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Historians have long lamented the lack of contemporary documentary sources for the Islamic middle ages and the inhibiting effect this has had on our understanding of this critically important period. Although the field is richly served by surviving evidence, much of it is hard to locate, difficult to access, and philologically intractable. Presenting a mixture of historical studies and new editions of Greek, Arabic and Coptic material from the seventh to the fifteenth century C.E. from Egypt and Palestine, Documents and the History of the Early Islamic World explores the untapped wealth of documentary sources available in collections around the world and shows how this exciting material can be used for historical analysis.

Documents and the History of the Early Islamic World presents new Greek, Arabic and Coptic material from the seventh to the fifteenth centuries C.E. from Egypt and Palestine and explores its rich potential for historical analysis.

Family offices are taking off. As the ranks of America's wealthy swell, having a \"money butler\" on hand to oversee the management of family finances is seen as a safe and effective way to coordinate and preserve personal wealth. But the phenomenon's rapid growth has meant that its control environment has often been left struggling to catch up. One of the safeguards that is available, however, is the audit. The article considers some of its benefits.

This study provides insights into conformational changes that lead to phospho-ubiquitin-induced PARKIN activation and how PARKIN is recruited to phospho-ubiquitin chains on mitochondria; the crystal structure of PARKIN in complex with phospho-ubiquitin also indicates that the pocket within PARKIN where phospho-ubiquitin binds carries amino acid residues that are mutated in patients with autosomal-recessive juvenile Parkinsonism. PARKIN activation mechanism revealed The enzymatic duo PARKIN and PINK1 are notable not only because they regulate the process of mitophagy, whereby the cell degrades its damaged mitochondria, but also because they are mutated in autosomal-recessive juvenile Parkinson disease (AR-JP). At a molecular level, PINK1 activates PARKIN by phosphorylating both the ubiquitin (Ub)-like (Ubl) domain of PARKIN and Ub molecules. David Komander and colleagues provide insights into conformational changes that lead to phosphoUb-induced PARKIN activation and how PARKIN recruits phosphoUb chains on mitochondria. The crystal structure of PARKIN in complex with phosphoUb also indicates that the pocket within PARKIN where phosphoUb binds carries amino acid residues that are mutated in patients with AR-JP. The E3 ubiquitin ligase PARKIN (encoded by PARK2 ) and the protein kinase PINK1 (encoded by PARK6 ) are mutated in autosomal-recessive juvenile Parkinsonism (AR-JP) and work together in the disposal of damaged mitochondria by mitophagy 1 , 2 , 3 . PINK1 is stabilized on the outside of depolarized mitochondria and phosphorylates polyubiquitin 4 , 5 , 6 , 7 , 8 as well as the PARKIN ubiquitin-like (Ubl) domain 9 , 10 . These phosphorylation events lead to PARKIN recruitment to mitochondria, and activation by an unknown allosteric mechanism 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . Here we present the crystal structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate pocket and harbours residues mutated in patients with AR-JP. PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl phosphorylation by PINK1, leading to conformational changes within the Ubl domain and stabilization of an open, active conformation of PARKIN. We redefine the role of the Ubl domain not only as an inhibitory 13 but also as an activating element that is restrained in inactive PARKIN and released by phosphoUb. Our work opens up new avenues to identify small-molecule PARKIN activators.

The inherently weak chiroptical responses of natural materials limit their usage for controlling and enhancing chiral light-matter interactions. Recently, several nanostructures with subwavelength scale dimensions were demonstrated, mainly due to the advent of nanofabrication technologies, as a potential alternative to efficiently enhance chirality. However, the intrinsic lossy nature of metals and the inherent narrowband response of dielectric planar thin films or metasurface structures pose severe limitations toward the practical realization of broadband and tailorable chiral systems. Here, we tackle these problems by designing all-dielectric silicon-based L-shaped optical metamaterials based on tilted nanopillars that exhibit broadband and enhanced chiroptical response in transmission operation. We use an emerging bottom-up fabrication approach, named glancing angle deposition, to assemble these dielectric metamaterials on a wafer scale. The reported strong chirality and optical anisotropic properties are controllable in terms of both amplitude and operating frequency by simply varying the shape and dimensions of the nanopillars. The presented nanostructures can be used in a plethora of emerging nanophotonic applications, such as chiral sensors, polarization filters, and spin-locked nanowaveguides. L-shaped silicon metamaterials are realized exhibiting broadband and enhanced chirality. The current work sets new benchmarks in the assembly of ultrathin dielectric chiral metamaterials that can efficiently control chiral light-matter interactions.

