Natural selection in a postglacial range expansion: the case of the colour cline in the European barn owl.
Gradients of variation--or clines--have always intrigued biologists. Classically, they have been interpreted as the outcomes of antagonistic interactions between selection and gene flow. Alternatively, clines may also establish neutrally with isolation by distance (IBD) or secondary contact between previously isolated populations. The relative importance of natural selection and these two neutral processes in the establishment of clinal variation can be tested by comparing genetic differentiation at neutral genetic markers and at the studied trait. A third neutral process, surfing of a newly arisen mutation during the colonization of a new habitat, is more difficult to test. Here, we designed a spatially explicit approximate Bayesian computation (ABC) simulation framework to evaluate whether the strong cline in the genetically based reddish coloration observed in the European barn owl (Tyto alba) arose as a by-product of a range expansion or whether selection has to be invoked to explain this colour cline, for which we have previously ruled out the actions of IBD or secondary contact. Using ABC simulations and genetic data on 390 individuals from 20 locations genotyped at 22 microsatellites loci, we first determined how barn owls colonized Europe after the last glaciation. Using these results in new simulations on the evolution of the colour phenotype, and assuming various genetic architectures for the colour trait, we demonstrate that the observed colour cline cannot be due to the surfing of a neutral mutation. Taking advantage of spatially explicit ABC, which proved to be a powerful method to disentangle the respective roles of selection and drift in range expansions, we conclude that the formation of the colour cline observed in the barn owl must be due to natural selection.


New hominids from East Turkana, Kenya.
Thirty-five new fossil hominid specimens are described. They were recovered from the Plio-Pleistocene sediments to the east of Lake Turkana (formerly Lake Rudolf). They include cranial and mandibular parts, teeth, and postcranial bones of upper and lower limbs. Parts of a single skeleton are also described. All of the specimens are described in anatomical detail and selected measurements are given. Some of the specimens are illustrated. It is proposed that they should be attributed to the family Hominidae, with genus and species undetermined until detailed comparative studies have been undertaken.


[Cow's milk allergy: guidelines for the diagnostic evaluation].
About 2% of the general population and up to 6% of children suffer from food allergy. Cow's milk is charged with a important role in infancy after weaning, since conventional formula are based on its procession. IgE-mediated and Non-IgE- mediated allergic reactions, which are different in manifestation and pathogenesis, can be distinguished. A special role play the exacerbation of atopic dermatitis and the gastrointestinal-food-hypersensitivity-reactions. Skin-prick-test and determination of specific IgE are important diagnostic tools beside medical history. The golden standard of diagnosis is the double-blind-placebo-controlled-food- challenge. The clear result from food-challenge allows to verify suspected food allergies or, on the other hand, to avoid unnecessary diets. Extensively-hydrolysed-formula or Amino-acidformula are a high nutritional value alternative in case of proved cow's milk allergy in infancy.


Evaluation of urinary plasminogen activator, its receptor, matrix metalloproteinase-9, and von Willebrand factor in pancreatic cancer.
Pancreatic cancer remains a devastating problem with the majority of patients succumbing to death from this disease. A hallmark of pancreatic cancer is the loss of basement membrane that may be attributed to the action of urinary plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9). These enzymes are also implicated in angiogenesis. uPA and microvessel density have been shown to be good prognostic indicators for breast and colon cancer. MMP-9 and microvessel density have not been investigated in pancreatic cancer. We have therefore investigated by immunohistochemistry: (a) frequency of uPA expression and its receptor uPAR and the site of synthesis of uPA by in situ hybridization (ISH); (b) MMP-9 and its coexpression with uPA; (c) microvessel density as determined by von Willebrand factor staining and its relationship to uPA and MMP-9 expression; and (d) correlation of these parameters with survival. Archival paraffin sections of 27 pancreatic tumors were semiquantitatively investigated by immunohistochemistry using the following antibodies: (a) monoclonal antibodies (MAbs) uPA(1) and uPA(2) (3689 and 394, respectively); (b) MAb uPAR, (no. 3932); (c) MAb MMP-9 (no. 936); and (d) rabbit anti-F8RA/vWF. ISH was performed using a uPA cDNA. Both uPA antibodies revealed overexpression of uPA (93%) often with uniform staining of tumor cells. uPAR and MMP-9 showed focal staining in only 52 and 37% of tumors, respectively. Morphologically normal appearing ductal cells in close proximity to tumors overexpressed uPA in contrast to distally located normal cells (P = <0.001). uPA staining was also investigated in pancreatic intraepithelial neoplasia (PanIN) lesions. PanIN 1A/B staining for uPA was seen in 8 cases (30%), that for PanIN 2 in 19 cases (70%), and for PanIN3 in 12 cases (44%). Lumen of microvessels in the tumor stroma also revealed staining of uPA in 10 cases (37%). ISH experiments revealed the presence of uPA mRNA not only in the cytoplasm of tumor cells but also in adjacent normal appearing ducts as well as in PanIN lesions. Patients with overexpression of uPA, uPAR, or MMP-9 had a trend toward poorer survival than those who did not express it. Microvessel density did not show any significant relationship with uPA, uPAR, and MMP-9 expression and survival. We conclude that uPA and MMP-9 are potential prognostic indicators in pancreatic cancer, whereas microvessel density may not be one. This study confirms our previous observation that uPA is made by the tumor cells themselves. Presence of uPA in vessels of tumor stroma suggests that uPA is in circulation, and its measurement and that of MMP-9 in the blood of these patients may aid in prognosis. Patients showing overexpression of uPA and MMP-9 have a trend toward shorter survival time.


Beyond revenge: neural and genetic bases of altruistic punishment.
It is still debated how altruistic punishment as one form of strong reciprocity has established during evolution and which motives may underlie such behavior. Recent neuroscientific evidence on the activation of brain reward regions during altruistic punishment in two-person one-shot exchange games suggests satisfaction through the punishment of norm violations as one underlying motive. In order to address this issue in more detail, we used fMRI during a one-shot economic exchange game that warrants strong reciprocity by introducing a third party punishment condition wherein revenge is unlikely to play a role. We report here that indeed, reward regions such as the nucleus accumbens showed punishment-related activation. Moreover, we provide preliminary evidence that genetic variation of dopamine turnover impacts similarly on punishment-related nucleus accumbens activation during both first person and third party punishment. The overall pattern of results suggests a common cognitive-affective-motivational network as the driving force for altruistic punishment, with only quantitative differences between first person and third party perspectives.


Clinical Outcomes in Patients With Atrial Fibrillation Treated With Non-Vitamin K Oral Anticoagulants Across Varying Body Mass Index.
Background There are conflicting data on outcomes in patients with atrial fibrillation treated with non-vitamin K oral anticoagulants across varying body mass index (BMI). We investigated cardiovascular and bleeding risk in patients with atrial fibrillation with varying BMI. Methods and Results Observational cohort study from the Swedish oral anticoagulation registry between August 2, 2011, and December 31, 2018. Primary outcomes were mortality, ischemic stroke/systemic embolism, and major bleeding. Baseline BMI (kg/m2) was analyzed continuously and categorized: underweight (<18.5 kg/m2), normal weight (18.5 to <25 kg/m2), preobesity (25 to <30 kg/m2), and obesity class I to III (30 to <35, 35 to <40, and ≥40 kg/m2). Adjusted Cox models and nonlinear relationships of BMI were modeled using restricted cubic splines. Non-vitamin K oral anticoagulant-treated patients with atrial fibrillation were included (n=26 047). At baseline, 602 (2.3%) were underweight, 9101 (34.9%) were normal weight, 9970 (38.3%) were preobese, 4280 (16.4%) were obese class I, 1486 (5.7%) were obese class II, and 608 (2.3%) were obese class III. Underweight and obesity class III were in adjusted continuous analysis associated with increased mortality and major bleeding, with lowest risk observed among preobese patients with BMI 28.2 and 26.2 kg/m2, respectively. In adjusted categorical analysis, underweight was associated with increased mortality (hazard ratio [HR], 1.77 [95% CI, 1.57-1.99]) and nonsignificant higher risk of major bleeding (HR, 1.23 [95% CI, 0.95-1.58]). Similarly, obesity class III was associated with increased mortality (HR, 1.67 [95% CI, 1.40-1.99]) and major bleeding (HR, 1.68 [95% CI, 1.29-2.17]). No significant association was observed between higher BMI and ischemic stroke/systemic embolism. Conclusions In non-vitamin K oral anticoagulant-treated patients with atrial fibrillation, there appears to be a U-shaped relationship between BMI and mortality and major bleeding.


Children's use of addition to solve two-digit subtraction problems.
Subtraction problems of the type M - S = ? can be solved with various mental calculation strategies. We investigated fourth- to sixth-graders' use of the subtraction by addition strategy, first by fitting regression models to the reaction times of 32 two-digit subtractions. These models represented three different strategy use patterns: the use of direct subtraction, subtraction by addition, and switching between the two strategies based on the magnitude of the subtrahend. Additionally, we compared performance on problems presented in two presentation formats, i.e., a subtraction format (81 - 37 = .) and an addition format (37 + . = 81). Both methods converged to the conclusion that children of all three grades switched between direct subtraction and subtraction by addition based on the combination of two features of the subtrahend: If the subtrahend was smaller than the difference, direct subtraction was the dominant strategy; if the subtrahend was larger than the difference, subtraction by addition was mainly used. However, this performance pattern was only observed when the numerical distance between subtrahend and difference was large. These findings indicate that theoretical models of children's strategy choices in subtraction should include the nature of the subtrahend as an important factor in strategy selection.


