bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulated Apoptosis of Genetically Modified Hematopoietic Stem and Progenitor Cells Via an Inducible Caspase-9 Suicide Gene in Rhesus Macaques
Authors: Barese Cecilia N. , Felizardo Tania C. , Sellers Stephanie E. , Keyvanfar Keyvan , Di Stasi Antonio , Metzger Mark E. , Krouse Allen E. , Donahue Robert E. , Spencer David M. , Dunbar Cynthia E.
Published: October 2014

The high risk of insertional oncogenesis reported in clinical trials using integrating retroviral vectors to genetically modify hematopoietic stem and progenitor cells (HSPCs) requires the development of safety strategies to minimize risks associated with novel cell and gene therapies. The ability to ablate genetically modified cells in vivo is desirable, should an abnormal clone emerge. Inclusion of “suicide genes” in vectors to facilitate targeted ablation of vector-containing abnormal clones in vivo is one potential safety approach. We tested whether the inclusion of the “inducible Caspase-9” (iCasp9) suicide gene in a gamma-retroviral vector facilitated efficient elimination of vector-containing HSPCs and their hematopoietic progeny in vivo long-term, in an autologous non-human primate transplantation model. Following stable engraftment of iCasp9 expressing hematopoietic cells in rhesus macaques, administration of AP1903, a chemical inducer of dimerization able to activate iCasp9, specifically eliminated vector-containing cells in all hematopoietic lineages long-term, suggesting activity at the HSPC level. Between 75% and 94% of vector-containing cells were eliminated by well-tolerated AP1903 dosing, but lack of complete ablation was linked to lower iCasp9 expression in residual cells. Further investigation of resistance mechanisms demonstrated upregulation of Bcl-2 in hematopoietic cell lines transduced with the vector and resistant to AP1903 ablation. These results demonstrate both the potential and the limitations of safety approaches using iCasp9 to HSPC-targeted gene therapy settings, in a model with great relevance to clinical development. Stem Cells  2015;33:91–100
Interrogation of a Context-Specific Transcription Factor Network Identifies Novel Regulators of Pluripotency
Authors: Kushwaha Ritu , Jagadish Nirmala , Kustagi Manjunath , Tomishima Mark J. , Mendiratta Geetu , Bansal Mukesh , Kim Hyunjae R. , Sumazin Pavel , Alvarez Mariano J. , Lefebvre Celine , Villagrasa-Gonzalez Patricia , Viale Agnes , Korkola James E. , Houldsworth Jane , Feldman Darren R. , Bosl George J. , Califano Andrea , Chaganti R. S. K.
Published: October 2014

The predominant view of pluripotency regulation proposes a stable ground state with coordinated expression of key transcription factors (TFs) that prohibit differentiation. Another perspective suggests a more complexly regulated state involving competition between multiple lineage-specifying TFs that define pluripotency. These contrasting views were developed from extensive analyses of TFs in pluripotent cells in vitro. An experimentally validated, genome-wide repertoire of the regulatory interactions that control pluripotency within the in vivo cellular contexts is yet to be developed. To address this limitation, we assembled a TF interactome of adult human male germ cell tumors (GCTs) using the Algorithm for the Accurate Reconstruction of Cellular Pathways (ARACNe) to analyze gene expression profiles of 141 tumors comprising pluripotent and differentiated subsets. The network (GCTNet) comprised 1,305 TFs, and its ingenuity pathway analysis identified pluripotency and embryonal development as the top functional pathways. We experimentally validated GCTNet by functional (silencing) and biochemical (ChIP-seq) analysis of the core pluripotency regulatory TFs POU5F1, NANOG, and SOX2 in relation to their targets predicted by ARACNe. To define the extent of the in vivo pluripotency network in this system, we ranked all TFs in the GCTNet according to sharing of ARACNe-predicted targets with those of POU5F1 and NANOG using an odds-ratio analysis method. To validate this network, we silenced the top 10 TFs in the network in H9 embryonic stem cells. Silencing of each led to downregulation of pluripotency and induction of lineage; 7 of the 10 TFs were identified as pluripotency regulators for the first time. Stem Cells  2015;33:367–377
Live Fluorescent RNA-Based Detection of Pluripotency Gene Expression in Embryonic and Induced Pluripotent Stem Cells of Different Species
Authors: Lahm Harald , Doppler Stefanie , Dreßen Martina , Werner Astrid , Adamczyk Klaudia , Schrambke Dominic , Brade Thomas , Laugwitz Karl-Ludwig , Deutsch Marcus-André , Schiemann Matthias , Lange Rüdiger , Moretti Alessandra , Krane Markus
Published: October 2014

