Extensive Admixture and Selective Pressure Across the Sahel Belt.
Genome-wide studies of African populations have the potential to reveal powerful insights into the evolution of our species, as these diverse populations have been exposed to intense selective pressures imposed by infectious diseases, diet, and environmental factors. Within Africa, the Sahel Belt extensively overlaps the geographical center of several endemic infections such as malaria, trypanosomiasis, meningitis, and hemorrhagic fevers. We screened 2.5 million single nucleotide polymorphisms in 161 individuals from 13 Sahelian populations, which together with published data cover Western, Central, and Eastern Sahel, and include both nomadic and sedentary groups. We confirmed the role of this Belt as a main corridor for human migrations across the continent. Strong admixture was observed in both Central and Eastern Sahelian populations, with North Africans and Near Eastern/Arabians, respectively, but it was inexistent in Western Sahelian populations. Genome-wide local ancestry inference in admixed Sahelian populations revealed several candidate regions that were significantly enriched for non-autochthonous haplotypes, and many showed to be under positive selection. The DARC gene region in Arabs and Nubians was enriched for African ancestry, whereas the RAB3GAP1/LCT/MCM6 region in Oromo, the TAS2R gene family in Fulani, and the ALMS1/NAT8 in Turkana and Samburu were enriched for non-African ancestry. Signals of positive selection varied in terms of geographic amplitude. Some genomic regions were selected across the Belt, the most striking example being the malaria-related DARC gene. Others were Western-specific (oxytocin, calcium, and heart pathways), Eastern-specific (lipid pathways), or even population-restricted (TAS2R genes in Fulani, which may reflect sexual selection).


Surgical Treatment of Nonlesional Neocortical Epilepsy: Long-term Longitudinal Study.
The proportion of surgery for nonlesional neocortical epilepsy has recently increased, with a decrease in surgery for mesial temporal lobe epilepsy. However, there are only a few studies regarding the long-term surgical outcome and the potential prognostic factors for patients with nonlesional neocortical epilepsy. To evaluate the long-term surgical outcome and to identify possible prognostic factors in patients with nonlesional neocortical epilepsy. In a surgical cohort from September 1995 to December 2005 at the Seoul National University Hospital, we included 109 consecutive patients without lesions identifiable by magnetic resonance imaging who underwent focal surgical resection for drug-resistant neocortical epilepsy. Follow-up information for at least 10 years was available for all but 1 patient. Univariate and standard multiple logistic regression analyses were performed to identify the predictors of surgical outcomes, and a generalized estimation equation model was used for the longitudinal multiple logistic regression analysis of up to 21 years of follow-up. The patients consisted of 64 men and 45 women with ages at surgery ranging from 7 to 56 years (mean [SD], 27.1 [7.8] years). At 1 year after surgery, 59 of 109 patients (54.1%) achieved seizure freedom, and 64 of 108 patients (59.3%) achieved seizure freedom at the last follow-up. Only 11 of 108 patients (10.2%) experienced definite changes in postoperative seizure status. Localizing patterns in functional neuroimaging (strongest odds ratio [OR], 0.30 [95% CI, 0.14-0.66] for fluorodeoxyglucose-positron emission tomography; 0.37 [95% CI, 0.15-0.87] for ictal single-photon emission computed tomography), concordant results in presurgical diagnostic evaluations (OR, 3.15 [95% CI, 1.42-7.02]), the presence of aura (OR, 3.49 [95% CI, 1.54-7.92]), and complete resection of areas of ictal onset with frequent interictal spikes during the intracranial electroencephalographic study (OR, 0.37 [95% CI, 0.16-0.85]) were favorable surgical outcome predictors. Our study showed that nearly 60% of patients with nonlesional neocortical epilepsy achieved freedom from long-term seizure, and that changes in postoperative seizure status were rarely observed. Several predictors of favorable surgical outcomes were identified, which can help select optimal candidates for surgical treatment among patients with nonlesional neocortical epilepsy.


Fast macro-scale transmission imaging of microvascular networks using KESM.
Accurate microvascular morphometric information has significant implications in several fields, including the quantification of angiogenesis in cancer research, understanding the immune response for neural prosthetics, and predicting the nature of blood flow as it relates to stroke. We report imaging of the whole mouse brain microvascular system at resolutions sufficient to perform accurate morphometry. Imaging was performed using Knife-Edge Scanning Microscopy (KESM) and is the first example of this technique that can be directly applied to clinical research. We are able to achieve ≈ 0.7μm resolution laterally with 1μm depth resolution using serial sectioning. No alignment was necessary and contrast was sufficient to allow segmentation and measurement of vessels.


The use of metaphor for understanding and managing psychotic experiences: A systematic review.
Subjective experiences of psychotic disorders are often not communicated because of the difficulty in articulating them. Metaphor is a valuable way of describing these experiences to others. Recovery in psychotic disorders involves consolidation and transitioning processes. The ontological and orientational types of metaphor seem to form the linguistic basis of these processes. The aim of this paper is to review and describe how metaphor may be used both as a strategy for people with psychotic disorders to articulate their subjective experiences of self, and also as an approach to support recovery. A systematic review of 28 studies was conducted, to examine the nature and function of metaphor used in studies involving an intervention or therapeutic method for psychosis. Sixteen studies contained first-person experiences, 24 studies used metaphor to consolidate the self of the person with psychotic disorder, and 19 studies used metaphor to transition the self of the person, although applied use of metaphor in this way was limited. The use of metaphor as a strategy is a potentially valuable way for both people with psychotic disorders to express their experiences, and for promotion of recovery within this population.


Assessment on patient outcomes of primary hip replacement: an interrupted time series analysis from 'The National Joint Registry of England and Wales'.
Effects of the UK Department of Health's national Enhanced Recovery After Surgery (ERAS) Programme on outcomes after primary hip replacement. Natural experimental study using interrupted time series to assess the changes in trends before, during and after ERAS implementation (April 2009 to March 2011). Surgeries in the UK National Joint Registry were linked with Hospital Episode Statistics containing inpatient episodes from National Health Service trusts in England and patient reported outcome measures. Patients aged ≥18 years from 2008 to 2016. Regression coefficients of monthly means of length of hospital stay, bed day cost, change in Oxford Hip Scores (OHS) 6 months post-surgery, complications 6 months post-surgery and revision rates 5 years post-surgery. 438 921 primary hip replacements were identified. Hospital stays shortened from 5.6 days in April 2008 to 3.6 in December 2016. There were also improvements in bed day costs (£7573 in April 2008 to £5239 in December 2016), positive change in self-reported OHS from baseline to 6 months post-surgery (17.7 points in April 2008 to 22.9 points in December 2016), complication rates (4.1% in April 2008 to 1.7% March 2016) and 5 year revision rates (5.9 per 1000 implant-years (95% CI 4.8 to 7.2) in April 2008 to 2.9 (95% CI 2.2 to 3.9) in December 2011). The positive trends in all outcomes started before ERAS was implemented and continued during and after the programme. Patient outcomes after hip replacement have improved over the last decade. A national ERAS programme maintained this improvement but did not alter the existing rate of change.


In Vivo Multimodal Magnetic Resonance Imaging Changes After N-Methyl-d-Aspartate-Triggered Spasms in Infant Rats.
Despite the serious neurodevelopmental sequelae of epileptic encephalopathy during infancy, the pathomechanisms involved remain unclear. To find potential biomarkers that can reflect the pathogenesis of epileptic encephalopathy, we explored the neurometabolic and microstructural sequelae after infantile spasms using a rat model of infantile spasms and in vivo magnetic resonance imaging techniques. Rats prenatally exposed to betamethasone were subjected to three rounds of intraperitoneal N-methyl-d-aspartate (NMDA) triggering of spasms or received saline injections (controls) on postnatal days (P) 12, 13, and 15. Chemical exchange saturation transfer imaging of glutamate (GluCEST) were performed at P15 and 22 and diffusion tensor imaging and additional spectroscopy (1H-MRI/MRS) of the cingulate cortex were serially done at P16, 23, and 30 and analyzed. Pathological analysis and western blotting were performed with rats sacrificed on P35. Within 24 h of the three rounds of NMDA-induced spasms, there was an acute increase in the GluCEST (%) in the cortex, hippocampus, and striatum. When focused on the cingulate cortex, mean diffusivity (MD) was significantly decreased during the acute period after multiple spasms with an increase in γ-aminobutyric acid (GABA), glutamate, and glutamine N-acetylaspartate-plus-N-acetylaspartylglutamate (tNAA), total choline, and total creatine. The juvenile rats also showed decreased MD on diffusion tensor imaging and significant decreases in taurine, tNAA, and macromolecules-plus-lipids in the cingulate cortex. Pathologically, there was a significant reduction in glial fibrillary acidic protein, myelin basic protein, and neuronal nuclei expression in the cingulate cortex of rats with NMDA-induced spasms. These neurometabolic and microstructural alterations after NMDA-triggered spasms might be potential imaging biomarkers of epileptic encephalopathy.


NOTCH activity differentially affects alternative cell fate acquisition and maintenance.
The pituitary is an essential endocrine gland regulating multiple processes. Regeneration of endocrine cells is of therapeutic interest and recent studies are promising, but mechanisms of endocrine cell fate acquisition need to be better characterised. The NOTCH pathway is important during pituitary development. Here, we further characterise its role in the murine pituitary, revealing differential sensitivity within and between lineages. In progenitors, NOTCH activation blocks cell fate acquisition, with time-dependant modulation. In differentiating cells, response to activation is blunted in the POU1F1 lineage, with apparently normal cell fate specification, while POMC cells remain sensitive. Absence of apparent defects in Pou1f1-Cre; Rbpjfl/fl mice further suggests no direct role for NOTCH signalling in POU1F1 cell fate acquisition. In contrast, in the POMC lineage, NICD expression induces a regression towards a progenitor-like state, suggesting that the NOTCH pathway specifically blocks POMC cell differentiation. These results have implications for pituitary development, plasticity and regeneration. Activation of NOTCH signalling in different cell lineages of the embryonic murine pituitary uncovers an unexpected differential sensitivity, and this consequently reveals new aspects of endocrine lineages development and plasticity.


