Reversing a granular flow on a vibratory conveyor

Experimental results are presented on the transport properties of granular materials on a vibratory conveyor. For circular oscillations of the shaking trough a non-monotonous dependence of the transport velocity on the normalized acceleration is observed. Two maxima are separated by a regime, where the granular flow is much slower and, in a certain driving range, even reverses its direction. A similar behavior is found for a single solid body with a low coefficient of restitution, whereas an individual glass bead of 1 mm diameter is propagated in the same direction for all accelerations.Comment: 4 pages, 5 figures, submitted to Applied Physics Letter

The morphology and application of stem cells in digestive system surgery

Background: Stem cells constitute a group of cells which possess the ability to self-renew as well as the capacity to differentiate into a vast number of different cells within the human organism. Moreover, stem cells are able to undergo a potentially unlimited number of divisions and this characteristic is clinically essential. Specific fields of its application include treatment of diseases mainly in the field of haematology, orthopaedics, surgery, dentistry, and neurology. Materials and methods: In the following work, the current knowledge concerning mechanisms of stem cell treatment in different parts of the digestive system with its diseases as well as adjacent therapy for surgery has been revised. Results: Stem cells therapy may be used in the treatment of various diseases of different parts of the digestive system. This also applies to the end part of the digestive tract (proctological diseases) because stem cells can be used to treat fistulas. Liposuction allows more recovery of mesenchymal stem cells, compared to previous bone marrow harvesting methods. Despite the application of stem cells in the treatment of different diseases used for many years so far, the therapeutic use for the regeneration of the gastrointestinal tract is still rare and unfamiliar. Conclusions: Regenerative medicine seems to be a promising tool in medical research, especially when insulated cells and designed biomaterials are taken into consideration. Major points of discussion include types of stem cells, their origin or differentiation for the treatment of many diseases

Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data

The Evaluation of Optic Nerves Using 7 Tesla 'Silent' Zero Echo Time Imaging in Patients with Leber's Hereditary Optic Neuropathy with or without Idebenone Treatment

Magnetic Resonance Imaging (MRI) of the Optic Nerve is difficult due to the fine extended nature of the structure, strong local magnetic field distortions induced by anatomy, and large motion artefacts associated with eye movement. To address these problems we used a Zero Echo Time (ZTE) MRI sequence with an Adiabatic SPectral Inversion Recovery (ASPIR) fat suppression pulse which also imbues the images with Magnetisation Transfer contrast. We investigated an application of the sequence for imaging the optic nerve in subjects with Leber's hereditary optic neuropathy (LHON). Of particular note is the sequence's near-silent operation, which can enhance image quality of the optic nerve by reducing the occurrence of involuntary saccades induced during Magnetic Resonance (MR) scanning

Characterization of growth and metabolism of the haloalkaliphile Natronomonas pharaonis

Natronomonas pharaonis is an archaeon adapted to two extreme conditions: high salt concentration and alkaline pH. It has become one of the model organisms for the study of extremophilic life. Here, we present a genome-scale, manually curated metabolic reconstruction for the microorganism. The reconstruction itself represents a knowledge base of the haloalkaliphile's metabolism and, as such, would greatly assist further investigations on archaeal pathways. In addition, we experimentally determined several parameters relevant to growth, including a characterization of the biomass composition and a quantification of carbon and oxygen consumption. Using the metabolic reconstruction and the experimental data, we formulated a constraints-based model which we used to analyze the behavior of the archaeon when grown on a single carbon source. Results of the analysis include the finding that Natronomonas pharaonis, when grown aerobically on acetate, uses a carbon to oxygen consumption ratio that is theoretically near-optimal with respect to growth and energy production. This supports the hypothesis that, under simple conditions, the microorganism optimizes its metabolism with respect to the two objectives. We also found that the archaeon has a very low carbon efficiency of only about 35%. This inefficiency is probably due to a very low P/O ratio as well as to the other difficulties posed by its extreme environment

Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis

Purpose We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. Methods Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. Results We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. Conclusion In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome

Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

Mutation of Archaeal Isopentenyl Phosphate Kinase Highlights Mechanism and Guides Phosphorylation of Additional Isoprenoid Monophosphates

I sopentenyl diphosphate (IPP) and its isomeric part-ner dimethylallyl diphosphate (DMAPP) are precur-sors for a diverse collection of primary and second-ary isoprenoid metabolites in all organisms. Following its formation, successive units of IPP are used together either with DMAPP, formed by the action of types I or II IPP isomerases, or with the IPP extended isoprenoid diphosphate chain, to biosynthesize C10, C15, or C20 oligoprenyl diphosphates known as geranyl diphos-phate (GPP), farnesyl diphosphate (FPP), and gera-nylgeranyl diphosphate (GGPP), respectively, as well as larger isoprenoid diphosphates. In plants and some mi-croorganisms, GPP, FPP, and GGPP also serve as start-ingmaterials for the biosynthesis of a large class of spe-cialized and often cyclic terpene hydrocarbons (1). FPP is the most ubiquitous of the three isoprenoid diphos-phate building blocks, as it resides at the juncture of bi

Molecular dynamics of ribosomal elongation factors G and Tu

Translation on the ribosome is controlled by external factors. During polypeptide lengthening, elongation factors EF-Tu and EF-G consecutively interact with the bacterial ribosome. EF-Tu binds and delivers an aminoacyl-tRNA to the ribosomal A site and EF-G helps translocate the tRNAs between their binding sites after the peptide bond is formed. These processes occur at the expense of GTP. EF-Tu:tRNA and EF-G are of similar shape, share a common binding site, and undergo large conformational changes on interaction with the ribosome. To characterize the internal motion of these two elongation factors, we used 25 ns long all-atom molecular dynamics simulations. We observed enhanced mobility of EF-G domains III, IV, and V and of tRNA in the EF-Tu:tRNA complex. EF-Tu:GDP complex acquired a configuration different from that found in the crystal structure of EF-Tu with a GTP analogue, showing conformational changes in the switch I and II regions. The calculated electrostatic properties of elongation factors showed no global similarity even though matching electrostatic surface patches were found around the domain I that contacts the ribosome, and in the GDP/GTP binding region

Metabolism of halophilic archaea

In spite of their common hypersaline environment, halophilic archaea are surprisingly different in their nutritional demands and metabolic pathways. The metabolic diversity of halophilic archaea was investigated at the genomic level through systematic metabolic reconstruction and comparative analysis of four completely sequenced species: Halobacterium salinarum, Haloarcula marismortui, Haloquadratum walsbyi, and the haloalkaliphile Natronomonas pharaonis. The comparative study reveals different sets of enzyme genes amongst halophilic archaea, e.g. in glycerol degradation, pentose metabolism, and folate synthesis. The carefully assessed metabolic data represent a reliable resource for future system biology approaches as it also links to current experimental data on (halo)archaea from the literature