julilili42/papers huggingface dataset:
Functional Relevance of the Anaphylatoxin Receptor C3aR for Platelet Function and Arterial Thrombus Formation Marks an Intersection Point Between Innate Immunity and Thrombosis
2018-05-25

Background: Platelets have distinct roles in the vascular system in that they are the major mediator of thrombosis, critical for restoration of tissue integrity, and players in vascular inflammatory conditions. In close spatiotemporal proximity, the complement system acts as the first line of defense against invading microorganisms and is a key mediator of inflammation. Whereas the fluid phase cross-talk between the complement and coagulation systems is well appreciated, the understanding of the pathophysiological implications of such interactions is still scant. Methods: We analyzed coexpression of the anaphylatoxin receptor C3aR with activated glycoprotein IIb/IIIa on platelets of 501 patients with coronary artery disease using flow cytometry; detected C3aR expression in human or murine specimen by polymerase chain reaction, immunofluorescence, Western blotting, or flow cytometry; and examined the importance of platelet C3aR by various in vitro platelet function tests, in vivo bleeding time, and intravital microscopy. The pathophysiological relevance of C3aR was scrutinized with the use of disease models of myocardial infarction and stroke. To approach underlying molecular mechanisms, we identified the platelet small GTPase Rap1b using nanoscale liquid chromatography coupled to tandem mass spectrometry. Results: We found a strong positive correlation of platelet complement C3aR expression with activated glycoprotein IIb/IIIa in patients with coronary artery disease and coexpression of C3aR with glycoprotein IIb/IIIa in thrombi obtained from patients with myocardial infarction. Our results demonstrate that the C3a/C3aR axis on platelets regulates distinct steps of thrombus formation such as platelet adhesion, spreading, and Ca 2+ influx. Using C3aR −/− mice or C3 −/− mice with reinjection of C3a, we uncovered that the complement activation fragment C3a regulates bleeding time after tail injury and thrombosis. Notably, C3aR −/− mice were less prone to experimental stroke and myocardial infarction. Furthermore, reconstitution of C3aR −/− mice with C3aR +/+ platelets and platelet depletion experiments demonstrated that the observed effects on thrombosis, myocardial infarction, and stroke were specifically caused by platelet C3aR. Mechanistically, C3aR-mediated signaling regulates the activation of Rap1b and thereby bleeding arrest after injury and in vivo thrombus formation. Conclusions: Overall, our findings uncover a novel function of the anaphylatoxin C3a for platelet function and thrombus formation, highlighting a detrimental role of imbalanced complement activation in cardiovascular diseases.
A high-fat diet stimulates fibroblast growth factor 23 formation in mice through TNFα upregulation
2018-05-25

Abstract Background/objectives Bone-derived fibroblast growth factor 23 (FGF23) is a hormone that suppresses renal phosphate reabsorption and calcitriol (i.e., 1,25(OH) 2 D 3 ) formation together with its co-receptor Klotho. FGF23- or Klotho-deficient mice suffer from rapid aging with multiple age-associated diseases, at least in part due to massive calcification. FGF23 is considered as a disease biomarker since elevated plasma levels are observed early in patients with acute and chronic disorders including renal, cardiovascular, inflammatory, and metabolic diseases. An energy-dense diet, which induces sequelae of the metabolic syndrome in humans and mice at least in part by enhancing pro-inflammatory TNFα formation, has recently been demonstrated to stimulate FGF23 production. Methods We investigated the relevance of TNFα for high-fat diet (HFD)-induced FGF23 formation in wild-type (tnf +/+ ) and TNFα-deficient (tnf −/− ) mice. Results Within 3 weeks, HFD feeding resulted in a strong increase in the serum FGF23 level in tnf +/+ mice. Moreover, it caused low-grade inflammation as evident from a surge in hepatic Tnfα transcript levels. TNFα stimulated Fgf23 transcription in UMR106 osteoblast-like cells. Serum FGF23 was significantly lower in tnf −/− mice compared to tnf +/+ mice following HFD. Serum phosphate and calcitriol were not significantly affected by genotype or diet. Conclusions We show that HFD feeding is a powerful stimulator of murine FGF23 production through TNFα formation.
PERSONALITY, VALUES, OR ATTITUDES? INDIVIDUAL-LEVEL ANTECEDENTS TO CREATIVE DEVIANCE
2018-05-25