Strictureplasty in diffuse Crohn's jejunoileitis: safe and durable.
As an alternative to resection, strictureplasty may allow for preservation of intestinal length and avoidance of short-bowel syndrome in patients with diffuse Crohn's jejunoileitis. However, the long-term durability of the procedure and its safety have not been confirmed. The purpose of this study was to report our experience with strictureplasty for diffuse Crohn's jejunoileitis. Between 1984 and 1999, 123 patients underwent a laparotomy that included an index strictureplasty for diffuse jejunoileitis. Patient history, operative details, and postoperative morbidities were obtained by chart review. Nineteen patients (15 percent) were receiving total parenteral nutrition for short-bowel syndrome, and 81 (66 percent) were taking chronic steroids. Total number of strictureplasties performed was 701 (median, 5/patient). Seventy percent of patients underwent a synchronous bowel resection. Follow-up information was determined by personal or phone interviews. Recurrence was defined as the need for reoperation, and risk was calculated by the Kaplan-Meier method. Patients with diffuse jejunoileitis were also compared with 219 patients with limited small-bowel Crohn's disease undergoing strictureplasty. The overall morbidity rate was 20 percent, with septic complications occurring in 6 percent. The surgical recurrence rate was 29 percent with a median follow-up period of 6.7 (range, 1-16) years. The recurrence rate in diffuse jejunoileitis patients did not differ from that seen in patients with limited small-bowel Crohn's disease (P = 0.38). Short duration of disease and short interval since last surgery were significant predictors of accelerated recurrence (P = 0.008 and 0.04, respectively). Strictureplasty is a safe and durable alternative to resection in diffuse Crohn's jejunoileitis. Patients with a short duration of disease and short interval since last surgery are at higher risk for accelerated recurrence. Patients with diffuse jejunoileitis do not appear to be at higher risk for recurrence than patients with more limited Crohn's disease.


Surgical outcomes of primary hip and knee replacements in patients with Parkinson's disease: a nationwide registry-based case-controlled study.
We evaluated the duration of hospitalisation, occurrence of infections, hip dislocations, revisions, and mortality following primary hip and knee replacement in 857 patients with Parkinson's disease and compared them with 2571 matched control patients. The data were collected from comprehensive nationwide Finnish health registers. The mean follow-up was six years (1 to 13). The patients with Parkinson's disease had a longer mean length of stay (21 days [1 to 365] vs 13 [1 to 365] days) and an increased risk for hip dislocation during the first post-operative year (hazard ratio (HR) 2.33, 95% confidence intervals (CI) 1.02 to 5.32). There was no difference in infection and revision rates, and one-year mortality. In longer follow-up, patients with Parkinson's disease had higher mortality (HR 1.94, 95% CI 1.68 to 2.25) and only 274 (34.7%) were surviving ten years after surgery. In patients with Parkinson's disease, cardiovascular and psychiatric comorbidity were associated with prolonged hospitalisation and cardiovascular diseases also with increased mortality.


The complication trends of adult spinal deformity surgery in Japan - The Japanese Scoliosis Society Morbidity and Mortality survey from 2012 to 2017.
The Japanese Scoliosis Society Morbidity & Mortality Committee performed a longitudinal nationwide complication survey of spinal deformity surgery from 2012 to 2017. The present study aimed to analyze the survey results and report the complication trends of adult spinal deformity surgery in Japan. All Japanese Scoliosis Society members were invited to participate in the survey. Adult spinal deformity was categorized into three groups by age: 20-39 years, 40-64 years and ≥65 years. Complications were grouped into death, blindness, neurological deficits (motor/sensory), infection, massive bleeding, hematoma, pneumonia, cardiac failure, deep vein thrombosis/pulmonary embolism, gastrointestinal perforation, and instrumentation failure. The surveys were performed in 2012, 2014, and 2017. The overall complication rates were 21.6%, 26.0%, and 25.4%, respectively. The complication rates differed significantly by age group in all years such that older patients had a higher complication rate than younger patients. The rate of neurological deficits, particularly motor deficits, significantly increased in 2014 (3.1%-5.5%), and decreased in 2017 (4.3%). Massive bleeding and postoperative hematoma decreased significantly year by year (8.0%, 4.8%, 2.5% and 1.3%, 0.5%, 0.3%, respectively). The complication rate of instrumentation failure remained high, increasing without significant difference (5.2%, 5.8%, 6.5%, respectively), and was more common in the middle-aged and older patients. Surgical complication rates in patients with adult spinal deformity remain high, especially neurological deficits and instrumentation failure in patients aged over 40 years. However, the complication rates of massive bleeding and postoperative hematoma decreased over this period.


Roles of nonhomologous end-joining pathways in surviving topoisomerase II-mediated DNA damage.
Topoisomerase II is a target for clinically active anticancer drugs. Drugs targeting these enzymes act by preventing the religation of enzyme-DNA covalent complexes leading to protein-DNA adducts that include single- and double-strand breaks. In mammalian cells, nonhomologous repair pathways are critical for repairing topoisomerase II-mediated DNA damage. Because topoisomerase II-targeting agents, such as etoposide, can also induce chromosomal translocations that can lead to secondary malignancies, understanding nonhomologous repair of topoisomerase II-mediated DNA damage may help to define strategies that limit this critical side effect on an important class of anticancer agents. Using Saccharomyces cerevisiae as a model eukaryote, we have determined the contribution of genes required for nonhomologous end-joining (NHEJ) for repairing DNA damage arising from treatment with topoisomerase II poisons, such as etoposide and 4'-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA). To increase cellular sensitivity to topoisomerase II poisons, we overexpressed either wild-type or drug-hypersensitive alleles of yeast topoisomerase II. Using this approach, we found that yku70 (hdf1), yku80 (hdf2), and other genes required for NHEJ were important for cell survival following exposure to etoposide. The clearest increase in sensitivity was observed with cells overexpressing an etoposide-hypersensitive allele of TOP2 (Ser740Trp). Hypersensitivity was also seen in some end-joining defective mutants exposed to the intercalating agent mAMSA, although the increase in sensitivity was less pronounced. To confirm that the increase in sensitivity was not solely due to the elevated expression of TOP2 or due to specific effects of the drug-hypersensitive TOP2 alleles, we also found that deletion of genes required for NHEJ increased the sensitivity of rad52 deletions to both etoposide and mAMSA. Taken together, these results show a clear role for NHEJ in the repair of DNA damage induced by topoisomerase II-targeting agents and suggest that this pathway may participate in translocations generated by drugs, such as etoposide.


Trends in HIV surveillance data in the EU/EEA, 2005 to 2014: new HIV diagnoses still increasing in men who have sex with men.
Human immunodeficiency virus (HIV) transmission remains significant in Europe. Rates of acquired immunodeficiency syndrome (AIDS) have declined, but not in all countries. New HIV diagnoses have increased among native and foreign-born men who have sex with men. Median CD4(+) T-cell count at diagnosis has increased, but not in all groups, and late diagnosis remains common. HIV infection and AIDS can be eliminated in Europe with resolute prevention measures, early diagnosis and access to effective treatment.


The nerve-electrode interface of the cochlear implant: current spread.
One of the fundamental facets of the cochlear implant that must be understood to predict accurately the effect of an electrical stimulus on the auditory nerve is the nerve-electrode interface. One aspect of this interface is the degree to which current delivered by an electrode spreads to neurons distant from it. This paper reports a direct mapping of this current spread using recordings from single units from the cat auditory nerve. Large variations were seen in the degree to which the different units are selective in responding to electrodes at different positions within the scala tympani. Three types of units could be identified based on the selectiveness of their response to the different electrodes in a linear array. The first type of unit exhibited a gradual increase in threshold as the stimulating site was moved from more apical to more basal locations within the scala tympani. The second type of unit exhibited a sharp local minimum, with rapid increases in threshold in excess of 6 dB/mm in the vicinity of the minimum. At electrode sites distant from the local minima the rate of change of the threshold approached that of the first type of units. The final type of unit also demonstrated a gradual change in threshold with changing electrode position, however, two local minima, one apical and one basal, could be identified. These three types are hypothesized to correspond to units which originate apical to the electrode array, along the electrode array and basal to the electrode array.


Granulopoiesis in chronic myeloid leukemia. II. serial cloning of blood and bone marrow cells in agar culture.
Colony-forming cells (CFC) and CFC in S-phase were assayed in chronic myeloid leukemia (CML). A correlation was found between leukocyte counts and CFC of blood, suggesting that the leukocytosis of CML depended on expansion of the committed granulopoietic stem cell compartment. Serial studies performed in four cases demonstrated a decrease of the CFC in S-phase during early stages of developing leukocytosis, which was consistent with the operation of growth control mechanisms. During later stages, serial studies revealed that sudden increments of CFC S-phase coincided with rapidly growing leukocytosis, which was consistent with leukemic cell populations escaping growth control. H-thymidine labeling indices for differentiated precursor cells showed slight variations not coinciding with variations of the CFC S-phase fraction. Cyclic oscillations of the white cell count were observed in one case. The white cell count and the fraction of CFC in S-phase displayed a direct relationship, indicating that the occurence of cycles was not likely to be due to a negative feedback mechanism elaborated by mature granulocytes. In another case, marked cycling of the CFC S-phase fraction was found without distinct oscillations of the white cell count. The present work has emphasized the necessity for serial assays of parameters of cell kinetics in vitro in CML since changing relationships were found between stem cell and differentiated cell kinetics during different phases of the disease.


