julilili42/papers huggingface dataset:
Lack of an Association between the Functional Polymorphism TREM-1 rs2234237 and the Clinical Course of Sepsis among Critically Ill Caucasian Patients—A Monocentric Prospective Genetic Association Study
2019-03-03

Sepsis is a life-threatening condition and a significant challenge for those working in intensive care, where it remains one of the leading causes of mortality. According to the sepsis-3 definition, sepsis is characterized by dysregulation of the host response to infection. The TREM-1 gene codes for the triggering receptor expressed on myeloid cells 1, which is part of the pro-inflammatory response of the immune system. This study aimed to determine whether the functional TREM-1 rs2234237 single nucleotide polymorphism was associated with mortality in a cohort of 649 Caucasian patients with sepsis. The 90-day mortality rate was the primary outcome, and disease severity and microbiological findings were analyzed as secondary endpoints. TREM-1 rs2234237 TT homozygous patients were compared to A-allele carriers for this purpose. Kaplan–Meier survival analysis revealed no association between the clinically relevant TREM-1 rs2234237 single nucleotide polymorphism and the 90-day or 28-day survival rate in this group of septic patients. In addition, the performed analyses of disease severity and the microbiological findings did not show significant differences between the TREM-1 rs2234237 genotypes. The TREM-1 rs2234237 genotype was not significantly associated with sepsis mortality and sepsis disease severity. Therefore, it was not a valuable prognostic marker for the survival of septic patients in the studied cohort.
Prominent T-Cell Responses against the Acetylcholine Receptor ε Subunit in Myasthenia Gravis
2019-03-03

The human acetylcholine receptor (AChR) is well characterized as the target antigen in myasthenia gravis (MG). Pathogenic antibody responses against the AChR alpha-chain have been investigated extensively and are of diagnostic and prognostic value. However, less is known on the pathogenetic relevance of T-cell responses against epitopes of the different AChR chains (alpha, epsilon, gamma). Using an enzyme-linked immunospot (ELISPOT) assay we measured T-cell responses against recombinant fragments and synthetic peptides of the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mrow><mml:mi>α</mml:mi></mml:mrow></mml:math> and the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mrow><mml:mi>ε</mml:mi></mml:mrow></mml:math> subunits of the human AChR in MG patients (n=15) and in healthy donors (HD; n=9). In MG, highest T-cell responses were noted against recombinantly expressed Epsilon 1-221. Among the synthetic peptides Epsilon 201-215 showed the most prominent T-cell response and represented the peptide with the most remarkable difference between MG and HD. Taken together, prominent T-cell responses against the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mrow><mml:mi>ε</mml:mi></mml:mrow></mml:math> subunit of the human AChR indicate an important role in the pathogenesis of MG.
Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease
2019-03-04

Abstract Introduction Four less well‐studied but promising “emerging” cerebrospinal fluid (CSF) biomarkers are elevated in late‐onset Alzheimer disease (AD): neurogranin, synaptosomal‐associated protein‐25 (SNAP‐25), visinin‐like protein 1 (VILIP‐1), and chitinase‐3‐like protein 1 (YKL‐40). Methods CSF neurogranin, SNAP‐25, VILIP‐1, and YKL‐40 were measured in families carrying autosomal‐dominant AD mutations. Results The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP‐25, VILIP‐1, and YKL‐40 were altered very early in the AD time course, approximately 15–19 years before estimated symptom onset. All CSF biomarkers predicted important AD‐related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. Discussion Early abnormalities in CSF tTau, pTau, SNAP‐25, VILIP‐1, and YKL‐40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.
Constitutive signaling activity of a receptor-associated protein links fertilization with embryonic patterning in Arabidopsis thaliana
2019-03-04