Creative deviance, i.e., the violation of a managerial order to stop working on a new idea, is an emerging topic in innovation research. Whereas the outcomes of this nonconforming behaviour are inherently ambiguous, its importance for corporations’ innovative capability is undisputed. We complement prior research on the organisational-level determinants of creative deviance by studying its individual-level antecedents. We hypothesise that risk propensity as a personality trait is positively related, whereas allocentrism as a personal value orientation and organisational commitment as a personal attitude are negatively related to creative deviance. Risk propensity is considered the strongest predictor, as it affects creative deviance both directly and indirectly through allocentrism and commitment. Data from 457 employees in a German high-tech corporation support our hypotheses. Our findings contribute to research on innovation management and organisational behaviour while yielding managerial recommendations for leadership and recruitment.
The outweigh of toxicity versus risk of recurrence for adjuvant interferon therapy: a survey in German melanoma patients and their treating physicians
2018-05-25

Both physicians and patients rated melanoma recurrence much lower than even severe IFN side effects. In direct comparison, physicians rated cancer-related scenarios more positively and accepted IFN toxicity for an even lower treatment benefit.
Storage and weathering of landslide debris in the eastern San Gabriel Mountains, California, USA: Implications for mountain solute flux
2018-05-25

Abstract The weathering of silicate minerals in mountain landscapes provides a critical source of chemical solutes in the global biogeochemical cycles that sustain life on Earth. Observations from across Earth's surface indicate that the greatest flux of chemical solute is derived from rapidly eroding landscapes, where landsliding often limits the development of a continuous soil cover. In this study, we evaluate how weathering of landslide debris deposits may supplement the chemical solute flux from rapidly eroding, bedrock‐dominated landscapes. We present new measurements of depositional surface and soil morphology, soil geochemistry, and luminescence‐based depositional ages from debris stored in Cow Canyon, a tributary to the East Fork of the San Gabriel River in the eastern San Gabriel Mountains of California. Cow Canyon deposits include locally derived debris emplaced by dry colluvial and debris flow processes. Deposits have planar, low‐angle, sloping surfaces with soils exhibiting a greater degree of weathering than nearby soils formed on bedrock. A ~33–40 ka depositional age of Cow Canyon deposits exceeds the estimated recurrence time for the largest landslides in the San Gabriel Mountains, suggesting the stored landslide debris may be a persistent source of chemical solute in this landscape. To quantitatively explore the significance of landslide debris on the landscape solute flux, we predict the flux of chemical solute from bedrock and debris soils using a generic, time‐dependent model of soil mineral weathering. Our modeling illustrates that debris soils may be a primary source of chemical solute for a narrow range of conditions delimited by the initial landslide debris porosity and the comparative soil age. Broadly, we conclude that while landslide debris may be an important local reservoir of chemical solute, it is unlikely to dominate the long‐term solute flux from rapidly eroding, bedrock‐dominated landscapes. © 2018 John Wiley &amp; Sons, Ltd.
Synthesis of a Leiodermatolide Analogue with a Dienyl Side Chain
2018-05-25

We explored the possibility of attaching a side chain to a leiodermatolide fragment by forming the C18/C19 double bond via Julia/Kocienski olefination. This worked with a δ ‐lactone surrogate, the meta ‐anisole derivative 17 in reasonable yield to give the acyclic pentaene 32 . However, due to problems during cleavage of the silyl ether at the 15‐OH, the corresponding macrolactone could not be obtained. Instead, it was possible to convert enal 31 by Tebbe olefination to pentaene 37 . This compound could be converted to macrolactone 41 from where the side chain truncated leiodermatolide analogues 42 (9‐ O ‐carbamoyl) and 43 (7‐ O ‐carbamoyl) were obtained. Both isomers were moderately cytotoxic highlighting the importance of the side chain with the δ ‐lactone.
Early activation of CD95 is limited and localized to the cytotoxic synapse
2018-05-25

