Miracle-dz/UniFAR-FTUs huggingface dataset:
Multitrace operators and the generalized AdS/CFT prescription

We show that multitrace interactions can be consistently incorporated into an extended AdS conformal field theory (CFT) prescription involving the inclusion of generalized boundary conditions and a modified Legendre transform prescription. We find new and consistent results by considering a self-contained formulation which relates the quantization of the bulk theory to the AdS/CFT correspondence and the perturbation at the boundary by double-trace interactions. We show that there exist particular double-trace perturbations for which irregular modes are allowed to propagate as well as the regular ones. We perform a detailed analysis of many different possible situations, for both minimally and nonminimally coupled cases. In all situations, we make use of a new constraint which is found by requiring consistency. In the particular nonminimally coupled case, the natural extension of the Gibbons-Hawking surface term is generated.
Mitochondrial disorders

Purpose of reviewWe present here a review of the most recent and relevant contributions on the genetic, biochemical and clinical aspects of mitochondrial biogenesis and disease. The field of mitochondrial medicine is evolving fast. After more than 10 years of investigation into mitochondrial DNA defects, a new impulse is now due to progress in three main areas of research. Recent findingsSome of the basic notions on mitochondrial genetics are being challenged by new data on fundamental biological functions such as mitochondrial DNA replication, transcription and the nuclear control of mitochondrial DNA variations, with important implications in the understanding of the molecular mechanisms of disease. The rapidly increasing identification of nuclear genes responsible for oxidative phosphorylation-related disorders, has greatly broadened the concept of mitochondrial disease. SummaryThe development of animal models and the use of multiple strategies are all accelerating our understanding of the pathogenesis in mitochondrial disorders, by integrating in-vivo, in-vitro and in-silico approaches. Finally, some interesting progress has recently been made on gene therapy, giving hope for the future treatment of these conditions.
A Defect in Interleukin-10 Leads to Enhanced Malarial Disease in Plasmodium chabaudi chabaudi Infection in Mice

ABSTRACT Infection of interleukin-10 (IL-10)-nonexpressing (IL-10−/−) mice with Plasmodium chabaudi chabaudi (AS) leads to exacerbated pathology in female mice and death in a proportion of them. Hypoglycemia, hypothermia, and loss in body weight were significantly greater in female IL-10−/−mice than in male knockout mice and all wild-type (WT) mice during the acute phase of infection. At this time, both female and male IL-10−/− mice produced more gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-12p40 mRNA than their respective WT counterparts. Inactivation of IFN-γ in IL-10−/− mice by the injection of anti-IFN-γ antibodies or by the generation of IL-10−/− IFN-γ receptor−/− double-knockout mice resulted in reduced mortality but did not affect body weight, temperature, or blood glucose levels. The data suggest that IFN-γ-independent pathways may be responsible for these pathological features of P. chabaudimalaria and may be due to direct stimulation of TNF-α by the parasite. Since male and female knockout mice both produce more inflammatory cytokines than their WT counterparts, it is likely that the mortality seen in females is due to the nature or magnitude of the response to these cytokines rather than the amount of IFN-γ or TNF-α produced.
Clearance of vonWillebrand factor

CécileV. Denis1, Olivier D. Christophe1, Beatrijs D. Oortwijn2, Peter J. Lenting2,3 1INSERM U770, Le Kremlin-Bicêtre, France; Univ. Paris-Sud, Le Kremlin-Bicêtre, France; 2Laboratory for Thrombosis and Haemostasis, Department of Clinical Chemistry & Haematology, University Medical Center Utrecht, Utrecht, the Netherlands; 3Crucell Holland B.V. , Department of Protein Discovery, Leiden, the Netherlands
Stochastic differential equation models for ion channel noise in Hodgkin-Huxley neurons.

