julilili42/papers huggingface dataset:
Poly[[tetramethanolbis[4-oxo-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-olato]disodium]–diethyl ether–methanol (1/1/2)]
2016-07-12

In the title compound, [Na 2 (C 16 H 7 Cl 3 N 5 O 2 ) 2 (CH 3 OH) 4 ]·C 4 H 10 O·2CH 3 OH, the central pyrazolo[3,4- d ]pyrimidine system makes dihedral angles of 82.98 (7)° with the trichlorophenyl ring and 13.11 (15)° with the pyridine ring. The sodium ion has an octahedral environment, being coordinated by four methanol molecules and one O and one N atom of two different heterocyclic ring systems.
Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4
2016-07-12

ABSTRACT Protocadherins (Pcdhs) are cell adhesion and signaling proteins used by neurons to develop and maintain neuronal networks, relying on trans homophilic interactions between their extracellular cadherin (EC) repeat domains. We present the structure of the antiparallel EC1-4 homodimer of human PcdhYB3, a member of the γ subfamily of clustered Pcdhs. Structure and sequence comparisons of α, β, and γ clustered Pcdh isoforms illustrate that subfamilies encode specificity in distinct ways through diversification of loop region structure and composition in EC2 and EC3, which contains isoform-specific conservation of primarily polar residues. In contrast, the EC1/EC4 interface comprises hydrophobic interactions that provide non-selective dimerization affinity. Using sequence coevolution analysis, we found evidence for a similar antiparallel EC1-4 interaction in non-clustered Pcdh families. We thus deduce that the EC1-4 antiparallel homodimer is a general interaction strategy that evolved before the divergence of these distinct protocadherin families.
European Guidelines (S1) on the use of high‐dose intravenous immunoglobulin in dermatology
2016-07-13

Abstract Background The treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis ( TEN ) with high‐dose intravenous immunoglobulin ( IVI g) is a well‐established procedure in dermatology. As treatment with IVI g is usually considered for rare clinical entities or severe clinical cases, the use of immunoglobulin is not generally based on data from randomized controlled trials that are usually required for the practice of evidence‐based medicine. Owing to the rarity of the indications for the use of IVI g, it is also unlikely that such studies will be available in the foreseeable future. Because the high costs of IVI g treatment also limit its first‐line use, the first clinical guidelines on its use in dermatological conditions were established in 2008 and renewed in 2011. Materials and methods The European guidelines presented here were prepared by a panel of experts nominated by the EDF and the EADV . The guidelines were developed to update the indications for treatment currently considered as effective and to summarize the evidence base for the use of IVI g in dermatological autoimmune diseases and TEN . Results and conclusion The current guidelines represent consensual expert opinions and definitions on the use of IVI g reflecting current published evidence and are intended to serve as a decision‐making tool for the use of IVI g in dermatological diseases.
Aridity-induced Miocene canyon incision in the Central Andes
2016-07-13

Abstract The relationship between the rise of the Andean mountain chain and the onset of aridity on its western margin is poorly understood. Canyon incision on both the eastern and western flanks of the chain is interpreted generally as a direct response to increased rock uplift, but may equally have been the result of climate change. Here we record some of the oldest canyon incision on the western Andean margin by tracking the downward migration of the local water table using (U-Th)/He hematite geochronology on vertical drill-core transects. Our data constrain the incision history of the Quebrada de Parca canyon in northern Chile from ca. 16 Ma to the present day. The erosional and topographic response of the Quebrada de Parca river suggests that incision was induced by a switch to a more arid climate in the middle Miocene, which reduced regional precipitation and river discharge. Geomorphic analysis of the modern river suggests that the Central Andes have gained only ∼700 m of elevation since incision began, and had therefore reached at least 50% of their current elevation by middle Miocene time. We thus conclude that the onset of aridity at ca. 16 Ma occurred subsequent to the main Andean uplift.
Receptor tyrosine kinase EphA7 is required for interneuron connectivity at specific subcellular compartments of granule cells
2016-07-13

