The surrounding rock of the Lannigou gold mine roadway is mainly sandstone, most of which contains thin interlayers of argillaceous and carbonaceous minerals. To explore the deformation and failure ...mechanism of interbedded sandstones under static load caused by surrounding rock stress, the macroscopic failure modes, macroscopic physical properties, and microscopic fracture surface characteristics of sandstones were studied from different inclination angles. Triaxial compression tests and scanning electron microscopy tests were conducted. The results show that the peak strength of the specimen changes in a "spoon"-shaped pattern with increasing inclination. With increasing confining pressure, the peak strength, peak strain, residual strength, and elastic modulus of specimens increase, which damages interlayers. The macroscopic failure mode is mainly affected by the interlayer without confining pressure, and both tensile-shear failure (0° and 90°) and composite failure (30° and 60°) occur. Under higher confining pressure, the effect of the interlayer is smaller, and the specimen shows shear-tensile failure (0°, 30°, 60°, and 90°). Furthermore, the propagation mode of microcracks and the microscopic failure mode of mineral crystals differ for different macroscopic failure modes. In this study, the microscopic mechanism of macroscopic failure of interbedded sandstone was identified, which is significant for practical engineering guidance.
Abstract Background Proteinuria is a prevalent symptom of pediatric nephrology, while kidney biopsy remains the gold standard for kidney tissue analysis, and it is currently controversial. We report ...the rare case that the mutation in the AMN gene was considered to cause chronically isolated proteinuria and also suggest that renal biopsy should be chosen with caution in children with chronic isolated non-nephrotic levels of proteinuria and that genetic testing may be feasible for the early precise diagnosis. Case presentation A 35-month-old boy presented with excessive urine foaming for more than half a month; his proteinuria was considered non-nephrotic range and urine protein electrophoresis was suggestive of mixed proteinuria; other than that, the investigations are non-specific. Given the child’s chronic isolated proteinuria and good renal function, we chose to refine the genetic test rather than a renal biopsy; a compound heterozygous variant was found in the AMN gene of this child which was caused by a point mutation in the father, and a partial chromosomal deletion in the mother. Conclusions Cubilin(encoded by CUBN), amnionless(encoded by AMN), and megalin form a multiligand receptor complex; CUBN or AMN gene variants have been implicated as a hereditary cause of megaloblastic anemia, proteinuria, and neurological impairment. In the past few decades, chronic isolated proteinuria caused by CUBN gene variants is benign, non-progressive, and has normal renal function. However, the child is the first reported case of isolated proteinuria of AMN gene mutation, indicating that the earlier diagnostic genetic sequencing in an otherwise well, not nephrotic proteinuria child may be a convenient, cost-effective, and harmless option, challenging the traditional paradigm.
Memristive devices are promising candidates to emulate biological computing. However, the typical switching voltages (0.2-2 V) in previously described devices are much higher than the amplitude in ...biological counterparts. Here we demonstrate a type of diffusive memristor, fabricated from the protein nanowires harvested from the bacterium Geobacter sulfurreducens, that functions at the biological voltages of 40-100 mV. Memristive function at biological voltages is possible because the protein nanowires catalyze metallization. Artificial neurons built from these memristors not only function at biological action potentials (e.g., 100 mV, 1 ms) but also exhibit temporal integration close to that in biological neurons. The potential of using the memristor to directly process biosensing signals is also demonstrated.