The random transitions of ion channels between conducting and nonconducting states generate a source of internal fluctuations in a neuron, known as channel noise. The standard method for modeling the states of ion channels nonlinearly couples continuous-time Markov chains to a differential equation for voltage. Beginning with the work of R. F. Fox and Y. -N. Lu [Phys. Rev. E 49, 3421 (1994)], there have been attempts to generate simpler models that use stochastic differential equation (SDEs) to approximate the stochastic spiking activity produced by Markov chain models. Recent numerical investigations, however, have raised doubts that SDE models can capture the stochastic dynamics of Markov chain models.We analyze three SDE models that have been proposed as approximations to the Markov chain model: one that describes the states of the ion channels and two that describe the states of the ion channel subunits. We show that the former channel-based approach can capture the distribution of channel noise and its effects on spiking in a Hodgkin-Huxley neuron model to a degree not previously demonstrated, but the latter two subunit-based approaches cannot. Our analysis provides intuitive and mathematical explanations for why this is the case. The temporal correlation in the channel noise is determined by the combinatorics of bundling subunits into channels, but the subunit-based approaches do not correctly account for this structure. Our study confirms and elucidates the findings of previous numerical investigations of subunit-based SDE models. Moreover, it presents evidence that Markov chain models of the nonlinear, stochastic dynamics of neural membranes can be accurately approximated by SDEs. This finding opens a door to future modeling work using SDE techniques to further illuminate the effects of ion channel fluctuations on electrically active cells.
Aortic Pulse-Wave Velocity and Its Relationship to Mortality in Diabetes and Glucose Intolerance: An Integrated Index of Vascular Function?

Background—Arterial distensibility measures, generally from pulse-wave velocity (PWV), are widely used with little knowledge of relationships to patient outcome. We tested whether aortic PWV predicts cardiovascular and all-cause mortality in type 2 diabetes and glucose-tolerance–tested (GTT) multiethnic population samples. Methods and Results—Participants were randomly sampled from (1) a type 2 diabetes outpatient clinic and (2) primary care population registers, from which nondiabetic control subjects were given a GTT. Brachial blood pressures and Doppler-derived aortic PWV were measured. Mortality data over 10 years’ follow-up were obtained. At any level of systolic blood pressure (SBP), aortic PWV was greater in subjects with diabetes than in controls. Mortality risk doubled in subjects with diabetes (hazard ratio 2.34, 95% CI 1.5 to 3.74) and in those with glucose intolerance (2.12, 95% CI 1.11 to 4.0) compared with controls. For all groups combined, age, sex, and SBP predicted mortality; the addition of PWV independently predicted all-cause and cardiovascular mortality (hazard ratio 1.08, 95% CI 1.03 to 1.14 for each 1 m/s increase) but displaced SBP. Glucose tolerance status and smoking were other independent contributors, with African-Caribbeans experiencing reduced mortality risk (hazard ratio 0.41, 95% CI 0.25 to 0.69). Conclusions—Aortic PWV is a powerful independent predictor of mortality in both diabetes and GTT population samples. In displacing SBP as a prognostic factor, aortic PWV is probably further along the causal pathway for arterial disease and may represent a useful integrated index of vascular status and hence cardiovascular risk.
Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis

Cellular dependence on growth factors for survival is developmentally programmed and continues in adult metazoans. Antigen-activated T cell apoptosis in the waning phase of the immune response is thought to be triggered by depletion of cytokines from the microenvironment. T cell apoptosis resulting from cytokine deprivation is mediated by reactive oxygen species (ROS), but their source and position in the apoptotic cascade is poorly understood. RNA interference approaches implicated the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neglect-induced apoptosis in T cells. Using mice deficient for the catalytic subunit gp91phox to characterize the molecular link to activated T cell apoptosis, we show that gp91phox-deficient T (T−/−) cells generated mitochondrial superoxide but had diminished hydrogen peroxide production in response to neglect, which, in turn, regulated Jun N-terminal kinase–dependent Bax activation and apoptosis. Activated T−/− cells were distinguished by improved survival after activation by superantigens in vivo, adoptive transfers into congenic hosts, and higher recall responses after immunization. Thus, the NADPH oxidase may regulate adaptive immunity in addition to its previously well-characterized role in the innate response.
Immature B Cell Egress from Bone Marrow Is SOCS3 Independent

