We introduce Springs, Sites, and Langevin Dynamics (SpringSaLaD), a comprehensive software platform for spatial, stochastic, particle-based modeling of biochemical systems. SpringSaLaD models ...biomolecules in a coarse-grained manner as a group of linked spherical sites with excluded volume. This mesoscopic approach bridges the gap between highly detailed molecular dynamics simulations and the various methods used to study network kinetics and diffusion at the cellular level. SpringSaLaD is a standalone tool that supports model building, simulation, visualization, and data analysis, all through a user-friendly graphical user interface that should make it more accessible than tools built into more comprehensive molecular dynamics infrastructures. Importantly, for bimolecular reactions we derive an exact expression relating the macroscopic on-rate to the various microscopic parameters with the inclusion of excluded volume; this makes SpringSaLaD more accurate than other tools, which rely on approximate relationships between these parameters.
Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related ...psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping.
Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia.
Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping.
These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping.
Compositional stratigraphy, generally composed of Al‐rich clay minerals overlying Fe/Mg‐rich clay minerals, is observed in many locations on Mars. Here we describe the occurrence of such ...mineralogical stratigraphy in settings where the protoliths are almost certainly pyroclastic materials. One such example includes altered rocks high on the summit and flanks of explosive volcanoes in Thaumasia Planum. These clay‐bearing deposits are most consistent with precipitation‐driven weathering of ash deposits. Considering explosive volcanism was pervasive in the Noachian, the early sedimentary record of Mars in some locations is likely dominated by glassy, fragmented, porous, chemically reactive materials with highly specific surface area. These pyroclastic deposits were potentially a critical geological component linking clay minerals to elements of Mars’ climate, weathering, and sedimentary puzzle.
Plain Language Summary
On Earth, basaltic volcanoes are not extremely explosive but on Mars, similar mafic volcanism would have been much more explosive due to lower crustal and atmospheric pressures. Volcanic ash should therefore be extremely widespread on the red planet. In this work, we show a link between the observed clay minerals seen from orbit via visible/near‐infrared spectroscopy and a geologic context within ash deposits formed from explosive volcanism. We suggest that the weathering of highly chemically reactive ash deposits can explain the origin of many layered clay‐bearing deposits on Mars. Volcanism may have produced ash deposits and driven climate excursions that led to weathering of the ash under somewhat warmer or wetter conditions.
Key Points
Smoking‐gun evidence of pedogenic weathering pyroclastic deposits was found on volcanoes at high elevations
Our results provide a contextual link between ancient precipitation‐driven pedogenic weathering sequences and explosive volcanism on Mars
Pyroclastics are likely a key component of Mars’ sedimentary record, and alteration of these deposits was perhaps a fundamental process on the early Mars
Mucolipidosis II is a neurometabolic lysosomal trafficking disorder of infancy caused by loss of mannose 6-phosphate targeting signals on lysosomal proteins, leading to lysosomal dysfunction and ...accumulation of non-degraded material. However, the identity of storage material and mechanisms of neurodegeneration in mucolipidosis II are unknown. We have generated 'knock-in' mice with a common mucolipidosis II patient mutation that show growth retardation, progressive brain atrophy, skeletal abnormalities, elevated lysosomal enzyme activities in serum, lysosomal storage in fibroblasts and brain and premature death, closely mimicking the mucolipidosis II disease in humans. The examination of affected mouse brains at different ages by immunohistochemistry, ultrastructural analysis, immunoblotting and mass spectrometric analyses of glycans and anionic lipids revealed that the expression and proteolytic processing of distinct lysosomal proteins such as α-l-fucosidase, β-hexosaminidase, α-mannosidase or Niemann-Pick C2 protein are more significantly impacted by the loss of mannose 6-phosphate residues than enzymes reaching lysosomes independently of this targeting mechanism. As a consequence, fucosylated N-glycans, GM2 and GM3 gangliosides, cholesterol and bis(monoacylglycero)phosphate accumulate progressively in the brain of mucolipidosis II mice. Prominent astrogliosis and the accumulation of organelles and storage material in focally swollen axons were observed in the cerebellum and were accompanied by a loss of Purkinje cells. Moreover, an increased neuronal level of the microtubule-associated protein 1 light chain 3 and the formation of p62-positive neuronal aggregates indicate an impairment of constitutive autophagy in the mucolipidosis II brain. Our findings demonstrate the essential role of mannose 6-phosphate for selected lysosomal proteins to maintain the capability for degradation of sequestered components in lysosomes and autophagolysosomes and prevent neurodegeneration. These lysosomal proteins might be a potential target for a valid therapeutic approach for mucolipidosis II disease.