The generation of induced pluripotent stem (iPS) cells has successfully been achieved in many species. However, the identification of truly reprogrammed iPS cells still remains laborious and the detection of pluripotency markers requires fixation of cells in most cases. Here, we report an approach with nanoparticles carrying Cy3-labeled sense oligonucleotide reporter strands coupled to gold-particles. These molecules are directly added to cultured cells without any manipulation and gene expression is evaluated microscopically after overnight incubation. To simultaneously detect gene expression in different species, probe sequences were chosen according to interspecies homology. With a common target-specific probe we could successfully demonstrate expression of the GAPDH house-keeping gene in somatic cells and expression of the pluripotency markers NANOG and GDF3 in embryonic stem cells and iPS cells of murine, human, and porcine origin. The population of target gene positive cells could be purified by fluorescence-activated cell sorting. After lentiviral transduction of murine tail-tip fibroblasts Nanog-specific probes identified truly reprogrammed murine iPS cells in situ during development based on their Cy3-fluorescence. The intensity of Nanog-specific fluorescence correlated positively with an increased capacity of individual clones to differentiate into cells of all three germ layers. Our approach offers a universal tool to detect intracellular gene expression directly in live cells of any desired origin without the need for manipulation, thus allowing conservation of the genetic background of the target cell. Furthermore, it represents an easy, scalable method for efficient screening of pluripotency which is highly desirable during high-throughput cell reprogramming and after genomic editing of pluripotent stem cells. Stem Cells  2015;33:392–402
Notch Signaling Regulates Motor Neuron Differentiation of Human Embryonic Stem Cells
Authors: Ben-Shushan Etti , Feldman Eva , Reubinoff Benjamin E.
Published: October 2014

In the pMN domain of the spinal cord, Notch signaling regulates the balance between motor neuron differentiation and maintenance of the progenitor state for later oligodendrocyte differentiation. Here, we sought to study the role of Notch signaling in regulation of the switch from the pMN progenitor state to differentiated motor neurons in a human model system. Human embryonic stem cells (hESCs) were directed to differentiate to pMN-like progenitor cells by the inductive action of retinoic acid and a Shh agonist, purmorphamine. We found that the expression of the Notch signaling effector Hes5 was induced in hESC-derived pMN-like progenitors and remained highly expressed when they were cultured under conditions favoring motor neuron differentiation. Inhibition of Notch signaling by a γ-secretase inhibitor in the differentiating pMN-like progenitor cells decreased Hes5 expression and enhanced the differentiation toward motor neurons. Conversely, over-expression of Hes5 in pMN-like progenitor cells during the differentiation interfered with retinoic acid- and purmorphamine-induced motor neuron differentiation and inhibited the emergence of motor neurons. Inhibition of Notch signaling had a permissive rather than an inductive effect on motor neuron differentiation. Our results indicate that Notch signaling has a regulatory role in the switch from the pMN progenitor to the differentiated motor neuron state. Inhibition of Notch signaling can be harnessed to enhance the differentiation of hESCs toward motor neurons. Stem Cells  2015;33:403–415
A Thyroid Hormone Receptor/KLF9 Axis in Human Hepatocytes and Pluripotent Stem Cells
Authors: Cvoro Aleksandra , Devito Liani , Milton Flora A. , Noli Laila , Zhang Aijun , Filippi Celine , Sakai Keiko , Suh Ji Ho , H. Sieglaff Douglas , Dhawan Anil , Sakai Takao , Ilic Dusko , Webb Paul
Published: October 2014

Biological processes require close cooperation of multiple transcription factors that integrate different signals. Thyroid hormone receptors (TRs) induce Krüppel-like factor 9 (KLF9) to regulate neurogenesis. Here, we show that triiodothyronine (T3) also works through TR to induce KLF9 in HepG2 liver cells, mouse liver, and mouse and human primary hepatocytes and sought to understand TR/KLF9 network function in the hepatocyte lineage and stem cells. Knockdown experiments reveal that KLF9 regulates hundreds of HepG2 target genes and modulates T3 response. Together, T3 and KLF9 target genes influence pathways implicated in stem cell self-renewal and differentiation, including Notch signaling, and we verify that T3 and KLF9 cooperate to regulate key Notch pathway genes and work independently to regulate others. T3 also induces KLF9 in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSC) and this effect persists during differentiation to definitive endoderm and hiPSC-derived hepatocytes. Microarray analysis reveals that T3 regulates hundreds of hESC and hiPSC target genes that cluster into many of the same pathways implicated in TR and KLF9 regulation in HepG2 cells. KLF9 knockdown confirms that TR and KLF9 cooperate to regulate Notch pathway genes in hESC and hiPSC, albeit in a partly cell-specific manner. Broader analysis of T3 responsive hESC/hiPSC genes suggests that TRs regulate multiple early steps in ESC differentiation. We propose that TRs cooperate with KLF9 to regulate hepatocyte proliferation and differentiation and early stages of organogenesis and that TRs exert widespread and important influences on ESC biology. Stem Cells  2015;33:416–428
Alternative Generation of CNS Neural Stem Cells and PNS Derivatives from Neural Crest-Derived Peripheral Stem Cells
Authors: Weber Marlen , Apostolova Galina , Widera Darius , Mittelbronn Michel , Dechant Georg , Kaltschmidt Barbara , Rohrer Hermann
Published: October 2014