Abstract Neuronal transmission is regulated by the local circuitry which is composed of principal neurons targeted at different subcellular compartments by a variety of interneurons. However, mechanisms that contribute to the subcellular localisation and maintenance of GABAergic interneuron terminals are poorly understood. Stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin and its interaction with the guanine nucleotide exchange factor collybistin. Lentiviral knockdown experiments in adult rats indicated that the receptor tyrosine kinase EphA7 is required for the stabilisation of basket cell terminals on proximal dendritic and somatic compartments of granular cells of the dentate gyrus. EphA7 deficiency and concomitant destabilisation of GABAergic synapses correlated with impaired long-term potentiation and reduced hippocampal learning. Reduced GABAergic innervation may be explained by an impact of EphA7 on gephyrin clustering. Overexpression or ephrin stimulation of EphA7 induced gephyrin clustering dependent on the mechanistic target of rapamycin (mTOR) which is an interaction partner of gephyrin. Gephyrin interactions with mTOR become released after mTOR activation while enhanced interaction with the guanine nucleotide exchange factor collybistin was observed in parallel. In conclusion, EphA7 regulates gephyrin clustering and the maintenance of inhibitory synaptic connectivity via mTOR signalling.
Steps towards Smarter Solutions in Optometry and Ophthalmology—Inter-Device Agreement of Subjective Methods to Assess the Refractive Errors of the Eye
2016-07-13

Purpose: To investigate the inter-device agreement and mean differences between a newly developed digital phoropter and the two standard methods (trial frame and manual phoropter). Methods: Refractive errors of two groups of participants were measured by two examiners (examiner 1 (E1): 36 subjects; examiner 2 (E2): 38 subjects). Refractive errors were assessed using a trial frame, a manual phoropter and a digital phoropter. Inter-device agreement regarding the measurement of refractive errors was analyzed for differences in terms of the power vector components (spherical equivalent (SE) and the cylindrical power vector components J0 and J45) between the used methods. Intraclass correlation coefficients (ICC’s) were calculated to evaluate correlations between the used methods. Results: Analyzing the variances between the three methods for SE, J0 and J45 using a two-way ANOVA showed no significant differences between the methods (SE: p = 0.13, J0: p = 0.58 and J45: p = 0.96) for examiner 1 and for examiner 2 (SE: p = 0.88, J0: p = 0.95 and J45: p = 1). Mean differences and ±95% Limits of Agreement for each pair of inter-device agreement regarding the SE for both examiners were as follows: Trial frame vs. digital phoropter: +0.10 D ± 0.56 D (E1) and +0.19 D ± 0.60 D (E2), manual phoropter vs. trial frame: −0.04 D ± 0.59 D (E1) and −0.12 D ± 0.49 D (E2) and for manual vs. digital phoropter: +0.06 D ± 0.65 D (E1) and +0.08 D ± 0.45 D (E2). ICCs revealed high correlations between all methods for both examiner (p &lt; 0.001). The time to assess the subjective refraction was significantly smaller with the digital phoropter (examiner 1: p &lt; 0.001; examiner 2: p &lt; 0.001). Conclusion: “All used subjective methods show a good agreement between each other terms of ICC (&gt;0.9). Assessing refractive errors using different subjective methods, results in similar mean differences and 95% limits of agreement, when compared to those reported in studies comparing subjective refraction non-cylcoplegic retinoscopy or autorefraction”.
Molecular Advances in Glioblastoma Neuropathology
2016-07-13

Glioblastoma is the most frequent and malignant brain tumor with a wide variety of morphological appearances. For a long time, the tumors were classified either as primary (“de novo”) glioblastomas that develop rapidly in elderly patients or as secondary glioblastomas with clinical or histological progression from low-grade diffuse astrocytoma or anaplastic astrocytoma. Recent data from the comprehensive genetic characterization of these tumors identified a number of common and diverging alterations and pathways that allow future stratification of glioblastomas into several age-dependent biological subgroups. While the histological classification of diffuse gliomas based on the WHO grading scheme is still necessary, the use of additional meaningful immunohistochemical (and mutation-specific) markers, such as IDH R132H, ATRX, and H3F3A K27M, has improved routine diagnosis. In recent years, the spectrum of clinically relevant molecular markers has expanded. The utility of MGMT, ATRX, TERT, H3F3A and LOH 1p/19q in predicting prognosis and response to therapy in routine diagnostic settings is discussed.
A time for feasting? Autarky in the Tajik Ferghana Valley at war, 1941–45
2016-07-13

The well-established narrative of the Soviet Union’s victory in the Great Patriotic War emphasizes the enormous sacrifices that it entailed, and the extraordinary sufferings of both the Red Army and the entire civilian population. Throughout the war years, however, reports of lavish feasting and conspicuous consumption taking place on collective farms in northern Tajikistan continued to be submitted to Moscow. The ‘culprits’ were usually local Soviet officials, who appear to have reverted to traditional redistributive practices and modes of patronage. I argue that such acts of ‘anti-Soviet sabotage’ do not necessarily prove that Central Asians understood themselves as colonized subjects making the most of a temporary reprieve from state intrusion. The war in fact casts into sharp relief the extent to which many local officials of the Tajik SSR perceived themselves as loyal Soviet citizens – and as good Muslims, too.
Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy
2016-07-14