Significance In flowering plants, membrane-associated kinases of the BRASSINOSTEROID SIGNALING KINASE (BSK) family are ubiquitous, receptor-associated signaling partners in various receptor kinase pathways, where they function in signaling relay. The Brassicaceae-specific BSK family member SHORT SUSPENSOR (SSP), however, acts as a patterning cue in the zygote, initiating the apical-basal patterning process in a signal-like manner. The SSP protein has lost a regulatory, intramolecular interaction and activates the MAPKKK YODA signaling pathway constitutively, in principle, enabling the protein to initiate embryonic patterning without receptor activation. We further show that the BSK family members BSK1 and BSK2, both conserved in flowering plants, activate the same signaling pathway in parallel to SSP and might constitute remnants of an older, canonical signaling pathway still active in Arabidopsis .
Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes
2019-03-04

Low 25-hydroxyvitamin D levels correlate with the prevalence of diabetes; however, the mechanisms remain uncertain. Here, we show that nutritional deprivation–responsive mechanisms regulate vitamin D metabolism. Both fasting and diabetes suppressed hepatic cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase responsible for the first bioactivation step. Overexpression of coactivator peroxisome proliferator–activated receptor γ coactivator 1-α (PGC-1α), induced physiologically by fasting and pathologically in diabetes, resulted in dramatic downregulation of CYP2R1 in mouse hepatocytes in an estrogen-related receptor α (ERRα)–dependent manner. However, PGC-1α knockout did not prevent fasting-induced suppression of CYP2R1 in the liver, indicating that additional factors contribute to the CYP2R1 repression. Furthermore, glucocorticoid receptor (GR) activation repressed the liver CYP2R1, suggesting GR involvement in the regulation of CYP2R1. GR antagonist mifepristone partially prevented CYP2R1 repression during fasting, suggesting that glucocorticoids and GR contribute to the CYP2R1 repression during fasting. Moreover, fasting upregulated the vitamin D catabolizing CYP24A1 in the kidney through the PGC-1α-ERRα pathway. Our study uncovers a molecular mechanism for vitamin D deficiency in diabetes and reveals a novel negative feedback mechanism that controls crosstalk between energy homeostasis and the vitamin D pathway.
A new nothosaur (Sauropterygia) from the Ladinian of Vellberg-Eschenau, southern Germany
2019-03-04

A new species of Nothosaurus from the Lower Keuper (Lettenkeuper, Ladinian, Erfurt Formation) of Vellberg-Eschenau, southern Germany, is described on the basis of a nearly complete skull that is only missing the lower jaw. Together with Nothosaurus edingerae, it is the only valid Nothosaurus species exclusively known from the Lower Keuper (Ladinian) of the Germanic Basin. Nothosaurus cristatus, sp. nov., differs from all other nothosaurs by exhibiting a postorbital that is excluded from the orbital margin by the postfrontal, the maxilla, and the jugal. The postfrontal and the maxilla form the posterior orbital margin exclusively. The parietal forms a pronounced and sharp crest anterior to the parietal foramen, which is unique among Nothosaurus. The ectopterygoid bears a long posterior process. A phylogenetic analysis of Nothosaurus cristatus, based on Liu et al. (2014, Scientific Reports 4:7142, doi: 10.1038/srep07142) with modified characters after Lin et al. (2017, Journal of Vertebrate Paleontology, doi: 10.1080/02724634.2017.1278703), yielded a nearly unchanged topology that supported the monophyly of (N. jagisteus (N. cristatus (N. mirabilis + N. tchernovi))).
Raman imaging of α-synuclein aggregates in a rat model of Parkinson’s disease
2019-03-04

