julilili42/papers huggingface dataset:
Understanding the role of genetic variability in LRRK2 in Indian population
2018-11-28

ABSTRACT Background Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. Objectives To resolve the role of LRRK2 in the Indian population. Methods We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. Results We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild‐type, the kinase domain variant showed 4‐fold increase in the kinase activity. Conclusions Our study, for the first time, identified novel missense variants for LRRK2 , specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society
Decision confidence: EEG correlates of confidence in different phases of a decision task
2018-11-28

Abstract Decision making is an essential part of daily life, in which balancing reasons and calculating risks to reach a certain confidence are important to make reasonable choices. To investigate the EEG correlates of confidence during decision making a study involving a forced choice recognition memory task was implemented. Subjects were asked to distinguish old from new pictures and rate their decision with either high or low confidence. Event-related potential (ERP) analysis was performed in four different phases covering all stages of decision making, including the information encoding, retrieval, decision formation, and feedback processing during the recognition task. Additionally, a single trial support-vector machine (SVM) classification was performed on the ERPs of each phase to get a measure of differentiability of the two levels of confidence on a single subject level. It could be shown that the level of decision confidence is significantly reflected in all stages of decision making but most prominently during feedback presentation. The main differences between high and low confidence can be found in the ERPs during feedback presentation after a correct answer, whereas almost no differences can be found in ERPs from feedback to wrong answers. In the feedback phase the two levels of confidence can be separated with a classification accuracy of up to 70 % on average over all subjects, therefore showing potential as a control state in a brain-computer Interface (BCI) application.
Neural activity related to volitional regulation of cortical excitability
2018-11-29

To date there exists no reliable method to non-invasively upregulate or downregulate the state of the resting human motor system over a large dynamic range. Here we show that an operant conditioning paradigm which provides neurofeedback of the size of motor evoked potentials (MEPs) in response to transcranial magnetic stimulation (TMS), enables participants to self-modulate their own brain state. Following training, participants were able to robustly increase (by 83.8%) and decrease (by 30.6%) their MEP amplitudes. This volitional up-versus down-regulation of corticomotor excitability caused an increase of late-cortical disinhibition (LCD), a TMS derived read-out of presynaptic GABAB disinhibition, which was accompanied by an increase of gamma and a decrease of alpha oscillations in the trained hemisphere. This approach paves the way for future investigations into how altered brain state influences motor neurophysiology and recovery of function in a neurorehabilitation context.
The BOLD sensitivity of rapid steady‐state sequences
2018-11-29

Purpose Relaxation and dephasing of water protons embedded in a vascular network is driven by local magnetic field inhomogeneities around deoxygenated blood vessels. These effects strongly depend on the relation between mean diffusion length and diameter of blood vessels, as well as on the chosen imaging sequence. In this work, the BOLD sensitivity of steady‐state sequences as a function of vessel size, field strength, and sequence parameters are analyzed. Methods Steady‐state magnetization within a network of artificial cylinders is simulated with Monte Carlo methods for different coherence pathways. In addition, measurements on microspheres were performed to confirm theoretical results. Results Simulations and phantom results demonstrate a vessel size‐dependent signal attenuation effect of all coherence pathways. Both the FID and ECHO pathways show a signal profile similar to spin echo sequences where in the static dephasing regime the effect of larger vessels is suppressed. Conclusion The BOLD effect measured in steady‐state sequences is most sensitive to microvessels and might therefore be closer to the underlying neuronal event compared to gradient echo sequences.
Quality of medicines in southern Togo: Investigation of antibiotics and of medicines for non-communicable diseases from pharmacies and informal vendors
2018-11-29

Substandard and falsified medicines represent a serious threat for public health and patient safety. Especially in low and middle-income countries, the prevalence of substandard and falsified medicines is reportedly high. However, reliable information on the prevalence of poor-quality medicines is scarce. In this study, 12 essential medicines, including antibiotics, antidiabetics, cardiac drugs and antiasthmatic drugs, were collected from six informal vendors and six licensed pharmacies in the southern part of Togo (regions Maritime and Plateaux). A mystery shopper approach was used in both types of outlets. In total, 64 samples were collected from licensed pharmacies and 30 from informal vendors. Both availability of medicines and prices of medicines were higher in licensed pharmacies than in informal vendors. 92 medicine samples were analyzed by visual examination, followed by chemical analysis for the content and for the dissolution of the active pharmaceutical ingredients according to the respective monographs of the United States Pharmacopoeia. 7 samples (8%) did not comply with the pharmacopoeial specifications, and one sample (1%) showed even extreme deviations. None of the samples was obviously falsified. However, one sample of amoxicillin capsules contained only 47% of the declared content of the active pharmaceutical ingredient, indicating that it may represent amoxicillin capsules 250 mg, rather than 500mg as declared on the label. Medicines stated to originate from Asia (i.e. mainly from India and China) showed a significantly higher proportion (24%) of non-compliant samples than those from Africa and Europe (4%, p = 0.007). High failure rates were observed in medicines both from informal vendors (13%) and from licensed pharmacies (5%), but the difference between both groups was not statistically significant (p = 0.152). The observed high prevalence of substandard medicines requires action from regulatory authorities and health care providers. Testing of selected samples for related substances indicated that inappropriate transport and storage conditions may have been an important cause for substandard quality.
How air pollution affects the eyes — a review
2018-11-29

