julilili42/papers huggingface dataset:
Disrupting a key hydrophobic pair in the oligomerization interface of the actinoporins impairs their pore‐forming activity
2016-12-21

Abstract Crystallographic data of the dimeric and octameric forms of fragaceatoxin C (FraC) suggested the key role of a small hydrophobic protein–protein interaction surface for actinoporins oligomerization and pore formation in membranes. However, site‐directed mutagenesis studies supporting this hypothesis for others actinoporins are still lacking. Here, we demonstrate that disrupting the key hydrophobic interaction between V60 and F163 (FraC numbering scheme) in the oligomerization interface of FraC, equinatoxin II (EqtII), and sticholysin II (StII) impairs the pore formation activity of these proteins. Our results allow for the extension of the importance of FraC protein–protein interactions in the stabilization of the oligomeric intermediates of StII and EqtII pointing out that all of these proteins follow a similar pathway of membrane disruption. These findings support the hybrid pore proposal as the universal model of actinoporins pore formation. Moreover, we reinforce the relevance of dimer formation, which appears to be a functional intermediate in the assembly pathway of some different pore‐forming proteins.
Recent advances in understanding and managing Crohn’s disease
2016-12-21

<ns4:p>There is consensus that inflammatory bowel diseases (IBDs) are the result of “dysregulated” immune reactivity towards commensal microorganisms in the intestine. This gut microbiome is clearly altered in IBD, but its primary or secondary role is still debated. The focus has shifted from adaptive to innate immunity, with its multitude of receptor molecules (Toll-like and NOD receptors) and antibacterial effector molecules (defensins, cathelicidin, and others). The latter appear to be at least partly deficient at different intestinal locations. Host genetics also support the notion that microbe–host interaction at the mucosa is the prime site of pathogenesis. In contrast, even the latest therapeutic antibodies are directed against secondary targets like cytokines and integrins identified decades ago. These so-called “biologicals” have disappointing long-term results, with the majority of patients not achieving remission in the long run. A promising approach is the development of novel drugs like defensin-derived molecules that substitute for the missing endogenous antibacterials.</ns4:p>
Cellular Innate Immunity: An Old Game with New Players
2016-12-22

Innate immunity is a rapidly evolving field with novel cell types and molecular pathways being discovered and paradigms changing continuously. Innate and adaptive immune responses are traditionally viewed as separate from each other, but emerging evidence suggests that they overlap and mutually interact. Recently discovered cell types, particularly innate lymphoid cells and myeloid-derived suppressor cells, are gaining increasing attention. Here, we summarize and highlight current concepts in the field, focusing on innate immune cells as well as the inflammasome and DNA sensing which appear to be critical for the activation and orchestration of innate immunity, and may provide novel therapeutic opportunities for treating autoimmune, autoinflammatory, and infectious diseases.
Genetic Modulation of Transcranial Direct Current Stimulation Effects on Cognition
2016-12-22

High inter-individual variability substantially challenges the explanatory power of studies on the modulation of cognitive functions with transcranial direct current stimulation (tDCS). These differences in responsivity have been linked with a critical state-dependency of stimulation effects. In general, genetic diversity is a decisive biological basis of variations in neuronal network functioning. Therefore, it is most likely that inter-individual variability of tDCS-induced changes in cognitive functions is due to specific interactions between genetically determined network properties and the specific type of stimulation. In this context, predominantly the brain-derived neurotrophic factor (BDNF) Val66Met and the catechol-O-methyltransferase (COMT) Val108/158Met polymorphisms have been investigated. The studies on the interaction between the BDNF Val66Met polymorphism and the effect of brain stimulation indicate a critical but yet heterogeneous interaction. But up to now, data on the interplay between this polymorphism and tDCS on cognitive functioning are not available. However, recently, the functional Val(108/158)Met polymorphism in the COMT gene, that is particularly involved in the regulation of executive functions by means of the dopaminergic tone in frontal brain areas, has been demonstrated to specifically predict the effect of tDCS on cognitive control. Following an inverted U-shaped function, the high dopaminergic activity in Met allele homozygous individuals has been shown to be associated with a reduction of executive functioning by anodal tDCS to the prefrontal cortex. Consistently, Val homozygous individuals with lower dopaminergic tone show a clear reduction of response inhibition with cathodal tDCS. These findings exemplify the notion of a complex but neurophysiologically consistent interaction between genetically determined variations of neuronal activity and tDCS, particularly in the cognitive domain. Consequently, a systematic analysis and consideration of genetic modulators of tDCS effects will be helpful to improve the efficacy of brain stimulation and particularly tDCS in the investigation and treatment of cognitive functions.
GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis
2016-12-23

