We describe the Geophysical Fluid Dynamics Laboratory's CM4.0 physical climate model, with emphasis on those aspects that may be of particular importance to users of this model and its simulations. ...The model is built with the AM4.0/LM4.0 atmosphere/land model and OM4.0 ocean model. Topics include the rationale for key choices made in the model formulation, the stability as well as drift of the preindustrial control simulation, and comparison of key aspects of the historical simulations with observations from recent decades. Notable achievements include the relatively small biases in seasonal spatial patterns of top‐of‐atmosphere fluxes, surface temperature, and precipitation; reduced double Intertropical Convergence Zone bias; dramatically improved representation of ocean boundary currents; a high‐quality simulation of climatological Arctic sea ice extent and its recent decline; and excellent simulation of the El Niño‐Southern Oscillation spectrum and structure. Areas of concern include inadequate deep convection in the Nordic Seas; an inaccurate Antarctic sea ice simulation; precipitation and wind composites still affected by the equatorial cold tongue bias; muted variability in the Atlantic Meridional Overturning Circulation; strong 100 year quasiperiodicity in Southern Ocean ventilation; and a lack of historical warming before 1990 and too rapid warming thereafter due to high climate sensitivity and strong aerosol forcing, in contrast to the observational record. Overall, CM4.0 scores very well in its fidelity against observations compared to the Coupled Model Intercomparison Project Phase 5 generation in terms of both mean state and modes of variability and should prove a valuable new addition for analysis across a broad array of applications.
Plain Language Summary
The Geophysical Fluid Dynamics Laboratory (GFDL) of the National Oceanic and Atmospheric Administration participates along with a number of model centers around the world in constructing state‐of‐the‐art climate models for use in studies for climate change and prediction. GFDL's latest multipurpose atmosphere‐ocean coupled climate model, CM4.0, is described here. It consists of GFDL's latest atmosphere and land models at about 100 km horizontal resolution and ocean and sea ice models at roughly 25 km horizontal resolution. A handful of standard experiments have been conducted with CM4.0 for participation in the Coupled Model Intercomparison Project Phase 6, an archive of climate model results utilized by the Intergovernmental Panel on Climate Change and the climate research community more generally. The model results have been extensively evaluated against observations. This paper makes the case that CM4.0 ranks high among state‐of‐the‐art coupled climate models by many measures of bias in the simulated climatology and in its ability to capture modes of climate variability such as the El Niño‐Southern Oscillation and Madden‐Julian Oscillation. The paper also discusses some potential weaknesses, including unrealistically large internal variability in the Southern Ocean and insufficient warming before 1990 in the simulation of the twentieth century.
Key Points
A team at GFDL has developed a new model of the physical climate system referred to as CM4.0
Strengths of model include ENSO simulation and small biases in TOA fluxes, precipitation, Arctic sea ice extent, and sea surface temperature
Problematic aspects include large variability in Southern Ocean and historical simulation with little warming prior to 1990
The advantages and disadvantages of the article "influenza/pneumonia vaccination status and influencing factors in patients with chronic obstructive pulmonary disease: a real-world cross-sectional ...study" were interpreted by methodological perspective. The importance of topic selection closely combined with clinical problems and needs was emphasized, and reasonable and feasible research methods to escort clinical research. This paper puts forward the necessity and practicality of improving the internal quality of research and paper writing under the framework of "one paper research and answering one question", analyzes the objectives, tasks and reasonable technical route of influencing factor research, and emphasizes that clinical research methods serve to answer clinical and scientific questions.
To maximize a desired product, metabolic engineers typically express enzymes to high, constant levels. Yet, permanent pathway activation can have undesirable consequences including competition with ...essential pathways and accumulation of toxic intermediates. Faced with similar challenges, natural metabolic systems compartmentalize enzymes into organelles or post-translationally induce activity under certain conditions. Here we report that optogenetic control can be used to extend compartmentalization and dynamic control to engineered metabolisms in yeast. We describe a suite of optogenetic tools to trigger assembly and disassembly of metabolically active enzyme clusters. Using the deoxyviolacein biosynthesis pathway as a model system, we find that light-switchable clustering can enhance product formation six-fold and product specificity 18-fold by decreasing the concentration of intermediate metabolites and reducing flux through competing pathways. Inducible compartmentalization of enzymes into synthetic organelles can thus be used to control engineered metabolic pathways, limit intermediates and favor the formation of desired products.