Current advances in tin cluster chemistry.
This perspective summarizes highlights and most recent advances in tin cluster chemistry, thereby addressing the whole diversity of (mostly) discrete units containing tin atoms. Although being a (semi-)metallic element, tin is in the position to occur both in formally positive or negative oxidation states in these molecules, which causes a broad range of fundamentally different properties of the corresponding compounds. Tin(iv) compounds are not as oxophilic and not as prone to hydrolysis as related Si or Ge compounds, hence allowing for easier handling and potential application. Nevertheless, their reactivity is high due to an overall reduction of bond energies, which makes tin clusters interesting candidates for functional compounds. Beside aspects that point towards bioactivity or even medical applications, materials composed of naked or ligand-protected tin clusters, with or without bridging ligands, show interesting optical, and ion/molecule-trapping properties.


Characterization of Dictyostelium discoideum cathepsin D.
Previous studies using magnetic purification of Dictyostelium discoideum endocytic vesicles led us to the identification of some major vesicle proteins. Using the same purification procedure, we have now focused our interest on a 44 kDa soluble vesicle protein. Microsequencing of internal peptides and subsequent cloning of the corresponding cDNA identified this protein as the Dictyostelium homolog of mammalian cathepsins D. The only glycosylation detected on Dictyostelium cathepsin D (CatD) is common antigen 1, a cluster of mannose 6-sulfate residues on N-linked oligosaccharide chains. CatD intracellular trafficking has been studied, showing the presence of the protein throughout the entire endocytic pathway. During the differentiation process, the catD gene presents a developmental regulation, which is also observed at the protein level. catD gene disruption does not alter significantly the cell behaviour, either in the vegetative form or the differentiation stage. However, modifications in the SDS-PAGE profiles of proteins bearing common antigen 1 were detected, when comparing parental and catD(-) cells. These modifications point to a possible role of CatD in the maturation of a few Dictyostelium lysosomal proteins.


Working Memory Integration Processes in Benign Childhood Epilepsy with Centrotemporal Spikes.
Benign epilepsy of childhood with centrotemporal spikes (BECTS) is the most frequent focal epilepsy in children; however, the pattern of affected memory processes remains controversial. Previous studies in BECTS imply deficits in complex working memory tasks, but not in simple modality-specific tasks. We studied working memory processes in children with BECTS by comparing performance in memory binding tasks of different complexities. We compared 17 children with BECTS (aged 6 to 13 years) to 17 healthy children matched for age, sex, and intelligence quotient. We measured spatial and verbal memory components separately and jointly on three single-binding tasks (binding of what and where; what and when; and where and when) and a combined-binding task (integration of what, where, and when). We also evaluated basic visuospatial memory functions with subtests of the Children's Memory Scale, and intellectual abilities with verbal tasks of the Wechsler Intelligence Scale for Children-Fourth Edition and the Raven Progressive Matrices. We found no difference between the BECTS and control groups in single-binding tasks; however, the children with BECTS performed significantly worse on the combined task, which included integration of spatial, verbal, and temporal information. We found no deficits in their intellectual abilities or basic visuospatial memory functions. Children with BECTS may have intact simple maintenance processes of working memory, but difficulty with high-level functions requiring attentional and executive resources. Our findings imply no specific memory dysfunction in BECTS, but suggest difficulties in integrating information within working memory, and possible frontal lobe disturbances.


Specific learning disorder: prevalence and gender differences.
Comprehensive models of learning disorders have to consider both isolated learning disorders that affect one learning domain only, as well as comorbidity between learning disorders. However, empirical evidence on comorbidity rates including all three learning disorders as defined by DSM-5 (deficits in reading, writing, and mathematics) is scarce. The current study assessed prevalence rates and gender ratios for isolated as well as comorbid learning disorders in a representative sample of 1633 German speaking children in 3rd and 4th Grade. Prevalence rates were analysed for isolated as well as combined learning disorders and for different deficit criteria, including a criterion for normal performance. Comorbid learning disorders occurred as frequently as isolated learning disorders, even when stricter cutoff criteria were applied. The relative proportion of isolated and combined disorders did not change when including a criterion for normal performance. Reading and spelling deficits differed with respect to their association with arithmetic problems: Deficits in arithmetic co-occurred more often with deficits in spelling than with deficits in reading. In addition, comorbidity rates for arithmetic and reading decreased when applying stricter deficit criteria, but stayed high for arithmetic and spelling irrespective of the chosen deficit criterion. These findings suggest that the processes underlying the relationship between arithmetic and reading might differ from those underlying the relationship between arithmetic and spelling. With respect to gender ratios, more boys than girls showed spelling deficits, while more girls were impaired in arithmetic. No gender differences were observed for isolated reading problems and for the combination of all three learning disorders. Implications of these findings for assessment and intervention of learning disorders are discussed.


Highlights from the Tenth International Symposium of Thrombosis and Anticoagulation (ISTA X), September 22 and 23, 2017, Salvador, Bahia, Brazil.
To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Tenth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on September 22 and 23, 2017. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes-the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.


Psychological distress and cigarette smoking among U.S. households by income: Considering the role of food insecurity.
Psychological distress and tobacco use are known to co-occur for many reasons, including vulnerabilities associated with socioeconomic disadvantage. Food insecurity-a stressful condition due to inconsistent food access-is linked with increased psychological distress and is also an independent risk factor for smoking. We investigated the association between psychological distress and cigarette smoking, examining distress occurring with or without food insecurity, and variations in the associations by socioeconomic status. We analyzed data from the 2015 U.S. Panel Study of Income Dynamics (n = 9048). A four-category variable was constructed based on responses to validated measures of psychological distress and of food insecurity: no distress and no food insecurity; food insecurity without distress; distress without food insecurity; and distress with food insecurity. Weighted, robust Poisson regression analysis examined associations with current smoking, with analyses stratified by socioeconomic status. Smoking prevalence was highest among respondents experiencing psychological distress with food insecurity (39%). Results showed that respondents with food insecurity alone had higher smoking prevalence (33%) than respondents with psychological distress alone (20%). Only among respondents above poverty, psychological distress without food insecurity was significantly associated with current smoking (prevalence ratio = 1.44; 95% CI [1.25, 1.65]). For respondents at/below poverty, psychological distress without food insecurity was not significantly associated with current smoking. Further examining how socioeconomic stressors, such as food insecurity, intersect with psychological distress is needed to address continued socioeconomic disparities in cigarette smoking and develop effective population-based interventions.


Identification and Characterization of a Novel, Cold-Adapted d-Xylobiose- and d-Xylose-Releasing Endo-β-1,4-xylanase from an Antarctic Soil Bacterium, Duganella sp. PAMC 27433.
Endo-β-1,4-xylanase is a key enzyme in the degradation of β-1,4-d-xylan polysaccharides through hydrolysis. A glycoside hydrolase family 10 (GH10) endo-β-1,4-xylanase (XylR) from Duganella sp. PAMC 27433, an Antarctic soil bacterium, was identified and functionally characterized. The XylR gene (1122-bp) encoded an acidic protein containing a single catalytic GH10 domain that was 86% identical to that of an uncultured bacterium BLR13 endo-β-1,4-xylanase (ACN58881). The recombinant enzyme (rXylR: 42.0 kDa) showed the highest beechwood xylan-degrading activity at pH 5.5 and 40 °C, and displayed 12% of its maximum activity even at 4 °C. rXylR was not only almost completely inhibited by 5 mM N-bromosuccinimide or metal ions (each 1 mM) including Hg2+, Ca2+, or Cu2+ but also significantly suppressed by 1 mM Ni2+, Zn2+, or Fe2+. However, its enzyme activity was upregulated (>1.4-fold) in the presence of 0.5% Triton X-100 or Tween 80. The specific activities of rXylR toward beechwood xylan, birchwood xylan, oat spelts xylan, and p-nitrophenyl-β-d-cellobioside were 274.7, 103.2, 35.6, and 365.1 U/mg, respectively. Enzymatic hydrolysis of birchwood xylan and d-xylooligosaccharides yielded d-xylose and d-xylobiose as the end products. The results of the present study suggest that rXylR is a novel cold-adapted d-xylobiose- and d-xylose-releasing endo-β-1,4-xylanase.


Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia.
CAMPATH-1H is a human immunoglobulin G1 (IgG1) anti-CD52 monoclonal antibody (MAb) that binds to nearly all B- and T-cell lymphomas and leukemias. We report the results of a multicenter phase II trial that used CAMPATH-1H in previously chemotherapy-treated patients with chronic lymphocytic leukemia (CLL). Twenty-nine patients who had relapsed after an initial response (n = 8) or were refractory (n = 21) to chemotherapy were treated with CAMPATH-1H administered as a 30-mg 2-hour intravenous (IV) infusion thrice weekly for a maximum period of 12 weeks. Eleven patients (38%) achieved a partial remission (PR) and one (4%) a complete remission (CR) (response rate, 42%; 95% confidence interval [CI], 23% to 61%). Three of eight patients (38%) with a relapse and nine of 21 refractory patients (43%) responded to CAMPATH-1H therapy. CLL cells were rapidly eliminated from blood in 28 of 29 patients (97%). CR in the bone marrow was obtained in 36% and splenomegaly resolved completely in 32%. Lymphadenopathy was normalized in only two patients (7%). The median response duration was 12 months (range, 6 to 25+). World Health Organization (WHO) grade IV neutropenia and thrombocytopenia developed in three (10%) and two patients (7%), respectively. Neutropenia and thrombocytopenia recovered in most responding patients during continued CAMPATH-1H treatment. Lymphopenia (< 0.5 x 10(9)/L) occurred in all patients. Two patients had opportunistic infections and four had bacterial septicemia. CAMPATH-1H had significant activity in patients with advanced and chemotherapy-resistant CLL. The most pronounced effects were noted in blood, bone marrow, and spleen. Preferential clearance of blood may allow harvesting of uncontaminated blood stem cells for use in high-dose chemotherapy protocols.