Neural crest-derived stem cells (NCSCs) from the embryonic peripheral nervous system (PNS) can be reprogrammed in neurosphere (NS) culture to rNCSCs that produce central nervous system (CNS) progeny, including myelinating oligodendrocytes. Using global gene expression analysis we now demonstrate that rNCSCs completely lose their previous PNS characteristics and acquire the identity of neural stem cells derived from embryonic spinal cord. Reprogramming proceeds rapidly and results in a homogenous population of Olig2-, Sox3-, and Lex-positive CNS stem cells. Low-level expression of pluripotency inducing genes Oct4, Nanog, and Klf4 argues against a transient pluripotent state during reprogramming. The acquisition of CNS properties is prevented in the presence of BMP4 (BMP NCSCs) as shown by marker gene expression and the potential to produce PNS neurons and glia. In addition, genes characteristic for mesenchymal and perivascular progenitors are expressed, which suggests that BMP NCSCs are directed toward a pericyte progenitor/mesenchymal stem cell (MSC) fate. Adult NCSCs from mouse palate, an easily accessible source of adult NCSCs, display strikingly similar properties. They do not generate cells with CNS characteristics but lose the neural crest markers Sox10 and p75 and produce MSC-like cells. These findings show that embryonic NCSCs acquire a full CNS identity in NS culture. In contrast, MSC-like cells are generated from BMP NCSCs and pNCSCs, which reveals that postmigratory NCSCs are a source for MSC-like cells up to the adult stage. Stem Cells  2015;33:574–588
Steady-State Creep Deformations and Stresses in FGM Rotating Thick Cylindrical Pressure Vessels
Authors: Nejad M. Z. , Hoseini Z. , Niknejad A. , Ghannad M.
Published: October 2014

In the present study, a closed-form analytical solution for the steady-state creep stresses of rotating thick cylindrical pressure vessels made of functionally graded materials (FGMs) is carried out. Norton's law governs the creep response of the material. Exact solutions for stresses and strain rate are obtained under the plane strain condition. How different material parameters involved in Norton's law affect radial and circumferential stresses together with the equivalent strain rate in rotating thick-walled cylindrical vessels under internal pressure is investigated. The result obtained shows that the property of FGMs has a significant influence on the equivalent creep strain rate and stresses distributions along the radial direction.
A Micromechanics Model for Effective Coupled Thermo-Electro-Elastic Properties of Macro Fiber Composites with Interdigitated Electrodes
Authors: Lezgy-Nazargah M.
Published: October 2014

In this study, a fully micromechanical model based on iso-field assumptions is developed for computing the effective coupled thermo-electro-elastic material properties of Macro Fiber Composites (MFCs) in the linear regime. The explicit formulations are derived using the thermo-electro-elastic constitutive equations under the iso-field assumptions and multiple loading conditions. The effects of piezoelectric fiber volume fraction and matrix properties on the effective material constants of MFCs are studied through some examples. In order to validate the accuracy of the present micromechanical formulations, comparisons have been made with other results available in the literature.
A Flat Asymptotic Frictionless Contact Subject to Normal Load and Bending Moment
Authors: Shao G.-Q. , Hong J. , Jiang X.-J. , Zhu L.-B. , Chen X. , Zhu Y.-S.
Published: October 2014

A calculation model is put forward to analyze the interfacial response of an elastic frictionless punch, pressed normally into a half-plane, and subject to bending moment throughout this paper to observe the important effect that different normal loads and bending moments on the contact pressure distribution and contact deformation. Results for the detailed considerations have been given to the specific different cases of ηc. A characteristic response of the punch to a surplus bending moment has been found. The small differences can be observed between both methods show characteristic features of the FEM model and the theoretical model. The presented numerical results illustrate the influences of the normal load and bending moment on the contact stresses. The results obtained can be used to analyze the crack nucleation in fretting when the punch is acted upon by the normal force and the bending moment.
Cavitation Bubble in Compressible Fluid Near the Rigid Wall Subjected to the Acoustic Wave with Arbitrary Incidence Angle in Three-Dimensional
Authors: Ye X. , Yao X.-L. , Sun L.-Q. , Wang B.
Published: October 2014

A balanced cavitation bubble is released near the rigid wall in the sound field generated by the incidence plane wave and its reflecting wave. With the modified boundary integral equation, the dynamics of bubble is solved considering the compressibility of fluid in this paper. Also the Bernoulli equation as the boundary condition for cavitation bubble in sound field is deduced using Euler equation. Since the arbitrary incidence angle of acoustic wave, the three-dimensional model is utilized. The bubble will expand or contract at first according to the initial phase of acting acoustic pressure on bubble surface. And during the contraction phase, the liquid jet with high speed will be generated pointing to rigid wall but be deflected to the incidence direction of acoustic wave. The oblique degree of jet will be affected by the incidence angle and initial distance between bubble center and rigid wall. The oscillation amplitude of bubble will be affected by the incidence amplitude and incidence frequency, but be limited by the rigid wall. Since the compressibility of fluid, the perturbation will propagate to the far-field. Thus the oscillation amplitude of bubble will be reduced.
Lactose inhibits regulatory T-cell-mediated suppression of effector T-cell interferon-γ and IL-17 production
Authors: Paasela Monika , Kolho Kaija-Leena , Vaarala Outi , Honkanen Jarno
Published: October 2014

