ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient's liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency

Effects of Exogenous Auditory Attention on Temporal and Spectral Resolution

Previous research in the visual domain suggests that exogenous attention in form of peripheral cueing increases spatial but lowers temporal resolution. It is unclear whether this effect transfers to other sensory modalities. Here, we tested the effects of exogenous attention on temporal and spectral resolution in the auditory domain. Eighteen young, normal-hearing adults were tested in both gap and frequency change detection tasks with exogenous cuing. Benefits of valid cuing were only present in the gap detection task while costs of invalid cuing were observed in both tasks. Our results suggest that exogenous attention in the auditory system improves temporal resolution without compromising spectral resolution

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO4 we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features

The genetic structure of the Turkish population reveals high levels of variation and admixture

The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl− channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis

Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

SummaryWe have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH

تطوير المواد الدراسية في تعليم مهارة الكتاب في برنامج الخاض لتعليم اللغة العربية في جامعة مولانا مالك ابراهم الإسلامية الحكومية مالانج

ABSTRAK Perkembangan Universitas Islam Negeri Maulana Malik Ibrahim Malang sebagai salah satu Perguruan Tinggi Islam yang berkembang pesat membutuhkan terobosan- terobosan yang handal. Salah satu hal penting yang tidak bisa dipisahkan adalah peranan penting dari PKPBA (Program Khusus Pengembangan Bahasa Arab). PKPBA sebagai sebuah unit pengembangan bahasa, telah berperan penting dalam membantu meningkatkan kemampuan berbahasa mahasiswa khususnya bahasa arab. Banyak dari mahasiswa yang pertama kali masuk PKPBA belum mengetahui bahasa Arab. Namun setelah belajar di PKPBA mereka mampu mengenal ilmu bahasa arab. Namun, tidak hanya berhenti pada mengetahui bahasa arab saja, program ini juga berupaya agar semua mahasiswa mampu untuk menguasai salah satu dari 4 ketrampilan bahasa yakni ketrampilan menulis. Tujuan dari peneliyian ini adalah untuk melengkapi proses pengembangan penyusunan materi ajar menulis dan mengetahui ke-efektifan materi yang dikembangkan. Penelitian ini menggunakan prosedur eksperimen dimana peneliti mendisain Pre-test dan Postest terhadap dua kelompok yakni kelompok eksperimen dan kelompok kontrol. Hasil penelitian ini adalah bahwa pembelajaran ketrampilan menulis dengan menggunakan buku ajar lebih efektif dari pada tanpa menggunakan buku ajar. Dengan indikasi bahwa t-test kelas eksperimen (J3) lebih efektif dengan indikasi bahwa t-test kelas kontrol adalah 3,4. dimana hasil ini lebih besar dari pada tingkat t-table 5% 2,059 dan tingkat 1% 2,787. Dari hasil ini menunjukan bahwa pengajaran menulis bahasa Arab efektif dengan menggunakan materi ajar yang telah disusun oleh peneliti. Hasil penelitian ini adalah: (1) Penyusunan materi ajar untuk PKPBA dimulai dengan membatasi tujuan pengajaran, kemudian menentukan pembagian materi sesuai dengan jumlah hari yang digunakan untuk pembelajaran dalam satu minggu. (2) Pembelajaran menulis bahasa Arab dengan menggunakan Materi ajar ini dinyatakan efektif. Dari hasil yang disebutkan diatas, sudah semestinya materi pengajaran menulis bahasa Arab dapat dimanfaatkan dengan benar dalam proses pengajaran, selain itu penulis berharap agar penelitian ini menjadi referensi untuk penelitian lanjutan yang berhubungan dengan penelitian ini sehingga dapat dikembangkan ke dalam desain materi ajar menulis untuk tingkat selanjutnya. ABSTRACT The expansion of State Islamic University Maulana Malik Ibrahim need some powerful breakthrough. One of the important things is the role of Intensive Arabic Program as unit for improving Arabic, have played an important for helping Arabic language improvement. Most of the students when the first time they enter to this Program, they haven’t yet Arabic knowledge. But after studying in this program for several months they could understand about Arabic. But is not enough in knowing the Arabic only, but this program also try to make all students are mastering one of these four skills, that is writing skill. This research aims at designing process of writing teaching material and finding out the effectiveness of writing teaching material using in Intensive Arabic Program of State Islamic University of Maulana Malik Ibrahim Malang. This research uses the experimental method that the researcher design pre-test and post-test for both groups (Experiment and Control group). This research reach the degree of t-test 3,4 this biggest than t-table at the level of 5% (2,059) and at the level 1% (2,787). This indicates that the use of writing Teaching Material in Arabic for improving writing skill is effective. And the result of this research are obtained bellow: (1) Preparing this teaching material process started by determining the goals, finding out the learning material based on the days in a week which used for teaching (2) The use of writing Teaching Material in Arabic for improving writing skill is effective. Based on these results, teaching material must be used as good as possible in teaching process. Besides, the researcher hopes that the research becomes the reference for further researchers which have a relation with this chapter and could be developed to other teaching material for advance grade