Suppressor of cytokine signaling (SOCS)-3 has been suggested to regulate CXCR4 signaling in a variety of human cell lines. In mice, conditional SOCS3 inactivation in hematopoietic cells including B-lineage lymphocytes has been reported to exacerbate CXCR4-signaling and focal adhesion kinase phosphorylation, which resulted in altered immature B cell distribution in bone marrow (BM) due to sustained α4β1 integrin-mediated adhesion to the extracellular matrix. However, a recent study examining conditional SOCS3 deletion specifically in B-lineage cells failed to detect significant roles in B-lineage cell retention in BM. In this study we carefully examined the role played by SOCS3 in CXCR4 signaling in developing B cell subsets. We show that in mice conditionally deficient in SOCS3 exclusively in B cells (Socs3 fl/fl Mb1 cre/+) there was no detectable difference in B cell development in BM and in periphery. We show that SOCS3 deficient and sufficient immature B cell subsets are similarly distributed between BM parenchyma and sinusoids, and are equally competent at exiting BM into peripheral blood. Furthermore, we found no significant differences in CXCR4 desensitization upon ligand exposure in developing B lymphocyte subsets. Consequently, SOCS3-deficient and sufficient B-lineage cell migration towards CXCL12 in vitro was undistinguishable, and B-lineage cell amoeboid motility within BM parenchyma was also unaffected by SOCS3-deficiency. Thus we conclude that SOCS3 has no detectable influence on biological processes known to be controlled by CXCR4 signaling.
Chaperones as integrators of cellular networks: Changes of cellular integrity in stress and diseases

The complex integrity of the cells and its sudden, but often predictable changes can be described and understood by the topology and dynamism of cellular networks. All these networks undergo both local and global rearrangements during stress and development of diseases. Here, we illustrate this by showing the stress‐induced structural rearrangement of the yeast protein–protein interaction network (interactome). In an unstressed state, the yeast interactome is highly compact, and the centrally organized modules have a large overlap. During stress, several original modules became more separated, and a number of novel modules also appear. A few basic functions such as theproteasome preserve their central position; however, several functions with high energy demand, such the cell‐cycle regulation loose their original centrality during stress. A number of key stress‐dependent protein complexes, such as the disaggregation‐specific chaperone, Hsp104 gain centrality in the stressed yeast interactome. Molecular chaperones, heat shock, or stress proteins became established as key elements in our molecular understanding of the cellular stress response. Chaperones form complex interaction networks (the chaperome) with each other and their partners. Here, we show that the human chaperome recovers the segregation of protein synthesis‐coupled and stress‐related chaperones observed in yeast recently. Examination of yeast and human interactomes shows that chaperones 1) are intermodular integrators of protein–protein interaction networks, which 2) often bridge hubs and 3) are favorite candidates for extensive phosphorylation. Moreover, chaperones 4) become more central in the organization of the isolated modules of the stressed yeast protein–protein interaction network, which highlights their importance in the decoupling and recoupling of network modules during and after stress. Chaperone‐mediated evolvability of cellular networks may play a key role in cellular adaptation during stress and various polygenic and chronic diseases, such as cancer, diabetes or neurodegeneration. © 2007 IUBMB IUBMB Life, 60(1): 10–18, 2008
Dissecting through barriers: A mixed‐methods study on the effect of interprofessional education in a dissection course with healthcare professional students

Healthcare delivery is reliant on a team‐based approach, and interprofessional education (IPE) provides a means by which such collaboration skills can be fostered prior to entering the workplace. IPE within healthcare programs has been associated with improved collaborative behavior, patient care and satisfaction, reduced clinical error, and diminished negative professional stereotypes. An intensive interprofessional gross anatomy dissection course was created in 2009 to facilitate IPE at McMaster University. Data were collected from five cohorts over five years to determine the influence of this IPE format on the attitudes and perceptions of students towards other health professions. Each year, 28 students from the medicine, midwifery, nursing, physician's assistant, physiotherapy, and occupational therapy programs were randomly assigned into interprofessional teams for 10 weeks. Sessions involved an anatomy and scope‐of‐practice presentation, a small‐group case‐based session, and a dissection. A before/after design measured changes in attitudes and perceptions, while focus group data elaborated on the student experience with the course. Pre‐ and postmatched data revealed significant improvements in positive professional identity, competency and autonomy, role clarity and attitudes toward other health professions. Qualitative analysis of intraprofessional focus group interviews revealed meaningful improvements in a number of areas including learning anatomy, role clarity, and attitudes towards other health professions. Anat Sci Educ 8: 305–316. © 2015 American Association of Anatomists.
Sufu and Kif7 in limb patterning and development