Nitriding, as one of the most widely used surface treatment, was often applied in order to improve the hardness, fatigue strength as well as wear and corrosion resistance of steels. The controlled ...gas nitriding resulted in a formation of a compound zone ε+(ε+γ′) of limited thickness close to the surface and the diffusion zone below it. It was easy to identify the two separate zones in the microstructure: more porous zone with only ε-Fe3N iron nitrides and zone with ε+γ′ iron nitrides' mixture (Fe3N + Fe4N). In this study, the laser modification without re-melting was carried out after the controlled gas nitriding in order to change microstructure. The nanomechanical properties of the zones with iron nitrides, observed in the compound zone, were examined using the nanoindenter with a Berkovich diamond tip. Young's modulus and hardness were measured and compared to the literature data. The load-displacement curves and the indentation images were shown for the selected measurements. The advantageous influence of laser heat treatment on the Young's modulus and hardness was confirmed for the outer ε zone as well as for the laser quenched diffusion zone. The higher average values of indentation modulus and hardness characterized ε iron nitrides (EIT = 165.72 ± 18.67 GPa and HIT = 9.90 ± 0.47 GPa) and laser quenched diffusion zone (EIT = 199.06 ± 28.80 GPa and HIT = 7.11 ± 0.61 GPa) after laser heat treatment. The diminished porosity of ε zone and the presence of martensite in the diffusion zone were the reason for such a situation. The laser heat treatment almost didn't influence the indentation modulus of zone with ε+γ′ iron nitrides' mixture (EIT = 175.27 ± 4.81 GPa), whereas its hardness was slightly increased (HIT = 11.87 ± 0.43 GPa). The conclusion regarding the percentage of the separate phases (ε and γ′) in this zone was ambiguous.
•Controlled gas nitriding provided the surface layer with iron nitrides close to the surface.•The two zones of iron nitrides were easy to identify: ε-Fe3N and ε+γ' (Fe3N + Fe4N).•After laser heat treatment, ε zone was characterized by a diminished porosity.•Nanoindenter was used for determining the Young's moduli and hardness of nitrides.•Laser heat treatment improved the nanomechanical properties of ε iron nitrides.
The selection of Gale crater as the Mars Science Laboratory landing site took over five years, involved broad participation of the science community via five open workshops, and narrowed an initial ...>50 sites (25 by 20 km) to four finalists (Eberswalde, Gale, Holden and Mawrth) based on science and safety. Engineering constraints important to the selection included: (1) latitude (±30°) for thermal management of the rover and instruments, (2) elevation (<−1 km) for sufficient atmosphere to slow the spacecraft, (3) relief of <100–130 m at baselines of 1–1000 m for control authority and sufficient fuel during powered descent, (4) slopes of <30° at baselines of 2–5 m for rover stability at touchdown, (5) moderate rock abundance to avoid impacting the belly pan during touchdown, and (6) a radar-reflective, load-bearing, and trafficable surface that is safe for landing and roving and not dominated by fine-grained dust. Science criteria important for the selection include the ability to assess past habitable environments, which include diversity, context, and biosignature (including organics) preservation. Sites were evaluated in detail using targeted data from instruments on all active orbiters, and especially Mars Reconnaissance Orbiter. All of the final four sites have layered sedimentary rocks with spectral evidence for phyllosilicates that clearly address the science objectives of the mission. Sophisticated entry, descent and landing simulations that include detailed information on all of the engineering constraints indicate all of the final four sites are safe for landing. Evaluation of the traversabilty of the landing sites and target “go to” areas outside of the ellipse using slope and material properties information indicates that all are trafficable and “go to” sites can be accessed within the lifetime of the mission. In the final selection, Gale crater was favored over Eberswalde based on its greater diversity and potential habitability.
Phosphodiesterases (PDEs) are important modulators of inflammation and wound healing. In this capacity, specific targeting of PDEs for the treatment of many diseases, including chronic obstructive ...pulmonary disease (COPD), has been investigated. Currently, treatment of COPD is suboptimal. PDE4 modulates the inflammatory response of the lung, and inhibition of PDE4 may be a novel, COPD‐specific approach toward more effective treatment strategies. This review describes the state of PDE4‐inhibitor therapy for use in COPD treatment.
Clinical Pharmacology & Therapeutics (2012); 91 1, 134–142. doi:10.1038/clpt.2011.266
Calcium/calmodulin-dependent protein kinase II (CaMKII) is a synaptic, autophosphorylating kinase that is essential for learning and memory. Previous models have suggested that CaMKII functions as a ...bistable switch that could be the molecular correlate of long-term memory, but experiments have failed to validate these predictions. These models involved significant approximations to overcome the combinatorial complexity inherent in a multisubunit, multistate system. Here, we develop a stochastic particle-based model of CaMKII activation and dynamics that overcomes combinatorial complexity without significant approximations. We report four major findings. First, the CaMKII model system is never bistable at resting calcium concentrations, which suggests that CaMKII activity does not function as the biochemical switch underlying long-term memory. Second, the steady-state activation curves are either laserlike or steplike. Both are characterized by a well-defined threshold for activation, which suggests that thresholding is a robust feature of this system. Third, transiently activated CaMKII can maintain its activity over the time course of many experiments, and such slow deactivation may account for the few reports of bistability in the literature. And fourth, under in vivo conditions, increases in phosphatase activity can increase CaMKII activity. This is a surprising and counterintuitive effect, as dephosphorylation is generally associated with CaMKII deactivation.
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