The immune system as a system of relations.
Progress in neuroimmunology established that the nervous and the immune systems are two functionally related physiological systems. Unique sensory and immune receptors enable them to control interactions of the organism with the inner and the outer worlds. Both systems undergo an experience-driven selection process during their ontogeny. They share the same mediators/neurotransmitters and use synapses for intercellular communication. They keep a memory of previous experiences. Immune cells can affect nervous cells, nervous cells can affect immune cells, and they regulate each other. I however argue that the two systems differ by three major points: 1) Unlike the nervous system, the immune system has a loose anatomical structure, in which molecular and cellular events mostly occur at random; 2) The immune system can respond to molecules of the living world whereas the nervous system can respond to phenomena of the physical world; 3) Responses of the immune system act both on the organism and on the stimulus that triggered the response, whereas responses of the nervous system act on the organism only. The nervous and the immune systems therefore appear as two complementary systems of relations that closely work together, and whose reactivities are well-suited to deal with physical and biological stimuli, respectively. Its ability both to adapt the organism to the living world and to adapt the living world to the organism endows the immune system with powerful adaptive properties that enable the organism to live in peace with itself and with other living beings, whether pathogens or commensals.


Population dynamics and in vitro antibody pressure of porcine parvovirus indicate a decrease in variability.
To estimate the impact of porcine parvovirus (PPV) vaccines on the emergence of new phenotypes, the population dynamic history of the virus was calculated using the Bayesian Markov chain Monte Carlo method with a Bayesian skyline coalescent model. Additionally, an in vitro model was performed with consecutive passages of the 'Challenge' strain (a virulent field strain) and NADL2 strain (a vaccine strain) in a PK-15 cell line supplemented with polyclonal antibodies raised against the vaccine strain. A decrease in genetic diversity was observed in the presence of antibodies in vitro or after vaccination (as estimated by the in silico model). We hypothesized that the antibodies induced a selective pressure that may reduce the incidence of neutral selection, which should play a major role in the emergence of new mutations. In this scenario, vaccine failures and non-vaccinated populations (e.g. wild boars) may have an important impact in the emergence of new phenotypes.


Aldehyde Dehydrogenase Gene Superfamily in Populus: Organization and Expression Divergence between Paralogous Gene Pairs.
Aldehyde dehydrogenases (ALDHs) constitute a superfamily of NAD(P)+-dependent enzymes that catalyze the irreversible oxidation of a wide range of reactive aldehydes to their corresponding nontoxic carboxylic acids. ALDHs have been studied in many organisms from bacteria to mammals; however, no systematic analyses incorporating genome organization, gene structure, expression profiles, and cis-acting elements have been conducted in the model tree species Populus trichocarpa thus far. In this study, a comprehensive analysis of the Populus ALDH gene superfamily was performed. A total of 26 Populus ALDH genes were found to be distributed across 12 chromosomes. Genomic organization analysis indicated that purifying selection may have played a pivotal role in the retention and maintenance of PtALDH gene families. The exon-intron organizations of PtALDHs were highly conserved within the same family, suggesting that the members of the same family also may have conserved functionalities. Microarray data and qRT-PCR analysis indicated that most PtALDHs had distinct tissue-specific expression patterns. The specificity of cis-acting elements in the promoter regions of the PtALDHs and the divergence of expression patterns between nine paralogous PtALDH gene pairs suggested that gene duplications may have freed the duplicate genes from the functional constraints. The expression levels of some ALDHs were up- or down-regulated by various abiotic stresses, implying that the products of these genes may be involved in the adaptation of Populus to abiotic stresses. Overall, the data obtained from our investigation contribute to a better understanding of the complexity of the Populus ALDH gene superfamily and provide insights into the function and evolution of ALDH gene families in vascular plants.


Association between biofuel exposure and adverse birth outcomes at high altitudes in Peru: a matched case-control study.
Nearly one-third of the Peruvian population burns biofuels for cooking. Similarly, approximately one-third of this population lives at high altitudes. Cooking with biofuels and living at high altitudes have been implicated in adverse perinatal outcomes. This study attempted to determine the risk of low birth weight (LBW) and/or preterm delivery in relation to biofuel use in inhabitants at high altitudes in Peru. A matched-case study was performed in two high-altitude cities. All subjects (n=190) were identified from public-hospital records. Cases were matched by hospital by week of birth and area of residence. Cases were defined as: women with an at-term but LBW newborn; or women with a preterm birth. Adjusted conditional logistic regression analyses were used to determine odds ratio. Fifty-two percent of the cases used biofuel whereas only 30% of the controls used biofuel. The use of biofuel for cooking was found to be strongly associated with increased risks of LBW, but was not significantly linked to preterm births.


Robust methods for accurate diagnosis using pan-microbiological oligonucleotide microarrays.
To address the limitations of traditional virus and pathogen detection methodologies in clinical diagnosis, scientists have developed high-throughput oligonucleotide microarrays to rapidly identify infectious agents. However, objectively identifying pathogens from the complex hybridization patterns of these massively multiplexed arrays remains challenging. In this study, we conceived an automated method based on the hypergeometric distribution for identifying pathogens in multiplexed arrays and compared it to five other methods. We evaluated these metrics: 1) accurate prediction, whether the top ranked prediction(s) match the real virus(es); 2) four accuracy scores. Though accurate prediction and high specificity and sensitivity can be achieved with several methods, the method based on hypergeometric distribution provides a significant advantage in term of positive predicting value with two to sixty folds the positive predicting values of other methods. The proposed multi-specie array analysis based on the hypergeometric distribution addresses shortcomings of previous methods by enhancing signals of positively hybridized probes.


Becker nevus syndrome.
Becker nevus syndrome is a phenotype characterized by the fundamental presence of Becker's nevus with ipsilateral hypoplasia of the breast or other skin, skeletal and/or muscular disorders. This syndrome generally originates at birth, intensifies significantly in adolescence and is one of the syndromes that constitute epidermal nevus syndrome. To the best of our knowledge, this is the first case published in the Brazilian literature of Becker nevus syndrome associated with Becker's nevus, ipsilateral breast hypoplasia and scoliosis in a 14-year-old girl.


An assessment of the operation of an external quality assessment (EQA) scheme in histopathology in the South Thames (West) region: 1995-1998.
To describe the design and organisation of a voluntary regional external quality assessment (EQA) scheme in histopathology, and to record the results obtained over a three year period. A protocol is presented in which circulation of EQA slides alternated with teaching sessions. Procedures for the choice of suitable cases, evaluation of submitted diagnoses, and feedback of results to participants are described. The use of teaching sessions, complementary to the slide circulations, and dealing with current diagnostic problems is also outlined. Participation rates in the nine slide circulations varied between 66% and 89%, mean 85%. Overall scores were predictably high but 4% of returns, from 10 pathologists, were unsatisfactory. These low scores were typically isolated or intermittent and none of the participants fulfilled agreed criteria for chronic poor performers. This scheme has been well supported and overall performances have been satisfactory. The design was sufficiently discriminatory to reveal a few low scores which are analysed in detail. Prompt feedback of results to participants with identification of all "incomplete" and "wrong" diagnoses is essential. Involvement of local histopathologists in designing, running, and monitoring such schemes is important.


Flosequinan in heart failure: acute haemodynamic and longer term symptomatic effects.
There is no single, simple test with which to evaluate new treatments for heart failure. Various methods need to be used, and a study of both the acute haemodynamic and longer term symptomatic effects of flosequinan, a new direct acting arteriolar and venous vasodilator, was therefore carried out in patients with heart failure. In one group of patients flosequinan increased cardiac output and caused a fall in pulmonary capillary wedge pressure, both effects lasting for 24 hours. In a double blind, placebo controlled study in another group flosequinan improved mean exercise tolerance from 9.9 to 12.7 minutes after four weeks of treatment. The drug also reduced perceived exertion during submaximal exercise and increased calf and therefore skeletal muscle blood flow. It reduced plasma renin activity and noradrenaline concentrations. Flosequinan possesses all the important properties of a drug likely to be of value in the treatment of heart failure.


Status epilepticus: risk factors and complications.
Status epilepticus is common and associated with significant mortality and complications. It affects approximately 50 patients per 100,000 population annually and recurs in >13%. History of epilepsy is the strongest single risk factor for generalized convulsive status epilepticus. More than 15% of patients with epilepsy have at least one episode of status epilepticus and low antiepileptic drug levels are a potentially modifiable risk factor. Other risks include young age, genetic predisposition, and acquired brain insults. Fever is a very common risk in children, as is stroke in adults. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Neuronal injury leading to temporal lobe epilepsy is probably mediated by excess excitation via activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and consequent elevated intracellular calcium that causes acute necrosis and delayed apoptotic cell death. Some forms of nonconvulsive status epilepticus may also lead to neuronal injury by this mechanism, but others may not. Based on clinical and experimental observations, complex partial status epilepticus is more likely to result in neuronal injury similar to generalized convulsive status epilepticus. Absence status epilepticus is much less likely to result in neuronal injury, and complications because it may be mediated primarily through excess inhibition. Future research strategies to prevent complications of status epilepticus include the study of new drugs (including NMDA antagonists, new drug delivery systems, and drug combinations) to stop seizure activity and prevent acute and delayed neuronal injury that leads to the development of epilepsy.


Use of horizontal ultrathin gel electrophoresis to analyze allelic deletions in chromosome band 11p15.5 in gliomas.
The prognosis for most patients with astrocytic glioma is poor, and postoperative life expectancy has not significantly improved in the last decade despite advances in diagnosis, surgery, and adjuvant therapy. Progress has been made, however, in cataloging the genetic alterations that occur in these tumors. Studying the allelic changes using loss of heterozygosity analysis has proven to be a reliable and rapid way of identifying genetic alterations fundamental to the pathology of this disease. In this study, we used a series of fluorescent-labeled markers and a new horizontal ultrathin gel electrophoresis technology (HUGE; GeneSys Technologies, Inc.) to analyze loss of heterozygosity on 11p15 in a series of 24 matched normal/tumor glioma pairs that included both anaplastic astrocytomas and glioblastomas. These studies significantly narrowed the region harboring a putative 11p15.5 glioma-associated gene and further suggest that a second gene involved in the pathogenesis of brain tumors may exist, centromeric, in bands 11p15.5-p15.4.