Structural and biochemical analyses of human USP30 explain the basis of Lys6-linkage preference and regulation by PINK1 and Parkin, shedding light onto how USP30 can act as a brake on mitophagy. Damaged mitochondria undergo mitophagy, a specialized form of autophagy that is initiated by the protein kinase PINK1 and the ubiquitin E3 ligase Parkin. Ubiquitin-specific protease USP30 antagonizes Parkin-mediated ubiquitination events on mitochondria and is a key negative regulator of mitophagy. Parkin and USP30 both show a preference for assembly or disassembly, respectively, of Lys6-linked polyubiquitin, a chain type that has not been well studied. Here we report crystal structures of human USP30 bound to monoubiquitin and Lys6-linked diubiquitin, which explain how USP30 achieves Lys6-linkage preference through unique ubiquitin binding interfaces. We assess the interplay between USP30, PINK1 and Parkin and show that distally phosphorylated ubiquitin chains impair USP30 activity. Lys6-linkage-specific affimers identify numerous mitochondrial substrates for this modification, and we show that USP30 regulates Lys6-polyubiquitinated TOM20. Our work provides insights into the architecture, activity and regulation of USP30, which will aid drug design against this and related enzymes.

Transcript elongation factors (TEFs) are a heterogeneous group of proteins that control the efficiency of transcript elongation of subsets of genes by RNA polymerase II (RNAPII) in the chromatin context. Using reciprocal tagging in combination with affinity purification and mass spectrometry, we demonstrate that in Arabidopsis thaliana, the TEFs SPT4/SPT5, SPT6, FACT, PAF1-C, and TFIIS copurified with each other and with elongating RNAPII, while P-TEFb was not among the interactors. Additionally, NAP1 histone chaperones, ATP-dependent chromatin remodeling factors, and some histone-modifying enzymes including Elongator were repeatedly found associated with TEFs. Analysis of double mutant plants defective in different combinations of TEFs revealed genetic interactions between genes encoding subunits of PAF1-C, FACT, and TFIIS, resulting in synergistic/epistatic effects on plant growth/development. Analysis of subnuclear localization, gene expression, and chromatin association did not provide evidence for an involvement of the TEFs in transcription by RNAPI (or RNAPIII). Proteomics analyses also revealed multiple interactions between the transcript elongation complex and factors involved in mRNA splicing and polyadenylation, including an association of PAF1-C with the polyadenylation factor CstF. Therefore, the RNAPII transcript elongation complex represents a platform for interactions among different TEFs, as well as for coordinating ongoing transcription with mRNA processing.

In this randomized trial, eculizumab, a humanized monoclonal antibody against C5 that inhibits terminal complement activation, was compared with placebo as a treatment for paroxysmal nocturnal hemoglobinuria. The antibody stabilized hemoglobin levels, decreased the need for transfusions, and improved the quality of life by reducing intravascular hemolysis. Eculizumab stabilized hemoglobin levels, decreased the need for transfusions, and improved the quality of life by reducing intravascular hemolysis. (Figure courtesy of Alexion Pharmaceuticals.) Paroxysmal nocturnal hemoglobinuria (PNH), an uncommon form of hemolytic anemia, results from the clonal expansion of hematopoietic stem cells that have somatic mutations in the X-linked gene PIG-A . 1 , 2 PIG-A mutations cause an early block in the synthesis of glycosylphosphatidylinositol (GPI) anchors, which tether many proteins to the cell surface. Consequently, the blood cells in patients with PNH have a partial deficiency (type II) or a complete deficiency (type III) of GPI-linked proteins. Intravascular hemolysis is a prominent feature of PNH and is the consequence of the absence of the GPI-linked complement regulatory protein CD59. 3 , 4 CD59 blocks the . . .

CRISPR-based diagnostics enable specific sensing of DNA and RNA biomarkers associated with human diseases. This is achieved through the binding of guide RNAs to a complementary sequence that activates Cas enzymes to cleave reporter molecules. Currently, most CRISPR-based diagnostics rely on target preamplification to reach sufficient sensitivity for clinical applications. This limits quantification capability and adds complexity to the reaction chemistry. Here we show the combination of a CRISPR–Cas-based reaction with a nanozyme-linked immunosorbent assay, which allows for the quantitative and colorimetric readout of Cas13-mediated RNA detection through catalytic metallic nanoparticles at room temperature (CrisprZyme). We demonstrate that CrisprZyme is easily adaptable to a lateral-flow-based readout and different Cas enzymes and enables the sensing of non-coding RNAs including microRNAs, long non-coding RNAs and circular RNAs. We utilize this platform to identify patients with acute myocardial infarction and to monitor cellular differentiation in vitro and in tissue biopsies from prostate cancer patients. We anticipate that CrisprZyme will serve as a universally applicable signal catalyst for CRISPR-based diagnostics, which will expand the spectrum of targets for preamplification-free, quantitative detection.The combination of catalytic platinum particles, nanozymes and a CRISPR-based reaction allows for the quantification of non-coding RNAs at the picomolar range. This assay, CrisprZyme, has a colorimetric readout and works at room temperature without preamplification.