Effects of Therapeutic Exercise Intensity on Cerebral Palsy Outcomes: A Systematic Review With Meta-Regression of Randomized Clinical Trials.
Background and Objective: Intensive physical therapy or exercise has been associated with favorable cerebral palsy (CP) outcomes, but few studies have investigated the effects of exercise intensity on the improvement in CP outcomes. In this study, we assessed the effects of intensive exercise-based therapy on improvement in gross motor function in children with CP. Methods: We searched three databases for randomized clinical trials evaluating the effects of therapeutic exercise training by using Gross Motor Function Measurement (GMFM) 66 and 88 among children with CP. Studies that used interventions in addition to therapeutic exercise were excluded from the present meta-analysis. Exercise intensity was defined using the number of training hours per day and duration of intervention (in weeks). The effects of the number of daily training hours and program duration on GMFM improvement were evaluated using meta-regression. Results: The comprehensive search returned 270 references, and 13 of 270 references met our eligibility criteria. The 13 trials recruited 412 children with CP. These trials measured motor improvements by using GMFM-66 (n = 8) and GMFM-88 (n = 5). The GMFM scores in the children who received the therapeutic intervention did not show significantly greater improvement than those of the children who received standard care. Meta-regression analysis revealed that the improvement in GMFM scores was positively associated with the number of daily training hours (point estimate = 0.549; p = 0.031) and program duration (point estimate = 0.067; p = 0.075). Discussion and Conclusions: Intensive physical exercise improved CP outcomes in the intervention and standard therapy groups. The duration of therapeutic intervention improved CP outcomes among the children who received the therapeutic intervention, while an increase in the number of daily training hours improved in CP outcomes in the children who received standard therapy.


An in planta-expressed polyketide synthase produces (R)-mellein in the wheat pathogen Parastagonospora nodorum.
Parastagonospora nodorum is a pathogen of wheat that affects yields globally. Previous transcriptional analysis identified a partially reducing polyketide synthase (PR-PKS) gene, SNOG_00477 (SN477), in P. nodorum that is highly upregulated during infection of wheat leaves. Disruption of the corresponding SN477 gene resulted in the loss of production of two compounds, which we identified as (R)-mellein and (R)-O-methylmellein. Using a Saccharomyces cerevisiae yeast heterologous expression system, we successfully demonstrated that SN477 is the only enzyme required for the production of (R)-mellein. This is the first identification of a fungal PKS that is responsible for the synthesis of (R)-mellein. The P. nodorum ΔSN477 mutant did not show any significant difference from the wild-type strain in its virulence against wheat. However, (R)-mellein at 200 μg/ml inhibited the germination of wheat (Triticum aestivum) and barrel medic (Medicago truncatula) seeds. Comparative sequence analysis identified the presence of mellein synthase (MLNS) homologues in several Dothideomycetes and two sodariomycete genera. Phylogenetic analysis suggests that the MLNSs in fungi and bacteria evolved convergently from fungal and bacterial 6-methylsalicylic acid synthases.


Immortalized hypothalamic gonadotropin-releasing hormone neurons.
The neuroendocrine hypothalamus has been intensively studied using whole animals and tissue slices. However, it has been difficult to approach questions at the molecular and cellular level. By targeting expression of the oncogene product, simian virus 40 T antigen, in transgenic mice using the regulatory domain of the rat gonadotropin-releasing hormone (GnRH) gene, we have produced specific hypothalamic tumours. These tumours have been cultured to produce clonal cell lines (GT-1 cells) that express T antigen, GnRH and many other neuronal markers, but do not express other hypothalamic hormones. These immortal cell lines have a distinctive neuronal phenotype, process the GnRH peptide accurately and secrete GnRH in a pulsatile pattern. Thus, by targeting oncogenesis to a defined population of neurons using the regulatory region of a gene that is expressed late in differentiation of that cell lineage, we have succeeded in immortalizing hypothalamic GnRH neurons. The GT-1 cell lines are an excellent model for future molecular, cell biological, physiological and biochemical investigations into the mechanisms involved in regulation of GnRH and the characteristics of an isolated central nervous system neuron. Their derivation demonstrates the utility of targeting tumorigenesis to specific differentiated neurons of the central nervous system in transgenic mice.


Systematic underestimation of treatment effects as a result of diagnostic test inaccuracy: implications for the interpretation and design of thromboprophylaxis trials.
Many clinical trials that have assessed strategies for the prevention of deep vein thrombosis have employed diagnostic tests that are less accurate than venography. The correct interpretation of these trials has been the subject of considerable debate. This paper attempts to quantify the likely effects of the use of inaccurate diagnostic tests (in particular fibrinogen scanning) on the validity and precision of estimates of treatment effects. It is shown that, if there is no difference in the rate of misclassification of deep vein thrombosis between study and control groups, then treatment effects will tend to be systematically underestimated in trials that only use inaccurate diagnostic tests. However, for trials in which there are no false positive diagnoses, such as those employing venography, the estimate of relative treatment effects will be unbiased. This phenomenon is demonstrated empirically by data from randomised trials of antiplatelet therapy. The implications of these findings are two-fold. First, so long as the accuracy of the test is the same in study and control groups, positive trial results cannot be ascribed to diagnostic test inaccuracy. Second, unbiased estimates of relative treatment effects can be obtained by using cheap, practicable and non-invasive screening tests that are supplemented by venographic assessment of positive test results. This would facilitate the conduct of much larger randomised trials than has generally been possible when mandatory venography was used; if future trials randomised some thousands of patients and employed confirmatory venography then they would provide both unbiased and precise estimates of relative treatment effects.


Computational and statistical tradeoffs via convex relaxation.
Modern massive datasets create a fundamental problem at the intersection of the computational and statistical sciences: how to provide guarantees on the quality of statistical inference given bounds on computational resources, such as time or space. Our approach to this problem is to define a notion of "algorithmic weakening," in which a hierarchy of algorithms is ordered by both computational efficiency and statistical efficiency, allowing the growing strength of the data at scale to be traded off against the need for sophisticated processing. We illustrate this approach in the setting of denoising problems, using convex relaxation as the core inferential tool. Hierarchies of convex relaxations have been widely used in theoretical computer science to yield tractable approximation algorithms to many computationally intractable tasks. In the current paper, we show how to endow such hierarchies with a statistical characterization and thereby obtain concrete tradeoffs relating algorithmic runtime to amount of data.


Short-range quantum magnetism of ultracold fermions in an optical lattice.
Quantum magnetism originates from the exchange coupling between quantum mechanical spins. Here, we report on the observation of nearest-neighbor magnetic correlations emerging in the many-body state of a thermalized Fermi gas in an optical lattice. The key to obtaining short-range magnetic order is a local redistribution of entropy, which allows temperatures below the exchange energy for a subset of lattice bonds. When loading a repulsively interacting gas into either dimerized or anisotropic simple cubic configurations of a tunable-geometry lattice, we observe an excess of singlets as compared with triplets consisting of two opposite spins. For the anisotropic lattice, the transverse spin correlator reveals antiferromagnetic correlations along one spatial axis. Our work facilitates addressing open problems in quantum magnetism through the use of quantum simulation.


Cooperation, clumping and the evolution of multicellularity.
The evolution of multicellular organisms represents one of the major evolutionary transitions in the history of life. A potential advantage of forming multicellular clumps is that it provides an efficiency benefit to pre-existing cooperation, such as the production of extracellular 'public goods'. However, this is complicated by the fact that cooperation could jointly evolve with clumping, and clumping could have multiple consequences for the evolution of cooperation. We model the evolution of clumping and a cooperative public good, showing that (i) when considered separately, both clumping and public goods production gradually increase with increasing genetic relatedness; (ii) in contrast, when the traits evolve jointly, a small increase in relatedness can lead to a major shift in evolutionary outcome—from a non-clumping state with low public goods production to a cooperative clumping state with high values of both traits; (iii) high relatedness makes it easier to get to the cooperative clumping state and (iv) clumping can be inhibited when it increases the number of cells that the benefits of cooperation must be shared with, but promoted when it increases relatedness between those cells. Overall, our results suggest that public goods sharing can facilitate the formation of well-integrated cooperative clumps as a first step in the evolution of multicellularity.


A Design-Based Stereologic Method to Quantify the Tissue Changes Associated with a Novel Drug-Eluting Tracheobronchial Stent.
Granulation tissue is a common complication of airway stenting, but no published methods can quantify the volume and type of tissue that develops. To use design-based stereology to quantify changes in tissue volume and type associated with airway stenting. We compared drug-eluting stents (DES) filled with gendine to standard silicone stents in pigs in an assessor-blinded randomized trial. Tracheal stents were placed via rigid bronchoscopy. After 1 month, animals were euthanized and necropsies were performed. Antimicrobial effects of the DES were assessed in trachea tissue samples, on the DES surface, and with residual gel from the DES reservoir. Tracheal thickness was measured using orthogonal intercepts. Design-based stereology was used to quantify the volume density of tissues using a point-counting method. The volume of each tissue was normalized to cartilage volume, which is unaffected by stenting. Pigs were randomized to DES (n = 36) or control stents (n = 9). The drug was successfully eluted from the DES, and the stent surface showed antibacterial activity. DES and controls did not differ in tissue microbiology, tracheal thickness, or granulation tissue volume. Compared to nonstented controls, stented airways demonstrated a 110% increase in soft-tissue volume (p = 0.005). Submucosal connective tissue (118%; p < 0.0001), epithelium (70%; p < 0.0001), submucosal glands (47%; p = 0.001), and smooth muscle (41%; p < 0.0001) increased in volume. Stenting doubles the volume of soft tissue in the trachea. Design-based stereology can quantify the tissue changes associated with airway stenting.