The vasopressin 1b receptor (Avpr1b) is critical for social memory and social aggression in rodents, yet little is known about its specific roles in these behaviors. Some clues to Avpr1b function can ...be gained from its profile of expression in the brain, which is largely limited to the pyramidal neurons of the CA2 region of the hippocampus, and from experiments showing that inactivation of the gene or antagonism of the receptor leads to a reduction in social aggression. Here we show that partial replacement of the Avpr1b through lentiviral delivery into the dorsal CA2 region restored the probability of socially motivated attack behavior in total Avpr1b knockout mice, without altering anxiety-like behaviors. To further explore the role of the Avpr1b in this hippocampal region, we examined the effects of Avpr1b agonists on pyramidal neurons in mouse and rat hippocampal slices. We found that selective Avpr1b agonists induced significant potentiation of excitatory synaptic responses in CA2, but not in CA1 or in slices from Avpr1b knockout mice. In a way that is mechanistically very similar to synaptic potentiation induced by oxytocin, Avpr1b agonist-induced potentiation of CA2 synapses relies on NMDA (N-methyl-D-aspartic acid) receptor activation, calcium and calcium/calmodulin-dependent protein kinase II activity, but not on cAMP-dependent protein kinase activity or presynaptic mechanisms. Our data indicate that the hippocampal CA2 is important for attacking in response to a male intruder and that the Avpr1b, likely through its role in regulating CA2 synaptic plasticity, is a necessary mediator.
Cells produce an extracellular matrix (ECM) with a stereotypic organization that is important for tissue function. The insect cuticle is a layered ECM that mainly consists of the polysaccharide ...chitin and associated proteins adopting a quasi‐crystalline structure. Our understanding of the molecular mechanisms deployed during construction of the highly ordered protein–chitin ECM so far is limited. In this study, we report on the role of the chitin deacetylase 1 (LmCDA1) in the organization of the protein–chitin ECM in the migratory locust Locusta migratoria, and LmCDA1 localizes predominantly to the apical tier of the protein–chitin ECM, but it is also found in lower regions. Reduction of LmCDA1 function correlates with lower amounts of chitin and impedes conversion of chitin to chitosan by deacetylation. Establishment of the quasi‐crystalline architecture of the protein–chitin ECM is, however, independent of LmCDA1 activity, but it is dependent on another chitin deacetylase, LmCDA2, which has no detectable effects on chitin deacetylation and, as shown previously, no influence on chitin content. Our data reveal that LmCDA1 and LmCDA2 act in parallel and independently from each other in defining the dimensions of the cuticle. Both enzymes are non‐uniformly distributed within the protein–chitin matrix, suggesting a site‐autonomous function.
Control of the lac operon with isopropyl β-D-1-thiogalactopyranoside (IPTG) has been used to regulate gene expression in Escherichia coli for countless applications, including metabolic engineering ...and recombinant protein production. However, optogenetics offers unique capabilities, such as easy tunability, reversibility, dynamic induction strength and spatial control, that are difficult to obtain with chemical inducers. We have developed a series of circuits for optogenetic regulation of the lac operon, which we call OptoLAC, to control gene expression from various IPTG-inducible promoters using only blue light. Applying them to metabolic engineering improves mevalonate and isobutanol production by 24% and 27% respectively, compared to IPTG induction, in light-controlled fermentations scalable to at least two-litre bioreactors. Furthermore, OptoLAC circuits enable control of recombinant protein production, reaching yields comparable to IPTG induction but with easier tunability of expression. OptoLAC circuits are potentially useful to confer light control over other cell functions originally designed to be IPTG-inducible.
Summary
Activated acid-sensing ion channel 1a (ASIC1a) is involved in acid-induced osteoclastogenesis by regulating activation of the transcription factor NFATc1. These results indicated that ASIC1a ...activation by extracellular acid may cause osteoclast migration and adhesion through Ca
2+
-dependent integrin/Pyk2/Src signaling pathway.
Introduction
Osteoclast adhesion and migration are responsible for osteoporotic bone loss. Acidic conditions promote osteoclastogenesis. ASIC1a in osteoclasts is associated with acid-induced osteoclastogenesis through modulating transcription factor NFATc1 activation. However, the influence and the detailed mechanism of ASIC1a in regulating osteoclast adhesion and migration, in response to extracellular acid, are not well characterized.
Methods
In this study, knockdown of ASIC1a was achieved in bone marrow macrophage cells using small interfering RNA (siRNA). The adhesion and migration abilities of osteoclast precursors and osteoclasts were determined by adhesion and migration assays, in vitro. Bone resorption was performed to measure osteoclast function. Cytoskeletal changes were assessed by F-actin ring formation. αvβ3 integrin expression in osteoclasts was measured by flow cytometry. Western blotting and co-immunoprecipitation were performed to measure alterations in integrin/Pyk2/Src signaling pathway.