Intrinsically disordered proteins (IDPs) often fold into stable structures upon specific binding. The roles of residual structure of unbound IDPs in coupling binding and folding have been under much ...debate. While many studies emphasize the importance of conformational flexibility for IDP recognition, it was recently demonstrated that stabilization the N-terminal helix of intrinsically disordered ACTR accelerated its binding to another IDP, NCBD of the CREB-binding protein. To understand how enhancing ACTR helicity accelerates binding, we derived a series of topology-based coarse-grained models that mimicked various ACTR mutants with increasing helical contents and reproduced their NCBD binding affinities. Molecular dynamics simulations were then performed to sample hundreds of reversible coupled binding and folding transitions. The results show that increasing ACTR helicity does not alter the baseline mechanism of synergistic folding, which continues to follow “extended conformational selection” with multiple stages of selection and induced folding. Importantly, these coarse-grained models, while only calibrated based on binding thermodynamics, recapitulate the observed kinetic acceleration with increasing ACTR helicity. However, the residual helices do not enhance the association kinetics via more efficient seeding of productive collisions. Instead, they allow the nonspecific collision complexes to evolve more efficiently into the final bound and folded state, which is the primary source of accelerated association kinetics. Meanwhile, reduced dissociation kinetics with increasing ACTR helicity can be directly attributed to smaller entropic cost of forming the bound state. Altogether, this study provides important mechanistic insights into how residual structure may modulate thermodynamics and kinetics of IDP interactions.
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•Mechanistic roles of residual structure in IDP binding remain intensely debated.•Topology-based modeling recapitulates increasing ACTR helicity enhances binding rate.•Residual helices mainly promote more efficient folding following binding.•Efficient folding upon binding is critical for achieving fast IDP association kinetics
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Efficient coarse-grained (CG) models can be coupled with atomistic force fields to accelerate the sampling of atomistic energy landscapes in the multi-scale enhanced sampling (MSES) framework. This ...approach may be particularly suitable for generating atomistic conformational ensembles of intrinsically disordered proteins (IDPs). While MSES is relatively robust to inherent CG artifacts, achieving optimal sampling efficiency requires CG modeling to generate the local and long-range fluctuations that are largely consistent with those at the atomistic level. Here, we describe a new hybrid resolution CG model (HyRes) for MSES simulations of disordered protein states, which is specifically designed to provide semi-quantitative secondary structure propensities together with a qualitative description of long-range nonspecific interactions. The HyRes model contains an atomistic description of the backbone with intermediate resolution side chains. The secondary structure propensities are tuned by adjusting the backbone hydrogen-bonding strength and the ϕ/ψ torsion profile. The sizes and covalent geometries of the side chains are parameterized to reproduce distributions derived from atomistic simulations. Lennard-Jones parameters for sidechain beads are assigned to reproduce statistical potentials derived from the protein structural database, and then globally parameterized with nonspecific electrostatic interactions to reproduce the free energy profiles of pair wise interactions and the key conformational properties of model peptides. Application of HyRes to MSES simulations of small IDPs suggests that it is capable of driving faster structural transitions at the atomistic level and increasing the convergence rate compared to the Cα-only Gō-like models previously utilized. With further optimization, we believe that the new CG model could greatly improve the efficiency of MSES simulations of the larger and more complex IDPs frequently involved in cellular signalling and regulation.
Epigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Using SPR and NMR, here we report a direct, ...μM interaction between EGCG and the tumor suppressor p53 (K
= 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the major binding site (K
= 4 ± 2 μM). Large scale atomistic simulations (>100 μs), SAXS and AUC demonstrate that EGCG-NTD interaction is dynamic and EGCG causes the emergence of a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for anti-tumor activity. Our work provides insights into the mechanisms for EGCG's anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.
The mouse is a promising model in the study of visual system function and development because of available genetic tools. However, a quantitative analysis of visual receptive field properties had not ...been performed in the mouse superior colliculus (SC) despite its importance in mouse vision and its usefulness in developmental studies. We have made single-unit extracellular recordings from superficial layers of the SC in urethane-anesthetized C57BL/6 mice. We first map receptive fields with flashing spot stimuli and show that most SC neurons have spatially overlapped ON and OFF subfields. With drifting sinusoidal gratings, we then determine the tuning properties of individual SC neurons, including selectivity for stimulus direction and orientation, spatial frequency tuning, temporal frequency tuning, response linearity, and size preference. A wide range of receptive field sizes and selectivity are observed across the population and in various subtypes of SC neurons identified morphologically. In particular, orientation-selective responses are discovered in the mouse SC, and they are not affected by cortical lesion or long-term visual deprivation. However, ON/OFF characteristics and spatial frequency tuning of SC neurons are influenced by cortical inputs and require visual experience during development. Together, our results provide essential information for future investigations on the functional development of the superior colliculus.
