julilili42/papers huggingface dataset:
The lipid profile of brown adipose tissue is sex-specific in mice
2014-08-13

Brown adipose tissue (BAT) is a thermogenic organ with a vital function in small mammals and potential as metabolic drug target in humans. By using high-resolution LC-tandem-mass spectrometry, we quantified 329 lipid species from 17 (sub)classes and identified the fatty acid composition of all phospholipids from BAT and subcutaneous and gonadal white adipose tissue (WAT) from female and male mice. Phospholipids and free fatty acids were higher in BAT, while DAG and TAG levels were higher in WAT. A set of phospholipids dominated by the residue docosahexaenoic acid, which influences membrane fluidity, showed the highest specificity for BAT. We additionally detected major sex-specific differences between the BAT lipid profiles, while samples from the different WAT depots were comparatively similar. Female BAT contained less triacylglycerol and more phospholipids rich in arachidonic and stearic acid whereas another set of fatty acid residues that included linoleic and palmitic acid prevailed in males. These differences in phospholipid fatty acid composition could greatly affect mitochondrial membranes and other cellular organelles and thereby regulate the function of BAT in a sex-specific manner.
Resting-state functional connectivity of the human hypothalamus
2014-08-14

The hypothalamus is of enormous importance for multiple bodily functions such as energy homeostasis. Especially, rodent studies have greatly contributed to our understanding how specific hypothalamic subregions integrate peripheral and central signals into the brain to control food intake. In humans, however, the neural circuitry of the hypothalamus, with its different subregions, has not been delineated. Hence, the aim of this study was to map the hypothalamus network using resting-state functional connectivity (FC) analyses from the medial hypothalamus (MH) and lateral hypothalamus (LH) in healthy normal-weight adults (n = 49). Furthermore, in a separate sample, we examined differences within the LH and MH networks between healthy normal-weight (n = 25) versus overweight/obese adults (n = 23). FC patterns from the LH and MH revealed significant connections to the striatum, thalamus, brainstem, orbitofrontal cortex, middle and posterior cingulum and temporal brain regions. However, our analysis revealed subtler distinctions within hypothalamic subregions. The LH was functionally stronger connected to the dorsal striatum, anterior cingulum, and frontal operculum, while the MH showed stronger functional connections to the nucleus accumbens and medial orbitofrontal cortex. Furthermore, overweight/obese participants revealed heightened FC in the orbitofrontal cortex and nucleus accumbens within the MH network. Our results indicate that the MH and LH network are tapped into different parts of the dopaminergic circuitry of the brain, potentially modulating food reward based on the functional connections to the ventral and dorsal striatum, respectively. In obese adults, FC changes were observed in the MH network.
Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members
2014-08-14

Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ≥ 0.34, p = <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the human population must give cause for concern to malaria elimination strategists in the Southeast Asian region.
Optimal control in evolutionary micromagnetism
2014-08-14

We consider an optimal control problem subject to the one-dimensional Landau–Lifshitz–Gilbert equation, which describes the evolution of magnetizations in S2. The problem is motivated in order to control switching processes of ferromagnets. Existence of an optimum and the first-order necessary optimality system are derived. We show (up to subsequences) convergence of state, adjoint and control variables of a time discretization (semi-implicit Euler method) for vanishing time step size. A main step here is to verify corresponding stability properties for the semidiscrete state, which is nontrivial since the iterates take values which only approximate S2. We use a perturbation argument within a variational discretization in order to show error bounds for the semidiscrete state variables, from which we may then infer uniform bounds for the semidiscrete state and also adjoint variables. Numerical studies underline these results and compare this discretization with a further variant, which bases on a projection strategy for the state equation to enhance iterates to better approximate S2.
TYING UP THE LOOSE ENDS OF NATIONAL SELF-DETERMINATION: BRITISH, FRENCH, AND AMERICAN EXPERTS IN PEACE PLANNING, 1917–1919
2014-08-14

ABSTRACT This article examines Allied peace planning during the latter stages of the First World War by comparing and connecting the British, French, and American expert groups. These academic experts were expected to apply the publicly announced programme of national self-determination to the local realities in Europe without losing sight of their governments’ geopolitical directives. Contacts and exchanges between the three groups, largely neglected in the literature, played a crucial role in shaping the experts’ work. At the same time, persisting national suspicion and the fragile institutional position of the experts prevented open debate on the precise meaning of national self-determination and thereby forestalled the development of a coherent Allied peace programme. This shortcoming would become a serious burden for the negotiations at the Paris Peace Conference and the early interwar period, in that it led to growing frustration and undermined Allied commitment to the Paris peace treaties.
Computational Study of van der Waals Complexes between Borylenes and Hydrocarbons
2014-08-14

