julilili42/papers huggingface dataset:
Enteric-coated mycophenolate sodium in the treatment of non-infectious intermediate uveitis: results of a prospective, controlled, randomised, open-label, early terminated multicentre trial
2017-09-13

Background/aims To evaluate the efficacy, safety and tolerability of enteric-coated mycophenolate sodium (EC-MPS) in combination with low-dose corticosteroids compared with a monotherapy with low-dose corticosteroids in subjects with non-infectious intermediate uveitis (IU). Methods Open-label, prospective, controlled, randomised multicentre trial. Patients were randomised in a 1:1 ratio to either the treatment group (prednisolone plus EC-MPS) or control group (prednisolone monotherapy). Patients in the control group who relapsed within 6 months changed to the crossover group (prednisolone plus EC-MPS). Maximum treatment duration was 15 months. The primary endpoint was the time to first relapse in the treatment group and control group. Results Forty-one patients at eight sites were analysed. Twenty-two patients were allocated to the treatment group, with 19 patients in the control group. A first relapse occurred in 9 patients (40.9%) in the treatment group and 15 patients (78.9%) in the control group (p=0.03). The median time to the first relapse was &gt;15 months for the treatment group and 2.8 months for the control group (p=0.07). The probability of relapse-free survival at month 15 was estimated to be 52.9% in the treatment group and 19.7% in the control group (p=0.01). 15 patients changed to the crossover group. Of these, only four patients developed a second relapse. No safety concerns arose during the trial. Only one patient had to discontinue EC-MPS due to increased liver enzymes. Conclusion EC-MPS can be considered an effective and well-tolerated immunosuppressive drug to prevent relapses in patients with chronic IU. Trial registration number EUDRACT number: 2009-009998-10, Results.
Aspartate tightens the anchoring of staphylococcal lipoproteins to the cytoplasmic membrane
2017-09-13

Abstract In gram‐negative bacteria, the ABC transporter Lol CDE complex translocates outer membrane‐specific lipoproteins (Lpp) from the inner membrane to the outer membrane. Lpp possessing aspartate (Asp) at position +2 are not translocated because it functions as a Lol CDE avoidance signal. In gram‐positive bacteria, lacking an outer membrane and the Lol system, Lpp are only anchored at the outer leaflet of the cytoplasmic membrane. However, the release of Lpp particularly in pathogenic or commensal species is crucial for immune modulation. Here, we provide evidence that in Staphylococcus aureus Asp at position +2 plays a role in withholding Lpp to the cytoplasmic membrane. Screening of published exoproteomic data of S. aureus revealed that Lpp mainly with Gly or Ser at position +2 were found in exoproteome, but there was no Lpp with Asp+2. The occurrence of Lpp with Asp+2 is infrequent in gram‐positive bacteria. In S. aureus USA 300 only seven of the 67 Lpp possess Asp+2; among them five Lpp represented Lpl lipoproteins involved in host cell invasion. Our study demonstrated that replacing the Asp+2 present in Lpl8 with a Ser enhances its release into the supernatant. However, there is no different release of Asp+2 and Ser+2 in mpr F mutant that lacks the positive charge of lysyl‐phosphatidylglycerol (Lys‐ PG ). Moreover, substitution of Ser+2 by Asp in SitC (MntC) did not lead to a decreased release indicating that in staphylococci positions +3 and +4 might also be important for a tighter anchoring of Lpp. Here, we show that Asp in position +2 and adjacent amino acids contribute in tightening the anchoring of Lpp by interaction of the negative charged Asp with the positive charged Lys‐ PG .
Visuo-perceptual capabilities predict sensitivity for coinciding auditory and visual transients in multi-element displays
2017-09-13

In order to obtain a coherent representation of the outside world, auditory and visual information are integrated during human information processing. There is remarkable variance among observers in the capability to integrate auditory and visual information. Here, we propose that visuo-perceptual capabilities predict detection performance for audiovisually coinciding transients in multi-element displays due to severe capacity limitations in audiovisual integration. In the reported experiment, we employed an individual differences approach in order to investigate this hypothesis. Therefore, we measured performance in a useful-field-of-view task that captures detection performance for briefly presented stimuli across a large perceptual field. Furthermore, we measured sensitivity for visual direction changes that coincide with tones within the same participants. Our results show that individual differences in visuo-perceptual capabilities predicted sensitivity for the presence of audiovisually synchronous events among competing visual stimuli. To ensure that this correlation does not stem from superordinate factors, we also tested performance in an unrelated working memory task. Performance in this task was independent of sensitivity for the presence of audiovisually synchronous events. Our findings strengthen the proposed link between visuo-perceptual capabilities and audiovisual integration. The results also suggest that basic visuo-perceptual capabilities provide the basis for the subsequent integration of auditory and visual information.
Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017
2017-09-14

