A synchrotron wide-angle x-ray scattering study of mung bean (Vigna radiata) primary cell walls was combined with published solid-state nuclear magnetic resonance data to test models for packing of ...(1→4)-β-glucan chains in cellulose microfibrils. Computer-simulated peak shapes, calculated for 36-chain microfibrils with perfect order or uncorrelated disorder, were sharper than those in the experimental diffractogram. Introducing correlated disorder into the models broaden the simulated peaks but only when the disorder was increased to unrealistic magnitudes. Computer-simulated diffractograms, calculated for 24- and 18-chain models, showed good fits to experimental data. Particularly good fits to both x-ray and nuclear magnetic resonance data were obtained for collections of 18-chain models with mixed cross-sectional shapes and occasional twinning. Synthesis of 18-chain microfibrils is consistent with a model for cellulose-synthesizing complexes in which three cellulose synthase polypeptides form a particle and six particles form a rosette.
Ultrasound exposure (USE) in the presence of microbubbles (MCB) (e.g. contrast agents used to enhance ultrasound imaging) increases plasmid transfection efficiency in vitro by several orders of ...magnitude. Formation of short-lived pores in the plasma membrane ('sonoporation'), up to 100 nm in effective diameter lasting a few seconds, is implicated as the dominant mechanism, associated with acoustic cavitation. Ultrasound enhanced gene transfer (UEGT) has also been successfully achieved in vivo, with reports of spatially restricted and therapeutically relevant levels of transgene expression. Loading MCB with nucleic acids and/or disease-targeting ligands may further improve the efficiency and specificity of UEGT such that clinical testing becomes a realistic prospect.
Chemists often use statistical analysis of reaction data with molecular descriptors to identify structure-reactivity relationships, which can enable prediction and mechanistic understanding. In this ...study, we developed a broadly applicable and quantitative classification workflow that identifies reactivity cliffs in 11 Ni- and Pd-catalyzed cross-coupling datasets using monodentate phosphine ligands. A distinctive ligand steric descriptor, minimum percent buried volume %
(min), is found to divide these datasets into active and inactive regions at a similar threshold value. Organometallic studies demonstrate that this threshold corresponds to the binary outcome of bisligated versus monoligated metal and that %
(min) is a physically meaningful and predictive representation of ligand structure in catalysis.
Genetics and Genomics of Pulmonary Arterial Hypertension Soubrier, Florent, MD, PhD; Chung, Wendy K., MD, PhD; Machado, Rajiv, PhD ...
Journal of the American College of Cardiology,
12/2013, Letnik:
62, Številka:
25
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic ...protein receptor type 2 ( BMPR2 ) as the major predisposing gene and activin A receptor type II-like kinase-1 ( ACVRL1 , also known as ALK1 ) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.
The physiological and biomechanical requirements of flight at high altitude have been the subject of much interest. Here, we uncover a steep relation between heart rate and wingbeat frequency (raised ...to the exponent 3.5) and estimated metabolic power and wingbeat frequency (exponent 7) of migratory bar-headed geese. Flight costs increase more rapidly than anticipated as air density declines, which overturns prevailing expectations that this species should maintain high-altitude flight when traversing the Himalayas. Instead, a "roller coaster" strategy, of tracking the underlying terrain and discarding large altitude gains only to recoup them later in the flight with occasional benefits from orographic lift, is shown to be energetically advantageous for flights over the Himalayas.
Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin ...transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of
Himipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.
In contrast to temporal coding by synaptically acting neurotransmitters such as glutamate, neuromodulators such as monoamines signal changes in firing rate. The two modes of signaling have been ...thought to reflect differences in release by different cells. We now find that midbrain dopamine neurons release glutamate and dopamine with different properties that reflect storage in different synaptic vesicles. The vesicles differ in release probability, coupling to presynaptic Ca2+ channels and frequency dependence. Although previous work has attributed variation in these properties to differences in location or cytoskeletal association of synaptic vesicles, the release of different transmitters shows that intrinsic differences in vesicle identity drive different modes of release. Indeed, dopamine but not glutamate vesicles depend on the adaptor protein AP-3, revealing an unrecognized linkage between the pathway of synaptic vesicle recycling and the properties of exocytosis. Storage of the two transmitters in different vesicles enables the transmission of distinct signals.