Background: The vertebrate digit pattern is defined by the morphogen Sonic hedgehog (Shh), which controls the activity of Gli transcription factors. Gli1, 2 and 3 are dynamically expressed during patterning. Downstream of Shh, their activity is regulated by Sufu and Kif7, core components of the Shh signaling cascade. The precise roles of these regulators during limb development have not been fully described. We analyze the role of Sufu and Kif7 in the limb and demonstrate that their loss has distinct and synergistic effects on Gli activity and digit pattern. Results: Using a series of mouse mutants, we show that Sufu and Kif7 are expressed throughout limb development and their deletion has distinct effects on Gli levels and limb formation. Concomitant deletion of Sufu and Kif7 results in constitutive pathway activity and severe limb truncation. This is consistent with the recently published two‐population model, which suggests that precocious activation of Shh signaling inhibits organizing center formation and limb outgrowth. Conclusions: Together, our findings demonstrate that perturbations of Sufu and Kif7 affect Gli activity and recapitulate the full spectrum of vertebrate limb defects, ranging from severe truncation to polydactyly. Developmental Dynamics 244:468–478, 2015. © 2014 Wiley Periodicals, Inc.
Novel Sialic Acid Transporter of Haemophilus influenzae

ABSTRACT Nontypeable Haemophilus influenzae is an opportunistic pathogen and a common cause of otitis media in children and of chronic bronchitis and pneumonia in patients with chronic obstructive pulmonary disease. The lipooligosaccharides, a major component of the outer membrane of H. influenzae, play an important role in microbial virulence and pathogenicity. N-Acetylneuraminic acid (sialic acid) can be incorporated into the lipooligosaccharides as a terminal nonreducing sugar. Although much of the pathway of sialic acid incorporation into lipooligosaccharides is understood, the transporter responsible for N-acetylneuraminic acid uptake in H. influenzae has yet to be characterized. In this paper we demonstrate that this transporter is a novel sugar transporter of the tripartite ATP-independent periplasmic transporter family. In the absence of this transporter, H. influenzae cannot incorporate sialic acid into its lipooligosaccharides, making the organism unable to survive when exposed to human serum and causing reduced viability in biofilm growth.
Increasing plant susceptibility to Agrobacterium infection by overexpression of the Arabidopsis nuclear protein VIP1

Agrobacterium is a unique model system as well as a major biotechnological tool for genetic manipulation of plant cells. It is still unknown, however, whether host cellular factors exist that are limiting for infection, and whether their overexpression in plant cells can increase the efficiency of the infection. Here, we examined the effect of overexpression in tobacco plants of an Arabidopsis gene, VIP1, which encodes a recently discovered cellular protein required for Agrobacterium infection. Our results indicate that VIP1 is imported into the plant cell nucleus via the karyopherin αdependent pathway and that elevated intracellular levels of VIP1 render the host plants significantly more susceptible to transient and stable genetic transformation by Agrobacterium, probably because of the increased nuclear import of the transferred-DNA.
Dual Origins of Dairy Cattle Farming – Evidence from a Comprehensive Survey of European Y-Chromosomal Variation