Key Points The posttreatment end point progression of FL within 24 months (POD24) is strongly associated with OS. A pretreatment clinicogenetic risk model (m7-FLIPI) predicts POD24 and OS and identifies the smallest subgroup with highest unmet need.
The cytosolic cochaperone Sti1 is relevant for mitochondrial biogenesis and morphology
2016-07-14

Most mitochondrial proteins are synthesized in the cytosol prior to their import into the organelle. It is commonly accepted that cytosolic factors are required for delivering precursor proteins to the mitochondrial surface and for keeping newly synthesized proteins in an import‐competent conformation. However, the identity of such factors and their defined contribution to the import process are mostly unknown. Using a presequence‐containing model protein and a site‐directed photo‐crosslinking approach in yeast cells we identified the cytosolic chaperones Hsp70 (Ssa1) and Hsp90 (Hsp82) as well as their cochaperones, Sti1 and Ydj1, as putative cytosolic factors involved in mitochondrial protein import. Deletion of STI1 caused both alterations in mitochondrial morphology and lower steady‐state levels of a subset of mitochondrial proteins. In addition, double deletion of STI1 with the mitochondrial import factors, MIM1 or TOM20 , showed a synthetic growth phenotype indicating a genetic interaction of STI1 with these genes. Moreover, recombinant cytosolic domains of the import receptors Tom20 and Tom70 were able to bind in vitro Sti1 and other cytosolic factors. In summary, our observations point to a, direct or indirect, role of Sti1 for mitochondrial functionality.
Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci
2016-07-14

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
Cation-Induced Hydration Effects Cause Lower Critical Solution Temperature Behavior in Protein Solutions
2016-07-14

The phase behavior of protein solutions is important for numerous phenomena in biology and soft matter. We report a lower critical solution temperature (LCST) phase behavior of aqueous solutions of a globular protein induced by multivalent metal ions around physiological temperatures. The LCST behavior manifests itself via a liquid-liquid phase separation of the protein-salt solution upon heating. Isothermal titration calorimetry and zeta-potential measurements indicate that here cation-protein binding is an endothermic, entropy-driven process. We offer a mechanistic explanation of the LCST. First, cations bind to protein surface groups driven by entropy changes of hydration water. Second, the bound cations bridge to other protein molecules, inducing an entropy-driven attraction causing the LCST. Our findings have general implications for condensation, LCST, and hydration behavior of (bio)polymer solutions as well as the understanding of biological effects of (heavy) metal ions and their hydration.
SGK1-dependent ENaC processing and trafficking in mice with high dietary K intake and elevated aldosterone
2016-07-14

We examined renal Na and K transporters in mice with deletions in the gene encoding the aldosterone-induced protein SGK1. The knockout mice were hyperkalemic, and had altered expression of the subunits of the epithelial Na channel (ENaC). The kidneys showed decreased expression of the cleaved forms of the γENaC subunit, and the fully glycosylated form of the βENaC subunits when animals were fed a high-K diet. Knockout animals treated with exogenous aldosterone also had reduced subunit processing and diminished surface expression of βENaC and γENaC. Expression of the three upstream Na transporters NHE3, NKCC2, and NCC was reduced in both wild-type and knockout mice in response to K loading. The activity of ENaC measured as whole cell amiloride-sensitive current ( I Na ) in principal cells of the cortical collecting duct (CCD) was minimal under control conditions but was increased by a high-K diet to a similar extent in knockout and wild-type animals. I Na in the connecting tubule also increased similarly in the two genotypes in response to exogenous aldosterone administration. The activities of both ROMK channels in principal cells and BK channels in intercalated cells of the CCD were unaffected by the deletion of SGK1. Acute treatment of animals with amiloride produced similar increases in Na excretion and decreases in K excretion in the two genotypes. The absence of changes in ENaC activity suggests compensation for decreased surface expression. Altered K balance in animals lacking SGK1 may reflect defects in ENaC-independent K excretion.
Distinct ERP signatures of word frequency, phrase frequency, and prototypicality in speech production.
2016-07-14

Recent studies have documented frequency effects for word n-grams, independently of word unigram frequency. Further studies have revealed constructional prototype effects, both at the word level as well as for phrases. The present speech production study investigates the time course of these effects for the production of prepositional phrases in English, using event related potentials (ERPs). For word frequency, oscillations in the theta range emerged. By contrast, phrase frequency showed a persistent effect over time. Furthermore, independent effects with different temporal and topographical signatures characterized phrasal prototypicality. In a simulation study we demonstrate that naive discrimination learning provides an alternative account of the data that is as least as powerful as a standard lexical predictor analysis. The implications of the current findings for models of language processing are discussed. (PsycINFO Database Record
Improving CT-Based PET Attenuation Correction in the Vicinity of Metal Implants by an Iterative Metal Artifact Reduction Algorithm of CT Data and Its Comparison to Dual-Energy–Based Strategies
2016-07-14