Perceived barriers to care and provider gender preferences among veteran men who have experienced military sexual trauma: a qualitative analysis.
Research suggests that there may be unique barriers to accessing care among men who have experienced sexual trauma. The primary goal of the current research was to elucidate potential barriers to accessing military sexual trauma (MST)-related care for male veterans. A secondary goal was to explore whether veterans have preferences regarding the gender of clinicians providing MST-related care. Qualitative analyses were used to examine data collected from semistructured interviews conducted with 20 male veterans enrolled in Veterans Health Administration care who reported MST but who had not received any MST-related mental health care. Veterans identified a number of potential barriers, with the majority of reported barriers relating to issues of stigma and gender. Regarding provider gender preferences, veterans were mixed, with 50% preferring a female provider, 25% a male provider, and 25% reporting no gender preference. These preliminary data suggest that stigma, gender, and knowledge-related barriers may exist for men regarding seeking MST-related care. Interventions to address potential barriers, such as outreach interventions and providing gender-specific psychoeducation, may increase access to care for male veterans who report MST.


Overwintering of Conidia of Venturia inaequalis and the Contribution to Early Epidemics of Apple Scab.
Overwintering of conidia of Venturia inaequalis associated with shoots and buds was determined, and the contribution to early spring epidemics of apple scab was evaluated during three consecutive seasons (1999 to 2001) in the Netherlands. Examinations of shoot samples collected before bud break showed that the percentage of shoots with superficial black fungal mycelia or conidia was above 65%, and the mean number of conidia on a 1-cm piece of shoot length ranged from 581 to 1,033. However, germination tests showed that the viability of conidia on shoots was less than 1.5%. No macroscopic scab lesions were detected on the scales of dormant buds. However, microscopic examinations of individual bud tissues demonstrated that the number of conidia was >3,000 per 100 buds in each year. The mean viability of conidia associated with buds ranged from 0.7 to 1.9% and from 3.7 to 10.5% for the outer and inner bud tissues, respectively. Results of field assessments at tight-cluster phenological stage showed that the percentage of infection caused by the viable overwintered conidia ranged from 0.3 to 3.8% in the various treatments. Our results indicated that conidia were unlikely to overwinter on the surface of shoots or outer bud tissues, where they were exposed to fluctuating environmental conditions, and, consequently, were unlikely to play a role in initiating an early epidemic of apple scab in the spring. However, our results indicated a risk from overwintered conidia in the inner bud tissues arising from a high level of scab the previous autumn. Therefore, orchards with high levels of apple scab, where ascosporic inoculum is much reduced, e.g., by sanitation, should be protected in early spring by means of fungicide treatment at green tip.


Cutting the brakes on hematopoietic regeneration by blocking TGFβ to limit chemotherapy-induced myelosuppression.
Hematopoietic stressors such as infection, bleeding, or toxic injury trigger a hematopoietic adaptation that sacrifices hematopoietic stem and progenitor cell (HSPC) quiescence to meet an urgent need for new blood cell production. Once the hematopoietic demands are adequately met, homeostasis must be restored. Transforming growth factor β (TGFβ) signaling is a central mediator mandating the return of HSPCs to quiescence after stress. Blockade of TGFβ signaling after hematopoietic stress delays the return of cycling HSPCs to quiescence and in so doing promotes hematopoietic stem cell (HSC) self-renewal and accelerates hematopoietic reconstitution. These findings open the door to new therapeutics that modulate the hematopoietic adaptation to stress. In this review, we will discuss the complex context-dependent activities of TGFβ in hematopoiesis and the potential benefits and limitations of using TGFβ pathway inhibitors to promote multilineage hematopoietic reconstitution after myelosuppressive chemotherapy.


Maternal hypomagnesemia alters renal function but does not program changes in the cardiovascular physiology of adult offspring.
Maternal undernutrition is known to adversely impact fetal health and development. Insults experienced in utero alter development of the fetus as it adapts to microenvironment stressors, leading to growth restriction and subsequent low birth weight. Infants born small for gestational age have significantly increased risk of developing cardiovascular and renal disease in later life, an effect that is often characterized by hypertension and reduced glomerular number. Maternal magnesium (Mg2+) deficiency during pregnancy impairs fetal growth, however, the long-term health consequences for the offspring remain unknown. Here, we used a mouse model of dietary Mg2+ deficiency before and during pregnancy to investigate cardiovascular and renal outcomes in male and female adult offspring at 6 months of age. There were no differences between groups in 24-h mean arterial pressure or heart rate as measured by radiotelemetry. Cardiovascular responses to aversive (restraint, dirty cage switch) and non-aversive (feeding response) stressors were also similar in all groups. There were no differences in nephron number, however, Mg2+-deficient offspring had increased urine flow (in both males and females) and reduced Mg2+ excretion (in males only). Despite evidence suggesting that maternal nutrient restriction programs for hypertension in adult offspring, we found that a moderate level of maternal dietary Mg2+ deficiency did not program for a nephron deficit, or alter cardiovascular function at 6 months of age. These data suggest there are no long-term adverse outcomes for the cardiovascular health of offspring of Mg2+ deficient mothers.


Decoherence in crystals of quantum molecular magnets.
Quantum decoherence is a central concept in physics. Applications such as quantum information processing depend on understanding it; there are even fundamental theories proposed that go beyond quantum mechanics, in which the breakdown of quantum theory would appear as an 'intrinsic' decoherence, mimicking the more familiar environmental decoherence processes. Such applications cannot be optimized, and such theories cannot be tested, until we have a firm handle on ordinary environmental decoherence processes. Here we show that the theory for insulating electronic spin systems can make accurate and testable predictions for environmental decoherence in molecular-based quantum magnets. Experiments on molecular magnets have successfully demonstrated quantum-coherent phenomena but the decoherence processes that ultimately limit such behaviour were not well constrained. For molecular magnets, theory predicts three principal contributions to environmental decoherence: from phonons, from nuclear spins and from intermolecular dipolar interactions. We use high magnetic fields on single crystals of Fe(8) molecular magnets (in which the Fe ions are surrounded by organic ligands) to suppress dipolar and nuclear-spin decoherence. In these high-field experiments, we find that the decoherence time varies strongly as a function of temperature and magnetic field. The theoretical predictions are fully verified experimentally, and there are no other visible decoherence sources. In these high fields, we obtain a maximum decoherence quality-factor of 1.49 × 10(6); our investigation suggests that the environmental decoherence time can be extended up to about 500 microseconds, with a decoherence quality factor of ∼6 × 10(7), by optimizing the temperature, magnetic field and nuclear isotopic concentrations.


A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus.
Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet. Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS). We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10-6 for rs612529 for association to atopic dermatitis (AD). Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment.


An assessment of the perceived benefits and challenges of participating in a practice-based research network.
A survey was conducted to describe the benefits of and challenges to practitioner participation in the Practitioners Engaged in Applied Research and Learning (PEARL) Network, a dental practice-based research network (PBRN). The results were compared with results from medical PBRNs across different tiers of participation (based on practitioner-investigators previous involvement with PEARL research protocols). A 39-item web-based survey addressed the benefits of PBRN participation on three levels: individual/practitioner, practice (office), and community/professional. Participants were also asked to rate challenges to participation. A total of 153 of 216 PEARL practitioner-investigators participated, a response rate of 71%. The majority (70%) was male, with a median of 23 years in private practice. 'Means to stay informed of new developments in my profession' was considered a 'very important' benefit for nearly three-quarters of the sample (71%). 'Opportunity to improve clinical procedures' was considered as 'very important' by 73% of respondents. In terms of benefits related to the community and profession, 65% of respondents reported 'means to directly contribute to the evidence base of dental practice' as being 'very important'. 'Disruption in practice routine/clinical practice' was considered the most important challenge to participation. The benefits of and challenges to participation identified did not differ across tiers of participation and were similar to benefits identified by participants in medical PBRNs. The results of this study will help facilitate the design of future PBRN protocols to encourage greater participation by the profession. Results suggest that practitioners with similar interests could be recruited to collaborative studies between medicine and dentistry.


Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy.
Recombinant adeno-associated virus (rAAV) vectors are considered promising for human gene replacement because they facilitate stable expression of therapeutic proteins in transduced tissues. Whether the success of gene therapy will be influenced by cellular immune responses targeting transgene-encoded proteins that are potentially immunogenic is unknown. Here we characterized CD8(+) T-cell activity against beta-galactosidase and enhanced green fluorescent protein, model antigens containing major histocompatibility complex (MHC) class I epitopes that are constitutively produced in murine skeletal muscle after rAAV vector transduction. Antigen-specific CD8(+) T cells were detected in the spleen and liver of mice within 7 days of muscle transduction. CD8(+) T-cell frequencies in these organs were stable, and effector functions were intact for months despite ongoing antigen production in muscle. CD8(+) T cells also infiltrated transduced muscle, where frequencies were at least 5-fold higher than in untransduced spleen and liver. Significantly, the majority of antigen-specific CD8(+) T cells in vector-transduced muscle were not functional. Loss of function in the muscle was associated with programmed death of the effector cells. Stable gene expression therefore depended on selective death of CD8(+) T cells at the site of antigen production, an effective mechanism for subverting immunity that is also potentially reversible.


Non-equilibrium supramolecular polymerization.
Supramolecular polymerization has been traditionally focused on the thermodynamic equilibrium state, where one-dimensional assemblies reside at the global minimum of the Gibbs free energy. The pathway and rate to reach the equilibrium state are irrelevant, and the resulting assemblies remain unchanged over time. In the past decade, the focus has shifted to kinetically trapped (non-dissipative non-equilibrium) structures that heavily depend on the method of preparation (i.e., pathway complexity), and where the assembly rates are of key importance. Kinetic models have greatly improved our understanding of competing pathways, and shown how to steer supramolecular polymerization in the desired direction (i.e., pathway selection). The most recent innovation in the field relies on energy or mass input that is dissipated to keep the system away from the thermodynamic equilibrium (or from other non-dissipative states). This tutorial review aims to provide the reader with a set of tools to identify different types of self-assembled states that have been explored so far. In particular, we aim to clarify the often unclear use of the term "non-equilibrium self-assembly" by subdividing systems into dissipative, and non-dissipative non-equilibrium states. Examples are given for each of the states, with a focus on non-dissipative non-equilibrium states found in one-dimensional supramolecular polymerization.


