Isoiminosugars are highly biological active substances. Herein, we report a concise synthetic approach for this class of compounds. The key step relies on a stereospecific 1,2-hydride shift in O-2 tosylated glycopyranosides leading to C-2 branched glycofuranosides.
View Article and Find Full Text PDFAs a corridor for population movement out of Africa, the southern Levant is a natural laboratory for research exploring the dynamics of the Middle-to-Upper Paleolithic transition. Yet, the number of well-preserved sites dating to the initial millennia of the Early Upper Paleolithic (EUP; ∼45-30 ka) remains limited, restricting the resolution at which we can study the biocultural and techno-typological changes evidenced across the transition. With EUP deposits dating to 45-39 ka cal BP, Mughr el-Hamamah, Jordan, offers a key opportunity to expand our understanding of EUP lifeways in the southern Levant.
View Article and Find Full Text PDFSelective covalent labelling of enzymes using small molecule probes has advanced the scopes of protein profiling. The covalent bond formation to a specific target is the key step of activity-based protein profiling (ABPP), a method which has become an indispensable tool for measuring enzyme activity in complex matrices. With respect to carbohydrate processing enzymes, strategies for ABPP so far involve labelling the active site of the enzyme, which results in permanent loss of activity.
View Article and Find Full Text PDFA new class of compounds inhibiting de-O-glycosylation of proteins has been identified. Highly substituted diaminocyclopentanes are impressively selective reversible non-transition state O-β-N-acetyl-d-glucosaminidase (O-GlcNAcase) inhibitors. The ease of preparative access and remarkable biological activities provide highly viable leads for the development of anti-tau-phosphorylation agents with a view to eventually ameliorating Alzheimer's disease.
View Article and Find Full Text PDFObjective: Pregnancy is characterized by well-defined immunological adaptions within the maternal immune cell compartment allowing the survival of a genetically disparate individual in the maternal womb. Phenotype and function of immune cells are largely determined by intracellular processing of external stimuli. Ubiquitinating and deubiquitinating enzymes are known to critically regulate immune signaling either by modulating the stability or the interaction of the signaling molecules.
View Article and Find Full Text PDFAn equilibrium between proinflammatory and anti-inflammatory immune responses is essential for maternal tolerance of the fetus throughout gestation. To study the participation of fetal tissue-derived factors in this delicate immune balance, we analyzed the effects of human chorionic gonadotropin (hCG) on murine Treg cells and Th17 cells , and on pregnancy outcomes, fetal and placental growth, blood flow velocities and remodeling of the uterine vascular bed . Compared with untreated CD4CD25 T cells, hCG increased the frequency of Treg cells upon activation of the LH/CG receptor.
View Article and Find Full Text PDFObjective: This experiment tested if balance performance differed between a standardized treadmill surface perturbation task and a clinical pull test and was affected by medication or the presence of body weight support in people with Parkinson's disease (PD).
Methods: Twenty-seven individuals were tested (14 PD in both ON- and OFF-medication states). Clinical pull test and rapid forward (backward fall) translations of the support surface were applied to induce postural reactions requiring at least 1 step to restore balance.
We developed potent and selective aminocyclopentane-derived inhibitors of human -acetyl-β-D-glucosaminidase (OGA) implicated in Alzheimer's disease. For example compound 13 was a nanomolar OGA inhibitor with 92 000-fold selectivity over human HexB. It was non-toxic and increased protein -GlcNAcylation in the culture of murine neural cells, showing new alternatives in the treatment of tauopathies.
View Article and Find Full Text PDFA set of cyclopentanoid α-galactosidase ligands was prepared from a partially protected ω-eno-aldose a reliable (2 + 3)-cycloaddition protocol with slightly modified conditions. The obtained -benzylisoxazolidine ring was selectively opened and the configuration of the hydroxymethylgroup was inverted. Consecutive deprotection provided an aminocyclopentane, which was -alkylated to furnish a set of potential α-galactosidase inhibitors.
View Article and Find Full Text PDFThe PROSPECT and STEREO collaborations present a combined measurement of the pure ^{235}U antineutrino spectrum, without site specific corrections or detector-dependent effects. The spectral measurements of the two highest precision experiments at research reactors are found to be compatible with χ^{2}/ndf=24.1/21, allowing a joint unfolding of the prompt energy measurements into antineutrino energy.
