We consider a system of N∈N mean-field interacting stochastic differential equations that are driven by Brownian noise and a single-site potential of the form z↦z4∕4−z2∕2. The strength of the noise ...is measured by a small parameter ε>0 (which we interpret as the temperature), and we suppose that the strength of the interaction is given by J>0. Choosing the empirical mean (P:RN→R, Px=1∕N∑ixi) as the macroscopic order parameter for the system, we show that the resulting macroscopic Hamiltonian has two global minima, one at −mε⋆<0 and one at mε⋆>0. Following this observation, we are interested in the average transition time of the system to P−1(mε⋆), when the initial configuration is drawn according to a probability measure (the so-called last-exit distribution), which is supported around the hyperplane P−1(−mε⋆). Under the assumption of strong interaction, J>1, the main result is a formula for this transition time, which is reminiscent of the celebrated Eyring–Kramers formula (see Bovier et al. (2004)) up to a multiplicative error term that tends to 1 as N→∞ and ε↓0. The proof is based on the potential-theoretic approach to metastability.
In the last chapter we add some estimates on the metastable transition time in the high-temperature regime, where ε=1, and for a large class of single-site potentials.
It is well-known that many diffusion equations can be recast as Wasserstein gradient flows. Moreover, in recent years, by modifying the Wasserstein distance appropriately, this technique has been ...transferred to further evolution equations and systems; see e.g. Maas (2011), Fathi and Simon (2016), Erbar (2016). In this paper we establish such a gradient flow representation for evolution equations that depend on a non-evolving parameter. These equations are connected to a local mean-field interacting spin system. We then use this gradient flow representation to prove a large deviation principle for the empirical process associated to this system. This is done by using the criterion established in Fathi (2016). Finally, the corresponding hydrodynamic limit is shown by using the approach initiated in Sandier and Serfaty (2004) and Serfaty (2011).
The present study was conducted to determine the predictive value of Selenium (Se) in the diagnosis of Geatational diabetes Mellitus (GDM).
This is a nested case-control study with 636 normal ...pregnant mothers in their 11th-13th weeks. Gestational diabetes screening was done in weeks 24-28. Twenty-five individuals were detected as GDM, and for every GDM two gestational age-matched normal pregnant women were selected. The blood selenium level was measured in both groups.
The serum Se level in the case group was lower than that of the control group (50.60 ± 10.88 versus 66.02 ± 10.57) in the first trimester. Also, in the second trimester, Se was lower in the case group (39.87 ± 10.23 versus 63.17 ± 10.22). The best cut-off point for selenium in order to predict the incidence of gestational diabetes in our study was 48.2. Pregnant women with selenium levels below 48.2 were more likely to develop gestational diabetes.
Serum selenium was lower in the GDM subjects compared with age-matched control group; the clinical concept and mechanism of this finding need to be investigated through further studies.
Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular ...karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.
Isocitrate lyase is important for lipid utilisation by Mycobacterium tuberculosis but its ICL2 isoform is poorly understood. Here we report that binding of the lipid metabolites acetyl-CoA or ...propionyl-CoA to ICL2 induces a striking structural rearrangement, substantially increasing isocitrate lyase and methylisocitrate lyase activities. Thus, ICL2 plays a pivotal role regulating carbon flux between the tricarboxylic acid (TCA) cycle, glyoxylate shunt and methylcitrate cycle at high lipid concentrations, a mechanism essential for bacterial growth and virulence.
Objective
To identify a genetic cause for migrating partial seizures in infancy (MPSI).
Methods
We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected ...family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22.
Results
In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1‐p16.3 and chromosome 11p15.4‐pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport.
Interpretation
We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22. Ann Neurol 2013;74:873–882
Background: Vitamin D has a role in the pathogenesis of many medical disorders, especially those of the central nervous system. It is essential in maintaining the bone health of children. However, ...patients with epilepsy are at high risk of developing vitamin D deficiency due to antiseizure medications (ASMs). Therefore, we aimed to assess the prevalence of vitamin D deficiency and related risk factors in children with epilepsy. Methods: This is the baseline report of a pragmatic, randomized, controlled, open-label trial that assessed the impact of vitamin D supplementation in preventing vitamin D deficiency (NCT03536845). We included children with epilepsy aged 2–16 years who were treated with ASMs from December 2017 to March 2021. Children with preexisting vitamin D metabolism problems, vitamin-D-dependent rickets, malabsorption syndromes, renal disease, and hepatic disease were excluded. The baseline demographic data, anthropometric measurements, seizure types, epilepsy syndromes, ASMs, and seizure control measures were recorded. Blood tests for vitamin D (25-hydroxyvitamin D 25(OH)D), serum calcium, serum phosphorus, and parathyroid hormone levels were performed. Based on vitamin D concentration, patients were categorized as deficient (<50 nmol/L), insufficient (74.9–50 nmol/L), or normal (>75 nmol/L). Results: Of 159 recruited children, 108 (67.92%) had generalized seizures, 44 (27.67%) had focal seizures, and 7 (4.4%) had unknown onset seizures. The number of children receiving monotherapy was 128 (79.0%) and 31 (19.1%) children were receiving polytherapy. The mean vitamin D concentration was 60.24 ± 32.36 nmol/L; 72 patients (45.28%) had vitamin D deficiency and 45 (28.3%) had vitamin D insufficiency. No significant difference in vitamin D concentration was observed between children receiving monotherapy and those receiving polytherapy. The main risk factors of vitamin D deficiency were obesity and receiving enzyme-inducer ASMs. Conclusions: The prevalence of vitamin D deficiency was high among children with epilepsy. Obese children with epilepsy and those on enzyme-inducer ASMs were at increased risk for vitamin D deficiency. Further studies are needed to establish strategies to prevent vitamin D deficiency.
ObjectivesAccording to the World Health Organization, depression is a common mental health illness that is characterised by a persistent feeling of sadness and loss of interest. The present study ...examined the association of two mental health variables (ie, depression, anxiety) with quality of life (QoL) and the sociodemographic characteristics of Afghan women living in urban areas under the rule of Taliban government in Afghanistan.DesignCross-sectional study administered between 10 November 2021 to 25 December 2021 among women.SettingAcross major provinces of Afghanistan (Herat, Mazar-e-Sharif, Kabul and Samangan).MeasurementsData were collected using a pretested structured questionnaire. Data entry was carried out using Microsoft Excel 2016. And then exported to IBM SPSS V.26 for Microsoft Windows. Logistic regression models were used to examine the association of depression, anxiety with QoL and sociodemographic characteristics among women (N=438).ResultsThe prevalence of depression symptoms was 80.4%, and the prevalence of mild to extremely severe anxiety was 81.0%. Depression symptoms among Afghan women were associated with being older, having more children, lower education level, other individuals’ bad behaviour, bad events experienced in the past month, and feeling physically ill. Multiple regression analysis indicated that low monthly household income (adjusted OR, AOR 2.260; 95% CI 1.179 to 4.331, p=0.014) poor physical domain of QoL (AOR 4.436; 95% CI 1.748 to 11.256, p=0.002) and poor psychological domain of QoL (AOR 23.499; 95% CI 7.737 to 71.369, p<0.001) were significantly associated with depression.ConclusionThe prevalence of depression was high among women living under the government of the Taliban in Afghanistan. Considering the high prevalence of depression, anxiety and their impact on QoL and the overall quality of healthcare services, international health organisations should implement programmes for regular screening of depression and anxiety, and there should be psychological counselling services available for vulnerable women living under the government of the Taliban.
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