New Two Global Hybrid Optimization Algorithms And Their Applications To The Design Of Microweve Circuits

Tez (Doktora) -- İstanbul Teknik Üniversitesi, Fen Bilimleri Enstitüsü, 1993Thesis (Ph.D.) -- İstanbul Technical University, Institute of Science and Technology, 1993Bu çalışmada bilgisayar destekli devre ve sistem tasarımında kullanılan çeşitli optimisasyon yöntemleri incelenerek mevcut yöntemlere göre daha hisli ve as sayıda fonksiyon incelemesi gerektiren global karma optimisasyon algoritmaları geliştirilmeye çalışılmış ve geliştirilen karma algoritmalar aktif ve pasif mikrodalga devrelerinin tasarımına uygulanmıştır. Bu algoritmalar türev bilgisi gerektirmemektedirler. Türev bilgisi gerektirmeme özelliği, türev bilgisini elde etmek için ek hesaplamalar yapılması zorunluluğunu ortadan kaldırdığı gibi algoritmaların basitliği bunların her tür probleme uygulanmasını da kolaylaştırmaktadır. Oluşturulan algoritmalar global optimisasyon için test fonksiyonlarına uygulanmış ve elde edilen sonuçlar fonksiyon inceleme sayısı, standard süre ve global minimumu bulma yüzdesi bakımlarından literatürde verilen çeşitli algoritmalara ait sonuçlarla karşılaştırılmıştır. Ayrıca yeni geliştirilen karma algoritmalar geniş bandlı kararlı mikrodalga kuvvetlendiricisi, parabolik iletim hattı ve filtre tasarım örneklerine uygulanarak elde edilen sonuçlar tartışılmıştır.Since the 1970s, significant progress has been made in the computer aided design of microwave circuits. In the initial design stage, the configuration and the topology of the circuit are determined. The performance of the initial circuit design is evaluated by computer-aided analysis methods. In the next stage of the CAD procedure, characteristics of a designed circuit computed by circuit analysis subroutines are compared with the given specifications. If the results do not satisfy the desired specifications, the circuit design parameters must be appropriately changed. The sequence of circuit analysis, comparison of circuit characteristics with design specifica tions, and then parameter modification is performed until acceptable performance goals for the circuit are met. This kind of CAD of microwave circuits is performed by using optimisation methods. Optimisation methods may also be used for parameter estimation of passive and active devices on the basis of experimental data. Optimisation in general means to determine the extreme value (maximum or, more often, minimum) of a mathematical function. The optimisation problem is to minimise the scalar function ü-UM (D subject to the inequality constraints: c(x)<0 (2) and equality constraint: /i(*)-0 (3) (vi) Here c{x) and h(x) are, in general nonlinear vector-valued functions of x: for example C(x)= cifx) C2(x).cmcfx), hDoktoraPh.D