View Article and Find Full Text PDFDifferent extensions of the standard model of particle physics, such as braneworld or mirror matter models, predict the existence of a neutron sterile state, possibly as a dark matter candidate. This Letter reports a new experimental constraint on the probability p for neutron conversion into a hidden neutron, set by the STEREO experiment at the high flux reactor of the Institut Laue-Langevin. The limit is p<3.
View Article and Find Full Text PDFObjective: The medial olivocochlear (MOC) reflex provides unmasking of sounds in noise, but its contribution to speech-in-noise perception remains unclear due to conflicting results. This study determined associations between MOC reflex strength and sentence recognition in noise in individuals with normal hearing.
Design: MOC reflex strength was assessed using contralateral inhibition of transient-evoked otoacoustic emissions (TEOAEs).
We assessed the feasibility of using hematological parameters (such as hemoglobin and reticulocyte mRNA) in dried blood spot (DBS) samples to test athletes for doping and to improve patient care. Hemoglobin and erythropoiesis-related mRNAs were measured in venous blood and DBSs from both healthy athletes and hemodialysis patients. We accurately measured hemoglobin changes over time in both venous blood and DBS samples.
View Article and Find Full Text PDFA short survey on selected β-galactosidase inhibitors as potential pharmacological chaperones for G -gangliosidosis and Morquio B associated mutants of human lysosomal β-galactosidase is provided highlighting recent developments in this particular area of lysosomal storage disorders and orphan diseases.
View Article and Find Full Text PDFThe mechanisms behind the evolution of complex genomic amplifications in cancer have remained largely unclear. Using whole-genome sequencing data of the pediatric tumor neuroblastoma, we here identified a type of amplification, termed 'seismic amplification', that is characterized by multiple rearrangements and discontinuous copy number levels. Overall, seismic amplifications occurred in 9.
View Article and Find Full Text PDFPurpose: We evaluated the predictive and prognostic value of circulating tumor DNA (ctDNA) in patients with Ewing sarcoma (EWS) treated in the EWING2008 trial.
Experimental Design: Plasma samples from 102 patients with EWS enrolled in the EWING2008 trial were obtained before and during induction chemotherapy. Genomic fusion sequence spanning primers and probes were used for highly specific and sensitive quantification of the levels of ctDNA by digital droplet PCR.
Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations.
View Article and Find Full Text PDFKallmann syndrome is the result of innate genetic defects in the fibroblast growth factor (FGF) regulated signaling network causing diminished signal transduction. One of the rare mutations associated with the syndrome alters the Sprouty (Spry)4 protein by converting the serine at position 241 into a tyrosine. In this study, we characterize the tyrosine Spry4 mutant protein in the primary human embryonic lung fibroblasts WI-38 and osteosarcoma-derived cell line U2OS.
View Article and Find Full Text PDFWe report a measurement of the antineutrino rate from the fission of ^{235}U with the STEREO detector using 119 days of reactor turned on. In our analysis, we perform several detailed corrections and achieve the most precise single measurement at reactors with highly enriched ^{235}U fuel. We measure an IBD cross section per fission of σ_{f}=(6.
View Article and Find Full Text PDFPodocyte injury has recently been described as unifying feature in idiopathic nephrotic syndromes (INS). Puumala hantavirus (PUUV) infection represents a unique RNA virus-induced renal disease with significant proteinuria. The underlying pathomechanism is unclear.
View Article and Find Full Text PDFThe scope of a series of -alkylated iminosugar based inhibitors in the d- as well as d- configuration towards their interaction with human lysosomal β-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis of -alkylated iminosugar scaffolds conjugated to a variety of terminal groups via a benzoic acid ester linker. The terminal groups such as nitrile, azide, alkyne, nonafluoro--butyl and amino substituents enable follow-up chemistry as well as visualisation experiments.
View Article and Find Full Text PDFGlycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4--isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a "strategic" hydroxyl group.
View Article and Find Full Text PDFDouble-strand breaks (DSBs) are the most toxic type of DNA lesions. Cells repair these lesions using either end protection- or end resection-coupled mechanisms. To study DSB repair choice, we present the Color Assay Tracing-Repair (CAT-R) to simultaneously quantify DSB repair via end protection and end resection pathways.
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