obtained when scripted actions are judged on the basis of general knowledge. However, a semantic congruity effect (a tendency for actions near the beginning of the series to be discriminated more quickly when subjects are asked which comes sooner, but for actions near the end to be discriminated more quickly when subjects are asked which comes later) was not evident. In Experiment 2, subjects read a passage about a person's visit to a restaurant in which both generic actions (e.g., ordering the meal) and particularized actions (e.g., salting the fries) were described. Symbolic distance had a greater effect on judgments of particularized actions than on judgments of generic actions. Congruity effects were found only for judgments of generic actions. To account for these effects, a model of temporal order judgments is proposed that considers both the manner in which situation-specific actions are encoded into memory at the time they are learned and the process of comparing the actions at the time they are judged.


The cell cycle regulator Cdh1 controls the pool sizes of hematopoietic stem cells and mature lineage progenitors by protecting from genotoxic stress.
Various key cell cycle components, especially G0/G1 regulators, have effects not only on cell proliferation but also on cell differentiation. Cdh1, one of the co-activators that maintain anaphase-promoting complex/cyclosome activity, plays a crucial role in the mitotic phase, but has recently been identified as a G0/G1 regulator, suggesting that the role of Cdh1 in cell differentiation. Here, we generated Cdh1 conditional gene-trap mice to examine Cdh1 functions in adult tissues by overcoming the embryonic lethality of Cdh1 homozygous gene-trap mice. We focused on the hematopoietic system and found that Cdh1-deficient mice exhibited a general decrease in mature lineage progenitor cells and a significant increase in short-term hematopoietic stem cells. This phenomenon became conspicuous by irradiation shortly after Cdh1 downregulation, suggesting that Cdh1 regulates the pool sizes of the hematopoietic stem cells and mature lineage progenitor cells by protecting cells from genotoxic stress. We also found that the irradiation-induced G2/M checkpoint was defective in Cdh1-deficient BM cells, causing the loss of stem/progenitor cells. This is the first report revealing Cdh1 function in adult hematopoiesis and showing a role of Cdh1 in a G2/M checkpoint regulation in vivo.


Kinetic mechanisms in morpholino-DNA surface hybridization.
Morpholinos (MOs) are DNA analogues whose uncharged nature can bring fundamental advantages to surface hybridization technologies such as DNA microarrays, by using MOs as the immobilized, or "probe", species. Advancement of MO-based diagnostics, however, is challenged by limited understanding of the surface organization of MO molecules and of how this organization impacts hybridization kinetics and thermodynamics. The present study focuses on hybridization kinetics between monolayers of MO probes and DNA targets as a function of the instantaneous extent of hybridization (i.e., duplex coverage), total probe coverage, and ionic strength. Intriguingly, these experiments reveal distinct kinetic stages, none of which are consistent with Langmuir kinetics. The initial stage, in which duplex coverage remains relatively sparse, indicates confluence of two effects: blockage of target access to unhybridized probes by previously formed duplexes and deactivation of the solid support due to consumption of probe molecules. This interpretation is consistent with a surface organization in which unhybridized MO probes localize near the solid support, underneath a layer of MO-DNA duplexes. As duplex coverage builds, provided saturation is not reached first, the initial stage can transition to an unusual regime characterized by near independence of hybridization rate on duplex coverage, followed by a prolonged approach to equilibrium. The possible origins of these more complex latter behaviors are discussed. Comparison with published data for DNA and peptide nucleic acid (PNA) probes is carried out to look for universal trends in kinetics. This comparison reveals qualitative similarities when comparable surface organization of probes is expected. In addition, MO monolayers are found capable of a broad range of reactivities that span reported values for PNA and DNA probes.