Galactose-deficient IgA1 was evaluated in patients with IgA nephropathy(IgAN) and controls in order to determine the predictive value of galactose-deficient IgA1 in cases of IgA nephropathy.
PubMed, ...EMBASE, Cochrane central register of controlled trials, CNKI, CBM disc, and VIP database were searched to identify eligible studies that evaluated a difference in aberrant IgA1 glycosylation in IgAN patients compared with controls. A meta-analysis was conducted to evaluate the impact of galactose-deficient IgA1(Gd-IgA1) levels in different groups.
A total of 22 studies (n = 1657) met inclusion criteria. The mean Newcastle-Ottawa Scale (NOS) score was 7.2 and ranged from 6 to 8. The standard mean difference(SMD) in the meta-analysis of 20 studies of the level of Gd-IgA1 in the serum and/or supernatant of cultured cells was higher in the IgAN group compared with healthy controls as well as in those with other renal diseases (SMD = 1.76, 95% CI = 1.18-2.34, P<0.00001; SMD = 1.05, 95% CI = 0.05-2.04, P = 0.04). The data synthesis suggested that IgAN patients had similar levels of serum Gd-IgA1, with no significant differences, compared with first-degree relatives and Henoch-Schonlein purpura nephritis (HSPN) patients (MD = 0.04, 95% CI = 0.00-0.08, P = 0.05; MD = -46.03, 95% CI = -217.70-125.64, P = 0.60). In addition, the combined MD of 5 studies indicated that there were no significant differences in Gd-IgA1 levels among patients with varying severities of IgAN (MD = 0.02, 95% CI = -0.02-0.05, P = 0.28).
The pooled evidence suggests that the level of Gd-IgA1 in the serum or supernatant of cultured cells from peripheral blood or tonsils may be a useful biomarker for predicting IgA nephropathy, though the level of Gd-IgA1 was not significantly associated with disease severity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The superior colliculus (SC) is the most prominent visual center in mice. Studies over the past decade have greatly advanced our understanding of the function, organization, and development of the ...mouse SC, which has rapidly become a popular model in vision research. These studies have described the diverse and cell-type-specific visual response properties in the mouse SC, revealed their laminar and topographic organizations, and linked the mouse SC and downstream pathways with visually guided behaviors. Here, we summarize these findings, compare them with the rich literature of SC studies in other species, and highlight important gaps and exciting future directions. Given its clear importance in mouse vision and the available modern neuroscience tools, the mouse SC holds great promise for understanding the cellular, circuit, and developmental mechanisms that underlie visual processing, sensorimotor transformation, and, ultimately, behavior.
Antiapoptotic Bcl-xL plays central roles in regulating programed cell death. Partial unfolding of Bcl-xL has been observed at the interface upon specific binding to the pro-apoptotic BH3-only protein ...PUMA, which in turn disrupts the interaction of Bcl-xL with tumor suppressor p53 and promotes apoptosis. Previous analysis of existing Bcl-xL structures and atomistic molecular dynamics (MD) simulations have suggested that substantial intrinsic structure heterogeneity exists at the BH3-only protein binding interface of Bcl-xL to facilitate its conformational transitions upon binding. In this study, enhanced sampling is applied to further characterize the interfacial conformations of unbound Bcl-xL in explicit solvent. Extensive replica exchange with solute tempering (REST) simulations, with a total accumulated time of 16 μs, were able to cover much wider conformational spaces for the interfacial region of Bcl-xL. The resulting structural ensembles are much better converged, with local and long-range structural features that are highly consistent with existing NMR data. These simulations further demonstrate that the BH3-only protein binding interface of Bcl-xL is intrinsically disordered and samples many rapidly interconverting conformations. Intriguingly, all previously observed conformers are well represented in the unbound structure ensemble. Such intrinsic structural heterogeneity and flexibility may be critical for Bcl-xL to undergo partial unfolding induced by PUMA binding, and likely provide a robust basis that allows Bcl-xL to respond sensitively to binding of various ligands in cellular signaling and regulation.
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IJS, KILJ, NUK, PNG, UL, UM
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