The kinesin superfamily (KIF) is a group of proteins that share a highly conserved motor domain. Except for some members, many KIF proteins have adenosine triphosphatase activity and ...microtubule‐dependent plus‐end motion ability. Kinesins participate in several essential cellular functions, including mitosis, meiosis and the transport of macromolecules. Increasing evidence indicates kinesin proteins play critical roles in the genesis and development of human cancers. Some kinesin proteins are associated with maligancy as well as drug resistance of solid tumor. Thus, targeting KIF therapy seems to be a promising anticancer strategy. Inhibitors of KIF such as kinesin spindle protein (KSP/Eg5) have entered clinical trials for monotherapy or in combination with other drugs, and kinesins other than Eg5 with various potential anticancer target characteristics are also constantly being discovered and studied. Here, we summarize the oncogenic roles of kinesin proteins and potential cancer therapy strategies that target KIF.
How proteins control the biogenesis of cellular lipid droplets (LDs) is poorly understood. Using
and human cells, we show here that seipin, an ER protein implicated in LD biology, mediates a discrete ...step in LD formation-the conversion of small, nascent LDs to larger, mature LDs. Seipin forms discrete and dynamic foci in the ER that interact with nascent LDs to enable their growth. In the absence of seipin, numerous small, nascent LDs accumulate near the ER and most often fail to grow. Those that do grow prematurely acquire lipid synthesis enzymes and undergo expansion, eventually leading to the giant LDs characteristic of seipin deficiency. Our studies identify a discrete step of LD formation, namely the conversion of nascent LDs to mature LDs, and define a molecular role for seipin in this process, most likely by acting at ER-LD contact sites to enable lipid transfer to nascent LDs.
During WWII, the US and Japan are enemies, however, after the war, the US occupy Japan and transform it into nowadays Japan. This paper analyzes the impact of the US occupation of Japan after the end ...of WWII on Japanese politics and economy by using the method of studies literature review. This paper also explores the process that makes Japan transform from feudal militarism into a parliamentary democracy country and summarizes the contributions of the US to Japan’s rebuilding. It can be concluded that the rise of nowadays Japan is built on the foundation of the influence of the US during the occupation.
This study investigated the influence of Coronavirus Disease 2019 (COVID-19) on lung function in early convalescence phase.
A retrospective study of COVID-19 patients at the Fifth Affiliated Hospital ...of Sun Yat-sen University were conducted, with serial assessments including lung volumes (TLC), spirometry (FVC, FEV1), lung diffusing capacity for carbon monoxide (DLCO),respiratory muscle strength, 6-min walking distance (6MWD) and high resolution CT being collected at 30 days after discharged.
Fifty-seven patients completed the serial assessments. There were 40 non-severe cases and 17 severe cases. Thirty-one patients (54.3%) had abnormal CT findings. Abnormalities were detected in the pulmonary function tests in 43 (75.4%) of the patients. Six (10.5%), 5(8.7%), 25(43.8%) 7(12.3%), and 30 (52.6%) patients had FVC, FEV1, FEV1/FVC ratio, TLC, and DLCO values less than 80% of predicted values, respectively. 28 (49.1%) and 13 (22.8%) patients had PImax and PEmax values less than 80% of the corresponding predicted values. Compared with non-severe cases, severe patients showed higher incidence of DLCO impairment (75.6%vs42.5%, p = 0.019), higher lung total severity score (TSS) and R20, and significantly lower percentage of predicted TLC and 6MWD. No significant correlation between TSS and pulmonary function parameters was found during follow-up visit.
Impaired diffusing-capacity, lower respiratory muscle strength, and lung imaging abnormalities were detected in more than half of the COVID-19 patients in early convalescence phase. Compared with non-severe cases, severe patients had a higher incidence of DLCO impairment and encountered more TLC decrease and 6MWD decline.