Abstract The addition of borylenes (RB) to prototypical carboncarbon multiple bonds (ethyne, ethene) and the insertion into a CH bond of methane involves weakly bound van der Waals complexes of the reaction partners according to computational chemistry methods. Geometries of all complexes were optimized using spin‐component scaled second‐order Møller–Plesset perturbation theory (SCS‐MP2) in combination with a quadruple‐ζ (def2‐QZVP) basis set. Energies were further refined using the coupled‐cluster (CCSD(T)) method in combination with basis sets up to quadruple‐ζ quality (def2‐QZVP and aug‐cc‐pVTZ). All of the complexes of borylenes studied correspond to shallow minima on their potential‐energy surfaces. Borylene complexes with ethyne are the most stable and those with methane are the least stable ones. Aminoborylene complexes BNHR with ethyne and ethene are stabilized mainly by NH ⋅⋅⋅ π interactions. Symmetry‐adapted perturbation theory (SAPT) was performed to analyze the nature of the interaction between borylene molecules and hydrocarbons. Most of the ethyne complexes are dominated by electrostatic interactions, whereas for most of the ethene and all of the methane complexes the interaction is mainly dispersive.
Zebrafish Bioassay-Guided Microfractionation Identifies Anticonvulsant Steroid Glycosides from the Philippine Medicinal PlantSolanum torvum
2014-08-15

Medicinal plants used for the treatment of epilepsy are potentially a valuable source of novel antiepileptic small molecules. To identify anticonvulsant secondary metabolites, we performed an in vivo, zebrafish-based screen of medicinal plants used in Southeast Asia for the treatment of seizures. Solanum torvum Sw. (Solanaceae) was identified as having significant anticonvulsant activity in zebrafish larvae with seizures induced by the GABAA antagonist pentylenetetrazol (PTZ). This finding correlates well with the ethnomedical use of this plant in the Philippines, where a water decoction of S. torvum leaves is used to treat epileptic seizures. HPLC microfractionation of the bioactive crude extract, in combination with the in vivo zebrafish seizure assay, enabled the rapid localization of several bioactive compounds that were partially identified online by UHPLC-TOF-MS as steroid glycosides. Targeted isolation of the active constituents from the methanolic extract enabled the complete de novo structure identification of the six main bioactive compounds that were also present in the traditional preparation. To partially mimic the in vivo metabolism of these triterpene glycosides, their common aglycone was generated by acid hydrolysis. The isolated molecules exhibited significant anticonvulsant activity in zebrafish seizure assays. These results underscore the potential of zebrafish bioassay-guided microfractionation to rapidly identify novel bioactive small molecules of natural origin.
Demo
2014-08-17

This demo presents a testbed for computer networking education. It leverages hardware virtualization to accommodate 6 PCs and 2 routers on a single testbed host to reduce costs, energy consumption, space requirements, and heat emission. The testbed excels by providing dedicated physical Ethernet and USB interfaces for virtual machines so that students can interconnect them with cables and switches like in a non-virtualized testbed
“Celtic migrations”: Fact or fiction? Strontium and oxygen isotope analysis of the Czech cemeteries of Radovesice and Kutná Hora in Bohemia
2014-08-18

ABSTRACT Strontium and oxygen isotope analysis of human remains from the early La Tène (fourth/third century BC) Czech cemeteries of Radovesice I (RAD I), Radovesice II (RAD II), and Kutná Hora were conducted to investigate the importance of residential changes during the period of the historic “Celtic migrations”. In the initial phases (LT A/B), the grave goods of these cemeteries are typical for the core area of the La Tène culture, while around 300 BC (LT B2) an alteration occurs and typical Bohemian styles arise, and connections to Moravia and the Danubian region become visible. The strontium isotope ratios are highly varied with 87 Sr/ 86 Sr values between 0.7062 and 0.7153 in Radovesice, and between 0.7082 and 0.7147 in Kutná Hora. The oxygen isotope data are more homogeneous and yield δ 18 O p ratios from 14.8‰ to 17.2‰ [mean: 16.2‰ ± 0.5 (1 σ )] in Radovesice, and from 14.9‰ to 17.3‰ [mean: 16.5‰ ± 0.6 (1 σ )] in Kutná Hora. Because the geological properties of the landscapes around the sites are variable and complex, most of the observed variations among the strontium isotope ratios may have been caused by agricultural practices, such as regularly changing farming land. Nevertheless, there are some individuals who differ completely from the regional isotopic baseline values. This suggests that at least a small part of the community migrated, which does not seem to be correlated with any particular phase of the La Tène period. Remarkably, it is mainly males who seem to be of nonlocal origin, and particularly those who were buried as warriors. Females, on the other hand, appear to have been more closely bonded to the Bohemian region. Whether the “foreign” individuals with differing isotopic compositions came from Moravia or the Danubian region remains debatable. Am J Phys Anthropol 155:496–512, 2014. © 2014 Wiley Periodicals, Inc.
Harmonisation of short-term in vitro culture for the expansion of antigen-specific CD8+ T cells with detection by ELISPOT and HLA-multimer staining
2014-08-18