Our interest in lactose as an immunomodulatory molecule results from studies showing that lactose binds to galectin-9, which has been shown to have various regulatory functions in the immune system including regulation of T-cell responses. Impaired regulation of T helper (Th)1 and Th17 type immune responses and dysfunction of regulatory T cells (Treg) have been implicated in many human immune-mediated diseases. In the present study, we investigated the effects of lactose on immune regulation using co-cultures of human peripheral blood mononuclear cell (PBMC)-derived Tregand effector T cells (Teff) obtained from twenty healthy adults. Treg, i.e. CD4+CD25+CD127−, were isolated from PBMC by immunomagnetic separation. The fraction of CD4+CD127−cells that was depleted of CD25+cells was used as Teff. Tregand Teffat a ratio 1:5 were activated and the effects of lactose on the secretion of interferon-γ (IFN-γ) and IL-17 were analysed using ELISA for protein and quantitative RT-PCR for mRNA. Tregdown-regulated the secretion of both IFN-γ (8·8–3·9 ng/ml,n20,P= 0·003) and IL-17 (0·83–0·64 ng/ml,n15,P= 0·04) in co-cultures, while in the presence of lactose the levels of secreted IFN-γ and IL-17 remained high and no down-regulation was observed (16·4v. 3·99 ng/ml,n20,P< 0·0001, and 0·74v. 0·64 ng/ml,n15,P= 0·005, respectively). We showed that lactose inhibits human Treg-mediated suppression of Th1 and Th17 immune responsesin vitro.
Erythrocyte DHA level as a biomarker of DHA status in specific brain regions ofn-3 long-chain PUFA-supplemented aged rats
Authors: Létondor Anne , Buaud Benjamin , Vaysse Carole , Fonseca Laurence , Herrouin Coralie , Servat Benjamin , Layé Sophie , Pallet Véronique , Alfos Serge
Published: October 2014

n-3 Long-chain PUFA (n-3 LC-PUFA), particularly EPA and DHA, play a key role in the maintenance of brain functions such as learning and memory that are impaired during ageing. Ageing is also associated with changes in the DHA content of brain membranes that could contribute to memory impairment. Limited studies have investigated the effects of ageing andn-3 LC-PUFA supplementation on both blood and brain fatty acid compositions. Therefore, we assessed the relationship between fatty acid contents in plasma and erythrocyte membranes and those in the hippocampus, striatum and cerebral cortex during ageing, and after a 5-month period of EPA/DHA supplementation in rats. In the blood, ageing was associated with an increase in plasma DHA content, whereas the DHA content remained stable in erythrocyte membranes. In the brain, ageing was associated with a decrease in DHA content, which was both region-specific and phospholipid class-specific. In EPA/DHA-supplemented aged rats, DHA contents were increased both in the blood and brain compared with the control rats. The present results demonstrated thatn-3 LC-PUFA level in the plasma was not an accurate biomarker of brain DHA status during ageing. Moreover, we highlighted a positive relationship between the DHA levels in erythrocyte phosphatidylethanolamine (PE) and those in the hippocampus and prefrontal cortex in EPA/DHA-supplemented aged rats. Within the framework of preventive dietary supplementation to delay brain ageing, these results suggest the possibility of using erythrocyte PE DHA content as a reliable biomarker of DHA status in specific brain regions.
Nasogastric nutrition is efficacious in severe acute pancreatitis: a systematic review and meta-analysis
Authors: Nally Deirdre M. , Kelly Enda G. , Clarke Mary , Ridgway Paul
Published: October 2014

In patients with severe acute pancreatitis (AP), enteral nutrition is delivered by nasojejunal (NJ) tube to minimise pancreatic stimulation. Nasogastric (NG) feeding represents an alternative route. The primary objective of this systematic review and meta-analysis was to evaluate the efficacy of NG feeding. Secondary objectives were to compare the NG and NJ routes and assess the side effects of the former. The primary endpoint was exclusive NG feeding with delivery of 75 % of nutritional targets. Additional outcomes included change to total parenteral nutrition (TPN), increased pain or disease severity, vomiting, diarrhoea, delivery rate reduction and tube displacement. Among the retrieved studies, six were found to be eligible for the qualitative review and four for the meta-analysis. NG nutrition was received by 147 patients; exclusive NG feeding was achieved in 90 % (133/147). Of the 147 patients, 129 (87 %) received 75 % of the target energy. In studies where all subjects received exclusive NG nutrition, 82 % (seventy-four of the ninety patients) received >75 % of the intended energy. Compared with NJ nutrition, there was no significant difference in the delivery of 75 % of nutritional targets (pooled risk ratio (RR) 1·02; 95 % CI 0·75, 1·38.) or no increased risk of change to TPN (pooled RR 1·05; 95 % CI 0·45, 2·48), diarrhoea (pooled RR 1·28; 95 % CI 0·62, 2·66), exacerbation of pain (pooled RR 1·10; 95 % CI 0·47, 2·61) or tube displacement (pooled RR 0·44; 95 % CI 0·11, 1·73). Vomiting and diarrhoea were the most common side effects of NG feeding (13·3 and 12·9 %, respectively). With respect to the delivery of nutrition, 11·2 % of the patients required delivery rate reduction and 3·4 % dislodged the tube. Other side effects included elevated levels of aspirates (9·1 %), abdominal distension (1·5 %), pain exacerbation (7·5 %) and increased disease severity (1·6 %). In conclusion, NG feeding is efficacious in 90 % of patients. Further research is required to optimise the delivery of NG nutrition and examine ‘gut-rousing’ approaches to nutrition in patients with severe AP.
Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection
Authors: Tiwari Shalbha , Pratyush Daliparthy Devi , Gupta Sanjeev Kumar , Singh Surya Kumar
Published: October 2014