Abstract Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.
Unveiling the Peptide Motifs of HLA-C and HLA-G from Naturally Presented Peptides and Generation of Binding Prediction Matrices
2017-09-14

Abstract The classical HLA-C and the nonclassical HLA-E and HLA-G molecules play important roles both in the innate and adaptive immune system. Starting already during embryogenesis and continuing throughout our lives, these three Ags exert major functions in immune tolerance, defense against infections, and anticancer immune responses. Despite these important roles, identification and characterization of the peptides presented by these molecules has been lacking behind the more abundant HLA-A and HLA-B gene products. In this study, we elucidated the peptide specificities of these HLA molecules using a comprehensive analysis of naturally presented peptides. To that end, the 15 most frequently expressed HLA-C alleles as well as HLA-E*01:01 and HLA-G*01:01 were transfected into lymphoblastoid C1R cells expressing low endogenous HLA. Identification of naturally presented peptides was performed by immunoprecipitation of HLA and subsequent analysis of HLA-bound peptides by liquid chromatographic tandem mass spectrometry. Peptide motifs of HLA-C unveil anchors in position 2 or 3 with high variances between allotypes, and a less variable anchor at the C-terminal end. The previously reported small ligand repertoire of HLA-E was confirmed within our analysis, and we could show that HLA-G combines a large ligand repertoire with distinct features anchoring peptides at positions 3 and 9, supported by an auxiliary anchor in position 1 and preferred residues in positions 2 and 7. The wealth of HLA ligands resulted in prediction matrices for octa-, nona-, and decamers. Matrices were validated in terms of their binding prediction and compared with the latest NetMHC prediction algorithm NetMHCpan-3.0, which demonstrated their predictive power.
The impact of GABAergic drugs on TMS-induced brain oscillations in human motor cortex
2017-09-14

Brain responses to transcranial magnetic stimulation (TMS) as measured with electroencephalography (EEG) have so far been assessed either by TMS-evoked EEG potentials (TEPs), mostly reflecting phase-locked neuronal activity, or time-frequency-representations (TFRs), reflecting oscillatory power arising from a mixture of both evoked (i.e., phase-locked) and induced (i.e., non-phase-locked) responses. Single-pulse TMS of the human primary motor cortex induces a specific pattern of oscillatory changes, characterized by an early (30-200 ms after TMS) synchronization in the α- and β-bands over the stimulated sensorimotor cortex and adjacent lateral frontal cortex, followed by a late (200-400 ms) α- and β-desynchronization over the stimulated and contralateral sensorimotor cortex. As GABAergic inhibition plays an important role in shaping oscillatory brain activity, we sought here to understand if GABAergic inhibition contributes to these TMS-induced oscillations. We tested single oral doses of alprazolam, diazepam, zolpidem (positive modulators of the GABAA receptor), and baclofen (specific GABAB receptor agonist). Diazepam and zolpidem enhanced, and alprazolam tended to enhance while baclofen decreased the early α-synchronization. Alprazolam and baclofen enhanced the early β-synchronization. Baclofen enhanced the late α-desynchronization, and alprazolam, diazepam and baclofen enhanced the late β-desynchronization. The observed GABAergic drug effects on TMS-induced α- and β-band oscillations were not explained by drug-induced changes on corticospinal excitability, muscle response size, or resting-state EEG power. Our results provide first insights into the pharmacological profile of TMS-induced oscillatory responses of motor cortex.
Towards Treatment of Stargardt Disease: Workshop Organized and Sponsored by the Foundation Fighting Blindness
2017-09-14