Aggregates of misfolded α-Synuclein in the brain represent a hallmark of Parkinson's disease (PD). In patients and animal models, phosphorylated α-Synuclein was detected in the gut, hence, raising the hypothesis that early-stage PD could be diagnosed based on colon tissues. Marker-independent technologies represent an ideal method to monitor disease progression and potentially detect early-stage aggregated α-Synuclein in vivo. Here, formalin-fixed, paraffinembedded colon tissues of a transgenic rat model were analyzed using Raman imaging. Detailed spectral and imagebased analysis was performed indicating the major spectral shifts that alter in PD rat tissues in the amide I region. Peak fitting and multivariate analysis specified an increase of β-sheet proteins in transgenic rat colon compared with wild-type colon. In summary, Raman imaging is capable to detect α-Synuclein aggregates in colon tissues of a PD rat model, indicating that it could be a useful tool to support diagnosis in PD pathology.
Chemical-Modified mRNA Therapy for Cystic Fibrosis by Targeting Lung Cells
2019-03-04

Gene deficiency diseases where there is lack of functional protein, have found a potential cure in the form of mRNA therapy (1) but major challenges for achieving higher bioavailability concerning ...
Diagnostic value of digital clock drawing test in comparison with CERAD neuropsychological battery total score for discrimination of patients in the early course of Alzheimer’s disease from healthy individuals
2019-03-05

Abstract The early detection of cognitive impairment or dementia is in the focus of current research as the amount of cognitively impaired individuals will rise intensely in the next decades due to aging population worldwide. Currently available diagnostic tools to detect mild cognitive impairment (MCI) or dementia are time-consuming, invasive or expensive and not suitable for wide application as required by the high number of people at risk. Thus, a fast, simple and sensitive test is urgently needed to enable an accurate detection of people with cognitive dysfunction and dementia in the earlier stages to initiate specific diagnostic and therapeutic interventions. We examined digital Clock Drawing Test (dCDT) kinematics for their clinical utility in differentiating patients with amnestic MCI (aMCI) or mild Alzheimer’s dementia (mAD) from healthy controls (HCs) and compared it with the diagnostic value of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery total score. Data of 381 participants (138 patients with aMCI, 106 patients with mAD and 137 HCs) was analyzed in the present study. All participants performed the clock drawing test (CDT) on a tablet computer and underwent the CERAD test battery and depression screening. CERAD total scores were calculated by subtest summation, excluding MMSE scores. All tablet variables (i.e. time in air, time on surface, total time, velocity, pressure, pressure/velocity relation, strokes per minute, time not painting, pen-up stroke length, pen-up/pen-down relation, and CDT score) during dCDT performance were entered in a forward stepwise logistic regression model to assess, which parameters best discriminated between aMCI or mAD and HC. Receiver operating characteristics (ROC) curves were constructed to visualize the specificity in relation to the sensitivity of dCDT variables against CERAD total scores in categorizing the diagnostic groups. dCDT variables provided a slightly better diagnostic accuracy of 81.5% for discrimination of aMCI from HCs than using CERAD total score (accuracy 77.5%). In aMCI patients with normal CDT scores, both dCDT (accuracy 78.0%) and CERAD total scores (accuracy 76.0%) were equally accurate in discriminating against HCs. Finally, in differentiating patients with mAD from healthy individuals, accuracy of both dCDT (93.0%) and CERAD total scores (92.3%) was excellent. Our findings suggest that dCDT is a suitable screening tool to identify early cognitive dysfunction. Its performance is comparable with the time-consuming established psychometric measure (CERAD test battery).
Understanding the Optical and Magnetic Properties of Ytterbium(III) Complexes
2019-03-05