A feasibility, toxicity, and early response study of etoposide, ifosfamide, and vincristine for the treatment of children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS) IV pilot study.
The purpose of this study was to determine the feasibility, toxicity, and early response of patients with clinical group III rhabdomyosarcoma (RMS) to a chemotherapy regimen of etoposide (ETOP), ifosfamide (IFOS), and vincristine (VCR) with hyperfractionated radiation therapy (XRT). Sixty-eight patients aged < 21 years, previously untreated, with clinical group III RMS or undifferentiated sarcoma with normal organ function were eligible for this study. Chemotherapy was as follows: weeks 0-8: IFOS 1.8 g/m2/day X 5 days every 3 weeks X 3 (with mesna), ETOP 100 mg/m2/day X 5 days every 3 weeks X 3, and VCR 1.5 mg/m2/week X 9; weeks 9-16: hyperfractionated XRT (except patients with parameningeal tumors with meningeal extension, who received XRT on day 0), IFOS/mesna weeks 9, 12, 16, and VCR weeks 9, 10, 11, 12, 16; weeks 20-99; IFOS/mesna q 3 weeks X 2, ETOP q 3 weeks X 2, and VCR weekly X 6 weeks. Four drug cycles were repeated every 9 weeks, beginning at week 29. In January 1991, the duration of therapy was reduced to 12 courses due to emerging evidence of IFOS-induced renal tubular dysfunction. Of the 62 patients evaluable for response, 45 (73%) achieved a complete response. There were three fatal toxicities due to infection. Life-threatening neutropenia was seen in 55 of 60 patients, and life-threatening infections occurred in 27 of 60 patients. Twenty-five patients (42%) developed some degree of neurotoxicity from vincristine. Eleven patients (18%) developed nephrotoxicity, 7 cases of which were severe; 6 of the 11 patients who developed nephrotoxicity were < 2 years old. This pilot study had toxicity and response rates comparable to the other two Intergroup Rhabdomyosarcoma Study (IRS)-IV pilot trials of vincristine-actinomycin-cyclophosphamide and vincristine-actinomycin-ifosfamide and is, therefore, being evaluated in the current IRS randomized trial. Due to the high incidence of life-threatening neutropenia and infections, the use of growth factors is now routine. Five of 11 patients who developed nephrotoxicity did so after more than eight courses of IFOS; therefore, the current randomized trial limits IFOS to a total of eight courses.


PARP, transcription and chromatin modeling.
Compaction mode of chromatin and chromatin highly organised structures regulate gene expression. Posttranslational modifications, histone variants and chromatin remodelers modulate the compaction, structure and therefore function of specific regions of chromatin. The generation of poly(ADP-ribose) (PAR) is emerging as one of the key signalling events on sites undergoing chromatin structure modulation. PAR is generated locally in response to stresses. These include genotoxic stress but also differentiation signals, metabolic and hormonal cues. A pictures emerges in which transient PAR formation is essential to orchestrate chromatin remodelling and transcription factors allowing the cell to adapt to alteration in its environment. This review summarizes the diverse factors of ADP-ribosylation in the adaptive regulation of chromatin structure and transcription.


Can a pentamethylcyclopentadienyl ligand act as a proton-relay in f-element chemistry? Insights from a joint experimental/theoretical study.
Isomerisation of buta-1,2-diene to but-2-yne by (Me(5)C(5))(2)Yb is a thermodynamically favourable reaction, with the Δ(r)G° estimated from experimental data at 298 K to be -3.0 kcal mol(-1). It proceeds in hydrocarbon solvents with a pseudo first-order rate constant of 6.4 × 10(-6) s(-1) and 7.4 × 10(-5) s(-1) in C(6)D(12) and C(6)D(6), respectively, at 20 °C. This 1,3-hydrogen shift is formally forbidden by symmetry and has to occur by an alternative pathway. The proposed mechanism for buta-1,2-diene to but-2-yne isomerisation by (Me(5)C(5))(2)Yb involves coordination of methylallene (buta-1,2-diene) to (Me(5)C(5))(2)Yb, and deprotonation of methylallene by one of the Me(5)C(5) ligands followed by protonation of the terminal methylallenyl carbon to yield the known coordination compound (Me(5)C(5))(2)Yb(η(2)-MeC[triple bond, length as m-dash]CMe). Computationally, this mechanism is not initiated by a single electron transfer step, and the ytterbium retains its oxidation state (II) throughout the reactivity. Experimentally, the influence of the metal centre is discussed by comparison with the reaction of (Me(5)C(5))(2)Ca towards buta-1,2-diene, and (Me(5)C(5))(2)Yb with ethylene. The mechanism by which the Me(5)C(5) acts as a proton-relay within the coordination sphere of a metal also rationalises the reactivity of (i) (Me(5)C(5))(2)Eu(OEt(2)) with phenylacetylene, (ii) (Me(5)C(5))(2)Yb(OEt(2)) with phenylphosphine and (iii) (Me(5)C(5))(2)U(NPh)(2) with H(2) to yield (Me(5)C(5))(2)U(HNPh)(2). In the latter case, the computed mechanism is the heterolytic activation of H(2) by (Me(5)C(5))(2)U(NPh)(2) to yield (Me(5)C(5))(2)U(H)(HNPh)(NPh), followed by a hydrogen transfer from uranium back to the imido nitrogen atom using one Me(5)C(5) ligand as a proton-relay. The overall mechanism by which hydrogen shifts using a pentamethylcyclopentadienyl ligand as a proton-relay is named Carambole in reference to carom billiards.


Vitamin D prevents endothelial damage induced by increased neutrophil extracellular traps formation in patients with systemic lupus erythematosus.
to investigate the effects of Vitamin D calcitriol/1,25(OH)2D3 on NETosis in systemic lupus erythematosus (SLE) patients with hypovitamin D. neutrophlis of five SLE patients with hypovitamin D were divided into 4 groups, P0 (0 nM/control), P1 (1 nM), P2 (10 nM), and P3 (100 nM) as cultured samples. Phorbol Myristate Acetate (PMA) was used to stimulate NETs formation. The supernatant was separated and cocultured with HUVECs. Externalization of Neutrophil Elastase (NE) and Myeloperoxidase (MPO) during NETosis was measured by immunofluorescence and ELISA respectively. Early and late apoptosis of endothelial cell was measured by flowcytometry using cell death kit (Annexin V and PI antibody). this study showed significant decrease in early apoptosis with 10 nM of 1,25(OH)2D3 compared to control group. Significance of NE externalization found in all treatment groups (p<0.05), while MPO absorbance in the same tendency but not statistically significant. Further analysis also found a moderate positive correlation between NE externalizations with early apoptosis. vitamin D 1,25(OH)2D3 could reduce endothelial damage by decreasing NETosis activity. This result may reveal the possibility of Vitamin D as supplementary therapy for SLE patients with hypovitamin D to prevent endothelial damage.


A quantitative spatial proteomics analysis of proteome turnover in human cells.
Measuring the properties of endogenous cell proteins, such as expression level, subcellular localization, and turnover rates, on a whole proteome level remains a major challenge in the postgenome era. Quantitative methods for measuring mRNA expression do not reliably predict corresponding protein levels and provide little or no information on other protein properties. Here we describe a combined pulse-labeling, spatial proteomics and data analysis strategy to characterize the expression, localization, synthesis, degradation, and turnover rates of endogenously expressed, untagged human proteins in different subcellular compartments. Using quantitative mass spectrometry and stable isotope labeling with amino acids in cell culture, a total of 80,098 peptides from 8,041 HeLa proteins were quantified, and their spatial distribution between the cytoplasm, nucleus and nucleolus determined and visualized using specialized software tools developed in PepTracker. Using information from ion intensities and rates of change in isotope ratios, protein abundance levels and protein synthesis, degradation and turnover rates were calculated for the whole cell and for the respective cytoplasmic, nuclear, and nucleolar compartments. Expression levels of endogenous HeLa proteins varied by up to seven orders of magnitude. The average turnover rate for HeLa proteins was ~20 h. Turnover rate did not correlate with either molecular weight or net charge, but did correlate with abundance, with highly abundant proteins showing longer than average half-lives. Fast turnover proteins had overall a higher frequency of PEST motifs than slow turnover proteins but no general correlation was observed between amino or carboxyl terminal amino acid identities and turnover rates. A subset of proteins was identified that exist in pools with different turnover rates depending on their subcellular localization. This strongly correlated with subunits of large, multiprotein complexes, suggesting a general mechanism whereby their assembly is controlled in a different subcellular location to their main site of function.


Effects of a maximal exercise test on neurocognitive function.
To examine the effects of a maximal exercise test on cognitive function in recreational athletes. A repeated-measures design was used to compare baseline with post-cognitive function and fatigue symptoms after a maximal exercise test. Division 1 American Midwestern University, (Michigan State University, Michigan, USA). 102 male and female recreational athletes. Participants in the experimental group (n = 54) were asked to perform a maximal treadmill exercise test to maximal oxygen uptake (VO2 max). Participants in the control group were asked to rest for 15 min. All participants were administered a neuropsychological test battery called Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) before and after exercise to measure neurocognitive function and fatigue symptoms. Results revealed a significant group (control, experimental) x time (baseline, post-test 1, post-test 2) interaction for verbal memory composite scores (p = 0.025). Specifically, verbal memory composite scores decreased in the experimental group from baseline to post-test 1 (p = 0.00). These values returned to baseline 3 days after the VO2 max test (p = 0.00). Further analysis on verbal memory composite scores demonstrated significant differences on immediate recall memory (p = 0.00) and delayed recall memory (p = 0.00). No significant differences were observed for visual memory (p = 0.54), motor processing speed (p = 0.68) and reaction time (p = 0.44) composite scores between the experimental and control groups. The results of this study suggest that a maximal exercise test attenuated a limiting effect on cognitive function. When utilising a neuropsychological test battery to evaluate a patient who has sustained a head injury, the test should not be administered immediately after a practice or a game session.