Accumulation of fluorescent metabolic byproducts of the visual (retinoid) cycle is associated with photoreceptor and retinal pigment epithelial cell death in both Stargardt disease and atrophic (nonneovascular) age-related macular degeneration (AMD). As a consequence of this observation, small molecular inhibitors of enzymes in the visual cycle were recently tested in clinical trials as a strategy to protect the retina and retinal pigment epithelium in patients with atrophic AMD. To address the clinical translational needs for therapies aimed at both diseases, a workshop organized by the Foundation Fighting Blindness was hosted by the Department of Pharmacology at Case Western Reserve University on February 17, 2017, at the Tinkham Veale University Center, Cleveland, OH, USA. Invited speakers highlighted recent advances in the understanding of the pathophysiology of Stargardt disease, in terms of its clinical characterization and the development of endpoints for clinical trials, and discussed the comparability of therapeutic strategies between atrophic age-related macular degeneration (AMD) and Stargardt disease. Investigators speculated that reducing the concentrations of visual cycle precursor substances and/or their byproducts may provide valid therapeutic options for the treatment of Stargardt disease. Here we review the workshop's presentations in the context of published literature to help shape the aims of ongoing research endeavors and aid the development of therapies for Stargardt disease.
Carbon monoxide poisoning from waterpipe smoking: a retrospective cohort study
2017-09-14

CO poisoning after waterpipe smoking may present in young adults with a wide variability of symptoms from none to unconsciousness. Therefore diagnosis should be suspected even in the absence of symptoms.
Lead Carbodiimides Related to the Mineral Bideauxite
2017-09-14

Solid state metathesis reactions of PbCl 2 with metal carbodiimides yielded multinary lead carbodiimide chlorides A Pb 2 Cl 3 (CN 2 ) ( A = Li, Na, Ag). Their crystal structures strongly relate to the mineral Bideauxite [AgPb 2 Cl 3 (OH,F) 2 ], all crystallizing in the space group Fd 3 m . The same crystal structure exists not only with chloride but also with bromide. Another compound obtained in this system is LiPbCl(CN 2 ) with a crystal structure that can be considered as the result of an intercalation of LiCl into the layered structure of Pb(CN 2 ).
Lack of association of MRI determined subclinical cardiovascular disease with dizziness and vertigo in a cross-sectional population-based study
2017-09-14

In this sample of participants without manifest cardiovascular diseases, subclinical left and right ventricular function and carotid structure were consistently not associated with dizziness and vertigo. Subclinical cerebrum measurements, however, tend to increase the risk for dizziness and vertigo, especially in men and in persons with prediabetes or diabetes.
Three decades following afforestation are sufficient to yield δ13C depth profiles
2017-09-14

Abstract Vertical gradients in stable carbon isotope ratios (δ 13 C) in soil profiles can serve to approximate decomposition of organic matter under field conditions. This study tested the time (0, 30, and ≥ 150 y) required for the development of vertical δ 13 C profiles in topsoil by comparing arable, afforested and continuously forested sites, and showed that three decades following afforestation of former cropland are sufficient to develop distinct δ 13 C depth profiles.
Plasticity during Sleep Is Linked to Specific Regulation of Cortical Circuit Activity
2017-09-15

Sleep is thought to be involved in the regulation of synaptic plasticity in two ways: by enhancing local plastic processes underlying the consolidation of specific memories and by supporting global synaptic homeostasis. Here, we briefly summarize recent structural and functional studies examining sleep-associated changes in synaptic morphology and neural excitability. These studies point to a global down-scaling of synaptic strength across sleep while a subset of synapses increases in strength. Similarly, neuronal excitability on average decreases across sleep, whereas subsets of neurons increase firing rates across sleep. Whether synapse formation and excitability is down or upregulated across sleep appears to partly depend on the cell's activity level during wakefulness. Processes of memory-specific upregulation of synapse formation and excitability are observed during slow wave sleep (SWS), whereas global downregulation resulting in elimination of synapses and decreased neural firing is linked to rapid eye movement sleep (REM sleep). Studies of the excitation/inhibition balance in cortical circuits suggest that both processes are connected to a specific inhibitory regulation of cortical principal neurons, characterized by an enhanced perisomatic inhibition via parvalbumin positive (PV+) cells, together with a release from dendritic inhibition by somatostatin positive (SOM+) cells. Such shift towards increased perisomatic inhibition of principal cells appears to be a general motif which underlies the plastic synaptic changes observed during sleep, regardless of whether towards up or downregulation.
SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family
2017-09-15

