Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. ...Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive.
A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder.
By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1.
We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems.
Not applicable.
Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.
Human skin is permanently exposed to microorganisms, but rarely infected. One reason for this natural resistance might be the existence of a 'chemical barrier' consisting in constitutively and ...inducibly produced antimicrobial peptides and proteins (AMPs). Many of these AMPs can be induced in vitro by proinflammatory cytokines or bacteria. Apart from being expressed in vivo in inflammatory lesions, some AMPs are also focally expressed in skin in the absence of inflammation. This suggests that non-inflammatory stimuli of endogenous and/or exogenous origin can also stimulate AMP synthesis without inflammation. Such mediators might be ideal 'immune stimulants' to induce only the innate antimicrobial skin effector molecules without causing inflammation.
As the dairy cow uses body energy reserves in early lactation, body condition scoring has become an integral part of dairy herd management. Several methods based on visual and tactile evaluation have ...been developed. Problems caused by the subjectivity of these techniques have been reported. Alternative approaches to predict energy reserves or energy balance in dairy cattle include metabolic profiling and measurement of live weight, heart girth, or skinfold thickness. A less common method to assess fat reserves in body tissues is measuring backfat thickness (BFT) by using ultrasound. An ultrasound technique has been established to predict carcass quality in beef cattle. A new aspect is the application of ultrasound as a monitoring tool in dairy herd management where another location has to be evaluated. This technique has been validated by relating BFT to total body fat (TBF) content and carcass BFT. Backfat thickness also has been related to other methods of body condition scoring. Target values for the development of BFT throughout lactation are available. The relationship between BFT and TBF content is highly significant although biased by multiple factors. A change in BFT of 1mm equates to approximately 5kg of TBF content. Measuring BFT by ultrasound is of added value compared with other body condition scoring systems because it is objective and precise. Changes in body condition can be detected and evaluated properly.
Optical fibre communication is the backbone of the internet. As essential core technologies are approaching their limits of size, speed and energy-efficiency, there is a need for new technologies ...that offer further scaling of data transmission capacity. Here we show that a single optical frequency-comb source based on a silicon nitride ring resonator supports data capacities in the petabit-per-second regime. We experimentally demonstrate transmission of 1.84 Pbit s–1 over a 37-core, 7.9-km-long fibre using 223 wavelength channels derived from a single microcomb ring resonator producing a stabilized dark-pulse Kerr frequency comb. We also present a theoretical analysis that indicates that a single, chip-scale light source should be able to support 100 Pbit s–1 in massively parallel space-and-wavelength multiplexed data transmission systems. Our findings could mark a shift in the design of future communication systems, targeting device-efficient transmitters and receivers.A microcomb source based on a silicon nitride ring resonator is shown to support petabit-per-second data transmission over a multicore optical fibre.
Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. ...Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.
Toll-like receptors (TLRs) play an important part in the innate immune recognition of invading microorganisms, initiating sufficient immune responses. Growing amounts of data suggest that the ability ...of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious or inflammatory disease. Most studies have focused on two cosegregating SNPs—Asp299Gly and Thr399Ile—within the gene encoding TLR4, the receptor for bacterial lipopolysaccharide. These SNPs are present in approximately 10% of white individuals, and have been found to be positively correlated with several infectious diseases. However, these SNPs seem to protect from atherosclerosis and related diseases, which is reviewed in this article also. Meanwhile, SNPs of genes encoding other TLRs—eg, TLR2, which recognises a wide variety of microbial ligands—have been reported, and preliminary studies indicate an impact on susceptibility to infectious and inflammatory diseases as well. This review summarises and discusses the results obtained, and draws conclusions from these data.
The development of an elasto-plastic phase-field model is presented which is able to predict nonlinear behavior of high performance concrete (HPC) during low-cycle fatigue. An elasto-plastic damage ...model which follows the Drucker–Prager yield criterion is formulated. For the modeling of unsymmetric tension–compression behavior of HPC two different continuous stepwise linearly approximated degradation functions for HPC in tension and in compression are used. The experimental three-point bending tests at low-cycle using notched beams of pure HPC are performed. Load–CMOD (crack mouth opening displacement) curves are plotted using the measured experimental data and residual stiffness–CMOD curves are calculated using these experimental Load–CMOD curves. The data used for the interpolation of degradation functions are calibrated using the experimental results for three-point bending tests. For that purpose the uniaxial tension and uniaxial compression tests and three-point bending beam test for HPC are simulated numerically. The accuracy of the proposed numerical model using the presented integration algorithm is verified by comparing the degradation of stiffness in numerical and experimental results.
The pseudo-ductile material behavior of fiber reinforced high performance concrete is mainly characterized by the fiber pullout process. Thereby, complex fiber–concrete interactions, i.e. interface ...debonding, concrete micro cracks, slippage, adhesion and further unknown processes, are commonly investigated in single-fiber pullout tests. The study in this contribution is based on the experimental results of Gebuhr etal., (2019) and compares three different numerical models applied to the fiber pullout test. An accurate and efficient model for fiber pullout behavior forms the basis for the prediction of the overall behavior by means of composite models or multi-scale approaches in subsequent studies.
•Three different numerical models applied to fiber pullout test are compared.•The study is based on the experimental results of Gebuhr etal., (2019).•Simulations methods are phase-field fracture, cohesive interface and a super-element.
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