The aim of this study is to present scientific reports concerning the influence of air pollution on eyes. Air pollution is nowadays a common problem. The most significant pollutants are carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), sulphur dioxide (SO2), particulate matters — PM10 and PM2.5. The main source of toxins in the air are cars, burning of the fuels and burning of the charcoal in household stoves. Most attention is paid to negative effects of air pollution on respiratory system, such as asthma and lung cancer, however, it is worth remembering that influence on the eyes is equally important. Children are especially vulnerable to the harmful effects of air pollution. Anterior segment of the eye is the most exposed. Substances, which are part of the smog have an irritating effect on the surface of the eye, cause disturbances in the tear film and an inflammation. Medical conditions associated with increased air pollution are mainly eye irritation, conjunctivitis, dry eye syndrome (DES), meibomian gland dysfunction (MGB) and blepharitis.
Comparison of spontaneous sensory recovery of noninnervated anteromedial thigh flap, latissimus dorsi flap, and gracilis muscle flap in lower extremity reconstruction: A prospective comparative study
2018-11-29

Background We evaluated the time course and differences in the sensory recovery of three commonly used free flaps for lower extremity reconstruction. Furthermore, the sensory recovery of skin‐grafted muscle and skin paddle in latissimus dorsi flaps (LDMF) were differentiated. Methods In a prospective study, 26 patients who had undergone free flap lower extremity reconstruction were enrolled. Among them, 9 received LDMF, 9 received gracilis muscle flaps (GMF), and 8 received anterior lateral thigh flaps (ALTF). The sensory recovery was investigated by using the Semmes–Weinstein test (SWT) at 6 and 12 months after the surgery. Results All flaps recorded spontaneous sensory recovery. The GMF showed the smallest anesthetic area after 12 months as compared with the ALTF and LDMF (1 ± 3% vs. 18 ± 39% ( p &lt; .05) vs. 35 ± 35% (p &lt; .05), respectively). Qualitatively, ALTF exhibited the best sensory recovery with the lowest SWT values (ALTF 4.57 ± 1.12 vs. GMF 5.01 ± 0.81 8 [ p &lt; .05], vs. LDMF 5.84 ± 0.52 [ p &lt; .05]). The sensory recovery of skin‐grafted muscle was superior to that of the skin paddle in the LDMF (anesthetic area 29 ± 36% vs. 54 ± 33% [ p &lt; .05], SWT 5.85 ± 0.60 vs. 6.30 ± 0.18 [ p &lt; .05], respectively). Conclusion All flaps displayed spontaneous sensory recovery potential over the investigation period, which appeared to be influenced by the flap type and size. The LDMF skin paddle showed lower potential for sensory recovery as compared with the skin‐grafted muscle area of the same flap. The GMF demonstrated a near‐complete sensory recovery after 12 months.
An Exploratory Study on the Central Nervous Correlates of Sexual Excitation and Sexual Inhibition
2018-11-29

The Sexual Inhibition/Sexual Excitation Scales (SIS/SES) measure sexual excitation and sexual inhibition proneness. We used SIS and SES scores of 62 heterosexual teleiophilic men (<i>M</i><sub>age</sub> 34.3, <i>SD</i> = 9.9) to predict brain activation levels during the presentation of male and female visual sexual stimuli in a magnetic resonance imaging (MRI) scanner. Statistical analyses revealed significant correlations. SES and SIS1 scores were positively associated with brain activation in various brain regions during the presentation of both male and female stimuli. SIS2 turned out to be a weaker predictor of brain activation, still revealing one significant correlation in the right lateral orbitofrontal cortex. Significant regions for SES and SIS1 were, among others, primary and supplementary motor areas, the caudate nucleus, the dorsal anterior cingulate cortex, anterior insula, and prefrontal areas. Our study can be seen as an exploratory investigation of SIS and SES with means of functional brain imaging. The results provide a promising contribution to the assertion of neurophysiological systems of sexual inhibition and excitation proneness.
Adverse effect of UV radiation on eyes — a review
2018-11-29

