julilili42/papers huggingface dataset:
Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
2014-07-02

GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
Neural Correlates of Finger Gnosis
2014-07-02

Neuropsychological studies have described patients with a selective impairment of finger identification in association with posterior parietal lesions. However, evidence of the role of these areas in finger gnosis from studies of the healthy human brain is still scarce. Here we used functional magnetic resonance imaging to identify the brain network engaged in a novel finger gnosis task, the intermanual in-between task (IIBT), in healthy participants. Several brain regions exhibited a stronger blood oxygenation level-dependent (BOLD) response in IIBT than in a control task that did not explicitly rely on finger gnosis but used identical stimuli and motor responses as the IIBT. The IIBT involved stronger signal in the left inferior parietal lobule (IPL), bilateral precuneus (PCN), bilateral premotor cortex, and left inferior frontal gyrus. In all regions, stimulation of nonhomologous fingers of the two hands elicited higher BOLD signal than stimulation of homologous fingers. Only in the left anteromedial IPL (a-mIPL) and left PCN did signal strength decrease parametrically from nonhomology, through partial homology, to total homology with stimulation delivered synchronously to the two hands. With asynchronous stimulation, the signal was stronger in the left a-mIPL than in any other region, possibly indicating retention of task-relevant information. We suggest that the left PCN may contribute a supporting visuospatial representation via its functional connection to the right PCN. The a-mIPL may instead provide the core substrate of an explicit bilateral body structure representation for the fingers that when disrupted can produce the typical symptoms of finger agnosia.
Whole genome sequencing (WGS), whole exome sequencing (WES) and clinical exome sequencing (CES) in patient care
2014-07-02

Abstract Next generation sequencing (NGS, also called Massively Parallel Sequencing) can be performed using a number of different platforms. The general process is very similar across them all: (1) extracted DNA is sheared into fragments (which, in targeted methods can be captured using probes); (2) these fragments are isolated physically on slides (usually called flow cells) or in emulsions and individually amplified, resulting in a library; and (3) the multiple individually amplified fragments are then simultaneously sequenced. After sequencing each fragment individually, the fragments must be re-assembled and the positions called using a series of bioinformatics algorithms. Excellent reviews are available that discuss the technical differences in detail. Recently, the value of NGS for diagnostics in patient care has been widely recognized and its applications include mutation detection in human genetics, molecular pathology and infectious agents as well as HLA typing, RNA sequencing and the detection of cell-free DNA. This paper focuses on applications of three different scales of NGS in human genetics diagnostics and evaluates its status based on our current understanding.
Photons in Fock Space and Beyond
2014-07-02

Volume I: From Classical to Quantized Radiation Systems: Solution Theory of Maxwell Equations in General Cavities Cohomological Fields Canonical Electrodynamics C*-Algebraic Statistical Electrodynamics Scattering Theory for Classical Fields Canonical (Field) Quantization and Weyl Algebras Quantized Maxwell Dynamics with Classical Sources Photon Wave Functions and Fock Space Finite Particles with Quantized Fields Deformation Quantization and Operator Ordering Infinite Heisenberg Group Optical and Coherent States in and Beyond Fock Space Volume II: Quantized Mesoscopic Radiation Models: Algebraic and Unitary Squeezing Diagonalization of Field Hamiltonians General Analysis of Squeezed States Algebraic Black Body Radiation and Ergodic Theory Mathematical Bloch Theory Fermion Field Algebra Particle-Hole Fields Classical Extended Fermion Algebra Mean Field Supporting States and Long Range Order Weakly Inhomogeneous Cluster Interactions Semiconductor-Photon Interactions Weakly Inhomogeneous BCS Models and Josephson Junctions Topological Effects for Junction Circuits General Mesoscopic Radiation Models Maxwell Dynamics as Collective Structure Mesoscopic Dicke Models Radiating Semiconductors Josephson Oscillators Microscopic and Macroscopic Quantum Structures Volume III: Mathematics for Photon Fields Hilbert Space Operators Sesquilinear Forms and Selfadjointness Vector Analysis in Sobolev Spaces with Boundary Conditions Non-Smooth Helmholtz-Hodge Decomposition Theory *-Algebras C*-Algebras von Neumann Algebras Modular Theory and Thermal Fields Convex State Space Approach Characterization of Quantum Theories Orthogonal State Decompositions Algebraic Ergodic Theory Algebraic Transition Probabilities Infinite Tensor Products Locally Convex Spaces Measures on Dual Spaces Field Dynamics and Perturbation Theory Manifolds and Fiber Bundles Gauge Bundles for (Q)ED
Prognostic Value and Link to Atrial Fibrillation of Soluble Klotho and FGF23 in Hemodialysis Patients
2014-07-03