During MHC‐I‐restricted antigen processing, peptides generated by cytosolic proteasomes are translocated by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum, ...where they bind to newly synthesized MHC‐I molecules. Dendritic cells and other cell types can also generate MHC‐I complexes with peptides derived from internalized proteins, a process called cross‐presentation. Here, we show that active proteasomes within cross‐presenting cell phagosomes can generate these peptides. Active proteasomes are detectable within endocytic compartments in mouse bone marrow‐derived dendritic cells. In TAP‐deficient mouse dendritic cells, cross‐presentation is enhanced by the introduction of human β2‐microglobulin, which increases surface expression of MHC‐I and suggests a role for recycling MHC‐I molecules. In addition, surface MHC‐I can be reduced by proteasome inhibition and stabilized by MHC‐I‐restricted peptides. This is consistent with constitutive proteasome‐dependent but TAP‐independent peptide loading in the endocytic pathway. Rab‐GTPase mutants that restrain phagosome maturation increase proteasome recruitment and enhance TAP‐independent cross‐presentation. Thus, phagosomal/endosomal binding of peptides locally generated by proteasomes allows cross‐presentation to generate MHC‐I‐peptide complexes identical to those produced by conventional antigen processing.
Synopsis
How cross‐presentation and Transporter associated with Antigen Processing (TAP) pathways produce the same spectrum of peptides for MHC‐I loading is poorly understood. New data show that active proteasomes enter endosomes and phagosomes in dendritic cells to process luminal proteins into peptides that are loaded onto MHC‐I independently of TAP function.
Active proteasomes enter the lumen of endolysosomal/phagosomal compartments in dendritic cells.
Human β2‐microglobulin stabilizes MHC‐I on the surface of TAP1‐negative mouse dendritic cells, thereby facilitating TAP‐independent cross‐presentation.
Rab‐GTPase mutants that inhibit maturation of endosomes/phagosomes further enhance TAP‐independent cross‐presentation.
TAP‐independent cross‐presentation and cell‐surface MHC‐I on TAP1−/− dendritic cells require proteasome activity.
Active proteasomes enter endosomes and phagosomes in dendritic cells to process luminal proteins into peptides for direct loading onto internalised MHC‐I.
PM2.5 samples in four representative periods were collected from a highly industrialized district in Shanghai, China. The concentrations of PM2.5 and PM2.5-bound PAHs were analyzed. Positive matrix ...factorization (PMF) model was used to identify the potential sources. Relationship between PAHs distribution and meteorological parameters was assessed meanwhile. The incremental lifetime cancer risks (ILCRs) model was applied to quantitatively evaluate the exposure risk of PAHs. Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLT) model was used to track the potential pollution area of PM2.5 along with a Potential Source Contribution Function (PSCF) and Concentration Weighted Trajectory (CWT) methods. The results showed concentrations of PM2.5 and PAHs ranged from 14.83 to 185.58 μg/m3, 2.58 to 123.62 ng/m3, respectively. The source apportionment model indicated that traffic emissions were the most important sources in each sampling season, which accounted for 38.44%, 34.48%, 39.04% and 45.03%, respectively. Spearman correlation coefficient showed that PAHs had negative correlation with ambient temperature and relative humidity in some periods, while had no significant correlation with atmospheric pressure and visibility. The average estimated lifetime cancer risk for total PAHs reached 4.7 × 10−5, 4.5 × 10−5 and 4.1 × 10−5, 4.0 × 10−5 to exposed children and adults in winter and autumn, respectively, meaning that PM2.5-bound PAHs had high potential risk. HYSPLIT model suggested that monsoon greatly influenced the air quality in both winter and autumn.
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•PM2.5 concentrations were obviously higher than US air quality standards.•PMF identified traffic emissions as the major source of PM2.5-bound PAHs.•The relationship between PM2.5 and PAHs was positive.•ILCRs indicated high cancer risks in autumn and winter.•HYSPLIT showed monsoon greatly influenced the PM2.5 concentrations.
RIMs and RIM-binding proteins (RBPs) are evolutionary conserved multidomain proteins of presynaptic active zones that are known to recruit Ca2+ channels; in addition, RIMs perform well-recognized ...functions in tethering and priming synaptic vesicles for exocytosis. However, deletions of RIMs or RBPs in mice cause only partial impairments in various active zone functions and have no effect on active zone structure, as visualized by electron micrographs, suggesting that their contribution to active zone functions is limited. Here, we show in synapses of the calyx of Held in vivo and hippocampal neurons in culture that combined, but not individual, deletions of RIMs and RBPs eliminate tethering and priming of synaptic vesicles, deplete presynaptic Ca2+ channels, and ablate active zone complexes, as analyzed by electron microscopy of chemically fixed synapses. Thus, RBPs perform unexpectedly broad roles at the active zone that together with those of RIMs are essential for all active zone functions.