The aim of this study is to discuss the association between ultraviolet radiation (UVR) and eye diseases. UVR which reaches the surface of the Earth consists of 95% UVA and 5% of UVB. Both acute and chronic exposure to UVR leads to pathological changes in the eye. There is strong evidence that UVR exposure causes photokeratitis, photoretinitis, climatic droplet keratopathy, cataract, pterygium, squamous cell carcinoma of cornea and conjunctiva, cancer of the eyelids (squamous cell and basal cell carcinoma). Association between UVR and pinguecula, AMD (age-related macular degeneration) and melanoma of the eyeball is ambiguous. UVR exposure occurs all day and all year long, which is why eye protection is necessary to avoid diseases induced by UVR. In particular childrens' eyes should be protected from the sun. Efficient protection is provided by accurate clothing, hats, eyeglasses or contact lenses blocking UV light.
Histories of Futures Past: Dystopian Fiction and the Historical Impulse
2018-11-29

Abstract This article traces the historical impulse in two intertextually connected dystopian texts – George Orwell’s 1984 (1949) and Margaret Atwood’s The Handmaid’s Tale (1985) – by reading the two novels in the context of the construction of historical narrative after the proclaimed ‘end of history’ in the twentieth century. It considers their representation of history within the framework of literary criticism of the historical novel (György Lukács), critical dystopias (Tom Moylan), and memory as an active, mediated engagement with the past (Astrid Erll and Ann Rigney). It looks, more specifically, at how the texts contrast personal experience and the meta-narrative contemplation of memory with institutionalized versions of history on different diegetic levels by juxtaposing the narrators’/focalizers’ view of history with that presented in the framework of pseudo-historical appendices that accompany and significantly modify the interpretations of both narratives.
Projective manifolds modeled after hyperquadrics
2018-11-29

We classify all projective manifolds with flat holomorphic conformal structure. The Kähler–Einstein case was treated by Kobayashi and Ochiai, there exists a very short list of possible manifolds. In the non-Kähler–Einstein case a classification was only known in small dimensions: by Kobayashi and Ochiai for complex surfaces and by the authors for projective threefolds. This paper completes the general case.
Invariant Natural Killer T Cells from Donor Lymphocyte Infusions (DLI-iNKTs) Contribute to Anti-Tumor Immunity after Allogeneic Hematopoietic Cell Transplantation
2018-11-29

Abstract Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment option for hematologic malignancies but relapse remains the most common cause of death. Infusion of donor lymphocytes (DLIs) can induce remission and prolong survival by exerting potent graft-versus-leukemia (GVL) effects. However, sufficient tumor control cannot be established in all patients. We showed previously that invariant natural killer T (iNKT) cells promote anti-tumor immunity in murine models of allogeneic HCT without exacerbating graft-versus-host disease (GVHD). We therefore studied iNKT cells in DLIs and investigated how culture-expanded iNKT cells from such DLIs (DLI-iNKTs) could lyse leukemia cells. We analyzed 63 cryopreserved DLI samples by flow cytometry. iNKT cells were identified using the PBS57-loaded CD1d tetramer. Under steady state conditions, iNKT cells represent 0.04% (range, 0.01-0.6) of live donor lymphocytes and need to undergo ex vivo expansion for further experiments and clinical application. We established a two-week protocol resulting in a 300-fold expansion of functional DLI-iNKTs with a purity of 94%. Interestingly, we observed a preferential expansion of CD4+ DLI-iNKTs. This subset turned out to be critical for tolerance induction and prevention of GVHD after allogeneic HCT. For degranulation and leukemia cell lysis assays, culture-expanded DLI-iNKTs were co-cultured with leukemia cells. CD107a as a marker of degranulation and iNKT-cell activity was upregulated on DLI-iNKTs upon engagement with leukemia cells that were subsequently lysed in a dose-dependent manner. We also observed an increased release of cytokines like IFN-γ (85 vs. 7 pg/ml, p=0.04). Moreover, the cytotoxic effects of culture-expanded DLI-iNKTs were CD1d-dependent: blocking the interaction between the MHC-I-like molecule CD1d and the T-cell receptor of DLI-iNKTs abrogated iNKT-cell degranulation and efficient leukemia cell lysis. Our results suggest that iNKT cells from DLIs are involved in anti-tumor immunity after allogeneic HCT and therefore may reduce the risk of relapse and improve progression-free and overall survival. Prior expansion of iNKT cells could promote beneficial effects on tumor control, immune tolerance and overall survival. Disclosures Handgretinger: Miltenyi Biotec: Patents &amp; Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding. Bethge:Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding.
Inhibition of DOT1L and PRMT5 Promotes Anti-Tumor Activity in a Human MLL Leukemia Model Induced By CRISPR/Cas9
2018-11-29