The absorption and emission spectra of three Yb<sup>3+</sup> complexes possessing D<sub>3</sub>, D<sub>2</sub>, and C<sub>2</sub> symmetries were analyzed with the aid of ab initio calculations based on Complete Active Space (CAS) self-consistent field wave functions (CAS(13,7)). The absorption spectra present contributions from both cold and hot bands, involving thermally populated excited sublevels of the <sup>2</sup>F<sub>7/2</sub> manifold. The high-resolution emission spectrum of the tris-picolinate complex [Yb(DPA)<sub>3</sub>]<sup>3-</sup> recorded at 77 K presents four components, while the complexes with macrocyclic ligands show both cold and hot emission bands, resulting in more than four components for the <sup>2</sup>F<sub>5/2</sub> → <sup>2</sup>F<sub>7/2</sub> transition. The combined information provided by the absorption and emission spectra allowed to identify most of the crystal field sublevels of the <sup>2</sup>F<sub>5/2</sub> and <sup>2</sup>F<sub>7/2</sub> states. The energies of these crystal field components are well-reproduced by the ab initio calculations, with deviations typically lower than 100 cm<sup>-1</sup>. The crystal field splitting is very sensitive to subtle changes of the Yb<sup>3+</sup> coordination environment. The magnetic anisotropy of [Yb(DPA)<sub>3</sub>]<sup>3-</sup> obtained with ab initio calculations was found to be extremely sensitive to changes in the twist angle of the upper and lower faces of the tricapped trigonal prismatic coordination polyhedron. Ab initio ligand field theory provides a straightforward chemical justification for the changes in magnetic anisotropy, which are responsible for the observed pseudocontact shifts in the NMR spectra.
Dynamic homeostasis modeling of Zn isotope ratios in the human body
2019-03-05

Abstract Recent research performed on volunteers and patients suggested that diet, health, and basal metabolic rates (BMR) are factors controlling the bodily Zn isotope compositions (isotopic homeostasis). However, our poor understanding of the variability of Zn distribution among the different organs and fluids of the human body, and the ensuing isotope fractionation, limits the use of this isotopic system as a typical diagnostic tool for cancers and for past hominin diet reconstructions. Using box model calculations, we investigated the dynamics of Zn isotope variability in blood and other body tissues as well as the consistency of the hypothesis of heavy Zn isotope accumulation through time in the human body. We compare the results of the model with data obtained from control feeding experiments and from archeological samples. Model simulations indicate that the absence of an aging drift in non-circumpolar populations cannot be explained by their lower BMR. We argue that the drift observed in the blood of a circumpolar population results from a differential diet between young and older individuals in this population. When applied to the δ66Zn measured in blood, bones, or teeth, the present box model also offers insight into the isotope composition of the human diet, and therefore into its nature. Applying the model to isotopic observations on the remains of past hominins is a promising tool for diet reconstruction.
Dual Antiplatelet or Dual Antithrombotic Therapy for Secondary Prevention in High-Risk Patients with Stable Coronary Artery Disease?
2019-03-05

Abstract Antithrombotic treatment is a key component of secondary prevention following acute coronary syndromes (ACS). Although dual antiplatelet therapy is standard therapy post-ACS, duration of treatment is the subject of ongoing debate. Prolonged dual antiplatelet therapy in high-risk patients with history of myocardial infarction reduced the risk of recurrent myocardial infarction, stroke or cardiovascular death. Similarly, in patients with stable coronary artery disease, two-thirds of whom had a history of myocardial infarction, dual antithrombotic therapy with very-low-dose rivaroxaban and aspirin also resulted in improved ischaemic outcomes. In the absence of head-to-head comparison, choosing the most appropriate treatment strategy can be challenging, particularly when it comes to balancing the risks of ischaemia and bleeding. We aim to review the evidence for currently available antithrombotic treatments and provide a practical algorithm to aid the decision-making process.
A retinal model of cerebral malaria
2019-03-05

Abstract Malaria is a causative factor in about 500.000 deaths each year world-wide. Cerebral malaria is a particularly severe complication of this disease and thus associated with an exceedingly high mortality. Malaria retinopathy is an ocular manifestation often associated with cerebral malaria, and presumably shares a substantial part of its pathophysiology. Here, we describe that indeed murine malaria retinopathy reproduced the main hallmarks of the corresponding human disease. In the living animal, we were able to follow the circulation and cellular localization of malaria parasites transgenically labelled with GFP via non-invasive in vivo retinal imaging. We found that malaria parasites cross the blood-retinal-barrier and infiltrate the neuroretina, concomitant with an extensive, irreversible, and long-lasting retinal neurodegeneration. Furthermore, anti-malarial treatment with dihydroartemisinin strongly diminished the load of circulating parasites but resolved the symptoms of the retinopathy only in part. In summary, we introduce here a novel preclinical model for human cerebral malaria that is much more directly accessible for studies into disease pathophysiology and development of novel treatment approaches. In vivo retinal imaging may furthermore serve as a valuable tool for the early diagnosis of the human disease.
Calcium Tetraalkylaluminate and Tetramethylgallate Complexes Supported by the Bulky Scorpionate Ligand TptBu,Me
2019-03-05

