Inhibiting tau protein improves the recovery of spinal cord injury in rats by alleviating neuroinflammation and oxidative stress.

After spinal cord injury, the concentrations of total and hyperphosphorylated tau in cerebrospinal fluid increase, and levels of both correlate with injury severity. Tau inhibition is considered effective therapy for many central nervous system diseases, including traumatic brain injury and Alzheimer's disease. However, whether it can play a role in the treatment of spinal cord injury remains unclear. In this study, the therapeutic effects of tau inhibition were investigated in a rat model of transection spinal cord injury by injecting the rats with a lentivirus encoding tau siRNA that inhibits tau expression. We found that tau inhibition after spinal cord injury down-regulated the levels of inflammatory mediators, including tumor necrosis factor-α, interleukin-6 and interleukin-1ß. It also led to a shift of activated microglial polarization from the M1 pro-inflammatory phenotype to the M2 anti-inflammatory phenotype, and reduced the amount of reactive oxygen species in the acute phase. Furthermore, the survival of residual neural cells around the injury epicenter, and neuronal and axonal regeneration were also markedly enhanced, which promoted locomotor recovery in the model rats. Collectively, our findings support the conclusion that tau inhibition can attenuate neuroinflammation, alleviate oxidative stress, protect residual cells, facilitate neurogenesis, and improve the functional recovery after spinal cord injury, and thus suggest that tau could be a good molecular target for spinal cord injury therapy.

Green and Large-Scale Preparation of Chiral Metal-Organic Frameworks via Mechanochemistry.

It is a significant challenge to construct chiral metal-organic frameworks (CMOFs) by developing a facile and green preparation strategy. In this work, CMOFs were first synthesized via a mechanochemical process by combining a truncated mixed ligand strategy and defect engineering theory. The simple, green, and rapid construction strategy could solvent-freely harvest gram-scale CMOFs with a hierarchical micro/mesoporous structure. The as-synthesized CMOFs were evaluated by Aldol asymmetric catalysis and exhibited excellent catalytic performance (conversion was up to 97.1%, the ee value was 44.3%, and the activity was still good after 5 cycles).

Defect-Engineered Chiral Metal-Organic Frameworks for Efficient Asymmetric Aldol Reaction.

By employment of a mixed truncated chiral ligand synthetic strategy, a defect-engineered chiral metal-organic framework with hierarchical micro/mesoporous structure was prepared, and it exhibited efficient heterogeneous catalytic activity and enantioselectivity for asymmetric aldol reaction.

ß-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion.

Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. ß-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that ß-arrestin 2 also promotes virus-induced production of IFN-ß and clearance of viruses in macrophages. ß-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstream stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of ß-arrestin 2 at Lys171 facilitates the activation of the cGAS-STING signaling and the production of IFN-ß. In vitro, viral infection induces the degradation of ß-arrestin 2 to facilitate immune evasion, while a ß-blocker, carvedilol, rescues ß-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of ß-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.

ß-arrestin 2 quenches TLR signaling to facilitate the immune evasion of EPEC.

The protein translocated intimin receptor (Tir) from enteropathogenic Escherichia coli shares sequence similarity with the host cellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). The ITIMs of Tir are required for Tir-mediated immune inhibition and evasion of host immune responses. However, the underlying molecular mechanism by which Tir regulates immune inhibition remains unclear. Here we demonstrated that ß-arrestin 2, which is involved in the G-protein-coupled receptor (GPCR) signal pathway, interacted with Tir in an ITIM-dependent manner. For the molecular mechanism, we found that ß-arrestin 2 enhanced the recruitment of SHP-1 to Tir. The recruited SHP-1 inhibited K63-linked ubiquitination of TRAF6 by dephosphorylating TRAF6 at Tyr288, and inhibited K63-linked ubiquitination and phosphorylation of TAK1 by dephosphorylating TAK1 at Tyr206, which cut off the downstream signal transduction and subsequent cytokine production. Moreover, the inhibitory effect of Tir on immune responses was diminished in ß-arrestin 2-deficient mice and macrophages. These findings suggest that ß-arrestin 2 is a key regulator in Tir-mediated immune evasion, which could serve as a new therapeutic target for bacterial infectious diseases.

Enterohemorrhagic Escherichia coli Tir inhibits TAK1 activation and mediates immune evasion.