Activation of AMP-activated protein kinase (AMPK) in endothelial cells regulates energy homeostasis, stress protection and angiogenesis, but the underlying mechanisms are incompletely understood. Using a label-free phosphoproteomic analysis, we identified glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1) as an AMPK substrate. GFAT1 is the rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP) and as such controls the modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). In the present study, we tested the hypothesis that AMPK controls O-GlcNAc levels and function of endothelial cells via GFAT1 phosphorylation using biochemical, pharmacological, genetic and in vitro angiogenesis approaches. Activation of AMPK in primary human endothelial cells by 5-aminoimidazole-4-carboxamide riboside (AICAR) or by vascular endothelial growth factor (VEGF) led to GFAT1 phosphorylation at serine 243. This effect was not seen when AMPK was down-regulated by siRNA. Upon AMPK activation, diminished GFAT activity and reduced O-GlcNAc levels were observed in endothelial cells containing wild-type (WT)-GFAT1 but not in cells expressing non-phosphorylatable S243A-GFAT1. Pharmacological inhibition or siRNA-mediated down-regulation of GFAT1 potentiated VEGF-induced sprouting, indicating that GFAT1 acts as a negative regulator of angiogenesis. In cells expressing S243A-GFAT1, VEGF-induced sprouting was reduced, suggesting that VEGF relieves the inhibitory action of GFAT1/HBP on angiogenesis via AMPK-mediated GFAT1 phosphorylation. Activation of GFAT1/HBP by high glucose led to impairment of vascular sprouting, whereas GFAT1 inhibition improved sprouting even if glucose level was high. Our findings provide novel mechanistic insights into the role of HBP in angiogenesis. They suggest that targeting AMPK in endothelium might help to ameliorate hyperglycaemia-induced vascular dysfunction associated with metabolic disorders.
Gas entrapment and microbial N2O reduction reduce N2O emissions from a biochar-amended sandy clay loam soil
2016-12-23

Abstract Nitrous oxide (N 2 O) is a potent greenhouse gas that is produced during microbial nitrogen transformation processes such as nitrification and denitrification. Soils represent the largest sources of N 2 O emissions with nitrogen fertilizer application being the main driver of rising atmospheric N 2 O concentrations. Soil biochar amendment has been proposed as a promising tool to mitigate N 2 O emissions from soils. However, the underlying processes that cause N 2 O emission suppression in biochar-amended soils are still poorly understood. We set up microcosm experiments with fertilized, wet soil in which we used 15 N tracing techniques and quantitative polymerase chain reaction (qPCR) to investigate the impact of biochar on mineral and gaseous nitrogen dynamics and denitrification-specific functional marker gene abundance and expression. In accordance with previous studies our results showed that biochar addition can lead to a significant decrease in N 2 O emissions. Furthermore, we determined significantly higher quantities of soil-entrapped N 2 O and N 2 in biochar microcosms and a biochar-induced increase in typical and atypical nosZ transcript copy numbers. Our findings suggest that biochar-induced N 2 O emission mitigation is based on the entrapment of N 2 O in water-saturated pores of the soil matrix and concurrent stimulation of microbial N 2 O reduction resulting in an overall decrease of the N 2 O/(N 2 O + N 2 ) ratio.
A shape to the microlithic Robberg from Elands Bay Cave (South Africa)
2016-12-23

