Fluxes and Warping for Gauge Couplings in F-theory

We compute flux-dependent corrections in the four-dimensional F-theory effective action using the M-theory dual description. In M-theory the 7-brane fluxes are encoded by four-form flux and modify the background geometry and Kaluza-Klein reduction ansatz. In particular, the flux sources a warp factor which also depends on the torus directions of the compactification fourfold. This dependence is crucial in the derivation of the four-dimensional action, although the torus fiber is auxiliary in F-theory. In M-theory the 7-branes are described by an infinite array of Taub-NUT spaces. We use the explicit metric on this geometry to derive the locally corrected warp factor and M-theory three-from as closed expressions. We focus on contributions to the 7-brane gauge coupling function from this M-theory back-reaction and show that terms quadratic in the internal seven-brane flux are induced. The real part of the gauge coupling function is modified by the M-theory warp factor while the imaginary part is corrected due to a modified M-theory three-form potential. The obtained contributions match the known weak string coupling result, but also yield additional terms suppressed at weak coupling. This shows that the completion of the M-theory reduction opens the way to compute various corrections in a genuine F-theory setting away from the weak string coupling limit.Comment: 46 page

Intersecting Brane Worlds -- A Path to the Standard Model ?

In this review we describe the general geometrical framework of brane world constructions in orientifolds of type IIA string theory with D6-branes wrapping 3-cycles in a Calabi-Yau 3-fold. These branes generically intersect in points on the internal space, and the patterns of intersections govern the chiral fermion spectra. We discuss how the open string spectra in intersecting brane models are constructed, how the Standard Model can be embedded, and also how supersymmetry can be realized in this class of string vacua. After the general considerations we specialize the discussion to the case of orbifold backgrounds with intersecting D6-branes and to the quintic Calabi-Yau manifold. Then, we discuss parts of the effective action of intersecting brane world models. Specifically we compute from the Born-Infeld action of the wrapped D-branes the tree-level, D-term scalar potential, which is important for the stability of the considered backgrounds as well as for questions related to supersymmetry breaking. Second, we review the recent computation concerning of gauge coupling unification and also of one-loop gauge threshold corrections in intersecting brane world models. Finally we also discuss some aspects of proton decay in intersecting brane world models.Comment: 31 pages, To appear in the proceedings of the RTN-workshop ``The quantum structure of spacetime and the geometric nature of fundamental interactions'', September 2003 in Copenhagen, revised version contains new refs and one corrected equatio

Testing association of rare genetic variants with resistance to three common antiseizure medications

OBJECTIVE: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). METHODS: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. RESULTS: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. SIGNIFICANCE: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance

CHD2 variants are a risk factor for photosensitivity in epilepsy

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2·17 × 10−5). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3·50 × 10−4). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability

Origin of Cosmic Magnetic Fields

We propose that the overlapping shock fronts from young supernova remnants produce a locally unsteady, but globally steady large scale spiral shock front in spiral galaxies, where star formation and therefore massive star explosions correlate geometrically with spiral structure. This global shock front with its steep gradients in temperature, pressure and associated electric fields will produce drifts, which in turn give rise to a strong sheet-like electric current, we propose. This sheet current then produces a large scale magnetic field, which is regular, and connected to the overall spiral structure. This rejuvenates the overall magnetic field continuously, and also allows to understand that there is a regular field at all in disk galaxies. This proposal connects the existence of magnetic fields to accretion in disks. We not yet address all the symmetries of the magnetic field here; the picture proposed here is not complete. X-ray observations may be able to test it already.Comment: 18 pages, no figures; to be published in Proc. Palermo Meeting Sept. 2002, Eds. N. G. Sanchez et al., The Early Universe and the Cosmic Microwave Background: Theory and Observation

Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP-001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 7 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions

Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Objective: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). Significance: In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments

Polygenic risk score analysis reveals shared genetic burden between epilepsy and psychiatric comorbidities

One in three people with epilepsy experiences psychiatric comorbidity, with higher rates in people with drug-resistant epilepsy. Despite their high heritabilities, finding genetic links between epilepsy and psychiatric disorders has proven difficult. We used polygenic risk scoring (PRS) to test whether people with epilepsy have an increased polygenic burden of common genetic variants for depression, anxiety, psychosis, and attention deficit/hyperactivity disorder (ADHD), and examined whether such polygenic burden influences the response to pharmacological treatment of epilepsy.MethodsPhenotype data in the UK Biobank were assessed to identify people with 1) epilepsy (n=8 488), 2) depression (n=143 440), 3) psychosis (n=2 357), 4) ADHD (n=89), and 5) anxiety (n=18 222. Using genotype data and restricting to Caucasian-ancestry samples (n=409 634), PRS for each psychiatric trait were calculated and multinomial regression was used to compare 1) population controls, 2) people with epilepsy and no psychiatric illness, 3) people with epilepsy and the psychiatric trait of interest, and 4) people with the psychiatric trait of interest and no epilepsy. Fixed-effect meta-analysis was used to compare psychiatric PRS in drug-resistant and drug-responsive epilepsy samples from the UK Biobank (n=1 640) and the EpiPGX consortium (n=3 449).ResultsAfter correction for multiple testing, people with epilepsy showed elevated PRS for depression (p<2 x10−16), psychosis (p=0.04) and ADHD (p<0.001). Patients with drug-resistant epilepsy had an increased PRS for psychosis (p=0.002) and depression (p=0.0004) relative to responsive cases.ConclusionWe present evidence that the common genetic basis of epilepsy overlaps with that of psychiatric conditions which are frequently comorbid in people with epilepsy. Common genetic variants that drive psychiatric illness are enriched in people with drug-resistant epilepsy. These results further our understanding of the genetic architecture of epilepsy and suggest a potential future role for polygenic interpretation of common variants in prognostic stratification, both for seizure-treatment outcomes and non-seizure comorbidities.R-AGR-0363 - EpiPGX part UL (01/11/2011 - 21/09/2016) - SCHNEIDER Reinhard3. Good health and well-bein

Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. METHODS: Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. RESULTS: Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. SIGNIFICANCE: Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS

Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as path