Many pathogens infect hosts through various immune evasion strategies. However, the molecular mechanisms by which pathogen proteins modulate and evade the host immune response remain unclear. Enterohemorrhagic Escherichia coli (EHEC) is a pathological strain that can induce mitogen-activated protein (MAP) kinase (Erk, Jnk and p38 MAPK) and NF-κB pathway activation and proinflammatory cytokine production, which then causes diarrheal diseases such as hemorrhagic colitis and hemolytic uremic syndrome. Transforming growth factor ß-activated kinase-1 (TAK1) is a key regulator involved in distinct innate immune signalling pathways. Here we report that EHEC translocated intimin receptor (Tir) protein inhibits the expression of EHEC-induced proinflammatory cytokines by interacting with the host tyrosine phosphatase SHP-1, which is dependent on the phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs). Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction. Taken together, these results suggest that EHEC Tir negatively regulates proinflammatory responses by inhibiting the activation of TAK1, which is essential for immune evasion and could be a potential target for the treatment of bacterial infection.

Tree clusters in savannas result from islands of soil moisture.

Tree clusters in savannas are commonly found in sizes that follow power laws with well-established exponents. We show that their size distributions could result from the space-time probabilistic structure of soil moisture, estimated over the range of rainfall observed in semiarid savannas; patterns of soil moisture display islands whose size, for moisture thresholds above the mean, follows power laws. These islands are the regions where trees are expected to exist and they have a fractal structure whose perimeter-area relationship is the same as observed in field data for the clustering of trees. When the impact of fire and herbivores is accounted for, as acting through the perimeter of the tree clusters, the power law of the soil moisture islands is transformed into a power law with the same exponents observed in the tree cluster data.

PLCß2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1.

Excessive or uncontrolled release of proinflammatory cytokines caused by severe viral infections often results in host tissue injury or even death. Phospholipase C (PLC)s degrade phosphatidylinositol-4, 5-bisphosphate (PI(4,5)P2) lipids and regulate multiple cellular events. Here, we report that PLCß2 inhibits the virus-induced expression of pro-inflammatory cytokines by interacting with and inhibiting transforming growth factor-ß-activated kinase 1 (TAK1) activation. Mechanistically, PI(4,5)P2 lipids directly interact with TAK1 at W241 and N245, and promote its activation. Impairing of PI(4,5)P2's binding affinity or mutation of PIP2-binding sites on TAK1 abolish its activation and the subsequent production of pro-inflammatory cytokines. Moreover, PLCß2-deficient mice exhibit increased expression of proinflammatory cytokines and a higher frequency of death in response to virus infection, while the PLCß2 activator, m-3M3FBS, protects mice from severe Coxsackie virus A 16 (CVA16) infection. Thus, our findings suggest that PLCß2 negatively regulates virus-induced pro-inflammatory responses by inhibiting phosphoinositide-mediated activation of TAK1.

Brønsted Basicity in Metal-Organic Framework-808 and Its Application in Base-Free Catalysis.

The Brønsted basicity in activated metal-organic framework-808 (hereinafter denoted as MOF-808a) was confirmed by the analyses of CO2-TPD-MS, in situ DRIFTS, and acid-base titration. MOF-808a exhibited efficient recyclable catalytic activities for Heck coupling and oxidation of alcohol as a one-pot tandem reaction in base-free catalysis. It is the first evidence of the Brønsted basicity in zirconium metal-organic frameworks (Zr-MOFs) and gave rise to a new opportunity to extend the catalytic application of Zr-MOFs.

[Impact of Mainstream Backwater on the Water Environment of the Tributaries of the Three Gorges Reservoir at Low Water Level].