The binding of zinc ions to Emericella nidulans endo-β-1,4-galactanase is essential for crystal formation.
A novel Emericella nidulans endo-β-1,4-galactanase (EnGAL) demonstrates a strong capacity to generate high levels of very potent prebiotic oligosaccharides from potato pulp, a by-product of the agricultural potato-starch industry. EnGAL belongs to glycoside hydrolase family 53 and shows high (72.5%) sequence identity to an endo-β-1,4-galactanase from Aspergillus aculeatus. Diffraction data extending to 2.0 Å resolution were collected from a crystal of EnGAL grown from conditions containing 0.2 M zinc acetate. The crystal structure showed a high similarity between EnGAL and other endo-β-1,4-galactanases belonging to GH53. It also revealed 15 zinc ions bound to the protein, one of which is located in the active site, where it is coordinated by residues Glu136 and Glu246 which comprise the catalytic machinery. The majority of the zinc ions are located on the surface of the enzyme, in some cases with side chains from two different molecules as ligands, thus explaining why the presence of zinc ions was essential for crystallization.


Systematic review of antidepressant therapies in Parkinson's disease.
Depression is the most common psychiatric disturbance in Parkinson's disease. We conducted a Cochrane systematic review to assess the efficacy and safety of antidepressant therapies in idiopathic Parkinson's disease. Relevant trials were identified from electronic databases, reference lists and queries to antidepressant manufacturers. Three randomised controlled trials examined oral antidepressants in 106 patients with Parkinson's disease. No eligible trials of electroconvulsive or behavioural therapy were found. In the first arm of the crossover trial by Andersen et al. (n=22), nortriptyline treated patients showed a larger improvement than placebo in a unique depression rating scale after 16 weeks although significance levels were not provided. A parallel group trial by Wermuth et al. (n=37) did not show any significant difference between citalopram and placebo in Hamilton score after 52 weeks. Rabey et al. (n=47) performed an open-label trial comparing fluvoxamine with amitriptyline. Similar numbers in each group had a 50% reduction in Hamilton score after 16 months. Major side effects including visual hallucinations and confusion were reported with fluvoxamine and amitriptyline. Insufficient data on the effectiveness and safety of antidepressant therapies in Parkinson's disease are available on which to make recommendations for their use. Large scale randomised controlled trials are urgently required.


A new family of dinuclear lanthanide complexes constructed from an 8-hydroxyquinoline Schiff base and β-diketone: magnetic properties and near-infrared luminescence.
Six phenoxo-O bridged dinuclear lanthanide(iii) complexes have been assembled utilizing the 2-[(4-nitrophenyl)imino]methyl-8-hydroxyquinoline (HL) and dibenzoylmethane (Hdbm) ligands: [Ln2(dbm)4L2] (Ln = Nd (1), Eu (2), Gd (3), Tb (4), Dy (5) and Er (6)). Complexes 1 and 6 exhibit the characteristic emission peaks of the corresponding Nd3+ and Er3+ ions, respectively. Meanwhile, the excitation wavelength (470 nm) for complex 1 is located in the visible-light region, confirming a practical application value. The studies on magnetic properties reveal that complex 3 features a magnetocaloric effect with a magnetic entropy change of -ΔSm = 14.36 J kg-1 K-1 at 4 K for ΔH = 7 T. What's more, the dynamic magnetic studies for complex 5 show that it exhibits slow magnetic relaxation behavior, typical of SMM behavior, resulting in an energy barrier of ΔE/kB = 75 K with the pre-exponential factor τ0 = 2.2 × 10-7 s. Meanwhile, this research demonstrates that the magnetic properties can be modulated by regulating the electron-donating/withdrawing effects of the substituents on the ligands.


A genetic determinant of the striatal dopamine response to alcohol in men.
Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [(11)C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.


Inducible gene expression by retrovirus-mediated transfer of a modified tetracycline-regulated system.
The ability to regulate gene expression via exogenous stimuli will facilitate the study of gene functions in mammalian cells. In the present study, we modified the tetracycline-controlled inducible system by the addition of the ligand-binding domain of the estrogen receptor to the carboxy terminus of the tTA transactivator. A single retroviral vector can transduce both the transactivator gene and the gene of interest controlled by the tTA-inducible promoter into mammalian cells. We show that cell lines expressing the transactivator can readily be established and that expression of the gene of interest depends on the removal of tetracycline and the addition of estrogen. By using this system, cell lines with inducible expression of the G protein of vesicular stomatitis virus, a potentially toxic gene product, were established. The combination of a powerful inducible system and retrovirus-mediated gene transfer can not only be used to study gene function but may also be applied in the future to clinical trials in human gene therapy.


Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease.
We have previously demonstrated that fetal nigral grafts can survive, reinnervate the striatum, and mediate clinically relevant recovery in a patient with Parkinson's disease (PD). Most previous autopsy cases have failed to identify meaningful numbers of viable grafted cells suggesting that differences in critical transplant variables determine graft viability. The present study evaluated the structural and functional correlates of fetal nigral transplantation in a second PD patient who received fetal nigral grafts according to our previously published transplant protocol. A 61-year-old woman with severe PD received bilateral fetal nigral grafts to the postcommissural putamen from seven donor fetuses (four right side and three left side) aged 6.5-9 weeks postconception. This patient died 19 months after surgery from a cause unrelated to the transplant surgery. Her postoperative clinical course was characterized by improved motor and activities of daily living scores during "off time," reduced "off time," and increased "on" time without dyskinesia. Positron emission tomography (PET) scans revealed a bilateral and progressive increase in fluorodopa (FD) uptake within the grafted putamen. Postmortem examination of the right hemisphere revealed large oval-shaped grafts containing more than 138,000 tyrosine-hydroxylase-immunoreactive (TH-ir) neurons. Grafted cells formed a seamless border with the host and provided dense TH-ir innervation to 78% of the host postcommissural putamen. Graft-mediated sprouting of host fibers was not observed. These data provide essential confirmation that, under appropriate transplant conditions, grafted nigral neurons can survive, reinnervate the host striatum, and provide clinical benefit to PD patients. These findings also support the concept that improved motor function and striatal FD uptake on PET after nigral grafting in PD are the result of the viability of grafted neurons and graft-derived reinnervation of the host striatum.


Candidates for novel RNA topologies.
Because the functional repertiore of RNA molecules, like proteins, is closely linked to the diversity of their shapes, uncovering RNA's structural repertoire is vital for identifying novel RNAs, especially in genomic sequences. To help expand the limited number of known RNA families, we use graphical representation and clustering analysis of RNA secondary structures to predict novel RNA topologies and their abundance as a function of size. Representing the essential topological properties of RNA secondary structures as graphs enables enumeration, generation, and prediction of novel RNA motifs. We apply a probabilistic graph-growing method to construct the RNA structure space encompassing the topologies of existing and hypothetical RNAs and cluster all RNA topologies into two groups using topological descriptors and a standard clustering algorithm. Significantly, we find that nearly all existing RNAs fall into one group, which we refer to as "RNA-like"; we consider the other group "non-RNA-like". Our method predicts many candidates for novel RNA secondary topologies, some of which are remarkably similar to existing structures; interestingly, the centroid of the RNA-like group is the tmRNA fold, a pseudoknot having both tRNA-like and mRNA-like functions. Additionally, our approach allows estimation of the relative abundance of pseudoknot and other (e.g. tree) motifs using the "edge-cut" property of RNA graphs. This analysis suggests that pseudoknots dominate the RNA structure universe, representing more than 90% when the sequence length exceeds 120 nt; the predicted trend for <100 nt agrees with data for existing RNAs. Together with our predictions for novel "RNA-like" topologies, our analysis can help direct the design of functional RNAs and identification of novel RNA folds in genomes through an efficient topology-directed search, which grows much more slowly in complexity with RNA size compared to the traditional sequence-based search.


Self-Control and Emotion Regulation Mediate the Impact of Karate Training on Satisfaction With Life.
Physical activity is an important determinant of a healthy lifestyle. Regular participation in sports-related activities contributes to the maintenance of good psychophysiological and social health. Long-term physical activity has a positive impact on subjective well-being and can reduce stress. Karate is a specific physical activity which focuses on self-regulation and self-development; therefore, it may reduce impulsivity and improve self-control. Good self-control is also related to satisfaction with life and well-being. The presented study aimed to examine the possible intermediate impact of self-control and emotion regulation on the relationship between karate training and satisfaction with life. Fifty-eight karate practitioners and fifty-nine control subjects participated in the research. The Satisfaction With Life Scale and the Brief Self-Control Scale were applied in order to assess life satisfaction and the general level of self-control. The Emotion Regulation Questionnaire was used to assess suppression and reappraisal, both of which are distinct aspects of emotion regulation. The direct and indirect relationships between karate training and satisfaction with life were investigated using a linear regression model that included self-control, suppression and reappraisal as mediating variables. No direct effects of karate training on satisfaction with life were found, whereas karate training was indirectly associated with satisfaction with life via the indirect path that leads through self-control and reappraisal. This indicates that self-control and reappraisal fully mediate the impact of karate training on subjective well-being. Karate training can therefore play an important role in shaping volitional and personality characteristics, both of which contribute to increasing the well-being of trainees.