Abstract MLL rearrangements play a crucial role in leukemogenesis. They are associated with a poor prognosis and new treatment strategies are urgently needed. Here, we used the CRISPR/Cas9 system to generate an innovative leukemia model based on 100% pure MLL-AF4/-AF9 rearranged cells derived from umbilical cord blood with indefinite growth in cell culture systems. Our model shared phenotypical, morphological and molecular features of patient leukemic cells faithfully mimicking the nature of the disease. Thus, it serves as ideal fundamental basis for pharmacological studies. The catalytic activity of disruptor of telomeric silencing 1-like histone methyltransferase (DOT1L) is critical for the transforming potential of MLL oncogenes. Therefore, inhibition of DOT1L deals as one specific therapeutic approach for MLL-rearranged leukemias currently tested in clinical trials. However, the previous success was limited by restricted response warranting further investigation of DOT1L combinations. Recently, it has been shown that the inhibition of protein arginine methyltransferase 5 (PRMT5) exhibits anti-tumoral activity against human cell lines in vitro and in MLL mouse models. Here, we used DOT1L (EPZ004777) and PRMT5 (EPZ015666) inhibitors alone or in combination in our human MLL-rearranged model demonstrating a dose-dependent reduced proliferation, impairment of cell cycle, upregulation of differentiation marker CD14 and apoptosis measured by flow cytometry and downregulation of known MLL target genes determined by qPCR. Strikingly, the combination of both compounds led to complementary anti-tumor effects. Our study provides a strong rationale for novel targeted combination therapies to improve the outcome of MLL-rearranged leukemias. Disclosures No relevant conflicts of interest to declare.
Fast track to the neocortex: A memory engram in the posterior parietal cortex
2018-11-30

Memories reach the cortex rapidly How fast do learning-induced anatomical changes occur in the brain? The traditional view postulates that neocortical memory representations reflect reinstatement processes initiated by the hippocampus and that a genuine physical trace develops only through reactivation over extended periods. Brodt et al. combined functional magnetic resonance imaging (MRI) with diffusion-weighted MRI during an associative declarative learning task to examine experience-dependent structural brain plasticity in human subjects (see the Perspective by Assaf). This plasticity was rapidly induced after learning, persisted for more than 12 hours, drove behavior, and was localized in areas displaying memory-related functional brain activity. These plastic changes in the posterior parietal cortex, and their fast temporal dynamics, challenge traditional views of systems memory consolidation. Science , this issue p. 1045 ; see also p. 994
Drug-associated thrombocytopenia
2018-11-30

Abstract Many drugs have been implicated in drug-induced immune thrombocytopenia (DITP). Patients with DITP develop a drop in platelet count 5 to 10 days after drug administration with an increased risk of hemorrhage. The diagnosis of DITP is often challenging, because most hospitalized patients are taking multiple medications and have comorbidities that can also cause thrombocytopenia. Specialized laboratory diagnostic tests have been developed and are helpful to confirm the diagnosis. Treatment of DITP involves discontinuation of the offending drug. The platelet count usually starts to recover after 4 or 5 half-lives of the responsible drug or drug metabolite. High doses of intravenous immunoglobulin can be given to patients with severe thrombocytopenia and bleeding. Although in most cases, DITP is associated with bleeding, life-threatening thromboembolic complications are common in patients with heparin-induced thrombocytopenia (HIT). Binding of antiplatelet factor 4/heparin antibodies to Fc receptors on platelets and monocytes causes intravascular cellular activation, leading to an intensely prothrombotic state in HIT. The clinical symptoms include a decrease in platelet counts by &gt;50% and/or new thromboembolic complications. Two approaches can help to confirm or rule out HIT: assessment of the clinical presentation using scoring systems and in vitro demonstration of antiplatelet factor 4/heparin antibodies. The cornerstone of HIT management is immediate discontinuation of heparin when the disease is suspected and anticoagulation using nonheparin anticoagulant. In this review, we will provide an update on the pathophysiology, diagnosis, and management of both DITP and HIT.
Origin of the current-driven breakdown in vanadium oxides: Thermal versus electronic
2018-11-30

We report the existence of two competing mechanisms in the current-driven electrical breakdown of vanadium sesquioxide ( ) and vanadium dioxide ( ) nanodevices. Our experiments and simulations show that the competition between a purely electronic (PE) mechanism and an electrothermal (ET) mechanism, suppressed in nanoscale devices, explains the current-driven insulator-to-metal phase transition (IMT). We find that the relative contribution of PE and ET effects is dictated by thermal coupling and resistivity, a discovery which disambiguates a long-standing controversy surrounding the physical nature of the current-driven IMT in vanadium oxides. Furthermore, we show that the electrothermally driven IMT occurs through a nanoscopic surface-confined filament. This nanoconfined filament has a very large thermal gradient, thus generating a large Seebeck-effect electric field.