The ultrastructural development of the macrogamete and formation of the oocyst wall of Toxoplasma gondii.
The macrogametes of Toxoplasma gondii develop within the epithelial cells of the cat ileum. As they develop the nucleus enlarges and dense patches of chromatin which were present in the nucleoplasm, disappear. Polysaccharide granules and lipid globules appear in the cytoplasm and increase in number during development. The wall-forming bodies of Type I (WFB I) appear before the wall-forming bodies of Type II (WFB II); WFB I are smaller, more osmiophilic and more numerous than the WFB II. The WFB I appear to form from vesicles produced by the smooth endoplasmic reticulum, and the WFB II form within the lacunae of the rough endoplasmic reticulum. Double membraned vacuoles appear to form from the nuclear membranes but the function of these is unknown. Throughout development the macrogamete retains a normal pellicle which possesses numerous micropores. The first evidence of oocyst wall formation is the appearance of participate matter in the parasitophorous vacuole which precipitates to form Layer 1 of the oocyst wall. Layers 2 and 3 are unit membranes which form between Layer 1 and the pellicle. During this development the organism has an organelle complement similar to that of the macrogamete. Layers 4 and 5 form between Layer 3 and the pellicle. Layer 4 is osmiophilic and its formation is accompanied by the disappearance of WFB I. Layer 5 is less osmiophilic than Layer 4 and its formation is accompanied by the disappearance of WFB II. The two innermost layers (Layers 4 & 5) in the oocyst wall of Toxoplasma are similar to those found in Isospora spp. and Eimeria spp. Toxoplasma seems to be unusual in that, firstly, it possesses an additional 3 layers and, secondly, all 5 layers are formed outside the pellicle of the original macrogamete.


A natural classification of the basic helix-loop-helix class of transcription factors.
A natural (evolutionary) classification is provided for 242 basic helix-loop-helix (bHLH) motif-containing proteins. Phylogenetic analyses of amino acid sequences describe the patterns of evolutionary change within the motif and delimit evolutionary lineages. These evolutionary lineages represent well known functional groups of proteins and can be further arranged into five groups based on binding to DNA at the hexanucleotide E-box, the amino acid patterns in other components of the motif, and the presence/absence of a leucine zipper. The hypothesized ancestral amino acid sequence for the bHLH transcription factor family is given together with the ancestral sequences of the subgroups. It is suggested that bHLH proteins containing a leucine zipper are not a natural, monophyletic group.


Normothermic Machine Preservation of the Liver: State of the Art.
This review aims to introduce the concept of normothermic machine perfusion (NMP) and its role in liver transplantation. By discussing results from recent clinical studies and highlighting the potential opportunities provided by this technology, we aim to provide a greater insight into NMP and the role it can play to enhance liver transplantation. NMP has recently been shown to be both safe and feasible in liver transplantation and has also demonstrated its superiority to traditional cold storage in terms of early biochemical liver function. Through the ability to perform a viability assessment during preservation and extend preservation times, it is likely that an increase in organ utilisation will follow. NMP may facilitate the enhanced preservation with improved outcomes from donors after cardiac death and steatotic livers. Furthermore, it provides the exciting potential for liver-directed therapeutic interventions. Evidence to date suggests that NMP facilitates the enhanced preservation of liver grafts with improved early post-transplant outcomes. The key role for this technology is to increase the number and quality of liver grafts available for transplantation and to reduce waiting list deaths.


Akirin links twist-regulated transcription with the Brahma chromatin remodeling complex during embryogenesis.
The activities of developmentally critical transcription factors are regulated via interactions with cofactors. Such interactions influence transcription factor activity either directly through protein-protein interactions or indirectly by altering the local chromatin environment. Using a yeast double-interaction screen, we identified a highly conserved nuclear protein, Akirin, as a novel cofactor of the key Drosophila melanogaster mesoderm and muscle transcription factor Twist. We find that Akirin interacts genetically and physically with Twist to facilitate expression of some, but not all, Twist-regulated genes during embryonic myogenesis. akirin mutant embryos have muscle defects consistent with altered regulation of a subset of Twist-regulated genes. To regulate transcription, Akirin colocalizes and genetically interacts with subunits of the Brahma SWI/SNF-class chromatin remodeling complex. Our results suggest that, mechanistically, Akirin mediates a novel connection between Twist and a chromatin remodeling complex to facilitate changes in the chromatin environment, leading to the optimal expression of some Twist-regulated genes during Drosophila myogenesis. We propose that this Akirin-mediated link between transcription factors and the Brahma complex represents a novel paradigm for providing tissue and target specificity for transcription factor interactions with the chromatin remodeling machinery.


Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years.
To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.


Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation.
Hepatocellular carcinoma (HCC) has the most rapidly rising cancer incidence in the US and Europe. The KLF6 tumor suppressor is frequently inactivated in HCC by loss-of-heterozygosity (LOH) and/or mutation. Here we have analyzed 33 HBV- and 40 HCV-related HCCs for mRNA expression of wildtype KLF6 (wtKLF6) as well as the KLF6 variant 1 (SV1), a truncated, growth-promoting variant that antagonizes wtKLF6 function. The HCV-related tumors analyzed represented the full histologic spectrum from cirrhosis and dysplasia to metastatic cancer. Expression of KLF6 mRNA is decreased in 73% of HBV-associated HCCs compared to matched surrounding tissue (ST), with reductions of approximately 80% in one-third of the patients. KLF6 mRNA expression is also reduced in dysplastic nodules from patients with HCV compared to cirrhotic livers (p<0.005), with an additional, marked decrease in the very advanced, metastatic stage (p<0.05). An increased ratio of KLF6SV1/wt KLF6 is present in a subset (6/33, 18%) of the HBV-related HCCs compared to matched ST. Reconstituting KLF6 in HepG2 cells by retroviral infection decreased proliferation and related markers including cyclin D1 and beta-catenin, increased cellular differentiation based on induction of albumin, E-cadherin, and decreased alpha fetoprotein. We conclude that reduced KLF6 expression is common in both HBV- and HCV-related HCCs and occurs at critical stages during cancer progression. Effects of KLF6 are attributable to regulation of genes controlling hepatocyte growth and differentiation.


Risk Factors for Lower-Extremity Injuries Among Contemporary Dance Students.
To determine whether student characteristics, lower-extremity kinematics, and strength are risk factors for sustaining lower-extremity injuries in preprofessional contemporary dancers. Prospective cohort study. Codarts University of the Arts. Forty-five first-year students of Bachelor Dance and Bachelor Dance Teacher. At the beginning of the academic year, the injury history (only lower-extremity) and student characteristics (age, sex, educational program) were assessed using a questionnaire. Besides, lower-extremity kinematics [single-leg squat (SLS)], strength (countermovement jump) and height and weight (body mass index) were measured during a physical performance test. Substantial lower-extremity injuries during the academic year were defined as any problems leading to moderate or severe reductions in training volume or in performance, or complete inability to participate in dance at least once during follow-up as measured with the Oslo Sports Trauma Research Center (OSTRC) Questionnaire on Health Problems. Injuries were recorded on a monthly basis using a questionnaire. Analyses on leg-level were performed using generalized estimating equations to test the associations between substantial lower-extremity injuries and potential risk factors. The 1-year incidence of lower-extremity injuries was 82.2%. Of these, 51.4% was a substantial lower-extremity injury. Multivariate analyses identified that ankle dorsiflexion during the SLS (OR 1.25; 95% confidence interval, 1.03-1.52) was a risk factor for a substantial lower-extremity injury. The findings indicate that contemporary dance students are at high risk for lower-extremity injuries. Therefore, the identified risk factor (ankle dorsiflexion) should be considered for prevention purposes.


The emerging role of insulin-like growth factor 1 receptor (IGF1r) in gastrointestinal stromal tumors (GISTs).
Recent years have seen a growing interest in insulin-like growth factor 1 receptor (IGF1R) in medical oncology. Interesting data have been reported also on IGF1r in gastrointestinal stromal tumors (GISTs) especially in children and in young adult patients whose disease does not harbour mutations on KIT and PDGFRA and are poorly responsive to conventional therapies. However, it is too early to reach conclusions on IGF1R as a novel therapeutic target in GIST because the receptor's biological role is still to be defined and the clinical significance in patients needs to be studied in larger studies. We update and comment the current literature on IGF1R in GISTs and discuss the future perspectives in this promising field.


[Cancer stem cells in malignant glioma-the mechanism of cancer initiation and the therapeutic development].
Malignant glioma is one of the most lethal diseases in adulthood. The median survival of patients with the Grade IV glioma, glioblastoma multiforme (GBM), is shorter than 15 months and the current first-line therapies for this devastating disease have only a palliative effect. The cancer stem cell hypothesis has recently attracted a great deal of attention, owing to the promise of a novel cellular target for the treatment of tumors including GBM. Recent studies have demonstrated that existence of cancer stem cells in brain tumors (BTSC) accounts, at least in part, for the intractability of malignant glioma. From the therapeutic standpoint, characterization of the mechanism for tumor initiation and maintenance of the "stem-like state" of BTSC is crucial. However, multiple heterogeneous subtypes of cancer stem cells have recently been identified from malignant glioma, making the idea of cancer stem cell complicated. In addition, in some cancer types (e.g. melanoma), a considerable proportion of tumor cells may possess the stem cell property, indicating cancer stem cells may not be a rare cell population in tumors, at least in some organs. Based on the extensive genetic and epigenetic characterization of tumor growth mechanisms, various molecularly-targeted therapies have already been applied for patients, demonstrating a varying degree of success in cancer treatment. A significant improvement in patient prognosis was achieved in several cancer types including leukemia and breast cancer. It is no doubt that continuous effort is required to bring hope for patients with malignant glioma. In this study, we summarize the recent findings and approaches in the cancer stem cell field, mainly focusing on malignant glioma stem cells, and also describe potential future directions in this area.