Impact of Public Health and Social Measures on the COVID-19 Pandemic in the United States and Other Countries: Descriptive Analysis.
The United States of America has the highest global number of COVID-19 cases and deaths, which may be due in part to delays and inconsistencies in implementing public health and social measures (PHSMs). In this descriptive analysis, we analyzed the epidemiological evidence for the impact of PHSMs on COVID-19 transmission in the United States and compared these data to those for 10 other countries of varying income levels, population sizes, and geographies. We compared PHSM implementation timing and stringency against COVID-19 daily case counts in the United States and against those in Canada, China, Ethiopia, Japan, Kazakhstan, New Zealand, Singapore, South Korea, Vietnam, and Zimbabwe from January 1 to November 25, 2020. We descriptively analyzed the impact of border closures, contact tracing, household confinement, mandated face masks, quarantine and isolation, school closures, limited gatherings, and states of emergency on COVID-19 case counts. We also compared the relationship between global socioeconomic indicators and national pandemic trajectories across the 11 countries. PHSMs and case count data were derived from various surveillance systems, including the Health Intervention Tracking for COVID-19 database, the World Health Organization PHSM database, and the European Centre for Disease Prevention and Control. Implementing a specific package of 4 PHSMs (quarantine and isolation, school closures, household confinement, and the limiting of social gatherings) early and stringently was observed to coincide with lower case counts and transmission durations in Vietnam, Zimbabwe, New Zealand, South Korea, Ethiopia, and Kazakhstan. In contrast, the United States implemented few PHSMs stringently or early and did not use this successful package. Across the 11 countries, national income positively correlated (r=0.624) with cumulative COVID-19 incidence. Our findings suggest that early implementation, consistent execution, adequate duration, and high adherence to PHSMs represent key factors of reducing the spread of COVID-19. Although national income may be related to COVID-19 progression, a country's wealth appears to be less important in controlling the pandemic and more important in taking rapid, centralized, and consistent public health action.


SHIP2, a factor associated with diet-induced obesity and insulin sensitivity, attenuates FGF signaling in vivo.
SH2-domain-containing inositol phosphatase 2 (SHIP2) belongs to a small family of phosphoinositide 5-phosphatases that help terminate intracellular signaling initiated by activated receptor tyrosine kinases. Mammalian SHIP2 is viewed primarily as an attenuator of insulin signaling and has become a prominent candidate target for therapeutic agents that are designed to augment insulin signaling. Despite this view, no signaling pathway has yet been demonstrated as being affected directly by SHIP2 function in vivo, and in vitro studies indicate that the protein may function in multiple signaling pathways. Here, we analyze the role of a SHIP2 family member in the early zebrafish embryo where developmental and gene expression defects can be used to assay specific signaling pathways. The zebrafish ship2a transcript is maternally supplied, and inhibiting the expression of its protein product results in the expansion of dorsal tissue fates at the expense of ventral ones. We show that the developmental defects are the result of perturbation of fibroblast growth factor (FGF) signaling in the early embryo. Loss of Ship2a leads to an increased and expanded expression of outputs of FGF-mediated signaling, including FGF-dependent gene expression and activated mitogen-activated protein kinase (MAPK) signaling. Our findings demonstrate that Ship2a attenuates the FGF signaling pathway in vivo and functions in the establishment of normal tissue patterning in the early embryo. We suggest that modulation of FGF signaling may be a principal function of SHIP2 in mammals.


Application of biomaterials for the detection of amyloid aggregates.
Amyloid aggregates, which include oligomers and fibrils, are considered to cause various diseases, and their detection is important. In this minireview, recent developments on biomaterials, such as proteins, nanoparticles, and chemical reagents, for detecting amyloid aggregates are discussed. In particular, the molecular chaperone prefoldin (PFD) exhibits interesting properties for the interaction and detection of amyloid oligomers. In fact, any molecule that can bind amyloid aggregates could be useful for their detection.


Obstructive sleep apnea is associated with seizure occurrence in older adults with epilepsy.
Although epileptic seizures occur more commonly in older adults, their occurrence in this age group is often unexplained. One unexplored precipitant of seizures in older adults is obstructive sleep apnea (OSA), which is also more common in this age group. Our objective was to investigate whether OSA is associated with seizure exacerbation in older adults with epilepsy. Polysomnography was performed in older adult patients with late-onset or worsening seizures (Group 1, n = 11) and those who were seizure-free or who had improvement of seizures (Group 2, n = 10). Patients in Group 1 had a significantly higher apnea-hypopnea index than patients in Group 2 (p = 0.002). Group 1 patients also had higher Epworth Sleepiness Scale scores (p = 0.009) and higher scores on the Sleep Apnea Scale of the Sleep Disorders Questionnaire (p = 0.04). The two groups were similar in age, body mass index, neck circumference, number of antiepileptic drugs currently used, and frequency of nocturnal seizures. Obstructive sleep apnea is associated with seizure exacerbation in older adults with epilepsy, and its treatment may represent an important avenue for improving seizure control in this population.


Women and agricultural productivity: Reframing the Issues.
Should agricultural development programmes target women in order to increase productivity? This article analyzes the challenges in distinguishing women's agricultural productivity from that of men. Most of the literature compares productivity on plots managed by women with those managed by men, ignoring the majority of agricultural households in which men and women are both involved in management and production. The empirical studies which have been carried out provide scant evidence for where the returns to projects may be highest, in terms of who to target. Yet, programmes that do not consider gendered responsibilities, resources and constraints, are unlikely to succeed, either in terms of increasing productivity or benefitting men and women smallholder farmers.


Parents with intellectual disabilities seeking professional parenting support: the role of working alliance, stress and informal support.
Delaying or refraining from seeking advice and support in difficult parenting situations is identified as an important risk factor for child abuse and neglect. This study tested whether the extent of delays in support seeking is associated with working alliance for parents with mild intellectual disabilities (MID) and whether the importance of working alliance may depend on parenting stress and availability of informal support. Delays in support seeking were measured as parental latency (time waited) to approach the support worker. This latency was assessed in the intended response to hypothetical situations (vignettes) and in the reported behavioral response to real life difficult parenting situations from the preceding weeks. Multiple regression analyses were conducted for testing main and interaction effects of predictors on latency for support seeking. Better quality of the working alliance was associated with shorter intended latency to seek support for parents with MID, if parents had little access to informal support. Higher parenting stress predicted a shorter latency for intended support seeking. Parental support seeking intentions were positively associated with support seeking behavior. A good quality of the working alliance might be important to connect needs of parents with MID to resources that professional support can offer, in particular for the most vulnerable parents. Parental reluctance to seek professional support may be the result of a combination of risk and protective factors and is not always a sign of poor working alliance. Implications for risk assessment and support practice are discussed.


Preoperative and postoperative pulmonary function tests in patients with atrial septal defect and their relation to pulmonary artery pressure and pulmonary:systemic flow ratio.
Pulmonary diffusing properties and lung volumes were investigated in 44 patients with atrial septal defect, and in 30 of them preoperative and postoperative data were obtained. The patients were divided into three groups according to mean pulmonary artery pressure: less than or equal to 15 mm Hg (group 1), 16-29 mm Hg (group 2), and greater than or equal to 30 mm Hg (group 3). Patients in groups 1 and 2 had a high carbon monoxide transfer test which became normal after surgical correction of their septal defect. In group 3, the carbon monoxide transfer test was normal both before and after operation. As mean pulmonary artery pressure increased there was a progressive reduction in both forced expiratory volume in one second and vital capacity. Patients in group 3 had a low forced expiratory volume in one second, a low vital capacity, and a reduced forced expiratory volume in one second:vital capacity ratio. These abnormalities were not corrected by surgical closure of the septal defect. Formulas were derived from the lung function data, to predict the mean pulmonary artery pressure and the pulmonary:systemic flow ratio. The values predicted when these two formulas were applied to data obtained for patients in this study correlated well with measured values.


1,7-Diethylguanosine formation in tRNA chemical ethylation by ethionine and ethylnitrosourea.
The mechanism of ethionine carcinogenesis and more generally the relationship between alkylation of nucleic acids by chemical carcinogens and oncogenesis still remain obscure. In the present study the rat liver tRNA ethylation by L-[ethyl-1-3H]ethionine was reinvestigated by examining in particular the highly radioactive 'pyrimidine-nucleotide-like' fraction found earlier in acid hydrolysates of hepatic tRNA from ethionine-treated rats. The following results were obtained: (1) ultraviolet-spectral and chromatographic analyses showed the presence of 1,7-diethylguanosine in this 'pyrimidine-nucleotide-like' fraction; (2) the dialkyl compound was recovered exclusively in the form of imidazole-ring-opened derivatives. When [1-14C]ethylnitrosourea was used as alkylating agent, the in vivo ethylation pattern of tRNA from various organs of rat showed an analogous radioactive 'pyrimidine-nucleotide-like' fraction as main radioactive product. On the contrary, tRNA ethylation pattern after in vitro reaction with [1-14C]ethylnitrosourea exhibited a main radioactivity peak (85% of the total radioactivity recovered) in coincidence of the chromatographic area of 1,7-diethylguanine. The 1,7-diethylguanosine moieties of tRNA were extremely labile both under physiological and alkaline conditions. The 1,7-diethylguanine-associated radioactivity was completely lost from [14C]ethyl-tRNA after only 7 h incubation at 37 degrees C and pH 7.3, while at pH 11.4 this process was preceded by the conversion of the 1,7-diethylguanosine residues into imidazole-ring-opened derivatives.


Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection.
In this report, we demonstrate that CD28(-/-) mice are severely impaired in the initial expansion of D(b)/NP366-374-specific CD8 T cells in response to influenza virus infection, whereas 4-1BB ligand (4-1BBL)(-/-) mice show no defect in primary T cell expansion to influenza virus. In contrast, 4-1BBL(-/-) mice show a decrease in D(b)/NP366-374-specific T cells late in the primary response. Upon secondary challenge with influenza virus, 4-1BBL(-/-) mice show a decrease in the number of D(b)/NP366-374-specific T cells compared to wild-type mice such that the level of the CD8 T cell expansion during the in vivo secondary response is reduced to the level of a primary response, with concomitant reduction of CTL effector function. In contrast, Ab responses, as well as secondary CD4 T cell responses, to influenza are unaffected by 4-1BBL deficiency. Thus, CD28 is critical for initial T cell expansion, whereas 4-1BB/4-1BBL signaling affects T cell numbers much later in the response and is essential for the survival and/or responsiveness of the memory CD8 T cell pool.