Vitamin D has been recognised as a potent immunomodulator and its deficiency is common in different population groups including patients with diabetic foot infection. Diabetic foot infection reflects the altered immune status of the host. As cytokine regulation plays a significant role in infection and wound-healing processes, the present study aimed to evaluate the association between vitamin D status and inflammatory cytokine profiles in patients with diabetic foot infection. The serum concentrations of vitamin D (25-hydroxyvitamin D), IL-1β, IL-6, TNF-α and interferon-γ (IFN-γ) were measured in 112 diabetic foot infection cases and 109 diabetic controls. Severe vitamin D deficiency (25-hydroxyvitamin D concentration < 25 nmol/l) was more common in cases than in controls (48·2v.20·5 %). Although age, duration of diabetes, HbA1C(glycosylated Hb) concentration and BMI were similar, cases had significantly higher concentrations of IL-6 (P≤ 0·001), IL-1β (P≤ 0·02) and TNF-α (P≤ 0·006) than controls. A significant negative correlation was also observed between 25-hydroxyvitamin D concentration and circulating concentrations of IL-1β (r− 0·323;P≤ 0·001) as well as IL-6 (r− 0·154;P≤ 0·04), but not between 25-hydroxyvitamin D and TNF-α and IFN-γ concentrations. Furthermore, a significant difference in IL-1β (P≤ 0·007) and IL-6 (P≤ 0·02) concentrations was observed in patients with severe 25-hydroxyvitamin D deficiency compared with patients with 25-hydroxyvitamin D concentration ≥ 25 nmol/l, and this difference was remarkable for TNF-α. In conclusion, severe vitamin D deficiency is associated with elevated inflammatory cytokine concentrations in diabetic patients, particularly in those with foot infection. A 25-hydroxyvitamin D concentration value < 25 nmol/l is suggested as the ‘cut-off’ for such immunological alterations in patients with diabetes mellitus.
A Two-Stage Theory of Discussant Influence on Vote Choice in Multiparty Systems
Authors: Schmitt-Beck Rüdiger , Partheymüller Julia
Published: October 2014

This article addresses two aspects of social network influence on voters’ electoral choices that are not well understood: the role of party systems as institutional contexts and the relationship between social pressure and information sharing as mechanisms of influence. It argues that in the cleavage-based multiparty systems of Western Europe, discussant influence at elections occurs in two stages. First, discussants place social pressure on voters to opt for parties from the same ideological camp. Secondly, by providing information, discussants influence which parties voters eventually choose out of these restricted ‘consideration sets’. The study tests these assumptions using a panel survey conducted at the 2009 German federal election. The first proposition is clearly confirmed, and the evidence supports the second proposition, although less unequivocally.
Places and Preferences: A Longitudinal Analysis of Self-Selection and Contextual Effects
Authors: Gallego Aina , Buscha Franz , Sturgis Patrick , Oberski Daniel
Published: October 2014

Contextual theories of political behaviour assert that the contexts in which people live influence their political beliefs and vote choices. Most studies, however, fail to distinguish contextual influence from self-selection of individuals into areas. This article advances understanding of this controversy by tracking the left–right position and party identification of thousands of individuals over an eighteen-year period in England before and after residential moves across areas with different political orientations. There is evidence of both non-random selection into areas and assimilation of new entrants to the majority political orientation. These effects are contingent on the type of area an individual moves into and contextual effects are weak and dominated by the larger effect of self-selection into areas.
Democracy and Multilateralism: The Case of Vote Buying in the UN General Assembly
Authors: Carter David B. , Stone Randall W.
Published: October 2014

Democracies are more supportive of US positions on important votes in the UN General Assembly than of nondemocracies. Is this because democracies share common perspectives, or does this pattern reflect coercion? Since 1985, US law has stipulated that the US State Department identify important votes and that aid disbursements reflect voting decisions. To unravel these alternative explanations, we introduce a strategic statistical model that allows us to estimate voting preferences, vulnerability to influence, and credibility of linkage, which are theoretical quantities of interest that are not directly observable. The results reject the hypothesis of shared democratic values: poor democracies have voting preferences that are more oppositional to US positions than autocracies, and they are more willing than autocracies to take symbolic stands that may cost them foreign aid. Democracies support US positions, however, because US aid linkages are more credible when directed toward democratic countries. Splitting the sample into Cold War and post–Cold War segments, we find that the end of the Cold War changed the way US linkage strategies treated allies and left- and right-leaning governments, but the effects of democracy remained constant.
Failure of deactivation in the default mode network: a trait marker for schizophrenia?
Authors: Landin-Romero R. , McKenna P. J. , Salgado-Pineda P. , Sarró S. , Aguirre C. , Sarri C. , Compte A. , Bosque C. , Blanch J. , Salvador R. , Pomarol-Clotet E.
Published: October 2014

Background.

Functional imaging studies in relatives of schizophrenic patients have had inconsistent findings, particularly with respect to altered dorsolateral prefrontal cortex activation. Some recent studies have also suggested that failure of deactivation may be seen.

Method.

A total of 28 patients with schizophrenia, 28 of their siblings and 56 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance was fitted to individual whole-brain maps from each set of patient–relative–matched pair of controls. Clusters of significant difference among the groups were then used as regions of interest to compare mean activations and deactivations among the groups.

Results.

In all, five clusters of significant differences were found. The schizophrenic patients, but not the relatives, showed reduced activation compared with the controls in the lateral frontal cortex bilaterally, the left basal ganglia and the cerebellum. In contrast, both the patients and the relatives showed significant failure of deactivation compared with the healthy controls in the medial frontal cortex, with the relatives also showing less failure than the patients. Failure of deactivation was not associated with schizotypy scores or presence of psychotic-like experiences in the relatives.

Conclusions.