Comparison of various doses of carbon 13-labeled aminopyrine for a carbon 13-labeled aminopyrine demethylation blood test in healthy dogs.
To determine an optimal dose of carbon 13 ((13)C)-labeled aminopyrine for use in a (13)C-aminopyrine demethylation blood test in healthy dogs. 9 adult dogs. Food was withheld from each dog for 12 hours. A 2-mL baseline blood sample was obtained from each dog and placed into an evacuated tube containing sodium heparin. Carbon 13-labeled aminopyrine was administered IV at doses of 1, 2, 5, or 10 mg/kg. Additional blood samples (2 mL) were obtained and placed into evacuated tubes containing sodium heparin 30, 45, 60, and 75 minutes after (13)C-aminopyrine administration. Hydrochloric acid was used to extract CO(2) from blood samples. The extracted gas was analyzed by fractional mass spectrometry to determine the percentage dose of (13)C administered as (13)C-aminopyrine and recovered in extracted gas (PCD). Gross evidence of clinical adverse effects was not detected in any dog after administration of (13)C-aminopyrine. The mean coefficient of variation (CV) for PCD was significantly lower than the mean CV for the summation of PCD values up to a given sampling time (CUMPCD). Mean PCD values among the 4 doses for each sample time were not significantly different. Administration of (13)C-aminopyrine at a dose of 2 mg/kg resulted in the lowest interindividual variability. The PCD is superior to CUMPCD for the quantification of aminopyrine demethylation. Administration of (13)C-(13)C-aminopyrine at a dose of 2 mg/kg is appropriate for use in the (13)C-aminopyrine demethylation blood test in healthy dogs.


Developmental expression of secretory beta-1,4-endoglucanases in the subventral esophageal glands of Heterodera glycines.
Two beta-1,4-endoglucanases (EGases), Hg-eng-1 and Hg-eng-2, were recently cloned from the soybean cyst nematode, Heterodera glycines, and their expression was shown in the subventral esophageal glands of hatched second-stage juveniles (J2). We examined the expression of these EGases in the subventral glands of all post-embryonic life stages of H. glycines by in situ hybridization and immunolocalization. The first detectable accumulation of EGase mRNAs occurred in the subventral glands of unhatched J2. EGase transcripts remained detectable in J2 after hatching and during subsequent root invasion. However, in late parasitic J2 and third-stage juveniles (J3), the percentage of individuals that showed EGase transcripts decreased. In female fourth-stage juveniles and adult females, EGase transcripts were no longer detected in the subventral glands. EGase hybridization signal reappeared in unhatched males coiled within the J3 cuticle, and transcripts were also present in the subventral glands of migratory adult males. Immunofluorescence labeling showed that EGase translation products are most abundantly present in the subventral glands of preparasitic J2, migratory parasitic J2, and adult males. The presence of EGases predominantly in the migratory stages suggests that the enzymes are used by the nematodes to soften the walls of root cells during penetration and intracellular migration.


Utilitarianism and the disabled: distribution of resources.
Utilitarianism is more convincing than resource egalitarianism or welfare egalitarianism as a theory of how resources should be distributed between disabled people and nondisabled people. Unlike resource egalitarianism, utilitarianism can redistribute resources to the disabled when they would benefit more from those resources than nondisabled people. Unlike welfare egalitarianism, utilitarianism can halt redistribution when the disabled would no longer benefit more than the nondisabled from additional resources. The author considers one objection to this view: it has been argued, by Sen and others, that there are circumstances under which utilitarianism would unfairly distribute fewer resources to the physically disabled than to nondisabled people, on the ground that the disabled would derive less benefit from those resources. In response, the author claims that critics of utilitarianism have fallaciously exaggerated the circumstances under which the disabled would benefit less than the nondisabled from additional resources. In those limited circumstances in which the disabled really would benefit less from resources, the author argues, it does not seem unfair to distribute fewer resources to them.


PheNetic: network-based interpretation of molecular profiling data.
Molecular profiling experiments have become standard in current wet-lab practices. Classically, enrichment analysis has been used to identify biological functions related to these experimental results. Combining molecular profiling results with the wealth of currently available interactomics data, however, offers the opportunity to identify the molecular mechanism behind an observed molecular phenotype. In this paper, we therefore introduce 'PheNetic', a user-friendly web server for inferring a sub-network based on probabilistic logical querying. PheNetic extracts from an interactome, the sub-network that best explains genes prioritized through a molecular profiling experiment. Depending on its run mode, PheNetic searches either for a regulatory mechanism that gave explains to the observed molecular phenotype or for the pathways (in)activated in the molecular phenotype. The web server provides access to a large number of interactomes, making sub-network inference readily applicable to a wide variety of organisms. The inferred sub-networks can be interactively visualized in the browser. PheNetic's method and use are illustrated using an example analysis of differential expression results of ampicillin treated Escherichia coli cells. The PheNetic web service is available at http://bioinformatics.intec.ugent.be/phenetic/.


Polymer-based microparticles in tissue engineering and regenerative medicine.
Different types of biomaterials, processed into different shapes, have been proposed as temporary support for cells in tissue engineering (TE) strategies. The manufacturing methods used in the production of particles in drug delivery strategies have been adapted for the development of microparticles in the fields of TE and regenerative medicine (RM). Microparticles have been applied as building blocks and matrices for the delivery of soluble factors, aiming for the construction of TE scaffolds, either by fusion giving rise to porous scaffolds or as injectable systems for in situ scaffold formation, avoiding complicated surgery procedures. More recently, organ printing strategies have been developed by the fusion of hydrogel particles with encapsulated cells, aiming the production of organs in in vitro conditions. Mesoscale self-assembly of hydrogel microblocks and the use of leachable particles in three-dimensional (3D) layer-by-layer (LbL) techniques have been suggested as well in recent works. Along with innovative applications, new perspectives are open for the use of these versatile structures, and different directions can still be followed to use all the potential that such systems can bring. This review focuses on polymeric microparticle processing techniques and overviews several examples and general concepts related to the use of these systems in TE and RE applications. The use of materials in the development of microparticles from research to clinical applications is also discussed.


Clinical psychologists' use of transformative models of psychosis.
Some theories (e.g. Jackson's Paradigm Shifting Hypothesis) and many personal accounts suggest that some psychotic crises, whilst distressing, can also be transformative, leading to growth and valued outcomes. However, little is known about the extent to which this idea informs mainstream mental health care. Clinical psychologists are influential advocates of psychosocial approaches more broadly: This study explored their use of transformative models. Twelve U.K. clinical psychologists were interviewed: Transcripts informed a grounded theory. No participants saw psychosis as a purely biological problem where the content of experiences is irrelevant. Two held a "biopsychosocial" model, viewing psychosis as an illness with psychosocial elements. Most either held a continuum view (i.e., schizotypy), in which psychosis proneness was also associated with positive attributes such as creativity or sensitivity, or a "fully psychological" view, seeing experiences as meaningful and/or as adaptive responses to events. Many believed that psychosis can be transformative in a broad sense, that is, lead to "post-traumatic growth." Some went further, believing that it can be a purposeful (e.g., an attempt, albeit painful and sometimes unsuccessful, to solve problems) or even a spiritual phenomenon. Participants' perspectives influenced their therapeutic approach: Those who saw experiences as purposeful were more likely to facilitate direct engagement with them and to support clients to explore potentially transformative aspects. However, this represented an extension of conventional approaches rather than being qualitatively different. More research is needed to clarify how widespread this approach is, to explore its utility, and to establish for whom and when it may be appropriate.


Informal parental traffic training and children's traffic accidents.
The aims of the present study were (a) to assess the relationship between informal traffic training by parents and their children's involvement in traffic accidents and (b) to identify factors contributing to this relationship. The first two studies involved questionnaires on informal parental traffic education, the child's exposure to traffic and traffic-related accidents. Both studies showed that rate of accidents increased with training, particularly for outdoor training. An accident analysis indicated that most accidents involved the use of the bicycle, and that the major part of the accidents resulted in light injuries and occurred when the child was practicing the act of manoeuvring the bicycle. An interview study with 10 preschool teachers identified two quite disparate traffic education goals: emphasis on cautiousness versus emphasis on independence. The major implications of the study are that efforts in traffic training should give more emphasis to bicycle use and should be planned and carried out in cooperation with the parents.


Dirty electricity elevates blood sugar among electrically sensitive diabetics and may explain brittle diabetes.
Transient electromagnetic fields (dirty electricity), in the kilohertz range on electrical wiring, may be contributing to elevated blood sugar levels among diabetics and pre-diabetics. By closely following plasma glucose levels in four Type 1 and Type 2 diabetics, we find that they responded directly to the amount of dirty electricity in their environment. In an electromagnetically clean environment, Type 1 diabetics require less insulin and Type 2 diabetics have lower levels of plasma glucose. Dirty electricity, generated by electronic equipment and wireless devices, is ubiquitous in the environment. Exercise on a treadmill, which produces dirty electricity, increases plasma glucose. These findings may explain why brittle diabetics have difficulty regulating blood sugar. Based on estimates of people who suffer from symptoms of electrical hypersensitivity (3-35%), as many as 5-60 million diabetics worldwide may be affected. Exposure to electromagnetic pollution in its various forms may account for higher plasma glucose levels and may contribute to the misdiagnosis of diabetes. Reducing exposure to electromagnetic pollution by avoidance or with specially designed GS filters may enable some diabetics to better regulate their blood sugar with less medication and borderline or pre-diabetics to remain non diabetic longer.


