Equivalence transformations for dendritic Y-junctions: a new definition of dendritic sub-unit

A sequence of equivalence transformations is used to represent the mathematical model of a simply branched neuron with non-homogeneous membrane properties and non-uniform geometry by an entirely equivalent model of an unbranched structure. The analysis indicates how neuronal morphology, in combination with its biophysical properties, shapes neuronal output in response to current input. The equivalence transformations described here reveal the types of operations that are likely to feature in the analysis of complex multi-branched structures, neuronal or otherwise. These transformations provide a new definition of dendritic sub-unit and a basis of a mechanism for characterising local and non-local signal processing within dendritic structures. It is anticipated that the capacity to transform biological neurons into an equivalent unbranched structure will make an important contribution to the understanding of the functional role of neuron geometry as well as to the construction of silicon neurons with realistic biological properties.     

Protein kinase C δ (PKCδ)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade regulates glycogen synthase kinase-3 (GSK-3) inhibition-mediated interleukin-10 (IL-10) expression in lipopolysaccharide (LPS)-induced endotoxemia

Glycogen synthase kinase-3 (GSK-3) modulates a wide array of cellular processes, including embryonic development, cell differentiation, survival, and apoptosis. Recently, it was reported that a GSK-3 inhibitor attenuates lipopolysaccharide (LPS)-induced septic shock and regulates the mortality of endotoxemic mice. However, the detailed mechanism of reduced mortality via GSK-3 inhibition is not well defined. Herein, we showed that GSK-3 inhibition induces extracellular signal-regulated kinase 1/2 (ERK1/2) activation under LPS-stressed conditions via protein kinase C δ (PKCδ) activation. Furthermore, PKCδ-induced ERK1/2 activation by the inhibition of GSK-3 provoked the production of interleukin (IL)-10, playing a crucial role in regulating endotoxemia. Using a mitogen-activated protein kinase kinase-1 (MEK-1) and PKCδ inhibitor, we confirmed that GSK-3 inhibition induces PKCδ and subsequent ERK1/2 activation, resulting in increased IL-10 expression under LPS-treated conditions. We verified that septic shock caused by LPS is attenuated by GSK-3 inhibition using a GSK-3 inhibitor. This relieved endotoxemia induced by GSK-3 inhibition was restored in an ERK1/2-dependent manner. Taken together, IL-10 expression produced by GSK-3 inhibition-induced ERK1/2 activation via PKCδ relieved LPS-mediated endotoxemia. This finding suggests that IL-10 hyperexpression resulting from GSK-3 inhibition-induced ERK activation could be a new therapeutic pathway for endotoxemia.     

Hepatocellular Carcinoma Cells Deteriorate the Biophysical Properties of Dendritic Cells

Dendritic cells (DCs) are potent antigen-presenting cells and induce antigen-specific immune responses in the organism. The dysfunction of DCs has been implicated in tumor-bearing host. In order to elucidate the effects of tumor microenvironment on the functions of DCs from interdisciplinary aspects, we characterized the biophysical properties of DCs co-cultured with hepatocellular carcinoma cells (HCC). The results showed that the biophysical characteristics of immature and mature DCs were severely impaired by HCC compared with those under normal conditions, including the increased osmotic fragilities, decreased cell membrane fluidities, increased membrane viscoelastic properties, dysfunction and increased expression of cytoskeleton protein F-actin, as well as the deteriorated transendothelium migration. The impaired biophysical properties of DCs may be one of many aspects of the immune escape mechanisms of tumors. These results are clinically and instructionally significant with regard to how to enhance efficiency of the anti-tumor therapy based on DCs. Zhu Zeng and Weijuan Yao contributed equally to this work.     

水电梯级开发对河流生境质量及纵向连通性影响评价——以五布河和藻渡河为例

河流物理生境是维持河流生物多样性及生态功能的关键因素。生境质量的好坏能反应河流健康的程度。以我国西南地区的五布河和藻渡河为例,采用河流生境调查方法(RHS)和树状水系连通性指数(DCI)定量评估水电梯级开发和水坝建设对河流物理生境质量和河流纵向连通性的影响。结果表明,水电梯级开发后,五布河干流未受水坝明显影响河段、库区河段、减水河段分别为20.48、43.34、18.09 km,占总长度的25.0%、52.9%、22.1%。藻渡河干流河口至双河口段未受水坝明显影响河段、库区河段、减水河段分别为58.61、8.28、18.99 km,占总长度的68.2%、9.6%、占22.1%。水电梯级开发后,五布河干流河流片段由26个增至29个,藻渡河干流河流片段由2个增至5个。两条河流纵向连通性分别降低了7.8%和38.0%。五布河坝下减水河段生境质量降低14.1%,库区河段生境质量变化不明显。藻渡河减水河段生境质量与近自然河段无显著差异;两座坝后式电站库区河段生境质量明显低于近自然河段。水电梯级开发对两条河流物理生境的影响与水坝位置选择、建坝前的自然阻隔数量与分布、河流地貌特征、水电资源开发方式等密切相关。     

Mammalian Target of Rapamycin Complex 1 (mTORC1) and 2 (mTORC2) Control the Dendritic Arbor Morphology of Hippocampal Neurons

Dendrites are the main site of information input into neurons. Their development is a multistep process controlled by mammalian target of rapamycin (mTOR) among other proteins. mTOR is a serine/threonine protein kinase that forms two functionally distinct complexes in mammalian cells: mTORC1 and mTORC2. However, the one that contributes to mammalian neuron development remains unknown. This work used short hairpin RNA against Raptor and Rictor, unique components of mTORC1 and mTORC2, respectively, to dissect mTORC involvement in this process. We provide evidence that both mTOR complexes are crucial for the proper dendritic arbor morphology of hippocampal neurons. These two complexes are required for dendritic development both under basal conditions and upon the induction of mTOR-dependent dendritic growth. We also identified Akt as a downstream effector of mTORC2 needed for proper dendritic arbor morphology, the action of which required mTORC1 and p70S6K1.     