Elands Bay Cave (EBC) is a key South African site allowing discussion of technological change and adaptations that occurred from the Upper Pleniglacial to the Holocene. In 2011, we set out a new field campaign aiming to clarify the nature and chronology of the earliest Robberg occupations at the site, a technocomplex whose appearance closely relates to the Last Glacial Maximum. Our results document the appearance of the Robberg technology at ca. 19 398–18 790 cal BP, succeeding a phase commonly referred to as the Early Later Stone Age. In this paper, we further develop the definition of the Robberg by providing a technological and functional study of the MOS1 lithic assemblage at EBC, dated to 14 605–14 278 cal BP. Our results show that EBC occupants dominantly selected local quartz in addition to heat-treated silcrete that was introduced from distances greater than 30 km. Robberg inhabitants applied different reduction strategies combining bipolar/anvil and soft stone hammer percussion. Reduction sequences were oriented toward the production of a set of small artefacts (&lt; 25 mm long) that can be generically classified as bladelets. The low incidence of retouched forms and the absence of geometrics, together with our functional study, testify to a flexible composite microlithic technology. We also discuss the raw material provisioning strategies of EBC Robberg inhabitants and develop the question of the intraand inter-assemblages variability. Finally, we attempt to discuss its temporal trends and conclude on the originality of the Robberg technology within the context of other Late Pleistocene microlithic traditions.
Metalloid Ge9R3– Clusters with Various Silyl Substituents: From Shielded to Open Cluster Cores
2016-12-23

The synthesis and characterization of the metalloid germanium clusters {Ge 9 [Si(SiMe 3 ) 2 (SiPh 3 )] 2 } 2– ( 1 ), {Ge 9 [Si(SiMe 3 ) 3 ][Si(SiMe 3 ) 2 (SiPh 3 )] 2 } – ( 2 ), {Ge 9 [Si(SiMe 3 ) 2 (Si i Pr 3 )] 3 } – ( 3 ), and [Ge 9 (SiH t Bu 2 ) 3 ] – ( 4 ), which were obtained by the reaction of the Zintl anion Ge 9 4– with different silyl halides, are presented. Compound 4 is the sterically least protected soluble Ge 9 R 3 – cluster known to date, and thus has interesting structural features and may open the way to new coordination modes of metalloid Ge 9 R 3 – clusters.
HLA class I-restricted MYD88 L265P-derived peptides as specific targets for lymphoma immunotherapy
2016-12-23

Genome sequencing has uncovered an array of recurring somatic mutations in different non-Hodgkin lymphoma (NHL) subtypes. If affecting protein-coding regions, such mutations may yield mutation-derived peptides that may be presented by HLA class I proteins and recognized by cytotoxic T cells. A recurring somatic and oncogenic driver mutation of the Toll-like receptor adaptor protein <i>MYD88</i>, Leu265Pro (L265P) was identified in up to 90% of different NHL subtype patients. We therefore screened the potential of <i>MYD88</i><sup>L265P</sup>-derived peptides to elicit cytotoxic T cell responses as tumor-specific neoantigens. Based on <i>in silico</i> predictions, we identified potential <i>MYD88</i><sup>L265P</sup>-containing HLA ligands for several HLA class I restrictions. A set of HLA class I <i>MYD88</i><sup>L265P</sup>-derived ligands elicited specific cytotoxic T cell responses for HLA-B*07 and -B*15. These data highlight the potential of <i>MYD88</i><sup>L265P</sup> mutation-specific peptide-based immunotherapy as a novel personalized treatment approach for patients with <i>MYD88</i><sup>L265P+</sup> NHLs that may complement pharmacological approaches targeting oncogenic MyD88 L265P signaling.
Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency
2016-12-23

Context and aims Functional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency. Methods An immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep). The analytical quality of bioLep was validated and compared to a conventional assay for immune-reactive leptin (irLep). Its clinical relevance was evaluated in a cohort of lean and obese children and adults as well as in children diagnosed with functional leptin deficiency and their parents. Results In the clinical cohort, a bioLep/irLep ratio of 1.07 (range: 0.80–1.41) was observed. Serum of patients with non-functional leptin due to homozygous amino acid exchanges (D100Y or N103K) revealed high irLep but non-detectable bioLep levels. Upon treatment of these patients with metreleptin, irLep levels decreased, whereas levels of bioLep increased continuously. In patient relatives with heterozygous amino acid exchanges, a bioLep/irLep ratio of 0.52 (range: 0.48–0.55) being distinct from normal was observed. Conclusions The new bioLep assay is able to diagnose impaired leptin bioactivity in severely obese patients with a homozygous gene defect and in heterozygous carriers of such mutations. The assay serves as a diagnostic tool to monitor leptin bioactivity during treatment of these patients.
Measurements of branching ratios for η decays into charged particles
2016-12-23