The cytotoxic synapse formed between cytotoxic T lymphocytes or natural killer cells expressing CD 95L and target cells with CD 95 on their surface is a key pathway for apoptosis induction by the immune system. Despite similarities with the immune synapse in antigen presenting cells, little is known about the role of the spatiotemporal organization of agonistic proteins/receptor interactions for CD 95 signaling. Here, we have developed an artificial cytotoxic synapse to examine how mobility and geometry of an anti‐ CD 95 agonistic antibody affect receptor aggregation and mobility, ie the first step of receptor activation. By measuring the distribution, diffusion coefficient, and fraction of immobile CD 95 receptor in living cells, we show that at short times, the initial activation of CD 95 occurs locally and is limited to the contact region of the cytotoxic synapse. This anisotropic activation of apoptotic signaling supports a role for confined interactions on the efficiency of signal transduction that may have implications for biomedical applications of extrinsic apoptosis induction.
ER stress and unfolded protein response in ocular health and disease
2018-05-26

The human eye is the organ that is able to react to light in order to provide sharp three‐dimensional and colored images. Unfortunately, the health of the eye can be impacted by various stimuli that can lead to vision loss, such as environmental changes, genetic mutations, or aging. Endoplasmic reticulum ( ER ) stress and unfolded protein response ( UPR ) signaling have been detected in many diverse ocular diseases, and chemical and genetic approaches to modulate ER stress and specific UPR regulatory molecules have shown beneficial effects in animal models of eye disease. This review highlights specific eye diseases associated with ER stress and UPR activity, based on a recent symposia exploring this theme.
Differential Resting-State Connectivity Patterns of the Right Anterior and Posterior Dorsolateral Prefrontal Cortices (DLPFC) in Schizophrenia
2018-05-28

In schizophrenia (SCZ), dysfunction of the dorsolateral prefrontal cortex (DLPFC) has been linked to the deficits in executive functions and attention. It has been suggested that, instead of considering the right DLPFC as a cohesive functional entity, it can be divided into two parts (anterior and posterior) based on its whole-brain connectivity patterns. Given these two subregions' differential association with cognitive processes, we investigated the functional connectivity (FC) profile of both subregions through resting-state data to determine whether they are differentially affected in SCZ. Resting-state magnetic resonance imaging (MRI) scans were obtained from 120 patients and 172 healthy controls (HC) at 6 different MRI sites. The results showed differential FC patterns for the anterior and posterior parts of the right executive control-related DLPFC in SCZ with the parietal, the temporal and the cerebellar regions, along with a convergent reduction of connectivity with the striatum and the occipital cortex. An increased psychopathology level was linked to a higher difference in posterior vs. anterior FC for the left IFG/anterior insula, regions involved in higher-order cognitive processes. In sum, the current analysis demonstrated that even between two neighboring clusters connectivity could be differentially disrupted in SCZ. Lacking the necessary anatomical specificity, such notions may in fact be detrimental to a proper understanding of SCZ pathophysiology.
A study on the reaction of 3-alkyl(aryl)imidazo[1,5-a]pyridines with ninhydrin
2018-05-28

Abstract The reaction of 3-alkyl(aryl)imidazo[1,5- a ]pyridines ( 1 ) with ninhydrin in dichloromethane at room temperature delivered good yields of the respective 2-hydroxy-2-(imidazo[1,5- a ]pyridine-1-yl)indene-1,3-diones. In the presence of dimethyl acetylenedicarboxylate (DMAD), this uncatalyzed electrophilic substitution reaction, involving C-1 (in 1 ) and the central C=O (in ninhydrin), takes precedence over the three-component 1,4-dipolar cycloaddition reaction. This selectivity is probably due to the higher electrophilicity of the carbonyl carbon-2 in ninhydrin as compared to that of the sp -carbon atoms in DMAD, augmented with the high nucleophilicity of carbon-1 in 1 .
Terminology of bioanalytical methods (IUPAC Recommendations 2018)
2018-05-29

Abstract Recommendations are given concerning the terminology of methods of bioanalytical chemistry. With respect to dynamic development particularly in the analysis and investigation of biomacromolecules, terms related to bioanalytical samples, enzymatic methods, immunoanalytical methods, methods used in genomics and nucleic acid analysis, proteomics, metabolomics, glycomics, lipidomics, and biomolecules interaction studies are introduced.
Functional diversification of Arabidopsis SEC1-related SM proteins in cytokinetic and secretory membrane fusion
2018-05-29