Clinical diagnosis of intracranial haemorrhage using Guy's Hospital score.
We tested the Guy's Hospital stroke diagnostic score using the clinical data from two independent samples of patients with acute stroke. These were 228 patients from the Oxfordshire community stroke project and 130 referred to the National Hospital for Nervous Diseases in London. The diagnosis was confirmed by computed tomography or necropsy in each case. The optimum cut off point on the clinical score for the differentiation of intracranial haemorrhage from infarction was found to be the same for both the patients in our study and those from whose data the score was derived originally. Set at this level, the score achieved a sensitivity for the diagnosis of haemorrhage of 81% and 88% in the patients from Oxford and London, respectively. In those from Oxford infarction was diagnosed with a sensitivity of 78% with an overall predictive accuracy of 78% with an overall London the sensitivity for infarction was also 78% with an overall predictive accuracy of 82%. When it is essential to exclude intracerebral blood before starting treatment in the small proportion of patients with stroke who require anticoagulation the Guy's Hospital score is not sufficiently accurate to replace computed tomography. The score is, however, the most accurate clinical means of differentiating haemorrhage from infarction as the cause of stroke. It is suggested that it should be used as a screening test in epidemiological studies and in large scale trials of low risk treatment for the secondary prevention of stroke when computed tomography in all cases is impracticable.


Caveolae mediate growth factor-induced disassembly of adherens junctions to support tumor cell dissociation.
Remodeling of cell-cell contacts through the internalization of adherens junction proteins is an important event during both normal development and the process of tumor cell metastasis. Here we show that the integrity of tumor cell-cell contacts is disrupted after epidermal growth factor (EGF) stimulation through caveolae-mediated endocytosis of the adherens junction protein E-cadherin. Caveolin-1 and E-cadherin closely associated at cell borders and in internalized structures upon stimulation with EGF. Furthermore, preventing caveolae assembly through reduction of caveolin-1 protein or expression of a caveolin-1 tyrosine phospho-mutant resulted in the accumulation of E-cadherin at cell borders and the formation of tightly adherent cells. Most striking was the fact that exogenous expression of caveolin-1 in tumor cells that contain tight, well-defined, borders resulted in a dramatic dispersal of these cells. Together, these findings provide new insights into how cells might disassemble cell-cell contacts to help mediate the remodeling of adherens junctions, and tumor cell metastasis and invasion.


Recombination and annealing pathways compete for substrates in making rrn duplications in Salmonella enterica.
Tandem genetic duplications arise frequently between the seven directly repeated 5.5-kb rrn loci that encode ribosomal RNAs in Salmonella enterica. The closest rrn genes, rrnB and rrnE, flank a 40-kb region that includes the purHD operon. Duplications of purHD arise by exchanges between rrn loci and form at a high rate (10(-3)/cell/division) that remains high in strains blocked for early steps in recombination (recA, recB, and/or recF), but drops 30-fold in mutants blocked for later Holliday junction resolution (ruvC recG). The duplication defect of a ruvC recG mutant was fully corrected by an added mutation in any one of the recA, recB, or recF genes. To explain these results, we propose that early recombination defects activate an alternative single-strand annealing pathway for duplication formation. In wild-type cells, rrn duplications form primarily by the action of RecFORA on single-strand gaps. Double-strand breaks cannot initiate rrn duplications because rrn loci lack Chi sites, which are essential for recombination between two separated rrn sequences. A recA or recF mutation allows unrepaired gaps to accumulate such that different rrn loci can provide single-strand rrn sequences that lack the RecA coating that normally inhibits annealing. A recB mutation activates annealing by allowing double-strand ends within rrn to avoid digestion by RecBCD and provide a new source of rrn ends for use in annealing. The equivalent high rates of rrn duplication by recombination and annealing pathways may reflect a limiting economy of gaps and breaks arising in heavily transcribed, palindrome-rich rrn sequences.


Order of onset of substance abuse and depression in a sample of depressed outpatients.
Drug abuse has been thought to cause depression, or to serve as a form of self-medication for depression. Our objective was to examine whether specific types of drug abuse preceded or followed the onset of depression. A retrospective, blinded case-controlled assessment of the drug and depressive history of depressed outpatients was conducted. Three hundred seventy-five patients with major depressive disorder were evaluated for comorbid drug dependence using the Structured Clinical Interview for DSM-III-R (SCID). They were selected from the psychiatric outpatient department of a metropolitan teaching hospital and grouped into homogeneous classes of drug dependence including alcohol, cannabis, cocaine, amphetamine, LSD, hypnosedative, opiate, and polysubstance use. We determined the percent of depressed patients with each specific type of drug abuse, their age of onset of depression and onset of specific drug abuse, and the mean number of lifetime depressive episodes for each patient. We found that alcohol dependence followed the onset of first life depression by 4.7 years (P = .02, two-tailed). Among polydrug-dependent patients, each drug abused followed the onset of depression, except for LSD, which coincided with the onset of depression. Among polydrug users, cocaine dependence occurred 6.8 years after the first major depressive episode (P = .007) and alcohol dependence 4.5 years after the onset of depression (P = .007). Opiate and sedative users had the least number of lifetime depressive episodes (3.7), and LSD and cocaine users had the greatest number (12.2). We conclude that alcohol and cocaine use in this sample of depressed outpatients conformed to a pattern of self-medication.


Alcohol and suicide in Russia, 1870-1894 and 1956-2005: evidence for the continuation of a harmful drinking culture across time?
Previous research suggests that a strong relation exists between alcohol consumption and suicide in Soviet and post-Soviet Russia. This study extends this analysis across a much longer historical time frame by examining the relationship between heavy drinking and suicide in tsarist and post-World War II Russia. Using alcohol poisoning mortality data as a proxy for heavy drinking, time-series analytical modeling techniques were used to examine the strength of the alcohol-suicide relation in the provinces of European Russia in the period 1870-1894 and for Russia in 1956-2005. During 1870-1894, a decreasing trend was recorded in heavy drinking in Russia that contrasted with the sharp increase observed in this phenomenon in the post-World War II period. A rising trend in suicide was recorded in both study periods, although the increase was much greater in the latter period. The strength of the heavy drinking-suicide relation nevertheless remained unchanged across time, with a 10% increase in heavy drinking resulting in a 3.5% increase in suicide in tsarist Russia and a 3.8% increase in post-World War II Russia. Despite the innumerable societal changes that have occurred in Russia across the two study periods and the growth in the level of heavy drinking, the strength of the heavy drinking-suicide relation has remained unchanged across time. This suggests the continuation of a highly detrimental drinking culture where the heavy episodic drinking of distilled spirits (vodka) is an essential element in the alcohol-suicide association.


The influence of cultural orientation, alcohol expectancies and self-efficacy on adolescent drinking behavior in Beijing.
We hypothesized that the drinking behavior of adolescents in China is influenced by expectancies and self-efficacy and that adolescents' cultural orientation towards western versus traditional Chinese values influences expectancies, self-efficacy and drinking behavior, with western values leading to more dysfunctional patterns of beliefs and drinking, and that these beliefs are influenced by students' gender and school environment. A total of 1020 high school students from Beijing completed the Chinese Adolescent Alcohol Expectancy, the Chinese Cultural Orientation and the Chinese Self-regulation Self-efficacy questionnaires. Results generally confirmed our hypotheses. Higher negative expectancies and higher self-efficacy reduced the likelihood of drinking significantly. Higher positive expectancies increased the likelihood of regular drinking but not occasional drinking. Having western cultural orientation increased the likelihood of drinking. Higher levels of western cultural orientation also increased positive expectancies, lowered negative expectancies and lowered self-efficacy. Having more western (less traditional) views towards traditional Chinese values decreased positive and negative expectancies. Gender influenced beliefs, with males having higher positive and lower negative expectancies, lower self-efficacy and more traditional cultural orientation. Students in key and general schools had less traditional cultural orientation and key school students had higher self-efficacy. Results indicate that cultural orientation influences adolescent drinking and this influence is mediated partially through cultural orientation influences on adolescent drinking expectancies and self-efficacy. Having more western and less traditional Chinese cultural orientation leads to more drinking, lower self-efficacy for regulating drinking and more risk-promoting alcohol expectancies.


Pharmacogenetics meets metabolomics: discovery of tryptophan as a new endogenous OCT2 substrate related to metformin disposition.
Genetic polymorphisms of the organic cation transporter 2 (OCT2), encoded by SLC22A2, have been investigated in association with metformin disposition. A functional decrease in transport function has been shown to be associated with the OCT2 variants. Using metabolomics, our study aims at a comprehensive monitoring of primary metabolite changes in order to understand biochemical alteration associated with OCT2 polymorphisms and discovery of potential endogenous metabolites related to the genetic variation of OCT2. Using GC-TOF MS based metabolite profiling, clear clustering of samples was observed in Partial Least Square Discriminant Analysis, showing that metabolic profiles were linked to the genetic variants of OCT2. Tryptophan and uridine presented the most significant alteration in SLC22A2-808TT homozygous and the SLC22A2-808G>T heterozygous variants relative to the reference. Particularly tryptophan showed gene-dose effects of transporter activity according to OCT2 genotypes and the greatest linear association with the pharmacokinetic parameters (Cl(renal), Cl(sec), Cl/F/kg, and Vd/F/kg) of metformin. An inhibition assay demonstrated the inhibitory effect of tryptophan on the uptake of 1-methyl-4-phenyl pyrinidium in a concentration dependent manner and subsequent uptake experiment revealed differential tryptophan-uptake rate in the oocytes expressing OCT2 reference and variant (808G>T). Our results collectively indicate tryptophan can serve as one of the endogenous substrate for the OCT2 as well as a biomarker candidate indicating the variability of the transport activity of OCT2.