The WASA-at-COSY experiment has collected events with\\n -mesons produced via the reaction at\\n . Using this data set, we evaluate the branching\\nratios of the decays , ,\\n and . The\\nbranching ratios are normalized to the \\ndecay. In addition an upper limit on a -violating asymmetry in\\n is extracted.\\n
“Cueing” for Levodopa-Induced Dyskinesias in Parkinson’s Disease
2016-12-23

We describe the case of an early-onset Parkinson's disease (PD) patient, suffering from a severe and unusual dyskinetic gait pattern, earlier described as "Silly walk." On presentation, the 58-year-old patient showed a painful, bizarre dyskinetic gait disorder, resulting in a significantly impairment of her social life. We developed an individual conservative training method for the patient, using "Cueing mechanisms," well known for treatment of Freezing in PD, to overcome her dyskinetic gait pattern. An impressive improvement was seen after the use of visual and acousting cues. We, therefore, conclude that it might be important for PD patients to recognize these specific movement abnormalities and start early with individualized training methods. Moreover, especially for "Silly walk" individuals, "Cueing" strategies can be an important new basis of conservative training methods for dyskinesia.
FUS Mislocalization and Vulnerability to DNA Damage in ALS Patients Derived hiPSCs and Aging Motoneurons
2016-12-25

Mutations within the <i>FUS</i> gene (Fused in Sarcoma) are known to cause Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease affecting upper and lower motoneurons. The <i>FUS</i> gene codes for a multifunctional RNA/DNA-binding protein that is primarily localized in the nucleus and is involved in cellular processes such as splicing, translation, mRNA transport and DNA damage response. In this study, we analyzed pathophysiological alterations associated with ALS related FUS mutations (mFUS) in human induced pluripotent stem cells (hiPSCs) and hiPSC derived motoneurons. To that end, we compared cells carrying a mild or severe mFUS in physiological- and/or stress conditions as well as after induced DNA damage. Following hyperosmolar stress or irradiation, mFUS hiPS cells recruited significantly more cytoplasmatic FUS into stress granules accompanied by impaired DNA-damage repair. In motoneurons wild-type FUS was localized in the nucleus but also deposited as small punctae within neurites. In motoneurons expressing mFUS the protein was additionally detected in the cytoplasm and a significantly increased number of large, densely packed FUS positive stress granules were seen along neurites. The amount of FUS mislocalization correlated positively with both the onset of the human disease (the earlier the onset the higher the FUS mislocalization) and the maturation status of the motoneurons. Moreover, even in non-stressed post-mitotic mFUS motoneurons clear signs of DNA-damage could be detected. In summary, we found that the susceptibility to cell stress was higher in mFUS hiPSCs and hiPSC derived motoneurons than in controls and the degree of FUS mislocalization correlated well with the clinical severity of the underlying ALS related mFUS. The accumulation of DNA damage and the cellular response to DNA damage stressors was more pronounced in post-mitotic mFUS motoneurons than in dividing hiPSCs suggesting that mFUS motoneurons accumulate foci of DNA damage, which in turn might be directly linked to neurodegeneration.
Activation of the glmS Ribozyme Confers Bacterial Growth Inhibition
2016-12-25

Abstract The ever‐growing number of pathogenic bacteria resistant to treatment with antibiotics call for the development of novel compounds with as‐yet unexplored modes of action. Here, we demonstrate the in vivo antibacterial activity of carba‐α‐ d ‐glucosamine (CGlcN). In this mode of action study, we provide evidence that CGlcN‐mediated growth inhibition is due to glmS ribozyme activation, and we demonstrate that CGlcN hijacks an endogenous activation pathway, hence utilizing a prodrug mechanism. This is the first report describing antibacterial activity mediated by activating the self‐cleaving properties of a ribozyme. Our results open the path towards a compound class with an entirely novel and distinct molecular mechanism.
A cultural take on the links between religiosity, identity, and meaning in life in religious emerging adults
2016-12-26