Significance Membrane fusion is a fundamental process of eukaryotic cells required for subcellular organization and cell–cell communication, involving SNARE proteins and regulatory Sec1/Munc18 (SM) proteins. In plant cytokinesis, membrane vesicles delivered to the cell-division plane fuse with one another to form the partitioning membrane, which requires cytokinesis-specific Qa-SNARE KNOLLE and interacting SM protein KEULE in Arabidopsis . KEULE has a paralog named SEC1B, which originated through gene duplication and subsequent functional diversification during angiosperm evolution. Biochemical interaction studies and analysis of relevant double mutants reveal that a predominant interaction of SEC1B with Qa-SNARE SYP132 entailed its preferential role in secretion, whereas KEULE acquired a unique role in cytokinesis through its interaction with cytokinesis-specific Qa-SNARE KNOLLE.
Along‐Axis Variations of Rift Width in a Coupled Lithosphere‐Mantle System, Application to East Africa
2018-05-29

Abstract Narrow and wide rifts are end‐member expressions of continental extension. Within the framework of passive rifting, the transition from wide to narrow rifts requires lowering the geothermal gradient. Reconciling this view with observational evidence for narrow rift zones in regions underlain by sublithospheric hot plume material, such as the eastern branch of the East African Rift, requires invoking preexisting weak zones for strain to localize in a warm crust. Based on thermomechanical numerical models, we show that along‐rift width variations can develop spontaneously as a consequence of spatial variations of the geotherm over an evolving mantle plume impinging a lithosphere subjected to ultraslow extension. The eastern branch of the East African Rift, with a narrow Kenya segment underlain by a mantle plume head and widening to the north and south in the colder regions of the Turkana depression and North Tanzania divergence, is in agreement with this numerical prediction.
Activated integrins identify functional antigen-specific CD8+T cells within minutes after antigen stimulation
2018-05-29

Significance Assessing antigen-specific T cells is crucial for our understanding of immune reactions against pathogens and tumors, and for evaluating immunotherapies in patients. Existing techniques to evaluate the functionality of T lymphocytes all rely on de novo expression of proteins, typically intracellular cytokines, and therefore require elaborated protocols and reagents. We have established a simple flow cytometry-based method to assess the functionality of CD8 + T cells by identifying immediate changes in the conformation and valency of cell surface integrins that occur within minutes following antigenic stimulation. Because of its robustness, sensitivity, and broad applicability, the assay can be rapidly implemented for the measurement and isolation of functional T cells for basic research and in the clinical setting.
Palmitate and insulin counteract glucose-induced thioredoxin interacting protein (TXNIP) expression in insulin secreting cells via distinct mechanisms
2018-05-29

Glucose and palmitate synergistically stimulate insulin secretion, but chronically elevated they induce apoptotic β-cell death. The glucotoxic effect has been attributed, at least partly, to the upregulation of the oxidative stress marker thioredoxin interacting protein (TXNIP). Palmitate downregulates TXNIP expression, the functional significance of which is still under debate. This study examines the mechanism and consequence of palmitate-mediated TXNIP regulation in insulin secreting cells. Palmitate (600 μM) reduced TXNIP mRNA levels in isolated human and mouse islets independently of FFAR1/GPR40. Similar effects of palmitate were observed in INS-1E cells and mimicked by other long chain fatty acids. The lowering of TXNIP mRNA was significant already 1 h after addition of palmitate, persisted for 24 h and was directly translated to changes in TXNIP protein. The pharmacological inhibition of palmitate-induced phosphorylation of AMPK, ERK1/2, JNK and PKCα/β by BML-275, PD98059, SP600125 and Gö6976, respectively, did not abolish palmitate-mediated TXNIP downregulation. The effect of palmitate was superimposed by a time-dependent (8 h and 24 h) decline of TXNIP mRNA and protein. This decline correlated with accumulation of secreted insulin into the medium. Accordingly, exogenously added insulin reduced TXNIP mRNA and protein levels, an effect counteracted by the insulin/IGF-1 receptor antagonist linsitinib. The inhibition of PI3K and Akt/PKB increased TXNIP mRNA levels. The histone deacetylase (HDAC1/2/3) inhibitor MS-275 completely abrogated the time-dependent, insulin-mediated reduction of TXNIP, leaving the effect of palmitate unaltered. Acute stimulation of insulin secretion and chronic accentuation of cell death by palmitate occurred independently of TXNIP regulation. On the contrary, palmitate antagonized glucose-augmented ROS production. In conclusion, glucose-induced TXNIP expression is efficiently antagonized by two independent mechanisms, namely via an autocrine activation of insulin/IGF-1 receptors involving HDAC and by palmitate attenuating oxidative stress of β-cells.
Complete Hydrogen Transfer: Tin Hydride Reactivity toward Adamantylisonitrile and Benzonitrile
2018-05-29