•RIM and RBP active zone proteins exhibit universal redundancy at synapses•Combined, but not individual, RIM and RBP deletion blocks synaptic vesicle priming•RIM/RBP-deficient synapses lack tethered vesicles and localized Ca2+ channels•Presynaptic combined RIM/RBP deletion impairs postsynaptic density organization
Acuna and colleagues show that combined, but not individual, deletions of the active zone proteins RIMs and RBPs severely impair all active zone functions and alter the trans-synaptic organization of postsynaptic receptors, suggesting unexpectedly broad, redundant functions for these proteins.
Spatial-temporal distributions, sources identification and risk assessment of polycyclic aromatic hydrocarbons (PAHs) in overlying water and surface sediments in urban river networks of Shanghai were ...studied. Analytical results showed that there was a significant seasonal variation in concentrations of ∑16PAHs in water, suspended particulate matter (SPM) and sediment phases in this study area. The PAHs pollution in these multi-phases were in the medium level compared with other areas around the world, and the levels of PAHs contamination in SPM and sediment phases in hierarchical rivers showed TS (the third-order stream) > FS (the first-order stream) > SS (the second-order stream). Two manners of isomer ratios and principal component analysis (PCA) were used to identify PAHs origins, and suggested that combustion processes are dominant for PAHs sources. The ratios of PAHs origins by fossil fuels combustion, coke burning and crude oil in hierarchical rivers were determined with FS > SS > TS in SPM and sediment phases, and the ratio of PAHs origins by traffic emissions was analyzed with TS > SS > FS. PAHs in water samples have a certain impact on aqueous ecological system especially due to the fact that the ∑ceq values of nine PAHs were calculated from 0.715 to 15.831 μg/L in winter, which inferred serious ecological risk to some special aquatic organisms. The calculations of MERMQ in sediment samples showed that the MERMQ values ranged from 0.021 to 1.209 in winter and 0.019 to 0.643 in summer, which suggested high toxicity at six sampling sites in winter and only one location in summer due to high levels of PAHs. Furthermore, the toxicity degree of sediments were demonstrated with TS > FS > SS.
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•There was a significant seasonal variation in ∑16PAHs concentrations in water, SPM and sediment phases in this study area.•Some variation of PAHs origins in hierarchical rivers were determined with FS > SS > TS in SPM and sediment phases.•Toxicity of PAHs in water and sediment samples has a certain impact on the aquatic ecological system.
PAHs levels and sources in urbanized river networks in Shanghai showed some differences and patterns between inputs and river types.
Existing retinex-based low-light image enhancement strategies focus heavily on crafting complex networks for Retinex decomposition but often result in imprecise estimations. To overcome the ...limitations of previous methods, we introduce a straightforward yet effective strategy for Retinex decomposition, dividing images into colormaps and graymaps as new estimations for reflectance and illumination maps. The enhancement of these maps is separately conducted using a diffusion model for improved restoration. Furthermore, we address the dual challenge of perturbation removal and brightness adjustment in illumination maps by incorporating brightness guidance. This guidance aids in precisely adjusting the brightness while eliminating disturbances, ensuring a more effective enhancement process. Extensive quantitative and qualitative experimental analyses demonstrate that our proposed method improves the performance by approximately 4.4% on the LOL dataset compared to other state-of-the-art diffusion-based methods, while also validating the model's generalizability across multiple real-world datasets.
Dynamin, which is encoded by three genes in mammals, is a GTPase implicated in endocytic membrane fission. Dynamin 1 and 3 are predominantly expressed in brain, whereas dynamin 2 is ubiquitously ...expressed. With the goal of assessing the impact of the lack of dynamin on cell physiology, we previously generated and characterized dynamin 1 and 2 double knockout (DKO) fibroblasts. These DKO cells were unexpectedly viable in spite of a severe impairment of clathrin-mediated endocytosis. As low-level expression of the dynamin 3 gene in these cells could not be excluded, we have now engineered dynamin 1, 2 and 3 triple KO (TKO) fibroblasts. These cells did not reveal any additional defects beyond what was previously observed in DKO fibroblasts. Surprisingly, although fluid-phase endocytosis and peripheral membrane ruffling were not impaired by the lack of all three dynamins, two structurally similar, widely used dynamin inhibitors, dynasore and Dyngo-4a, robustly inhibited these two processes both in wild-type and TKO cells. Dynamin TKO cells will be useful tools for the further exploration of dynamin-dependent processes and the development of more specific dynamin inhibitors.
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