Identity and meaning in life are core developmental assets in emerging adulthood. We analysed how religiosity is related to these intentional strivings in emerging adults enrolled in theological education, by depicting (1) identity strivings and meaning in life accounts in faith narratives (Study 1) and (2) links between personal identity and meaning in life profiles and religious beliefs, behaviours, and subjective experiences (Study 2). Both studies highlighted that a Foreclosed status, with high personal commitment and reduced exploration, was dominant in faith narratives and personal identity profiles. Also, in narratives meaning in life was reflected by a strong focus on presence of meaning through religious insights. Nonetheless, global meaning in life profiles indicated that many emerging adults were searching for a meaning in their lives, while reporting lower levels of presence of meaning. Identity Achievement and High Presence–High Search profiles were linked to the highest levels of subjective, behavioural, and cognitive religiosity. We highlighted the multidimensionality of identity and meaning in life strivings in emerging adults attending theological schools. We pointed out that even in a somewhat foreclosed cultural context (e.g., Romanian Christian Orthodox theological schools), religion represents a dynamic social and ideological context for self‐development. Statement of contribution What is already known on this subject? Religious beliefs increase in emerging adults, doubled by decreases in religious behaviours, linked to an adherence to a more personal approach to religion. Religious youth are more committed to their faith and also explore identity and life meaning in relation to their religious strivings. Youth religious exemplars report close links between their religious faith and strivings for meaningful life goals. What does this study add? We investigated Christian Orthodox theology students, for whom religion is a normative dimension of personal and vocational development. A Foreclosed status, with high personal commitment and reduced exploration was dominant in faith narratives and in personal identity profiles. Many emerging adults were searching for a meaning in their lives, while at the same time reporting lower levels of presence of meaning. Identity Achievement and High Presence–High Search profiles were linked to higher levels of subjective, behavioural, and cognitive religiosity.
Prognostic parameters and outcome after re-irradiation for progressive glioblastoma
2016-12-26

The favourable results regarding overall survival are probably due to patient selection for re-irradiation. If technically feasible, stereotactic radiosurgery or hypofractionated regimes should be preferred. In this highly selected re-irradiation cohort, only some of the well-known prognostic factors of the primary tumour setting were found to influence overall survival significantly. In contrast, also some patients presenting with unfavourable predictive parameters showed an encouraging course of disease and thus should not be excluded from re-irradiation.
Plate fixation of periprosthetic femur fractures: What happens to the cement mantle?
2016-12-26

Osteosynthesis of periprosthetic femur fractures by screw fixation around the implanted prosthetic stem is currently regarded as the biomechanically superior option compared with cerclage. The aim of this biomechanical study was damage analysis of the cement mantle after revision screw insertion. A prosthetic stem (Bicontact) was implanted in 20 cadaveric femora in cemented technique. A locking compression plate (Synthes) was then applied to the lateral femur at the level of the prosthetic stem. The method of plate fixation to the femur was assigned randomly to three groups: bicortical non-locking screws, monocortical locking screws, and bicortical locking screws. This was followed by applying a fluctuating axial load (2100 N, 0.5 Hz) for 20,000 cycles. After testing, macroscopic and microscopic evaluations of the cement mantle were conducted. Cracks formed in the cement mantle in 14% of the 80 screw holes. The type of screw (bicortical or monocortical; locking or non-locking) had no significant effect on the number of cracks (p = 0.52). The relationship between manifestation of crack damage and cement mantle thickness was not significant (p = 0.36), whereas the relationship between crack formation and screw position was significant (p = 0.019). Those screws whose circumference was only partially within the cement mantle yielded a significantly lower number of cracks compared with screws positioned completely within the cement mantle or even touching the prosthetic stem. In order to reduce the incidence of crack formation in the cement mantle during plate osteosynthesis of periprosthetic femur fractures, the screws should not be either placed within the cement mantle or make direct contact with the stem.