Deranged calcium-phosphate metabolism contributes to the burden of morbidity and mortality in dialysis patients. This study aimed to assess the association of the phosphaturic hormone fibroblast growth factor 23 (FGF23) and soluble Klotho with all-cause mortality. We measured soluble Klotho and FGF23 levels at enrolment and two weeks later in 239 prevalent hemodialysis patients. The primary hypothesis was that low Klotho and high FGF23 are associated with increased mortality. The association between Klotho and atrial fibrillation (AF) at baseline was explored as secondary outcome. AF was defined as presence of paroxysmal, persistent or permanent AF. During a median follow-up of 924 days, 59 (25%) patients died from any cause. Lower Klotho levels were not associated with mortality in a multivariable adjusted analysis when examined either on a continuous scale (HR 1.25 per SD increase, 95% CI 0.84-1.86) or in tertiles, with tertile 1 as the reference category (HR for tertile two 0.65, 95% CI 0.26-1.64; HR for tertile three 2.18, 95% CI 0.91-2.23). Higher Klotho levels were associated with the absence of AF in a muItivariable logistic regression analysis (OR 0.66 per SD increase, 95% CI 0.41-1.00). Higher FGF23 levels were associated with mortality risk in a multivariable adjusted analysis when examined either on a continuous scale (HR 1.45 per SD increase, 95% CI 1.05-1.99) or in tertiles, with the tertile 1 as the reference category (HR for tertile two 1.63, 95% CI 0.64-4.14; HR for tertile three 3.91, 95% CI 1.28-12.20). FGF23 but not Klotho levels are associated with mortality in hemodialysis patients. Klotho may be protective against AF.
Quantifying patient adherence during active orthodontic treatment with removable appliances using microelectronic wear-time documentation
2014-07-03

The daily wear time of removable appliances during the active phase of orthodontic therapy can be routinely quantified using integrated microelectronic sensors. The relationship between orthodontist and patient seems to play a key role in patient adherence. Wear-time documentation provides the basis for more individualized wear-time recommendations for patients with removable appliances. This could result in a more efficient, shorter, and less painful orthodontic therapy.
Diet‐induced obesity accelerates the onset of terminal phenotypes in α‐synuclein transgenic mice
2014-07-03

Abstract Parkinson's disease ( PD ) and diabetes belong to the most common neurodegenerative and metabolic syndromes, respectively. Epidemiological links between these two frequent disorders are controversial. The neuropathological hallmarks of PD are protein aggregates composed of amyloid‐like fibrillar and serine‐129 phosphorylated (pS129) α‐synuclein ( AS ). To study if diet‐induced obesity could be an environmental risk factor for PD ‐related α‐synucleinopathy, transgenic ( TG ) mice, expressing the human mutant A30P AS in brain neurons, were subjected after weaning to a lifelong high fat diet ( HFD ). The TG mice became obese and glucose‐intolerant, as did the wild‐type controls. Upon aging, HFD significantly accelerated the onset of the lethal locomotor phenotype. Coinciding with the premature movement phenotype and death, HFD accelerated the age of onset of brainstem α‐synucleinopathy as detected by immunostaining with antibodies against pathology‐associated pS129. Amyloid‐like neuropathology was confirmed by thioflavin S staining. Accelerated onset of neurodegeneration was indicated by Gallyas silver‐positive neuronal dystrophy as well as astrogliosis. Phosphorylation of the activation sites of the pro‐survival signaling intermediate Akt was reduced in younger TG mice after HFD . Thus, diet‐induced obesity may be an environmental risk factor for the development of α‐synucleinopathies. The molecular and cellular mechanisms remain to be further elucidated. image Life‐long high fat diet (HFD) induces obesity and glucose intolerance in a transgenic mouse model for α‐synucleinopathy and thereby leads to decreased life span as well as accelerated age of onset of the terminal phenotype. This is accompanied by increased neuroinflammation and premature α‐synuclein pathology in the brainstems of the HFD‐fed mice.
Analysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy
2014-07-03

Summary Rolandic epilepsy (RE) and its atypical variants (atypical rolandic epilepsy, ARE) along the spectrum of epilepsy–aphasia disorders are characterized by a strong but largely unknown genetic basis. Two genes with a putative ( ELP4 ) or a proven ( SRPX2 ) function in neuronal migration were postulated to confer susceptibility to parts of the disease spectrum: the ELP4 gene to centrotemporal spikes and SRPX2 to ARE. To reexamine these findings, we investigated a cohort of 280 patients of European ancestry with RE/ARE for the etiological contribution of these genes and their close interaction partners. We performed next‐generation sequencing and single‐nucleotide polymorphism (SNP)–array based genotyping to screen for sequence and structural variants. In comparison to European controls we could not detect an enrichment of rare deleterious variants of ELP4 , SRPX2 , or their interaction partners in affected individuals. The previously described functional p.N327S variant in the X chromosomal SRPX2 gene was detected in two affected individuals (0.81%) and also in controls (0.26%), with some preponderance of male patients. We did not detect an association of SNPs in the ELP4 gene with centrotemporal spikes as previously reported. In conclusion our data do not support a major role of ELP4 and SRPX2 in the etiology of RE/ARE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .
4Flu - an individual based simulation tool to study the effects of quadrivalent vaccination on seasonal influenza in Germany
2014-07-03