Ex vivo ELISPOT and multimer staining are well-established tests for the assessment of antigen-specific T cells. Many laboratories are now using a period of in vitro stimulation (IVS) to enhance detection. Here, we report the findings of a multi-centre panel organised by the Association for Cancer Immunotherapy Immunoguiding Program to investigate the impact of IVS protocols on the detection of antigen-specific T cells of varying ex vivo frequency. Five centres performed ELISPOT and multimer staining on centrally prepared PBMCs from 3 donors, both ex vivo and following IVS. A harmonised IVS protocol was designed based on the best-performing protocol(s), which was then evaluated in a second phase on 2 donors by 6 centres. All centres were able to reliably detect antigen-specific T cells of high/intermediate frequency both ex vivo (Phase I) and post-IVS (Phase I and II). The highest frequencies of antigen-specific T cells ex vivo were mirrored in the frequencies following IVS and in the detection rates. However, antigen-specific T cells of a low/undetectable frequency ex vivo were not reproducibly detected post-IVS. Harmonisation of the IVS protocol reduced the inter-laboratory variation observed for ELISPOT and multimer analyses by approximately 20 %. We further demonstrate that results from ELISPOT and multimer staining correlated after (P < 0.0001 and R (2) = 0.5113), but not before IVS. In summary, IVS was shown to be a reproducible method that benefitted from method harmonisation.
Stimulation of Suicidal Erythrocyte Death by Sulforaphane
2014-08-18

Abstract Sulforaphane, an isothiocyanate from cruciferous vegetable, counteracts malignancy. The effect is at least in part due to the stimulation of suicidal death or apoptosis of tumour cells. Mechanisms invoked in sulforaphane‐induced apoptosis include mitochondrial depolarization and altered gene expression. Despite the lack of mitochondria and nuclei, erythrocytes may, similar to apoptosis of nucleated cells, enter eryptosis, a suicidal cell death characterized by cell shrinkage and phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca 2+ ‐activity ([Ca 2+ ] i ). This study explored whether sulforaphane stimulates eryptosis. Cell volume was estimated from forward scatter, phosphatidylserine exposure at the cell surface from annexin V binding and [Ca 2+ ] i from Fluo‐3 fluorescence. A 48‐hr treatment of human erythrocytes with sulforaphane (50–100 μM) significantly decreased forward scatter, significantly increased the percentage of annexin V binding cells and significantly increased [Ca 2+ ] i . The effect of sulforaphane (100 μM) on annexin V binding was significantly blunted but not abrogated by the removal of extracellular Ca 2+ . Sulforaphane (100 μM) significantly increased ceramide formation. In conclusion, sulforaphane stimulates suicidal erythrocyte death or eryptosis, an effect at least partially, but not exclusively, due to the stimulation of Ca 2+ entry and ceramide formation.
University Gynaecology and Obstetrics, quo vadis? A Department of Women’s Health—University Women’s Hospital of the future?
2014-08-18

Methodological diversity and inter-professionalism build the appropriate base for the further development of research fields. At the same time, the Department creates space for the consolidation of the core areas and the integration of sub-disciplines (clinical and scientific) to maintain the unity of this discipline. Via the scientific monitoring of the implementation, suitable elements can be highlighted for transfer to other facilities.
4‐bromopropofol decreases action potential generation in spinal neurons by inducing a glycine receptor‐mediated tonic conductance
2014-08-18