A series of heteroleptic calcium complexes supported by the superbulky scorpionate ligand tris(3-tBu-5-Me-pyrazolyl)borato (TptBu,Me) was synthesized and characterized comprehensively. Tetramethylaluminate complex (TptBu,Me)Ca(AlMe4) was obtained from either [Ca(AlMe4)2]n and KTptBu,Me according to a salt metathesis protocol or via amide elimination from (TptBu,Me)Ca[N(SiMe3)2] with AlMe3. Using the amide-elimination approach and AlEt3 gave the corresponding tetraethylaluminate complex (TptBu,Me)Ca(AlEt4). Treatment of (TptBu,Me)Ca(AlMe4) with the Lewis bases thf and 4-(dimethylamino)pyridine (dmap) afforded the donor-coordinated species (TptBu,Me)Ca(AlMe4)(thf)2 and (TptBu,Me)Ca(AlMe4)(dmap), respectively. While in the absence of donor molecules the tetramethylaluminato ligand is coordinated in a η2 fashion, the thf and dmap adducts exhibit a η1-coordinated AlMe4 ligand in the solid state. Our investigations did not point at the occurrence of any donor-induced cleavage of the Ca–AlMe4 unit toward putative [Ca]–Me species. This was also true for the corresponding tetramethylgallate complex (TptBu,Me)Ca(GaMe4), which was accessed via a donor-assisted aluminate/gallate exchange or amide elimination.
Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy
2019-03-05

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Faculty Opinions recommendation of Impaired immune surveillance accelerates accumulation of senescent cells and aging.
2019-03-05

Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues.However, senescent cells accumulate in tissues in advanced age, where they might promote tissue degeneration and malignant transformation.The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown.Here we show that Prf1 -/-mice with impaired cell cytotoxicity exhibit both higher senescent-cell tissue burden and chronic inflammation.They suffer from multiple age-related disorders and lower survival.Strikingly, pharmacological elimination of senescent-cells by ABT-737 partially alleviates accelerated aging phenotype in these mice.In LMNA +/G609G progeroid mice, impaired cell cytotoxicity further promotes senescent-cell accumulation and shortens lifespan.ABT-737 administration during the second half of life of these progeroid mice abrogates senescence signature and increases median survival.Our findings shed new light on mechanisms governing senescentcell presence in aging, and could motivate new strategies for regenerative medicine.
IR spectroscopy: Suitable method for determination of curing degree and crosslinking type in melamine–formaldehyde resins
2019-03-06

ABSTRACT Melamine–formaldehyde (MF) resins are widely used as adhesives and finishing materials in the wood industry. During resin cure, either methylene ether or methylene bridges are formed, leading to the formation of a three‐dimensional resin network. Not only the curing degree, but also the chemical species present in the cured resin determine the quality of the final product. Analytical methods allowing a detailed investigation of network formation are of great benefit to manufacturers. In the present work, resin cure of an MF precondensate is studied at different temperatures (100–200 °C) without considering the initial pH as a factor. Isoconversional kinetic analysis based on exothermal curing enthalpies enables calculation of the crosslinking degree at a given time/temperature regime. A semiquantitative determination of the chemical groups present is performed based on solid‐state nuclear magnetic resonance data. Fourier transform infrared spectroscopy has shown to be a fast and reliable analytical tool with high sensitivity toward functional groups and with great potential for at‐line process control. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136 , 47691.