To prevent the eutrophication of tributaries and guarantee water quality and safety in the Three Gorges Reservoir, research on the impact of mainstream backwater on tributary water environments is of great significance. The investigation and sampling of the Yangtze mainstream and its major tributaries in the reservoir region were performed from August 7 to August 12, 2016, through which the overall hydrochemical environment of the Three Gorges Reservoir has been revealed, and the impact of mainstream backwater on the hydrochemical characteristics of main tributaries has been determined during the low water level operation period. The results showed the following:① The electrical conductivity of the mainstream varied from 291 µS·cm-1 to 336 µS·cm-1, whereas that of the mainstream backwater unaffected zone of the tributary varied from 183.7 µS·cm-1 to 518 µS·cm-1. The electrical conductivity of the mainstream backwater affected zone of the tributary varied from 267 µS·cm-1 to 330 µS·cm-1, which was close to the mainstream variation range. ② The variation range of the δD and δ18 O values of the mainstream were -81.60‰--75.16‰ and -11.57‰--0.26‰, whereas that of the mainstream backwater unaffected zone of tributaries were -59.94‰--43.67‰ and -9.00‰--6.04‰; those of the mainstream backwater affected zone of tributary were -77.85‰--50.75‰ and -11.06‰--7.33‰, which showed the same pattern as those of electrical conductivity and mass concentration of main anions and cations. This means that the mainstream affected the waterbody composition of tributaries through backwater as well as the chemical characterization of tributary water. The extent of mainstream backwater influence on tributaries was negatively correlated to the distance between the tributary estuary and Three Gorges Dam as well as tributary discharge. The hydrochemical characteristics of the mainstream backwater unaffected zone of the tributary were related to the tributary catchment properties. Tributaries with denser populations and higher proportions of cultivated land have poorer water quality. Mainstream backwater can pollute tributaries of better water quality and optimize those with poor water quality.

Posttranslational Modification Control of Inflammatory Signaling.

Inflammation is usually the defensive reaction of the immune system to the invasion of pathogen and the exogenous objects. The activation of inflammation helps our body to eliminate pathogenic microbe, virus, and parasite harming our health, while under many circumstances inflammation is the direct cause of the pathological damage in tissues and dysfunction of organs. The posttranslational modification (PTM) of the inflammatory pathways, such as TLR pathways, RLR pathways, NLR pathway, intracellular DNA sensors, intracellular RNA sensors, and inflammasomes, is crucial in the regulation of these signaling trails. Ubiquitination, phosphorylation, polyubiquitination, methylation, and acetylation are the main forms of the PTM, and they respectively play different roles in signaling regulation. The effects of the PTM range from the production of pro-inflammatory factors and the interaction between adaptors and receptors to cell translocation in response to the infectious or other dangerous factors. In this chapter, we will have an overview of the different ways of the posttranslational modifications in different inflammatory signaling pathways and their essential roles in regulation of inflammation.

[Hydrological Performance Assessment of Permeable Parking Lots in High Water Areas].

In order to evaluate the hydrological performance of permeable pavements in mitigating the surface runoff, four pilot-scale permeable pavement units were constructed in Shanghai and compared with impervious pavements. Three of the permeable facilities with waterproof liners included a pervious concrete pavement (facility Ⅰ), permeable interlocking concrete pavement using cement stabilized macadam as the base course (facility Ⅱ) and permeable interlocking concrete pavement using macadam as the base course (facility Ⅲ). The other two facilities were a conventional permeable interlocking concrete pavement without a liner (facility Ⅳ) and an impervious concrete pavement control (facility 0). V-notch flow meters, data loggers, and a rainfall meter were mounted to monitor the hydrological data. A double-ring infiltrometer was applied to evaluate the infiltration rate of the pavements. During the one-year experiment, the surface runoff and the underdrain discharge flow rate of the four pilot-scale facilities were continuously monitored in actual rainfall and the total volume reduction, peak flow reduction, and peak concentrating time of different facilities were investigated. The results showed that the surface steady infiltration rates of permeable interlocking concrete pavements were less than those of the pervious concrete, and the surface steady infiltration rates of the two types of surface layers decreased after one year of usage. The surface runoff reduction of the four facilities showed no significant differences. The water volume reduction rate of the three types of facilities was weak. The annual total volume reduction rates were 24.2%, 28.5%, and 28.4%, and the controlled rainfall amounts were 5.2 mm, 7.8 mm, and 7.8 mm. The peak flow reduction rate and the time to the peak flow of facility Ⅰ were smaller than those of facility Ⅱ and facility Ⅲ. The peak flow reduction rate and the time to the peak flow of the three facilities showed significant negative correlation with rainfall intensity.

Modulation of host signaling in the inflammatory response by enteropathogenic Escherichia coli virulence proteins.

To successfully infect host cells and evade the host immune response, a type III secretion system (T3SS) is commonly used by enteric bacterial pathogens such as enteropathogenic Escherichia coli (EPEC). Recent findings have revealed that various effectors are injected into host cells through the T3SS and exert an inhibitory effect on inflammatory signaling pathways, subverting the immune responses to these pathogens. Here we review recent studies aimed at addressing the modulation of several important inflammatory signaling pathways modulated by EPEC effector proteins, such as the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, which provides insight into the unfinished work in this unexplored field and helps to identify novel positions in inflammatory signaling networks for EPEC effectors.Cellular & Molecular Immunology advance online publication, 31 October 2016; doi:10.1038/cmi.2016.52.