Enzymic activities in the pancreas, digestive tract and feces of rats fed raw or heated soy flour.
Trypsin, chymotrypsin and amylase levels were determined in the pancreas, all along the intestinal tract, and in the feces of rats fed raw or heated soy flour diets. The levels of all enzymes measured in the pancreas in the non-fasted state were lower in the raw than in the heated soy flour-fed rats. Fasting equalized these levels. Trypsin and amylase tended to be lower, and chymotrypsin was significantly higher in the intestinal tracts of raw soy flour-fed rats than in the group fed heated soy flour; the greatest differences were found in the ileum. Trypsin and chymotrypsin levels in the feces were higher in the group fed raw soy flour than in the group fed heated soy flour. Amylase in the feces of the raw soy flour-fed rats was higher at the beginning of the experiment and dropped sharply to be even lower than in the heated soy flour-fed rats at days 13 to 14 of the experiment. It was concluded that measuring the enzymic levels in the feces is a very sensitive method for determining whether a test diet induces hypersecretion of digestive enzymes in rats. This method can be used from the start of feeding the experimental diet. As the animal need not be killed, the effect of the test diet upon enzymic secretion can be studied as a function of time, and it might be suitable to studies with large animals.


Revisiting Protocols for the NMR Analysis of Bacterial Metabolomes.
Over the past decade, metabolomics has emerged as an important technique for systems biology. Measuring all the metabolites in a biological system provides an invaluable source of information to explore various cellular processes, and to investigate the impact of environmental factors and genetic modifications. Nuclear magnetic resonance (NMR) spectroscopy is an important method routinely employed in metabolomics. NMR provides comprehensive structural and quantitative information useful for metabolomics fingerprinting, chemometric analysis, metabolite identification and metabolic pathway construction. A successful metabolomics study relies on proper experimental protocols for the collection, handling, processing and analysis of metabolomics data. Critically, these protocols should eliminate or avoid biologically-irrelevant changes to the metabolome. We provide a comprehensive description of our NMR-based metabolomics procedures optimized for the analysis of bacterial metabolomes. The technical details described within this manuscript should provide a useful guide to reliably apply our NMR-based metabolomics methodology to systems biology studies.


Drive level dependence of the resonant frequency in BAW quartz resonators and his modeling.
The influence of the excitation current on the resonant frequency and its mathematical description makes necessary the introduction of a nonlinear impedance characteristic of the piezoelectric resonator. This influence was modeled by the nonlinear electrical equivalent circuit; the equivalent series resistance and equivalent motional capacitance are taken to be functions of the amplitude of the excitation current by means of the relations derived in the work. The equivalent circuit was analyzed by the method of equivalent linearization. The relationships between the amplitudes of voltage applied on the AT-cut resonator and the first current harmonics or phase-frequency dependence of the excited resonator, respectively, are derived. Amplitude jumps and dynamic temperature change phenomena are discussed.


[The mandatory medical insurance through eyes of medical personnel].
The article considers the results of sociological survey carries out among medical personnel of the Moscowskaya oblast in August-September 2013. The purpose of the study was to examine opinions of medical personnel about system of mandatory insurance in conditions of implementation of the new law regulating system of mandatory medical insurance during last three years. The sampling included 932 respondents that corresponds approximately 1% of all medical personnel in the oblast. It is established that even 20 years later after the moment of organization of the system of mandatory medical insurance not all medical personnel is oriented in it. More than 70% of respondents consider this system too convoluted and over bureaucratized and only 22.2% of respondents assume that medical insurance organizations defense interests of patient and 25.8% feel no impact of mandatory medical insurance funds on functioning of medical organizations. Most of respondents consider functions of mandatory medical insurance organizations and mandatory medical insurance funds as controlling only. Only 31% of respondents support the actual system of mandatory medical insurance.


High-resolution structure of a papaya plant-defense barwin-like protein solved by in-house sulfur-SAD phasing.
The first crystal structure of a barwin-like protein, named carwin, has been determined at high resolution by single-wavelength anomalous diffraction (SAD) phasing using the six intrinsic S atoms present in the protein. The barwin-like protein was purified from Carica papaya latex and crystallized in the orthorhombic space group P212121. Using in-house Cu Kα X-ray radiation, 16 cumulative diffraction data sets were acquired to increase the signal-to-noise level and thereby the anomalous scattering signal. A sequence-database search on the papaya genome identified two carwin isoforms of 122 residues in length, both containing six S atoms that yield an estimated Bijvoet ratio of 0.93% at 1.54 Å wavelength. A systematic analysis of data quality and redundancy was performed to assess the capacity to locate the S atoms and to phase the data. It was observed that the crystal decay was low during data collection and that successful S-SAD phasing could be obtained with a relatively low data multiplicity of about 7. Using a synchrotron source, high-resolution data (1 Å) were collected from two different crystal forms of the papaya latex carwin. The refined structures showed a central β-barrel of six strands surrounded by several α-helices and loops. The β-barrel of carwin appears to be a common structural module that is shared within several other unrelated proteins. Finally, the possible biological function of the protein is discussed.


Atrial Fibrillation Catheter Ablation Improves 1-Year Follow-Up Cognitive Function, Especially in Patients With Impaired Cognitive Function.
Although atrial fibrillation (AF) has a risk of cognitive dysfunction, it is not clear whether AF catheter ablation improves or worsens cognitive function. This prospective case-control study sought to assess the 1-year serial changes in the cognitive function with or without AF catheter ablation. We evaluated the Montreal Cognitive Assessment score in 308 patients (71.4% male, 60.6±9.1 years of age, 34.1% persistent AF) who underwent AF ablation (ablation group) and 50 AF patients on medical therapy who met the same indication for AF ablation (control group), at baseline and 3 and 12 months after enrollment. Cognitive impairment was defined as a published cutoff score of <23 points. To exclude any learning effects, we used the practice-adjusted reliable change index for assessing the cognitive changes. Preablation cognitive impairment was detected in 18.5% (57/308). The Montreal Cognitive Assessment score significantly improved 1 year after radiofrequency catheter ablation in both overall ablation group (24.9±2.9-26.4±2.5; P<0.001) and the propensity-matched ablation group (25.4±2.4-26.5±2.3; P<0.001), but not in the control group (25.4±2.5-24.8±2.5; P=0.012). Preablation cognitive impairment (odds ratio, 13.70; 95% CI, 4.83-38.87; P<0.001) was independently associated with an improvement in the 1-year post-ablation cognitive function. In the reliable change index analyses, 94.7% of propensity-matched ablation group showed an improved/stable cognitive function at the 1-year follow-up. Catheter ablation of AF, at least, does not deteriorate the cognitive function, but rather improves the performance on 1-year follow-up neurocognitive tests, especially in patients with a preablation cognitive impairment.


twist and snail as positive and negative regulators during Drosophila mesoderm development.
twist and snail are members of the helix-loop-helix and zinc-finger protein families, respectively, and determine the development of the mesoderm in Drosophila. This paper analyzes their role in mesoderm development by examining how they affect the expression of downstream genes. twist and snail act by regulating gene expression in the mesoderm and in neighboring regions, and have distinct roles in this process. snail prevents expression in the mesoderm of genes that are destined to be active only in more lateral or dorsal regions. twist is required for the activation of downstream mesodermal genes. twist is also required for the full expression of snail and for the maintenance of its own expression. Only the absence of both twist and snail results in the complete loss of all mesodermal characteristics.


A national propensity-adjusted analysis of adjuvant radiotherapy in the treatment of resected pancreatic adenocarcinoma.
The benefit of adjuvant radiotherapy (RT) for resected pancreatic adenocarcinoma remains controversial after randomized clinical trials. In this national-level US study, a propensity score (conditional probability of receiving RT) was used to adjust for potential confounding in nonrandomized designs from treatment group differences. Patients were identified from the Surveillance, Epidemiology, and End Results (SEER) registry (1988-2005 dataset). Multivariate analyses to determine the effect of RT on overall survival were performed using propensity-adjusted Cox proportional hazards and Kaplan-Meier analyses. In total, 5676 patients with resected pancreatic adenocarcinoma were identified, and 40.8% of those patients had received adjuvant RT. Univariate predictors of survival included age, race, marital status, disease stage, tumor size, tumor extension, tumor grade, lymph node status, year of diagnosis, type of resection, and receipt of RT (all P < .002). In a Cox model, independent predictors of improved survival included white race, married status, earlier stage, smaller tumors, well differentiated tumors, negative lymph node (N0) status, recent diagnosis, and receipt of RT (all P < .05). In a propensity-adjusted proportional hazards regression, the benefit of adjuvant treatment that included RT remained significant after adjusting for the likelihood of receiving RT (hazard ratio, 0.773; 95% confidence interval, 0.714-0.836; P < .0001). Within all 5 propensity strata, Kaplan-Meier survival differed significantly (P < .0001 [lowest and highest probability strata] and P = .0165 [middle stratum with a "pseudorandom" probability of RT]). Adjuvant RT for resected pancreatic adenocarcinoma was associated with a significant survival advantage in a large national database, even after using propensity score methods to adjust for differences between treatment groups. The authors concluded that adjuvant RT should be considered for all appropriate patients who have resected pancreatic adenocarcinoma.