Cryo-immunology: A review of the literature and proposed mechanisms for stimulatory versus suppressive immune responses

The use of cryosurgery to ablate tumors is expanding, primarily due to its technical ease and minimal morbidity. A potential secondary advantage to the in situ freezing of malignant disease is the cryo-immunologic response, the generation of an anti-tumor immune response triggered by the natural absorption of the malignant tissue. While initially proposed based on clinical observations of distant disease regressing after cryoablation of a primary tumor, results from preclinical studies have been mixed and the existence of a cryo-immunologic response has been controversial. Recent studies have shed light on the potential mechanism by which cryoablation may modulate the immune system, also reveals that both immunostimulatory and immunosuppressive responses may be triggered. This article reviews the existing evidence regarding tumor cryo-immunology and puts forward hypotheses regarding patient, tumor and technical factors that may influence the resultant immune response and warrant further investigation.     

Construction of Ordered Atomic Donor–Acceptor Architectures in bcc IrGa Intermetallic Compounds toward Highly Electroactive and Stable Overall Water Splitting

Benefiting from ordered atomic structures and strong d-orbital interactions, intermetallic compounds (IMCs) are promising electrocatalysts for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Herein, the body-centered cubic IrGa IMCs with atomic donor–acceptor architectures are synthesized and anchored on the nitrogen-doped reduced graphene oxide (i.e., IrGa/N-rGO). Structural characterizations and theoretical calculations reveal that the electron-rich Ir sites are atomically dispersed in IrGa/N-rGO, facilitating the electron transfer between Ir atoms and adsorbed species, which can efficiently decrease the energy barriers of the potential determining step for both HER and OER. Impressively, the IrGa/N-rGO||IrGa/N-rGO exhibits excellent performance for overall water splitting in alkaline medium, requiring a low cell voltage of 1.51 V to achieve 10 mA cm⁻², meanwhile, exhibiting no significant degradation for 100 h. This work demonstrates that the rational design of noble metal electrocatalysts with donor–acceptor architectures is beneficial for catalytic reactions in energy conversion applications.     

Downregulation of STAT3 phosphorylation enhances tumoricidal effect of IL-15-activated dendritic cell against doxorubicin-resistant lymphoma and leukemia via TNF-α

Although disputed by some, increasing evidence suggests that TNF-α synergies with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant IL-15 in combination with the STAT3 inhibitor cucurbitacin-I in a doxorubicin-resistant murine lymphoma model. The significance of the work is to understand and design effective strategies in doxorubicin resistant lymphomas. TNF-α is downregulated in dendritic cells from mice with Dalton's lymphoma and shows an inverse relationship with disease progression. Doxorubicin-resistant DL cells have elevated levels of Bcl-2 and Mcl-1 and increased phosphorylation of STAT3. These cells are refractory to dendritic cell derived TNF-α. Doxorubicin resistant Dalton's lymphoma is susceptible to dendritic cell derived TNF-α upon stimulation with the STAT3 inhibitor cucurbitacin-I, which downregulates STAT3 and other survival molecules. The combined treatment of low dose of cucurbitacin-I and rIL-15 is ineffective in mice with doxorubicin resistant Dalton's lymphoma, but a similar therapy prolongs the survival of mice transplanted with parental Dalton's lymphoma. Doxorubicin resistant Dalton's lymphoma responds to therapy with high doses of cucurbitacin-I and rIL-15. Dendritic cell derived from mice responded positively to the therapy and regained their tumoricidal properties with respect to growth inhibition and killing of DL tumor cells. Similar to DL, DC derived from CML patients are impaired in TNF-α expression and are unable to restrict the growth of drug-resistant lymphoma and leukemia cells. This combination approach could be used as a new therapeutic strategy for aggressive and highly metastatic doxorubicin resistant lymphoma.     

Mycobacterial and mouse HSP70 have immuno-modulatory effects on dendritic cells

Previously, it has been shown that heat shock protein 70 (HSP70) can prevent inflammatory damage in experimental autoimmune disease models. Various possible underlying working mechanisms have been proposed. One possibility is that HSP70 induces a tolerogenic phenotype in dendritic cells (DCs) as a result of the direct interaction of the antigen with the DC. Tolerogenic DCs can induce antigen-specific regulatory T cells and dampen pathogenic T cell responses. We show that treatment of murine DCs with either mycobacterial (Mt) or mouse HSP70 and pulsed with the disease-inducing antigen induced suppression of proteoglycan-induced arthritis (PGIA), although mouse HSP70-treated DCs could ameliorate PGIA to a greater extent. In addition, while murine DCs treated with Mt- or mouse HSP70 had no significantly altered phenotype as compared to untreated DCs, HSP70-treated DCs pulsed with pOVA (ovalbumin peptide 323–339) induced a significantly increased production of IL-10 in pOVA-specific T cells. IL-10-producing T cells were earlier shown to be involved in Mt HSP70-induced suppression of PGIA. In conclusion, this study indicates that Mt- and mouse HSP70-treated BMDC can suppress PGIA via an IL-10-producing T cell-dependent manner.