Proteomic insights into the temperature responses of a cold-adaptive archaeon Methanolobus psychrophilus R15.

Cold-adaptive methanogens contribute significantly to methane emission from the cold area, while the cold-adaptive mechanisms used by Archaea remain elusive. Methanolobus psychrophilus R15, a cold-adaptive methanogen isolated from a Tibetan plateau wetland, grows at 0-25 °C and optimally at 18 °C when isolated; however, it grows optimally at 30 °C after culturing at 18 °C for several years. Aiming to gain insights into the protein profiles that are involved in optimal growth and cold adaptation of this methanogen, here, we performed a comparative proteomic study using 2D DIGE on the cultures grown at 30, 18 and 4 °C. 1439 protein spots (3167 ORFs annotated in the R15 genome) were detected, and 202 of 322 differentially expressed protein spots were identified by MALDI-TOF/TOF. The protein abundance of most enzymes involved in methanogenesis, energy conservation and central metabolism were increased at 30 °C, while most ribosome proteins were decreased at 30 °C. Proteasome and ROS scavengers increased expressions at 4 °C, suggesting more aberrant proteins and ROS formed at lower temperatures. Different from the cold-adaptive Methanococcoides burtonii, some chaperones were increased at 4 °C, implying that protein folding was impaired at cold in this psychrophilic archaeon. This study indicates that diverse cold-adaptive mechanisms can be used by different methanogenic Archaea.

Psychrotolerant methanogenic archaea: diversity and cold adaptation mechanisms.

Because of their diversity and abundance in a wide range of environments, particularly in cold regions, cold-adaptive archaea are expected to play a pivotal role in material recycling in cold environments. Methanogenic archaea are ubiquitous on earth and produce a large amount of methane (CH(4)) as their main carbon metabolite. Methanogens are the most laboratory amendable archaea. The few psychrophilic archaea that have been cultured to date are mainly affiliated with methanogens, thus make them a good model for investigating mechanisms of archaeal cold adaptation. Studies of psychrotolerant methanogens have been ongoing since the 1990s. Using Methanococcoides burtonii, a methanogen isolated from Ace Lake in Antarctica, extensive studies on the genomic characteristics associated with cold adaptation have been carried out by the Cavicchioli laboratory. We recently analyzed the genome of another psychrophilic methanogen and identified the gene repertoire associated with cold adaptation. This review summarizes recent studies of psychroactive methanogens, particularly their diversity, the genomics and proteomics associated with their cold adaptation, and the cellular components and proteins likely involved in their cold protection.

The genome and transcriptome of a newly described psychrophilic archaeon, Methanolobus psychrophilus R15, reveal its cold adaptive characteristics.

We analysed the cold-responsive gene repertoire for a psychrophilic methanogen, Methanolobus psychrophilus R15 through genomic and RNA-seq assayed transcriptomic comparisons for cultures at 18°C (optimal temperature) versus 4°C. The differences found by RNA-seq analysis were verified using quantitative real time-PCR assay. The results showed that as in the Antarctic methanogen, Methanococcoides burtonii, genes for methanogenesis, biosynthesis and protein synthesis were all downregulated by the cold in R15. However, the RNA polymerase complex was upregulated at cold, as well as a gene cluster for a putative exosome complex, suggesting that exosome-mediated RNA decay may be cold-accelerated. Unexpectedly, the chaperonin genes for both thermosome and GroES/EL were all upregulated at 4°C. Strain R15 possessed eight protein families for oxygen detoxification, including both anaerobe-specific superoxide reductase (SOR) and the aerobe-typical superoxide dismutase (SOD)-catalase oxidant-removing system, implying the higher oxidative tolerance. Compared with a mesophilic methanogen, R15 survived in higher paraquat, a redox-cycling drug. Moreover, 71 one-component systems and 50 two-component systems for signal transduction ranked strain R15, together with M. burtonii, as being highly adaptive among archaea. Most of them exhibited cold-enhanced expression, indicating their involvement in cold adaptation. This study has added new perspectives on the cold adaptation of methanogenic archaea.