Both schizophrenic patients and their relatives show altered task-related deactivation in the medial frontal cortex. This in turn suggests that default mode network dysfunction may function as a trait marker for schizophrenia.
Long-term efficacy of indicated prevention of depression in non-professional caregivers: randomized controlled trial
Authors: Otero P. , Smit F. , Cuijpers P. , Torres A. , Blanco V. , Vázquez F. L.
Published: October 2014

Background

Although depression is a common problem among non-professional caregivers, only one trial has evaluated the efficacy of indicated prevention targeting this population and the long-term efficacy is unknown. The aim of this study was to evaluate the long-term efficacy of a brief intervention for the indicated prevention of depression in a sample of female caregivers.

Method

A randomized controlled trial was conducted involving 173 participants (mean age 53.9 years) who were allocated to the intervention (n = 89) or the usual-care control group (n = 84). Blinded interviewers conducted assessments at 1, 3, 6 and 12 months of follow-up. The main outcome measure was the incidence of major depression and the secondary outcomes were compliance with treatment, depressive symptoms, emotional distress and caregiver burden.

Results

At the 12-month follow-up, a lower incidence of depression as evaluated using the Structured Clinical Interview for Axis I Disorders of the DSM-IV was found in the intervention group compared with the control group (10.1%v.25.0%). The relative risk was 0.40 and statistically significant [χ2 = 6.68, degrees of freedom = 1,p = 0.010, 95% confidence interval (CI) 0.20–0.81], and the number needed to treat was 7 (95% CI 4–27). There was a significant delay in the onset of depression in the intervention group (p = 0.008). The good complier caregivers had a lower incidence of depression. The intervention effect on depressive symptoms, emotional distress and caregiver burden were maintained for 12 months.

Conclusions

This is the first study to demonstrate that a brief problem-solving intervention can prevent the onset of depression among non-professional caregivers over the longer term.
Pause and utterance duration in child-directed speech in relation to child vocabulary size
Authors: MARKLUND ULRIKA , MARKLUND ELLEN , LACERDA FRANCISCO , SCHWARZ IRIS-CORINNA
Published: October 2014

This study compares parental pause and utterance duration in conversations with Swedish speaking children at age 1;6 who have either a large, typical, or small expressive vocabulary, as measured by the Swedish version of the McArthur-Bates CDI. The adjustments that parents do when they speak to children are similar across all three vocabulary groups; they use longer utterances than when speaking to adults, and respond faster to children than they do to other adults. However, overall pause duration varies with the vocabulary size of the children, and as a result durational aspects of the language environment to which the children are exposed differ between groups. Parents of children in the large vocabulary size group respond faster to child utterances than do parents of children in the typical vocabulary size group, who in turn respond faster to child utterances than do parents of children in the small vocabulary size group.
Depression means different things: A qualitative study of psychiatrists' conceptualization of depression in the palliative care setting
Authors: Ng Felicity , Crawford Gregory B. , Chur-Hansen Anna
Published: October 2014

Objective:

Medical practitioners conceptualize depression in different ways, which adds to the challenges of its diagnosis and treatment, as well as research in the palliative care setting. Psychiatric assessment is often considered the “gold standard” for diagnosis, therefore how psychiatrists conceptualize depression in this setting is pertinent. Our study aimed to investigate this issue.

Method:

Psychiatrists working in palliative care in Australia were individually interviewed using a semistructured approach. Nine participants were interviewed to reach data saturation. Interview transcripts were analyzed for themes.

Results:

Three overarching themes were identified: (1) depression means different things; (2) depression is conceptualized using different models; and (3) depression is the same concept within and outside of the palliative care setting. Participants explicitly articulated the heterogeneous nature of depression and described a different breadths of concepts, ranging from a narrow construct of a depressive illness to a broader one that encompassed depressive symptoms and emotions. However, depressive illness was a consistent concept, and participants considered this in terms of phenotypic subtypes. Participants used three models (spectral, dichotomous, and mixed) to relate various depressive presentations.

Significance of Results:

Psychiatrists did not subscribe to a unitary model of depression but understood it as a heterogeneous concept comprised of depressive illness and other less clearly defined depressive presentations. Given the influence of psychiatric opinion in the area of depression, these findings may serve as a platform for further discussions to refine the concepts of depression in the palliative care setting, which in turn may improve diagnostic and treatment outcomes.
Autophagy as a pro‐death pathway
Authors: Denton Donna , Xu Tianqi , Kumar Sharad
Published: October 2014

The evolutionarily conserved catabolic process of autophagy involves the degradation of cytoplasmic components through lysosomal enzymes. Basal levels of autophagy maintain cellular homeostasis and under stress conditions high levels of autophagy are induced. It is often under such stress conditions that high levels of autophagy and cell death have been observed, leading to the idea that autophagy may act as an executioner of cell death. However the notion of autophagy as a cell death mechanism has been controversial and remains mechanistically undefined. There is now growing evidence that in specific contexts autophagy can indeed facilitate cell death. The pro‐death role of autophagy is however complicated due to the extensive cross‐talk between different signalling pathways. This review summarises the examples of where autophagy acts as a means of cell death and discusses the association of autophagy with the different cell death pathways.
Genetic indicators of iron limitation in wild populations of Thalassiosira oceanica from the northeast Pacific Ocean
Authors: Chappell P Dreux , Whitney LeAnn P , Wallace Joselynn R , Darer Adam I , Jean-Charles Samua , Jenkins Bethany D
Published: October 2014