Vaccination with TIV substantially reduces the Influenza incidence compared to no vaccination. Depending on the assumed degree of B lineage cross protection, QIV further reduces Influenza B incidence by 11-33%.
WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells
2014-07-03

Members of the WD-repeat protein interacting with phosphoinositides (WIPI) family are phosphatidylinositol 3-phosphate (PI3P) effectors that are essential for the formation of autophagosomes. Autophagosomes, unique double-membraned organelles, are characteristic for autophagy, a bulk degradation mechanism with cytoprotective and homeostatic function. Both, WIPI-1 and WIPI-2 are aberrantly expressed in several solid tumors, linking these genes to carcinogenesis. We now found that the expression of WIPI-1 was significantly reduced in a large cohort of 98 primary acute myeloid leukemia (AML) patient samples (complex karyotypes; t(8;21); t(15,17); inv(16)). In contrast, the expression of WIPI-2 was only reduced in acute promyelocytic leukemia (APL), a distinct subtype of AML (t(15,17)). As AML cells are blocked in their differentiation, we tested if the expression levels of WIPI-1 and WIPI-2 increase during all-trans retinoic acid (ATRA)-induced neutrophil differentiation of APL. According to the higher WIPI-1 expression in granulocytes compared with immature blast cells, WIPI-1 but not WIPI-2 expression was significantly induced during neutrophil differentiation of NB4 APL cells. Interestingly, the induction of WIPI-1 expression was dependent on the transcription factor PU.1, a master regulator of myelopoiesis, supporting our notion that WIPI-1 expression is reduced in AML patients lacking proper PU-1 activity. Further, knocking down WIPI-1 in NB4 cells markedly attenuated the autophagic flux and significantly reduced neutrophil differentiation. This result was also achieved by knocking down WIPI-2, suggesting that both WIPI-1 and WIPI-2 are functionally required and not redundant in mediating the PI3P signal at the onset of autophagy in NB4 cells. In line with these data, downregulation of PI3KC3 (hVPS34), which generates PI3P upstream of WIPIs, also inhibited neutrophil differentiation. In conclusion, we demonstrate that both WIPI-1 and WIPI-2 are required for the PI3P-dependent autophagic activity during neutrophil differentiation, and that PU.1-dependent WIPI-1 expression is significantly repressed in primary AML patient samples and that the induction of autophagic flux is associated with neutrophil differentiation of APL cells.
The water mites (Acari: Hydrachnidia) of the standing waters of Corsica, Sardinia and Sicily: review and new data
2014-07-03

A compilation of our present knowledge of the water mites (Acari: Hydrachnidia) adapted to life in standing waters on the three large islands in the western Mediterranean (Corsica, Sardinia and Sicily) is provided. In addition to published data, this study deals with a rich volume of new material from recent field work, mostly deriving from intermittent ponds and pools, an extremely poorly investigated yet peculiar habitat type in the Mediterranean area. Species richness of water mites reported for the standing waters of the three islands amounts to 91 species. Out of the 47 species for which we present new distributional data, Hydrachna incisa Halbert, 1903, Hydrachna leegei Koenike, 1895, Piersigia limophila Protz, 1896, Hydryphantes crassipalpis Koenike, 1914 and Piona laminata (Thor, 1900) have not been recorded previously from the Mediterranean area. Most of these species were believed to have typical North European distributions. In addition to these, a further 13 species are recorded for the first time from the area covered. In total, 11 species are new for Italy, seven more are new for Sicily, three for Sardinia and seven for Corsica. Redescriptions are given of Axonopsis complanata (Müller, 1776) (A. graeca, nov. syn), Brachypoda baderi (reported for the first time after the original description from Abruzzo, Italy, synonymization with B. mutila rejected) and B. mutila (recorded for the first time outside Algeria with certainty). For each species, information is given on habitat preference and geographical distribution; the significance of the data is discussed under perspectives of zoogeography and nature protection. The completeness of our knowledge for the three investigated island is assessed using rarefaction curves and non-parametric estimators of species richness; while Sicily can be considered fairly well known, Corsica and Sardinia require further sampling to assess their water mite diversity.
The Brainstem Pathologies of Parkinson's Disease and Dementia with Lewy Bodies
2014-07-04