Open reading frame expression vectors: a general method for antigen production in Escherichia coli using protein fusions to beta-galactosidase.
We have developed an Escherichia coli plasmid vector for the identification and expression of foreign DNA segments that are open reading frames (ORFs). The 5' end of ompF, an E. coli gene encoding an abundant outer membrane protein, is used to provide a strong, regulated promoter, translation initiation site, and signal sequence for export from the cytoplasm. This sequence is coupled to the lacZ gene of E. coli so that expression of beta-galactosidase requires ompF transcription and translation signals. However, this hybrid gene is LacZ- because lacZ is out of frame with respect to ompF. Restriction enzyme recognition sites are located between ompF and lacZ to allow convenient insertion of DNA fragments. If an insert is an ORF of the correct length, ompF and lacZ become realigned in frame, resulting in a LacZ+ gene that produces a tribrid protein with the translation product of the insert sandwiched between OmpF and beta-galactosidase. The LacZ+ phenotype thus identifies clones containing an expressed ORF. To demonstrate the vector's utility we inserted a fragment from the herpes virus thymidine kinase gene and used the resulting tribrid protein to raise antibodies that precipitate thymidine kinase from herpes virus-infected cells. We also inserted a fragment from the E. coli lexA gene to produce a tribrid protein that is precipitated by antiserum raised with LexA protein. Thus, tribrid fusion proteins can be used to produce or detect antibodies and also to identify the product of a cloned gene.


Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice.
Patients with sickle cell disease (SCD) can have recurrent episodes of vaso-occlusive crises, which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use results in continued and increasing pain. Many believe that this phenomenon results from opioid-induced tolerance or hyperalgesia or that SCD pain involves non-opioid-responsive mechanisms. Dexmedetomidine, a specific α2-adrenoreceptor agonist, which has sedative and analgesic properties, reduces opioid requirements, and can facilitate opioid withdrawal in clinical settings. We hypothesized that dexmedetomidine would ameliorate the nociception phenotype of SCD mice. Townes and BERK SCD mice, strains known to have altered nociception phenotypes, were used in a crossover preclinical trial that measured nocifensive behavior before and after treatment with dexmedetomidine or vehicle. In a linear dose-effect relationship, over 60-min, dexmedetomidine, compared with vehicle, significantly increased hot plate latency in Townes and BERK mice (P≤0.006). In sickle, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickle and control mice as it decreased wakefulness scores compared with vehicle (all P<0.001). Interestingly, the effects of dexmedetomidine on hot plate latency and wakefulness scores were different in sickle and control mice, i.e., dexmedetomidine-related increases in hotplate latency and decreases in wakefulness scores were significantly smaller in Townes sickle compared to control mice. In conclusion, these findings of beneficial effects of dexmedetomidine on the nociception phenotype in SCD mice might support the conduct of studies of dexmedetomidine in SCD patients.


Integration of an RF coil and commercial field camera for ultrahigh-field MRI.
To develop an RF coil with an integrated commercial field camera for ultrahigh field (7T) neuroimaging. The RF coil would operate within a head-only gradient coil and be subject to the corresponding design constraints. The RF coil can thereafter be used for subject-specific correction of k-space trajectories-notably in gradient-sensitive sequences such as single-shot spiral imaging. The transmit and receive performance was evaluated before and after the integration of field probes, whereas field probes were evaluated when in an optimal configuration external to the coil and after their integration. Diffusion-weighted EPI and single-shot spiral acquisitions were employed to evaluate the efficacy of correcting higher order field perturbations and the consequent effect on image quality. Field probes had a negligible effect on RF-coil performance, including the transmit efficiency, transmit uniformity, and mean SNR over the brain. Modest reductions in field-probe signal lifetimes were observed, caused primarily by nonidealities in the gradient and shim fields of the head-only gradient coil at the probe positions. The field-monitoring system could correct up to second-order field perturbations in single-shot spiral imaging. The integrated RF coil and field camera was capable of concurrent-field monitoring within a 7T head-only scanner and facilitated the subsequent correction of k-space trajectories during spiral imaging.


Expression of a retinoblastoma transgene results in dwarf mice.
Introduction of the normal retinoblastoma gene (RB) into different tumor cells possessing inactivated RB genes suppresses their tumorigenicity in nude mice. These results suggest that RB replacement is a potential strategy for developing future clinical treatments of cancer. In a transgenic mouse model, we found that the quantity of RB protein in a given cell may play an important role in dictating its effect. Four founder mice containing 1-7 copies of a human RB cDNA transgene under the transcriptional control of the human RB promoter were generated. Most of the transgenic mice were smaller than nontransgenic littermates. This effect was found as early as embryonic day 15. The degree of dwarfism correlated roughly with the copy number of the transgene and the corresponding level of RB protein. The expression pattern of the transgene products was similar to that of the endogenous mouse RB gene with regard to tissue and temporal distribution. Transferring the transgene to RB deficient mice, which are nonviable, resulted in the development of normal, healthy mice, indicating that the human RB gene can functionally complement the mouse homolog. These studies demonstrate that the effect of RB on overall mouse development is closely dependent upon its dosage.


Fluorescence lifetime imaging of lignin autofluorescence in normal and compression wood.
Wood cell walls fluoresce as a result of UV and visible light excitation due to the presence of lignin. Fluorescence spectroscopy has revealed characteristic spectral differences in various wood types, notably normal and compression wood. In order to extend this method of characterising cell walls we examined the fluorescence lifetime of wood cell walls using TCSPC (Time-Correlated Single Photon Counting) as a method of potentially detecting differences in lignin composition and measuring the molecular environment within cell walls. The fluorescence decay curves of both normal and compression wood from pine contain three exponential decay components with a mean lifetime of τm = 473 ps in normal wood and 418 ps in compression wood. Lifetimes are spatially resolved to different cell wall layers or cell types where individual lifetimes are shown to have a log-normal distribution. The differences in fluorescence lifetime observed in pine compression wood compared to normal wood, are associated with known differences in cell wall composition such as increased p-hydroxyphenyl content in lignin as well as novel deposition of β(1,4)-Galactan. Our results indicate increased deposition of lignin fluorophores with shorter lifetimes in the outer secondary wall of compression wood. We have demonstrated the usefulness of fluorescence lifetime imaging for characterising wood cell walls, offering some advantages over conventional fluorescence imaging/spectroscopy. For example, we have measured significant changes in fluorescence lifetime resulting from changes to lignin composition as a result of compression wood formation that complement similar changes in fluorescence intensity.


New approaches in small animal echocardiography: imaging the sounds of silence.
Systolic and diastolic dysfunction of the left ventricle (LV) is a hallmark of most cardiac diseases. In vivo assessment of heart function in animal models, particularly mice, is essential to refining our understanding of cardiovascular disease processes. Ultrasound echocardiography has emerged as a powerful, noninvasive tool to serially monitor cardiac performance and map the progression of heart dysfunction in murine injury models. This review covers current applications of small animal echocardiography, as well as emerging technologies that improve evaluation of LV function. In particular, we describe speckle-tracking imaging-based regional LV analysis, a recent advancement in murine echocardiography with proven clinical utility. This sensitive measure enables an early detection of subtle myocardial defects before global dysfunction in genetically engineered and rodent surgical injury models. Novel visualization technologies that allow in-depth phenotypic assessment of small animal models, including perfusion imaging and fetal echocardiography, are also discussed. As imaging capabilities continue to improve, murine echocardiography will remain a critical component of the investigator's armamentarium in translating animal data to enhanced clinical treatment of cardiovascular diseases.


[Characteristics of δ-Aminolevulinic Acid Dehydratase of the Cold-Water Sponge Halisarca dujardinii].
δ-Aminolevulinic acid dehydratase (ALAD) is a key enzyme of the cytoplasmic heme biosynthesis pathway. The primary structure of the ALAD gene, the multimeric structure of the ALAD/hemB protein, and ALAD expression during the annual reproductive cycle were studied in the cold-water marine sponge Halisarca dujardinii. The results implicated the GATA-1 transcription factor and DNA methylation in regulating ALAD expression. Re-aggregation of sponge cells was accompanied by a decrease in ALAD expression and a change in the cell content of an active ALAD/hemB form. Further study of heme biosynthesis and the role of ALAD/hemB in morphogenesis of basal animals may provide new opportunities for treating pathologies in higher animals.


A Rare Variation of the Axillary Nerve Formed as Direct Branch of the Upper Trunk.
The brachial plexus has a complex anatomical structure from its origin in the neck and through its course in the axillary region. Knowledge of variations of the brachial plexus has important clinical applications especially in relation to trauma and surgical procedures of upper limb. The present study has reported a rare variation of the brachial plexus where the "axillary nerve" arising as a direct branch from the upper trunk instead from the posterior cord. Once the "axillary nerve" was given off, the remaining superior trunk had joined with the anterior division of middle trunk in the formation of the lateral cord. The posterior cord was formed by the union of posterior divisions of the middle and inferior trunks. The "axillary nerve" has given off braches to subscapularis, latissimus dorsi, deltoid and teres minor muscles while having given a "communicating branch" for the posterior cord. The current report indicates an anatomical variation not documented so far which may help in planning safe surgical procedures in this region and to explain unusual resulting complications.