Assessing the iron (Fe) nutritional status of natural diatom populations has proven challenging as physiological and molecular responses can differ in diatoms of the same genus. We evaluated expression of genes encoding flavodoxin (FLDA1) and an Fe-starvation induced protein (ISIP3) as indicators of Fe limitation in the marine diatom Thalassiosira oceanica. The specificity of the response to Fe limitation was tested in cultures grown under Fe- and macronutrient-deficient conditions, as well as throughout the diurnal light cycle. Both genes showed a robust and specific response to Fe limitation in laboratory cultures and were detected in small volume samples collected from the northeast Pacific, demonstrating the sensitivity of this method. Overall, FLDA1 and ISIP3 expression was inversely related to Fe concentrations and offered insight into the Fe nutritional health of T. oceanica in the field. As T. oceanica is a species tolerant to low Fe, indications of Fe limitation in T. oceanica populations may serve as a proxy for severe Fe stress in the overall diatom community. At two shallow coastal locations, FLD1A and ISIP3 expression revealed Fe stress in areas where dissolved Fe concentrations were high, demonstrating that this approach may be powerful for identifying regions where Fe supply may not be biologically available.
Genomes and gene expression across light and productivity gradients in eastern subtropical Pacific microbial communities
Authors: Dupont Chris L , McCrow John P , Valas Ruben , Moustafa Ahmed , Walworth Nathan , Goodenough Ursula , Roth Robyn , Hogle Shane L , Bai Jing , Johnson Zackary I , Mann Elizabeth , Palenik Brian , Barbeau Katherine A , Craig Venter J , Allen Andrew E
Published: October 2014

Transitions in community genomic features and biogeochemical processes were examined in surface and subsurface chlorophyll maximum (SCM) microbial communities across a trophic gradient from mesotrophic waters near San Diego, California to the oligotrophic Pacific. Transect end points contrasted in thermocline depth, rates of nitrogen and CO2 uptake, new production and SCM light intensity. Relative to surface waters, bacterial SCM communities displayed greater genetic diversity and enrichment in putative sulfur oxidizers, multiple actinomycetes, low-light-adapted Prochlorococcus and cell-associated viruses. Metagenomic coverage was not correlated with transcriptional activity for several key taxa within Bacteria. Low-light-adapted Prochlorococcus, Synechococcus, and low abundance gamma-proteobacteria enriched in the>3.0-μm size fraction contributed disproportionally to global transcription. The abundance of these groups also correlated with community functions, such as primary production or nitrate uptake. In contrast, many of the most abundant bacterioplankton, including SAR11, SAR86, SAR112 and high-light-adapted Prochlorococcus, exhibited low levels of transcriptional activity and were uncorrelated with rate processes. Eukaryotes such as Haptophytes and non-photosynthetic Aveolates were prevalent in surface samples while Mamielles and Pelagophytes dominated the SCM. Metatranscriptomes generated with ribosomal RNA-depleted mRNA (total mRNA) coupled to in vitro polyadenylation compared with polyA-enriched mRNA revealed a trade-off in detection eukaryotic organelle and eukaryotic nuclear origin transcripts, respectively. Gene expression profiles of SCM eukaryote populations, highly similar in sequence identity to the model pelagophyte Pelagomonas sp. CCMP1756, suggest that pelagophytes are responsible for a majority of nitrate assimilation within the SCM.
Origin and ecological selection of core and food-specific bacterial communities associated with meat and seafood spoilage
Authors: Chaillou Stéphane , Chaulot-Talmon Aurélie , Caekebeke Hélène , Cardinal Mireille , Christieans Souad , Denis Catherine , Hélène Desmonts Marie , Dousset Xavier , Feurer Carole , Hamon Erwann , Joffraud Jean-Jacques , La Carbona Stéphanie , Leroi Françoise , Leroy Sabine , Lorre Sylvie , Macé Sabrina , Pilet Marie-France , Prévost Hervé , Rivollier Marina , Roux Dephine , Talon Régine , Zagorec Monique , Champomier-Vergès Marie-Christine
Published: October 2014

The microbial spoilage of meat and seafood products with short shelf lives is responsible for a significant amount of food waste. Food spoilage is a very heterogeneous process, involving the growth of various, poorly characterized bacterial communities. In this study, we conducted 16S ribosomal RNA gene pyrosequencing on 160 samples of fresh and spoiled foods to comparatively explore the bacterial communities associated with four meat products and four seafood products that are among the most consumed food items in Europe. We show that fresh products are contaminated in part by a microbiota similar to that found on the skin and in the gut of animals. However, this animal-derived microbiota was less prevalent and less abundant than a core microbiota, psychrotrophic in nature, mainly originated from the environment (water reservoirs). We clearly show that this core community found on meat and seafood products is the main reservoir of spoilage bacteria. We also show that storage conditions exert strong selective pressure on the initial microbiota: alpha diversity in fresh samples was 189±58 operational taxonomic units (OTUs) but dropped to 27±12 OTUs in spoiled samples. The OTU assemblage associated with spoilage was shaped by low storage temperatures, packaging and the nutritional value of the food matrix itself. These factors presumably act in tandem without any hierarchical pattern. Most notably, we were also able to identify putative new clades of dominant, previously undescribed bacteria occurring on spoiled seafood, a finding that emphasizes the importance of using culture-independent methods when studying food microbiota.
Methane-fed microbial microcosms show differential community dynamics and pinpoint taxa involved in communal response
Authors: Oshkin Igor Y , Beck David A C , Lamb Andrew E , Tchesnokova Veronika , Benuska Gabrielle , McTaggart Tami L , Kalyuzhnaya Marina G , Dedysh Svetlana N , Lidstrom Mary E , Chistoserdova Ludmila
Published: October 2014