Background Diversity patterns of livestock species are informative to the history of agriculture and indicate uniqueness of breeds as relevant for conservation. So far, most studies on cattle have focused on mitochondrial and autosomal DNA variation. Previous studies of Y-chromosomal variation, with limited breed panels, identified two Bos taurus (taurine) haplogroups (Y1 and Y2; both composed of several haplotypes) and one Bos indicus (indicine/zebu) haplogroup (Y3), as well as a strong phylogeographic structuring of paternal lineages. Methodology and Principal Findings Haplogroup data were collected for 2087 animals from 138 breeds. For 111 breeds, these were resolved further by genotyping microsatellites INRA189 (10 alleles) and BM861 (2 alleles). European cattle carry exclusively taurine haplotypes, with the zebu Y-chromosomes having appreciable frequencies in Southwest Asian populations. Y1 is predominant in northern and north-western Europe, but is also observed in several Iberian breeds, as well as in Southwest Asia. A single Y1 haplotype is predominant in north-central Europe and a single Y2 haplotype in central Europe. In contrast, we found both Y1 and Y2 haplotypes in Britain, the Nordic region and Russia, with the highest Y-chromosomal diversity seen in the Iberian Peninsula. Conclusions We propose that the homogeneous Y1 and Y2 regions reflect founder effects associated with the development and expansion of two groups of dairy cattle, the pied or red breeds from the North Sea and Baltic coasts and the spotted, yellow or brown breeds from Switzerland, respectively. The present Y1-Y2 contrast in central Europe coincides with historic, linguistic, religious and cultural boundaries.
TRYPANOSOMA SAIMIRII RODHAIN, A JUNIOR SYNONYM OF TRYPANOSOMA RANGELI TEJERA

In the present study, we used sodium dodecyl sulfate-polyacrylamide gel electrophoresis to compare polypeptides of trypanosomes isolated by hemoculture of squirrel monkeys displaying Trypanosoma saimirii blood trypomastigotes, with other trypanosomes that infect primates to evaluate the validity of T. saimirii. The polypeptide profiles of trypanosomes isolated directly from squirrel monkeys or after their passage in mice were identical to those of 3 standard strains of T. rangeli, but they were distinct from those of T. cruzi, T. conorhini, and T. minasense. These results strengthen previous morphological and biological findings by Rodhain on trypanosomes of the squirrel monkey and lead to the conclusion that T. saimirii is indeed a junior synonym of T. rangeli.
A parametric family of elliptic curves

Let k ≥ 3 be an integer and let Ek be the elliptic curve given by Ek : y = ((k − 1)x + 1)((k + 1)x + 1)(4kx + 1). It is proven that if rank (Ek(Q)) = 1 or k ≤ 1000, then all integer points on Ek are given by (x, y) ∈ {(0,±1), (16k − 4k,±(128k − 112k + 20k − 1))}. The same result is also proven for two subfamilies with rank equal 2 and for one subfamily with rank equal 3.
Nucleocytoplasmic Shuttling of the Cdc42p Exchange Factor Cdc24p

Cdc24p, the GDP/GTP exchange factor for the regulator of actin cytoskeleton Cdc42p, localizes to sites of polarized growth. Here we show that Cdc24p shuttles in and out of the yeast nucleus during vegetative growth. Far1p is necessary and sufficient for nuclear accumulation of Cdc24p, suggesting that its nuclear import occurs via an association with Far1p. Nuclear export is triggered either by entry into the cell cycle or by mating pheromone. As Far1p is degraded upon entry into the cell cycle, cell cycle–dependent export of Cdc24p occurs in the absence of Far1p, whereas during mating similar export kinetics indicate that a Cdc24p–Far1p complex is exported. Our results suggest that the nucleus serves as a store of preformed Cdc24p–Far1p complex which is required for chemotropism.
Distribution of garlic virus A in different garlic production regions of Argentina.

Comparative tests using inmunosorbent electron microscopy plus decoration and ELISA with antibodies against Garlic virus A (GarV-A) and Garlic virus C (GarV-C) coat proteins showed that they specifically recognize the respective viruses. On this basis, the GarV-A antiserum was used in DAS-ELISA tests to study the distribution of GarV-A in different regions of Argentina. A total of 2655 samples, representing 115 garlic fields were analyzed. GarV-A was detected in 64%, 51%, 43% and 35% of samples collected in San Juan, Mendoza, Cordoba and Buenos Aires Provinces, respectively. Positive samples were not found in plants from Santa Cruz Province. Distribution among different garlic cultivars showed that this virus was present in 33%, 46%, 53%, 70% and 43% of plants belonging to cvs ‘Colorado’, ‘Chino’, ‘Violeta Frances’, ‘Blanco’ and ‘Rosado Paraguayo’, respectively. Negative results were obtained in samples of cvs ‘Castano-INTA’ and ‘Violeta Santacruceno’.