Results
Our results showed that blockade of ASIC1a using ASIC1a-siRNA inhibited acid-induced osteoclast precursor migration and adhesion, as well as osteoclast adhesion and bone resorption; we also demonstrated that inhibition of ASIC1a decreased the cell surface αvβ3 integrin and β3 protein expression. Moreover, blocking of ASIC1a inhibited acidosis-induced actin ring formation and reduced Pyk2 and Src phosphorylation in osteoclasts and also inhibited the acid-induced association of the αvβ3 integrin/Src/Pyk2.
Conclusion
Together, these results highlight a key functional role of ASIC1a/αvβ3 integrin/Pyk2/Src signaling pathway in migration and adhesion of osteoclasts.
As the potential role of the complement system in diabetic nephropathy (DN) is increasingly reported, this study aimed to investigate C1q and C3c deposition as seen on renal histopathology, as well ...as its association with clinical and pathological parameters, in DN patients.
Renal biopsy specimens from 161 DN patients were investigated using direct immunofluorescence, light, and electron microscopy. For direct immunofluorescence, staining for C1q and C3c on fresh-frozen renal tissue was performed immediately after biopsy. Complement deposition was defined as the presence of C1q or C3c of at least 1 + on a 0–4 + Scale. The association between complement deposition and clinicopathological data was also analyzed.
On direct immunofluorescence microscopy, C1q and C3c were detected in specimens from 44/161 (27.3%) and 89/161 (55.3%) patients, respectively. Regarding clinical data, patients with C1q deposition had a significantly higher level of urinary protein (7.25 ± 4.20 g/24 h vs. 4.97 ± 3.76 g/24 h; P < 0.01) and significantly lower estimated glomerular filtration rate (eGFR; 34.16 ± 25.21 mL/min/1.73 m2 vs. 51.17 ± 31.56 mL/min/1.73 m2, respectively; P < 0.01), whereas patients with vs. without C3c deposition had a significantly lower eGFR (40.09 ± 27.97 mL/min/1.73 m2 vs. 54.48 ± 32.49 mL/min/1.73 m2, respectively; P < 0.01). On renal histopathology, patients with C1q deposition had significantly higher Scores for interstitial fibrosis and tubular atrophy (IFTA), interstitial inflammation and vascular lesions (P < 0.01, P < 0.05 and P < 0.05, respectively), whereas patients with C3c deposition had significantly higher IFTA Scores and proportions of global sclerosis (P < 0.01 and P < 0.01, respectively).
Complement deposition of C1q and C3c on renal histopathology is associated with more severe kidney damage in patients with DN.
•Four different atomic component metallic glasses were studied under nanoindentation tests to determine their strain rate sensitivities of hardness.•Strain rate sensitivity of four different BMGs ...were calculated, the mechanism and influencing factors of negative SRS are studied.•The variation trends along with different factors were observed and discussed, creep behavior was observed and we note that the study of the creep behavior can be useful of exploring the deformation mechanism of metallic glasses.
Nanoindentation tests were conducted on Pd40Cu30Ni10P20, (Fe0.6Co0.4)0.75B0.2Si0.0596Nb4, Zr48Cu34Pd2Al8Ag8 and Zr48Cu32Ni4Al8Ag8 bulk metallic glasses to determine their strain rate sensitivities of hardness. Strain rate sensitivities for different experimental conditions were calculated, it was found that all specimens exhibit negative strain rate sensitivity. Different variation trend of strain rate sensitivity values along with different factors were observed, these observations were utilized to discuss the reasons for negative strain rate sensitivity, and its dependence on the composition and other factors of metallic glasses.
Soil organic matter (SOM) is a key property determining soil functions and a major form of carbon stored in soil. Understanding the spatial and temporal variability of SOM and the driving forces ...responsible for spatial and temporal changes is important to assess regional soil quality and carbon sequestration potential and, particularly, to establish better practices for land use and management. We evaluated the spatio‐temporal change in SOM content from 1979–1982 to 2006 and its driving forces in Jiangsu Province, East China, using geostatistics. The results showed that mean SOM content increased from 16.60 ± 8.50 to 18.31 ± 8.32 g/kg over a 26‐yr period. The maps of SOM generated by ordinary kriging represented the increasing trend from north to south across the province in the two periods. The level of SOM in 1979–1982 affected the pattern of change: the SOM increasing in areas initially with a small content while decreasing in areas having a large content. The map of SOM change showed that the rate of increase decreased from north to south within the province. Increased fertilizer application promoted crop production with more residual biomass being retained in the soil, which resulted in increased SOM content. Land use changes to paddy, upland or forest improved SOM content, whereas abandoning land reduced SOM content.
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