Abstract Parkinson's disease ( PD ) and dementia with L ewy bodies ( DLB ) are among the human synucleinopathies, which show alpha‐synuclein immunoreactive neuronal and/or glial aggregations and progressive neuronal loss in selected brain regions (eg, substantia nigra, ventral tegmental area, pedunculopontine nucleus). Despite several studies about brainstem pathologies in PD and DLB , there is currently no detailed information available regarding the presence of alpha‐synuclein immunoreactive inclusions (i) in the cranial nerve, precerebellar, vestibular and oculomotor brainstem nuclei and (ii) in brainstem fiber tracts and oligodendroctyes. Therefore, we analyzed the inclusion pathologies in the brainstem nuclei ( L ewy bodies, LB ; L ewy neurites, LN ; coiled bodies, CB ) and fiber tracts ( LN , CB ) of PD and DLB patients. As reported in previous studies, LB and LN were most prevalent in the substantia nigra, ventral tegmental area, pedunculopontine and raphe nuclei, periaqueductal gray, locus coeruleus, parabrachial nuclei, reticular formation, prepositus hypoglossal, dorsal motor vagal and solitary nuclei. Additionally we were able to demonstrate LB and LN in all cranial nerve nuclei, premotor oculomotor, precerebellar and vestibular brainstem nuclei, as well as LN in all brainstem fiber tracts. CB were present in nearly all brainstem nuclei and brainstem fiber tracts containing LB and/or LN . These findings can contribute to a large variety of less well‐explained PD and DLB symptoms (eg, gait and postural instability, impaired balance and postural reflexes, falls, ingestive and oculomotor dysfunctions) and point to the occurrence of disturbances of intra‐axonal transport processes and transneuronal spread of the underlying pathological processes of PD and DLB along anatomical pathways.
TCF-1-mediated Wnt signaling regulates Paneth cell innate immune defense effectors HD-5 and -6: implications for Crohn's disease
2014-07-04

Wnt signaling regulates small intestinal stem cell maintenance and Paneth cell differentiation. In patients with ileal Crohn's disease (CD), a decrease of Paneth cell α-defensins has been observed that is partially caused by impaired TCF-4 and LRP6 function. Here we show reduced expression of the Wnt signaling effector TCF-1 (also known as TCF-7) in patients with ileal CD. Reporter gene assays and in vitro promoter binding analysis revealed that TCF-1 activates α-defensin HD-5 and HD-6 transcription in cooperation with β-catenin and that activation is mediated by three distinct TCF binding sites. EMSA analysis showed binding of TCF-1 to the respective motifs. In ileal CD patients, TCF-1 mRNA expression levels were significantly reduced. Moreover, we found specifically reduced expression of active TCF-1 mRNA isoforms. Tcf-1 knockout mice exhibited reduced cryptdin expression in the jejunum, which was not consistently seen at other small intestinal locations. Our data provide evidence that TCF-1-mediated Wnt signaling is disturbed in small intestinal CD, which might contribute to the observed barrier dysfunction in the disease.
The origin of echinoid shell beds in siliciclastic shelf environments: three examples from the Miocene of Sardinia, Italy
2014-07-04

Three mass accumulations of sea urchins from the Miocene of Sardinia show a number of taphonomic features which set them apart from previously described echinoid assemblages from the Cenozoic in which they represent: (1) monotypic assemblages; (2) include very well-preserved remains of either regular or spatangoid echinoids; and (3) originate in deeper water environments. These accumulations are compared using a detailed sedimentological and taphonomic analysis including preservational fabrics, taphonomic signatures, size frequency distributions, density of occurrences and preferred orientations. The possible role of gregarious behaviour contributing to mass occurrences and the specific sedimentary events leading to the excellent preservation are discussed. The interpreted depositional environment of all three deposits is that of a storm-dominated, siliciclastic shelf environment. A phymosomatid assemblage represents rapid burial through obrution of a highly dense, freshly dead community. A Brissopsis-dominated spatangoid assemblage represents a mixed accumulation of parautochthonous and transported skeletons. The third assemblage consisting of regular echinoid spines and rare tests represents a composite tempestite. Differences in the depositional environments are related to their position along onshore offshore gradient with the first two beds originated in a deeper setting than that of the spine accumulation. This study shows that the preservation of assemblages containing complete regular echinoids and spatangoids is higher in deeper water settings than in shallow water environments.
Draft Genome Sequence of Marine Actinomycete Streptomyces sp. Strain NTK 937, Producer of the Benzoxazole Antibiotic Caboxamycin
2014-07-04

ABSTRACT Streptomyces sp. strain NTK 937 is the producer of the benzoxazole antibiotic caboxamycin, which has been shown to exert inhibitory activity against Gram-positive bacteria, cytotoxic activity against several human tumor cell lines, and inhibition of the enzyme phosphodiesterase. In this genome announcement, we present a draft genome sequence of Streptomyces sp. NTK 937 in which we identified at least 35 putative secondary metabolite biosynthetic gene clusters.