Adamantylisonitrile and benzonitrile were reacted with bulky substituted organotin trihydride [Ar*SnH3] [Ar* = (C6H3-2,6-Trip2), Trip = 2,4,6-triisopropylphenyl]. They do not show any reaction at room temperature as well as at 80 °C. After activation of the organotin trihydride with diethylmethylamine in the isonitrile case three hydrogen atoms were transferred from the tin atom to the isonitrile unit and a carbon tin bond was formed to give an intramolecular adduct between a diorganostannylene and a dialkylamine. Benzonitrile as well as adamantylisonitrile react both with low-valent organotin hydride [Ar*SnH]2. Benzonitrile shows an insertion reaction with the low-valent organotin hydride to yield a dimeric insertion product, whereas the isonitrile carbon atom of adamantylisonitrile abstracts three hydrogen atoms from the low-valent organotin hydride to give an equimolar mixture between (adamantylmethylamido)organostannylene and a bis(isonitrile)distannyne adduct.
Putin's Peaks: Russian Election Data Revisited
2018-05-29

Abstract Two years ago, Dmitry Kobak, Sergey Shpilkin and Maxim S. Pshenichnikov uncovered anomalies in Russia's election data. Following President Vladimir Putin's re-election in March this year, they take a fresh look at two new sets of data – but find much the same story within
Electron and fluorescence spectra of a water molecule irradiated by an x-ray free-electron laser pulse
2018-05-29

With the highly intense x-ray light generated by x-ray free-electron lasers (XFELs), molecular samples can be ionized many times in a single pulse. Here we report on a computational study of molecular spectroscopy at the high x-ray intensity provided by XFELs. Calculated photoelectron, Auger electron, and x-ray fluorescence spectra are presented for a single water molecule that reaches many electronic hole configurations through repeated ionization steps. The rich details shown in the spectra depend on the x-ray pulse parameters in a nonintuitive way. We discuss how the observed trends can be explained by the competition of microscopic electronic transition processes. A detailed comparison between spectra calculated within the independent-atom model and within the molecular-orbital framework highlights the chemical sensitivity of the spectral lines of multiple-hole configurations. Our results demonstrate how x-ray multiphoton ionization-related effects such as charge-rearrangement-enhanced x-ray ionization of molecules and frustrated absorption manifest themselves in the electron and fluorescence spectra.
Reduced Performance During a Sentence Repetition Task by Continuous Theta-Burst Magnetic Stimulation of the Pre-supplementary Motor Area
2018-05-29

The pre-supplementary motor area (pre-SMA) is engaged in speech comprehension under difficult circumstances such as poor acoustic signal quality or time-critical conditions. Previous studies found that left pre-SMA is activated when subjects listen to accelerated speech. Here, the functional role of pre-SMA was tested for accelerated speech comprehension by inducing a transient "virtual lesion" using continuous theta-burst stimulation (cTBS). Participants were tested (1) prior to (pre-baseline), (2) 10 min after (test condition for the cTBS effect), and (3) 60 min after stimulation (post-baseline) using a sentence repetition task (formant-synthesized at rates of 8, 10, 12, 14, and 16 syllables/s). Speech comprehension was quantified by the percentage of correctly reproduced speech material. For high speech rates, subjects showed decreased performance after cTBS of pre-SMA. Regarding the error pattern, the number of incorrect words without any semantic or phonological similarity to the target context increased, while related words decreased. Thus, the transient impairment of pre-SMA seems to affect its inhibitory function that normally eliminates erroneous speech material prior to speaking or, in case of perception, prior to encoding into a semantically/pragmatically meaningful message.