We report observations on the dynamics of bacterial communities in response to methane stimulus in laboratory microcosm incubations prepared with lake sediment samples. We first measured taxonomic compositions of long-term enrichment cultures and determined that, although dominated by Methylococcaceae types, these cultures also contained accompanying types belonging to a limited number of bacterial taxa, methylotrophs and non-methylotrophs. We then followed the short-term community dynamics, in two oxygen tension regimens (150 μm and 15 μm), observing rapid loss of species diversity. In all microcosms, a single type of Methylobacter represented the major methane-oxidizing partner. The accompanying members of the communities revealed different trajectories in response to different oxygen tensions, with Methylotenera species being the early responders to methane stimulus under both conditions. The communities in both conditions were convergent in terms of their assemblage, suggesting selection for specific taxa. Our results support prior observations from metagenomics on distribution of carbon from methane among diverse bacterial populations and further suggest that communities are likely responsible for methane cycling, rather than a single type of microbe.
Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts
Authors: Keller Johannes , Catala-Lehnen Philip , Huebner Antje K. , Jeschke Anke , Heckt Timo , Lueth Anja , Krause Matthias , Koehne Till , Albers Joachim , Schulze Jochen , Schilling Sarah , Haberland Michael , Denninger Hannah , Neven Mona , Hermans-Borgmeyer Irm , Streichert Thomas , Breer Stefan , Barvencik Florian , Levkau Bodo , Rathkolb Birgit , Wolf Eckhard , Calzada-Wack Julia , Neff Frauke , Gailus-Durner Valerie , Fuchs Helmut , de Angelis Martin Hrab[ebreve] , Klutmann Susanne , Tsourdi Elena , Hofbauer Lorenz C. , Kleuser Burkhard , Chun Jerold , Schinke Thorsten , Amling Michael
Published: October 2014

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.
Genome flux and stasis in a five millennium transect of European prehistory
Authors: Gamba Cristina , Jones Eppie R. , Teasdale Matthew D. , McLaughlin Russell L. , Gonzalez-Fortes Gloria , Mattiangeli Valeria , Domboróczki László , Kővári Ivett , Pap Ildikó , Anders Alexandra , Whittle Alasdair , Dani János , Raczky Pál , Higham Thomas F. G. , Hofreiter Michael , Bradley Daniel G , Pinhasi Ron
Published: October 2014

The Great Hungarian Plain was a crossroads of cultural transformations that have shaped European prehistory. Here we analyse a 5,000-year transect of human genomes, sampled from petrous bones giving consistently excellent endogenous DNA yields, from 13 Hungarian Neolithic, Copper, Bronze and Iron Age burials including two to high (~22 × ) and seven to ~1 × coverage, to investigate the impact of these on Europe’s genetic landscape. These data suggest genomic shifts with the advent of the Neolithic, Bronze and Iron Ages, with interleaved periods of genome stability. The earliest Neolithic context genome shows a European hunter-gatherer genetic signature and a restricted ancestral population size, suggesting direct contact between cultures after the arrival of the first farmers into Europe. The latest, Iron Age, sample reveals an eastern genomic influence concordant with introduced Steppe burial rites. We observe transition towards lighter pigmentation and surprisingly, no Neolithic presence of lactase persistence.
Higher omega-3 index is associated with increased insulin sensitivity and more favourable metabolic profile in middle-aged overweight men
Authors: Albert Benjamin B. , Derraik José G. B. , Brennan Christine M. , Biggs Janene B. , Smith Greg C. , Garg Manohar L. , Cameron-Smith David , Hofman Paul L. , Cutfield Wayne S.
Published: October 2014

We assessed whether omega-3 index (red blood cell concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) was associated with insulin sensitivity and other metabolic outcomes in 47 overweight men aged 46.5 ± 5.1 years. Participants were assessed twice, 16 weeks apart. Insulin sensitivity was assessed by the Matsuda method from an oral glucose tolerance test. Linear associations were examined; stratified analyses were carried out with participants separated according to the omega-3 index: lower tertiles (LOI; n = 31) and highest tertile (HOI; n = 16). Increasing omega-3 index was correlated with higher insulin sensitivity (r = 0.23; p = 0.025), higher disposition index (r = 0.20; p = 0.054) and lower CRP concentrations (r = −0.39; p < 0.0001). Insulin sensitivity was 43% higher in HOI than in LOI men (Matsuda index 6.83 vs 4.78; p = 0.009). Similarly, HOI men had disposition index that was 70% higher (p = 0.013) and fasting insulin concentrations 25% lower (p = 0.038). HOI men displayed lower nocturnal systolic blood pressure (−6.0 mmHg; p = 0.025) and greater systolic blood pressure dip (14.7 vs 10.8%; p = 0.039). Men in the HOI group also had lower concentrations of CRP (41% lower; p = 0.033) and free fatty acids (21% lower, p = 0.024). In conclusion, higher omega-3 index is associated with increased insulin sensitivity and a more favourable metabolic profile in middle-aged overweight men.