Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome

Background Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS. Methods Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment. Results Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP. Conclusions Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected

On the experimental verification of quantum complexity in linear optics

The first quantum technologies to solve computational problems that are beyond the capabilities of classical computers are likely to be devices that exploit characteristics inherent to a particular physical system, to tackle a bespoke problem suited to those characteristics. Evidence implies that the detection of ensembles of photons, which have propagated through a linear optical circuit, is equivalent to sampling from a probability distribution that is intractable to classical simulation. However, it is probable that the complexity of this type of sampling problem means that its solution is classically unverifiable within a feasible number of trials, and the task of establishing correct operation becomes one of gathering sufficiently convincing circumstantial evidence. Here, we develop scalable methods to experimentally establish correct operation for this class of sampling algorithm, which we implement with two different types of optical circuits for 3, 4, and 5 photons, on Hilbert spaces of up to 50,000 dimensions. With only a small number of trials, we establish a confidence >99% that we are not sampling from a uniform distribution or a classical distribution, and we demonstrate a unitary specific witness that functions robustly for small amounts of data. Like the algorithmic operations they endorse, our methods exploit the characteristics native to the quantum system in question. Here we observe and make an application of a "bosonic clouding" phenomenon, interesting in its own right, where photons are found in local groups of modes superposed across two locations. Our broad approach is likely to be practical for all architectures for quantum technologies where formal verification methods for quantum algorithms are either intractable or unknown.Comment: Comments welcom

Tinjauan hukum Islam terhadap praktik simpanan wadiah berjangka di BMT Tegal Ijo Desa Gandul Kecamatan Pilangkenceng Kabupaten Madiun

Penelitian ini bertujuan untuk menjawab permasalahan tentang “Bagaimana Praktik Simpanan Wadiah Berjangka di BMT Tegal Ijo Desa Gandul Kecamatan Pilangkenceng Kabupaten Madiun, dan Bagaimana Hukum Islam Terhadap Praktik Simpanan Wadiah Berjangka di BMT Tegal Ijo Desa Gandul Kecamatan Pilangkenceng Kabupaten Madiun”.Teknik pengumpulan data yang digunakan dalam penelitian ini adalah wawancara (interview) dan dokumentasi. Setelah data terkumpul, data diolah dan dianalisis dengan pola pikir deduktif yaitu menggambarkan prinsip umum simpanan wadiah dalam hukum Islam untuk kemudian di deduksi untuk menganalisa praktik simpanan wadiah berjangka yang terjadi dilapangan. Kesimpulan yang didapatkan tentu bersifat khusus. Hasil penelitian ini menyimpulkan bahwa praktik simpanan wadiah berjangka di BMT Tegal Ijo Desa Gandul Kecamatan Pilangkenceng Kabupaten Madiun memberikan bonus pada awal perjanjian, dan menjadikan produk ini sebagai investasi yang menghasilkan keuntungan, padahal wadiah hanyalah titipan, bukan dana yang bisa di investasikan, sekalipun dana tersebut diinvestasikan, nasabah (penitip) dan pihak BMT tidak boleh saling menjanjikan untuk menghasilkan keuntungan harta tersebut. Dalam melakukan praktik simpanan wadiah berjangka hendaknya BMT Tegal Ijo Desa Gandul Kecamatan Pilangkenceng Kabupaten Madiun tidak memberikan bonus diawal perjanjian, karena hal ini adalah perbuatan yang haram, mengingat didalamnya adalah unsur riba (tambahan) yang dilarang dalam syariat Islam

A transient presence: black visitors and sojourners in Imperial Germany, 1884-1914

The onset of German colonial rule in Africa brought increasing numbers of Black men and women to Germany. Pre-1914 the vast majority of these Africans can best be described as visitors or sojourners and the Black population as a whole was a transient one. This makes recovering their presence in the archival record exceptionally difficult and it is not surprising that the existing historiography almost exclusively focuses on individual biographies of well documented lives. Through utilising a number of newly digitised archival materials, particularly the Hamburg Passenger Lists, this article draws upon a database with information on 1092 individuals from sub-Saharan Africa who spent time in Germany over the period 1884-1914 in order to add considerable bread and depth to our understanding of the Black presence as a whole. It provides increasing empirical detail about the make-up and character of this fluid population - where visitors came from, why they came to Germany, their age on arrival - as well as more accurate detail on the temporal and, to a lesser extent, spatial distribution of visitors

Bi-allelic pathogenic variants in HS2ST1 cause a syndrome characterized by developmental delay and corpus callosum, skeletal and renal abnormalities

Heparan sulfate belongs to the group of glycosaminoglycans (GAGs), highly sulphated linear polysaccharides. Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is one of several specialized enzymes required for heparan sulfate synthesis and catalyzes the transfer of the sulfate groups to the sugar moiety of heparan sulfate. We report biallelic pathogenic variants in the HS2ST1 gene in four individuals from three unrelated families. Affected individuals showed facial dysmorphism with coarse face, upslanted palpebral fissures, broad nasal tip, and wide mouth, developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, flexion contractures, brachydactyly of hands and feet with broad fingertips and toes, and uni- or bilateral renal agenesis in three individuals. HS2ST1 variants cause a reduction in HS2ST1 mRNA and decreased or absent heparan sulfate 2-O-sulfotransferase 1 in two of three fibroblast cell lines derived from affected individuals. The heparan sulfate synthesized by the individual 1 cell line lacks 2-O-sulfated domains but had an increase in N- and 6-O-sulfated domains demonstrating functional impairment of the HS2ST1. As heparan sulfate modulates FGF-mediated signaling, we found a significantly decreased activation of the MAP kinases ERK1/2 in FGF-2-stimulated cell lines of affected individuals that could be restored by addition of heparin, a GAG similar to heparan sulfate. Focal adhesions in FGF-2-stimulated fibroblasts of affected individuals showed an increased length and concentrated at the cell periphery. Our data demonstrate that a heparan sulfate synthesis deficit causes a novel recognizable syndrome and emphasize a role for 2-O-sulfated heparan sulfate in human neuronal, skeletal and renal development

Tim50’s presequence receptor domain is essential for signal driven transport across the TIM23 complex

The Tim50 subunit of the mitochondrial TIM23 complex contains a presequence-binding domain that is essential for viability and precursor transport across the inner membrane

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.© 2023. The Author(s)