Intracardiac versus transesophageal echocardiography for left atrial appendage occlusion with watchman.
Left atrial appendage occlusion (LAAO) is mostly performed by transesophageal echocardiography (TEE) guidance. Intracardiac echocardiography (ICE) may be an alternative imaging modality for LAAO that precludes the need for general anesthesia or sedation. All consecutive single center, single operator LAAO candidates were analyzed. Baseline clinical and procedural characteristics and in-hospital outcomes were compared between patients in whom a Watchman was implanted with ICE vs. TEE guidance. In 76 consecutive patients the Watchman device was deployed under ICE in 32 patients (42%) and under TEE guidance in 44 patients (58%). Baseline characteristics were comparable between groups, except that patients in the TEE group were older (81 [75-85] years vs. 75 [68-80] years, P = 0.007). Total injected contrast media as well as fluoroscopy time were comparable between groups (90 ml [54-140] vs. 85 ml [80-110], P = 0.86 and 7.9 min [6.4-15.5] vs. 9.8 min [7.0-13.2], P = 0.51, for TEE vs. ICE, respectively). However, time from femoral venous puncture to transseptal puncture and to closure was longer in the ICE group (14 min [7.3-20] vs. 6 min [3.3-11], P = 0.007 and 48 min [40-60] vs. 34.5 min [27-44], P = 0.003, respectively). In the TEE group one patient suffered esophageal erosion with bleeding, which was managed conservatively and one non-LAAO related in-hospital mortality occurred in an 88-year-old patient. Device implantation success rate was 100% in both groups. No device embolization, no significant peri-device leak, no tamponade, no stroke, and no access site bleeding occurred in any patient. Total hospital stay for stand-alone LAAO was comparable between groups (2 days [2-2] vs. 2 days [2-3.3], P = 0.17, in ICE vs. TEE, respectively). ICE guidance for LAAO with the Watchman device is feasible and comparable to TEE and may become the preferred imaging modality for LAAO. © 2016 Wiley Periodicals, Inc.


cDNA cloning and expression analysis of the human UDPglucose dehydrogenase.
A cDNA clone encoding the human UDPglucose dehydrogenase was isolated from a liver cDNA library. The cDNA is 2,355 bp in length with an open reading frame which is capable of encoding a protein of 494 residues. The predicted primary sequence of the gene product is in good agreement with that of the bovine enzyme determined previously found by means of protein sequencing. Two major transcripts of the UDPglucose dehydrogenase gene with sizes of 2.8 and 2.35 kb, respectively, were observed by Northern analysis. The gene was found to be expressed in a variety of tissues with the highest level in liver, consistent with the physiological function of the enzyme in excretion of endo- and xenobiotics compounds.


Characterisation of muscarinic receptor subtypes in avian smooth muscle.
The identity of the muscarinic receptor subtype in the chick ileum was investigated in functional and binding studies. Preliminary studies [Choo, L.-K., Mitchelson, F., Napier, P. 1988. J. Auton. Pharmacol. 8, 259-266] suggested apparent avian and mammalian family differences in the muscarinic receptor profile of ileal smooth muscle. In the current study, further characterisation was undertaken using a greater range of antagonists exhibiting high affinity for specific muscarinic receptor subtypes. Dissociation constants from functional and binding experiments were compared with published values for antagonists at each of the five muscarinic receptor subtypes. Linear regression and correlation analyses revealed the receptor initiating the contractile response was most likely of the muscarinic M(3) receptor subtype as the slope of the linear regression was 1.01+/-0.14 and the corresponding correlation coefficient (r) was 0.95. The mammalian muscarinic M(5) receptor subtype also showed a high correlation with the data giving a slope of 0.89+/-0.27 and r value of 0.76. These findings were in direct contrast to those from binding experiments in which the single binding site detected was of the muscarinic M(2) receptor subtype. The slope of the linear regression was 1.14+/-0.24 with an r value of 0.87. Thus, these results suggest that there exists a high proportion of the muscarinic M(2) receptor subtype within the tissue that does not contribute to the functional response.


cFOS as a biomarker of activity maturation in the hippocampal formation.
We explored the potential for cFOS expression as a marker of functional development of "resting-state" waking activity in the extended network of the hippocampus and entorhinal cortex. We examined sleeping and awake mice at (P)ostnatal days 5, 9, 13, and 17 as well as in adulthood. We find that cFOS expression is state-dependent even at 5 days old, with reliable staining occurring only in the awake mice. Even during waking, cFOS expression was rare and weak at P5. The septal nuclei, entorhinal cortex layer (L)2, and anterodorsal thalamus were exceptional in that they had robust cFOS expression at P5 that was similar to or greater than in adulthood. Significant P5 expression was also observed in the dentate gyrus, entorhinal cortex L6, postsubiculum L4-6, ventral subiculum, supramammillary nucleus, and posterior hypothalamic nucleus. The expression in these regions grew stronger with age, and the expression in new regions was added progressively at P9 and P13 by which point the overall expression pattern in many regions was qualitatively similar to the adult. Six regions-CA1, dorsal subiculum, postsubiculum L2-3, reuniens nucleus, and perirhinal and postrhinal cortices-were very late developing, mostly achieving adult levels only after P17. Our findings support a number of developmental principles. First, early spontaneous activity patterns induced by muscle twitches during sleep do not induce robust cFOS expression in the extended hippocampal network. Second, the development of cFOS expression follows the progressive activation along the trisynaptic circuit, rather than birth date or cellular maturation. Third, we reveal components of the egocentric head-direction and theta-rhythm circuits as the earliest cFOS active circuits in the forebrain. Our results suggest that cFOS staining may provide a reliable and sensitive biomarker for hippocampal formation activity development, particularly in regard to the attainment of a normal waking state and synchronizing rhythms such as theta and gamma.


A virophage at the origin of large DNA transposons.
DNA transposons are mobile genetic elements that have shaped the genomes of eukaryotes for millions of years, yet their origins remain obscure. We discovered a virophage that, on the basis of genetic homology, likely represents an evolutionary link between double-stranded DNA viruses and Maverick/Polinton eukaryotic DNA transposons. The Mavirus virophage parasitizes the giant Cafeteria roenbergensis virus and encodes 20 predicted proteins, including a retroviral integrase and a protein-primed DNA polymerase B. On the basis of our data, we conclude that Maverick/Polinton transposons may have originated from ancient relatives of Mavirus, and thereby influenced the evolution of eukaryotic genomes, although we cannot rule out alternative evolutionary scenarios.


Association between anaemia and adult depression: a systematic review and meta-analysis of observational studies.
Several observational studies have been conducted to investigate the link between anaemia and adult depression but have shown inconsistent results. This systematic review and meta-analysis was performed to investigate this association. A comprehensive search of four electronic databases (PubMed, EMBASE, PsycINFO and the Cochrane Library) was conducted to identify relevant papers published up to November 2019 for the systematic review and meta-analysis. The Newcastle-Ottawa Scale was used to assess the methodological quality of selected studies. A random-effects model was used to draw metaestimates of the relationship between anaemia and adult depression. A total of 9706 papers were retrieved, and 14 observational epidemiological studies (9 case-control studies and 5 prospective cohort studies) comprising 10 764 cases of depression were finally included in this meta-analysis. The mean age of the participants ranged from 38.4 to 75.0 years. A significant association was identified between low haemoglobin levels and adult depression (OR or relative risk 1.43; 95% CI 1.23 to 1.65). Subgroup analyses according to study design, mean age, diagnostic criteria of anaemia, geographical region, number of participants, methodological quality and adjustment for various confounding factors such as education, smoking, comorbid disorders, physical activity, alcohol intake and medication use showed similar results. The current study showed that anaemia was related to an increased risk of adult depression. One of the important limitations of our study was a moderate degree of heterogeneity due to the variety of assessment tools used to identify depression and the existence of publication bias. Another limitation of this meta-analysis was the lack of prospective cohort studies.


A Bayesian framework for estimating the risk ratio of hospitalization for people with comorbidity infected by SARS-CoV-2 virus.
Estimating the hospitalization risk for people with comorbidities infected by the SARS-CoV-2 virus is important for developing public health policies and guidance. Traditional biostatistical methods for risk estimations require: (i) the number of infected people who were not hospitalized, which may be severely undercounted since many infected people were not tested; (ii) comorbidity information for people not hospitalized, which may not always be readily available. We aim to overcome these limitations by developing a Bayesian approach to estimate the risk ratio of hospitalization for COVID-19 patients with comorbidities. We derived a Bayesian approach to estimate the posterior distribution of the risk ratio using the observed frequency of comorbidities in COVID-19 patients in hospitals and the prevalence of comorbidities in the general population. We applied our approach to 2 large-scale datasets in the United States: 2491 patients in the COVID-NET, and 5700 patients in New York hospitals. Our results consistently indicated that cardiovascular diseases carried the highest hospitalization risk for COVID-19 patients, followed by diabetes, chronic respiratory disease, hypertension, and obesity, respectively. Our approach only needs (i) the number of hospitalized COVID-19 patients and their comorbidity information, which can be reliably obtained using hospital records, and (ii) the prevalence of the comorbidity of interest in the general population, which is regularly documented by public health agencies for common medical conditions. We developed a novel Bayesian approach to estimate the hospitalization risk for people with comorbidities infected with the SARS-CoV-2 virus.


General and oral manifestations of human immunodeficiency virus infection: a general overview with guidelines for infection control in the dental practice.
The human immunodeficiency virus (HIV-1), responsible for the acquired immunodeficiency syndrome, has in the span of a decade become an epidemic of global proportions. Oral lesions, head and neck diseases are often the first manifestations of HIV-1 infection and AIDS. It is essential for all dentists to familiarize themselves with the oral manifestations of HIV-infection as well as the dental management of such manifestations. In addition to all health care, professionals should become acquainted with the "universal precautions" recommended by the Centers for Disease Control, in order to protect themselves, their staff, and their patients to minimize, if not totally eliminate, any risk of infectious disease transmission in the health care setting. This paper presents a general overview of the human immunodeficiency virus; oral manifestations of HIV-infection; "universal precautions" and guidelines for the control of infection in the dental practice.


Mechanics rules cell biology.
Cells in the musculoskeletal system are subjected to various mechanical forces in vivo. Years of research have shown that these mechanical forces, including tension and compression, greatly influence various cellular functions such as gene expression, cell proliferation and differentiation, and secretion of matrix proteins. Cells also use mechanotransduction mechanisms to convert mechanical signals into a cascade of cellular and molecular events. This mini-review provides an overview of cell mechanobiology to highlight the notion that mechanics, mainly in the form of mechanical forces, dictates cell behaviors in terms of both cellular mechanobiological responses and mechanotransduction.