Objective The aim of this study was to evaluate the potential of iterative metal artifact reduction (IMAR) for the improvement of computed tomography (CT)–based position emission tomography (PET) attenuation correction in the vicinity of metal implants and compare it with dual-energy–based metal artifact reduction strategies. Methods A dedicated dental phantom was constructed consisting of a cylindrical tube filled with [18-F]FDG solution (5300 mL and 50.9 MBq) containing 2 artificial jaws with 1 nonprecious alloy fixed dental prosthesis and 3 single tooth crowns in the lower jaw. Computed tomography measurements of the phantom were acquired on a stand-alone dual-energy CT scanner equipped with IMAR capabilities. A series of 24 CT data sets were obtained using different scan parameters and monoenergetic extrapolation of dual-energy CT acquisitions with and without IMAR reconstruction. Position emission tomography measurements of the phantom were performed on a state-of-art PET/CT scanner. Position emission tomography data were reconstructed using all 24 previously acquired CT data sets. Relative errors in the quantification of activity concentrations using the different CT scanning and reconstruction parameters were quantified by placement of regions of interest within the phantom. Results Metal artifacts of different extent were observed in all CT data sets. A marked reduction in CT metal artifacts was observed using IMAR. In general, activity concentrations were overestimated/underestimated in areas of high/low-density metal artifacts, respectively. Relative errors in PET quantification ranged between −71% and +70% without IMAR. Using IMAR, these errors were reduced to a range between −40% and +12%. Averaged absolute values of relative PET quantification errors were 27% and 7% without and with the use of IMAR ( P &lt; 0.001), respectively. Iterative metal artifact reduction was superior compared with dual-energy–based metal artifact reduction strategies, and the combination of both strategies did not result in further significant improvement of PET quantification. Conclusions The use of IMAR in PET/CT is a promising approach for markedly improving image quality and PET quantification in the vicinity of metal implants. Further clinical studies are necessary to assess the clinical performance of this algorithm in patients.
Subretinal electrical stimulation reveals intact network activity in the blind mouse retina
2016-07-14

Retinal degeneration ( rd) leads to progressive photoreceptor cell death, resulting in vision loss. Stimulation of the inner-retinal neurons by neuroprosthetic implants is one of the clinically approved vision-restoration strategies, providing basic visual percepts to blind patients. However, little is understood as to what degree the degenerating retinal circuitry and the resulting aberrant hyperactivity may prevent the stimulation of physiological electrical activity. Therefore, we electrically stimulated ex vivo retinas from wild-type ( wt; C57BL/6J) and blind ( rd10 and rd1) mice using an implantable subretinal microchip and simultaneously recorded and analyzed the retinal ganglion cell (RGC) output with a flexible microelectrode array. We found that subretinal anodal stimulation of the rd10 retina and wt retina evoked similar spatiotemporal RGC-spiking patterns. In both retinas, electrically stimulated ON and a small percentage of OFF RGC responses were detected. The spatial selectivity of the retinal network to electrical stimuli reveals an intact underlying network with a median receptive-field center of 350 μm in both retinas. An antagonistic surround is activated by stimulation with large electrode fields. However, in rd10 and to a higher percentage, in rd1 retinas, rhythmic and spatially unconfined RGC patterns were evoked by anodal or by cathodal electrical stimuli. Our findings demonstrate that the surviving retinal circuitry in photoreceptor-degenerated retinas is preserved in a way allowing for the stimulation of temporally diverse and spatially confined RGC activity. Future vision restoration strategies can build on these results but need to avoid evoking the easily inducible rhythmic activity in some retinal circuits.
The notorious R.N.A. in the spotlight - drug or target for the treatment of disease
2016-07-14

mRNA is an attractive drug target for therapeutic interventions. In this review we highlight the current state, clinical trials, and developments in antisense therapy, including the classical approaches like RNaseH-dependent oligomers, splice-switching oligomers, aptamers, and therapeutic RNA interference. Furthermore, we provide an overview on emerging concepts for using RNA in therapeutic settings including protein replacement by in-vitro-transcribed mRNAs, mRNA as vaccines and anti-allergic drugs. Finally, we give a brief outlook on early-stage RNA repair approaches that apply endogenous or engineered proteins in combination with short RNAs or chemically stabilized oligomers for the re-programming of point mutations, RNA modifications, and frame shift mutations directly on the endogenous mRNA.