•Dopamine neurons release glutamate and dopamine with different probability•Coreleased glutamate and dopamine differ in coupling to presynaptic Ca2+ channels•Neurons make two types of synaptic vesicle that differ in response to stimulation•AP-3 is required specifically for formation of synaptic vesicles storing dopamine
In this work on glutamate corelease by dopamine neurons, Silm et al. show that an individual neuron expresses two classes of synaptic vesicle that form through distinct mechanisms and transmit distinct information due to differences in frequency dependence.
Protein succinylation has recently emerged as an important and common post-translation modification (PTM) that occurs on lysine residues. Succinylation is notable both in its size (e.g., at 100 Da, ...it is one of the larger chemical PTMs) and in its ability to modify the net charge of the modified lysine residue from + 1 to - 1 at physiological pH. The gross local changes that occur in proteins upon succinylation have been shown to correspond with changes in gene activity and to be perturbed by defects in the citric acid cycle. These observations, together with the fact that succinate is generated as a metabolic intermediate during cellular respiration, have led to suggestions that protein succinylation may play a role in the interaction between cellular metabolism and important cellular functions. For instance, succinylation likely represents an important aspect of genomic regulation and repair and may have important consequences in the etiology of a number of disease states. In this study, we developed DeepSuccinylSite, a novel prediction tool that uses deep learning methodology along with embedding to identify succinylation sites in proteins based on their primary structure.
Using an independent test set of experimentally identified succinylation sites, our method achieved efficiency scores of 79%, 68.7% and 0.48 for sensitivity, specificity and MCC respectively, with an area under the receiver operator characteristic (ROC) curve of 0.8. In side-by-side comparisons with previously described succinylation predictors, DeepSuccinylSite represents a significant improvement in overall accuracy for prediction of succinylation sites.
Together, these results suggest that our method represents a robust and complementary technique for advanced exploration of protein succinylation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Sperm DNA damage is considered a predictive factor for the clinical outcomes of patients undergoing ART. Laboratory evidence suggests that zygotes and developing embryos have adopted ...specific response and repair mechanisms to repair DNA damage of paternal origin. We have conducted a systematic review in accordance with guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to identify and review the maternal mechanisms used to respond and repair sperm DNA damage during early embryonic development, how these mechanisms operate and their potential clinical implications. The literature search was conducted in Ovid MEDLINE and Embase databases until May 2021. Out of 6297 articles initially identified, 36 studies were found to be relevant through cross referencing and were fully extracted. The collective evidence in human and animal models indicate that the early embryo has the capacity to repair DNA damage within sperm by activating maternally driven mechanisms throughout embryonic development. However, this capacity is limited and likely declines with age. The link between age and decreased DNA repair capacity could explain decreased oocyte quality in older women, poor reproductive outcomes in idiopathic cases and patients who present high sperm DNA damage. Ultimately, further understanding mechanisms underlying the maternal repair of sperm DNA damage could lead to the development of targeted therapies to decrease sperm DNA damage, improved oocyte quality to combat incoming DNA insults or lead to development of methodologies to identify individual spermatozoa without DNA damage.
Degradation of coral reef ecosystems began centuries ago, but there is no global summary of the magnitude of change. We compiled records, extending back thousands of years, of the status and trends ...of seven major guilds of carnivores, herbivores, and architectural species from 14 regions. Large animals declined before small animals and architectural species, and Atlantic reefs declined before reefs in the Red Sea and Australia, but the trajectories of decline were markedly similar worldwide. All reefs were substantially degraded long before outbreaks of coral disease and bleaching. Regardless of these new threats, reefs will not survive without immediate protection from human exploitation over large spatial scales.
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