Background and Purpose Impaired function of spinal strychnine‐sensitive glycine receptors gives rise to chronic pain states and movement disorders. Therefore, increased activity of glycine receptors should help to treat such disorders. Although compounds targeting glycine receptors with a high selectivity are lacking, halogenated analogues of propofol have recently been considered as potential candidates. Therefore we asked whether 4‐bromopropofol attenuated the excitability of spinal neurons by promoting glycine receptor‐dependent inhibition. Experimental Approach The actions of sub‐anaesthetic concentrations of propofol and 4‐bromopropofol were investigated in spinal tissue cultures prepared from mice. Drug‐induced alterations in action potential firing were monitored by extracellular multi‐unit recordings. The effects on GABA A and glycine receptor‐mediated inhibition were quantified by whole‐cell voltage‐clamp recordings. Key Results Low concentrations of 4‐bromopropofol (50 nM ) reduced action potential activity of ventral horn neurons by about 30%, compared with sham‐treated slices. This effect was completely abolished by strychnine (1 μ M). In voltage‐clamped neurons, 4‐bromopropofol activated glycine receptors, generating a tonic current of 65 ± 10 pA , while GABA A ‐ and glycine receptor‐mediated synaptic transmission remained unaffected. Conclusions and Implications The highest glycine levels in the CNS are found in the ventral horn of the spinal cord, a region mediating pain‐induced motor reflexes and participating in the control of muscle tone. 4‐Bromopropofol may serve as a starting point for the development of non‐sedative, non‐addictive, muscle relaxants and analgesics to be used to treat low back pain.
Membrane pathology and microglial activation of mice expressing membrane anchored or membrane released forms of Aβ and mutated human Alzheimer's precursor protein (APP)
2014-08-18

Aims A lzheimer's disease and the transmissible spongiform encephalopathies or prion diseases accumulate misfolded and aggregated forms of neuronal cell membrane proteins. Distinctive membrane lesions caused by the accumulation of disease‐associated prion protein ( PrP d ) are found in prion disease but morphological changes of membranes are not associated with A β in A lzheimer's disease. Membrane changes occur in all prion diseases where PrP d is attached to cell membranes by a glycosyl‐phosphoinositol ( GPI ) anchor but are absent from transgenic mice expressing anchorless PrP d . Here we investigate whether GPI membrane attached A β may also cause prion‐like membrane lesions. Methods We used immunogold electron microscopy to determine the localization and pathology of A β accumulation in groups of transgenic mice expressing anchored or unanchored forms of A β or mutated human A lzheimer's precursor protein. Results GPI attached A β did not replicate the membrane lesions of PrP d . However, as with PrP d in prion disease, A β peptides derived from each transgenic mouse line initially accumulated on morphologically normal neurite membranes, elicited rapid glial recognition and neurite A β was transferred to attenuated microglial and astrocytic processes. Conclusions GPI attachment of misfolded membrane proteins is insufficient to cause prion‐like membrane lesions. Prion disease and murine A β amyloidosis both accumulate misfolded monomeric or oligomeric membrane proteins that are recognized by glial processes and acquire such misfolded proteins prior to their accumulation in the extracellular space. In contrast to prion disease where glial cells efficiently endocytose PrP d to endolysosomes, activated microglial cells in murine A β amyloidosis are not as efficient phagocytes.
AXL Mediates Resistance to Cetuximab Therapy
2014-08-19

Abstract The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical outcome. In this study, we show that overexpression of the oncogenic receptor tyrosine kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non–small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated, and tightly associated with EGFR expression in cells resistant to cetuximab (CtxR cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in CtxR cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in CtxR cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft models, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL-targeting drugs to treat cetuximab-resistant cancers. Cancer Res; 74(18); 5152–64. ©2014 AACR.
Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis
2014-08-19

Significance It has been reported that elevation of cGMP and activation of cGMP-dependent protein kinase I (cGKI) by inhibition of PDE5 activity with sildenafil prevents cardiac hypertrophy. We studied the roles of cGKI and PDE5 inhibition on angiotensin (AII)-induced hypertrophy and fibrosis using control (Ctr) mice and mice expressing cGKI only in cells where the smooth muscle SM22α promotor is active (βRM). In Ctr mice, sildenafil did not reduce the AII-induced increase of cardiomyocyte (CM) size or myocyte hypertrophic markers but did reduce fibrosis. In βRM mice, sildenafil had little or no effect on markers of fibrosis. These results show that the sildenafil/cGMP/cGKI cascade can have an inhibitory effect on cardiac fibrosis but not on CM hypertrophy.