Objective To demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes. Methods Combined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family. Results 5 of 6 affected subjects shared cHSP as a common disease phenotype. Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age &gt;10–20 years. This benign phenotypic cluster and disease progression is strikingly divergent to the severe infantile phenotype of all SERAC1 cases reported so far. Two family members showed a more multisystemic juvenile-onset cHSP, indicating an intermediate phenotype between the benign oligosystemic cHSP and the classic infantile SERAC1 cluster. The homozygous splice mutation led to loss of the full-length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling. These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype. Conclusions Our findings add SERAC1 to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset ‘Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like’ syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding SERAC1 deficiency spectrum.
Alterations in the α2δ ligand, thrombospondin‐1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies
2017-09-15

Summary Objectives Thrombospondins, which are known to interact with the α 2 δ subunit of voltage‐sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin‐1 was altered in the brain of WAG /Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS 1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies ( IGE / GGE s). Methods We measured the transcripts of thrombospondin‐1 and α 2 δ subunit, and protein levels of α 2 δ, Rab3A, and the vesicular glutamate transporter, VGLUT 1, in the somatosensory cortex and ventrobasal thalamus of presymptomatic and symptomatic WAG /Rij rats and in two control strains by real‐time polymerase chain reaction ( PCR) and immunoblotting. We examined the genetic variants of THBS 1 and CACNA 2D1 in two independent cohorts of patients affected by IGE / GGE recruited through the Genetic Commission of the Italian League Against Epilepsy ( LICE ) and the Euro EPINOMICS ‐Co GIE Consortium. Results Thrombospondin‐1 messenger RNA (mRNA ) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG /Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT 1 protein levels were also reduced in the ventrobasal thalamus of WAG /Rij rats. Genetic variants of THBS 1 were significantly more frequent in patients affected by IGE / GGE than in nonepileptic controls, whereas the frequency of CACNA 2D1 was unchanged. Significance These findings suggest that thrombospondin‐1 may have a role in the pathogenesis of IGE / GGE s.
Attentional fluctuations induce shared variability in macaque primary visual cortex
2017-09-15

Summary Variability in neuronal responses to identical stimuli is frequently correlated across a population. Attention is thought to reduce these correlations by suppressing noisy inputs shared by the population. However, even with precise control of the visual stimulus, the subject’s attentional state varies across trials. While these state fluctuations are bound to induce some degree of correlated variability, it is currently unknown how strong their effect is, as previous studies generally do not dissociate changes in attentional strength from changes in attentional state variability. We designed a novel paradigm that does so and find both a pronounced effect of attentional fluctuations on correlated variability at long timescales and attention-dependent reductions in correlations at short timescales. These effects predominate in layers 2/3, as expected from a feedback signal such as attention. Thus, significant portions of correlated variability can be attributed to fluctuations in internally generated signals, like attention, rather than noise.
Analysis of blood-based gene expression in idiopathic Parkinson disease
2017-09-16

We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers.
Spontaneous mechanical and electrical activities of human calf musculature at rest assessed by repetitive single‐shot diffusion‐weighted MRI and simultaneous surface electromyography
2017-09-17

Purpose Assessment of temporal and spatial relations between spontaneous mechanical activities in musculature (SMAM) at rest as revealed by diffusion‐weighted imaging (DWI) and electrical muscular activities in surface EMG (sEMG). Potential influences of static and radiofrequency magnetic fields on muscular activity on sEMG measurements at rest were examined systematically. Methods Series of diffusion‐weighted stimulated echo planar imaging were recorded with concurrent sEMG measurements. Electrical activities in sEMG were analyzed by non‐parametric Friedman and two‐sample Kolmogorov–Smirnov test. Direct correlation of both modalities was investigated by temporal mapping of electrical activity in sEMG to DWI repetition interval. Results Electrical activities in sEMG and number of visible SMAMs in DWI showed a strong correlation (ρ = 0.9718). High accordance between sEMG activities and visible SMAMs in DWI in a near‐surface region around sEMG electrodes was achieved. Characteristics of sEMG activities were almost similar under varying magnetic field conditions. Conclusion Visible SMAMs in DWI have shown a close and direct relation to concurrent signals recorded by sEMG. MR‐related magnetic fields had no significant effects on findings in sEMG. Hence, appearance of SMAMs in DWI should not be considered as imaging artifact or as effects originating from the special conditions of MR examinations. Spatial and temporal distributions of SMAMs indicate characteristics of spontaneous (microscopic) mechanical muscular action at rest. Therefore, DWI techniques should be considered as non‐invasive tools for studying physiology and pathophysiology of spontaneous activities in resting muscle. Magn Reson Med 79:2784–2794, 2018. © 2017 International Society for Magnetic Resonance in Medicine.