Recognition of extremophilic archaeal viruses by eukaryotic cells:a promising nanoplatform from the third domain of life

Viruses from the third domain of life, Archaea, exhibit unusual features including extreme stability that allow their survival in harsh environments. In addition, these species have never been reported to integrate into human or any other eukaryotic genomes, and could thus serve for exploration of novel medical nanoplatforms. Here, we selected two archaeal viruses Sulfolobus monocaudavirus 1 (SMV1) and Sulfolobus spindle shaped virus 2 (SSV2) owing to their unique spindle shape, hyperthermostable and acid-resistant nature and studied their interaction with mammalian cells. Accordingly, we followed viral uptake, intracellular trafficking and cell viability in human endothelial cells of brain (hCMEC/D3 cells) and umbilical vein (HUVEC) origin. Whereas SMV1 is efficiently internalized into both types of human cells, SSV2 differentiates between HUVECs and hCMEC/D3 cells, thus opening a path for selective cell targeting. On internalization, both viruses localize to the lysosomal compartments. Neither SMV1, nor SSV2 induced any detrimental effect on cell morphology, plasma membrane and mitochondrial functionality. This is the first study demonstrating recognition of archaeal viruses by eukaryotic cells which provides good basis for future exploration of archaeal viruses in bioengineering and development of multifunctional vectors

A fast-multi-pole accelerated method of fundamental solutions for 2-D broadband scattering of SH waves in an infinite half space

The traditional method of fundamental solution (T-MFS) is known as an effective method for solving the scattering of elastic waves, but the T-MFS is inefficient in solving large-scale or broadband frequency problems. Therefore, in order to improve the performance in efficiency and memory requirement for treating practical complex 2-D broadband scattering problems, a new algorithm of fast multi-pole accelerated method of fundamental solution (FM-MFS) is proposed. Taking the 2-D scattering of SH waves around irregular scatterers in an elastic half-space as an example, the implementation steps are presented in detail. Based on the accuracy and efficiency verification, the FM-MFS is applied to solve the broadband frequency scattering of plane SH waves around group cavities, inclusions, a V-shaped canyon and a semi-elliptical hill. It shows that, compared with T-MFS, the FM-MFS has great advantages in reducing the consumed CPU time and memory for 2-D broadband scattering. Besides, the FM-MFS has excellent adaptability both for broad-frequency and complex-shaped scattering problems

Aluminum impairs rat neural cell mitochondria in vitro.

Exposure to aluminum has been reported to lead to neurotoxicity. Mitochondria are important organelles involved in maintaining cell function. This study investigates the effect of aluminum on mitochondria in rat neural cells. The ultrastructure of mitochondria was observed, and the cell death rate (CDR), reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and 3-[4,5demethyl-2-thiazalyl]-2,-5diphenyl-2H-tetrazolium bromide (MTT) were measured to investigate the effect of aluminum on the mitochondrial structure and its function in neural cells. Results observed from the mitochondrial ultrastructure show that aluminum may impair the mitochondrial membrane and cristae. Increased CDR, enhanced ROS, decreased MMP, and decreased enzyme activity in mitochondria were observed in the Al-exposed neurons (100 – 500 μM). The present study demonstrates that alteration in the mitochondrial structure and function plays an important role in neurotoxic mechanisms induced by aluminum

C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes

Poly(2-methyl-2-oxazoline) (PMOXA) is an alternative promising polymer to poly(ethylene glycol) (PEG) for design and engineering of macrophage-evading nanoparticles (NPs). Although PMOXA-engineered NPs have shown comparable pharmacokinetics and in vivo performance to PEGylated stealth NPs in the murine model, its interaction with elements of the human innate immune system has not been studied. From a translational angle, we studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived organically modified silica NPs (PMOXA-coated NPs) of approximately 100 nm in diameter with human complement system, blood leukocytes, and macrophages and compared their performance with PEGylated and uncoated NP counterparts. Through detailed immunological and proteomic profiling, we show that PMOXA-coated NPs extensively trigger complement activation in human sera exclusively through the classical pathway. Complement activation is initiated by the sensing molecule C1q, where C1q binds with high affinity (Kd = 11 \ub1 1 nM) to NP surfaces independent of immunoglobulin binding. C1q-mediated complement activation accelerates PMOXA opsonization with the third complement protein (C3) through the amplification loop of the alternative pathway. This promoted NP recognition by human blood leukocytes and monocyte-derived macrophages. The macrophage capture of PMOXA-coated NPs correlates with sera donor variability in complement activation and opsonization but not with other major corona proteins, including clusterin and a wide range of apolipoproteins. In contrast to these observations, PMOXA-coated NPs poorly activated the murine complement system and were marginally recognized by mouse macrophages. These studies provide important insights into compatibility of engineered NPs with elements of the human innate immune system for translational steps

SARS-CoV-2 bivalent mRNA vaccine with broad protection against variants of concern

IntroductionThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has rapidly spread around the globe. With a substantial number of mutations in its Spike protein, the SARS-CoV-2 Omicron variant is prone to immune evasion and led to the reduced efficacy of approved vaccines. Thus, emerging variants have brought new challenges to the prevention of COVID-19 and updated vaccines are urgently needed to provide better protection against the Omicron variant or other highly mutated variants.Materials and methodsHere, we developed a novel bivalent mRNA vaccine, RBMRNA-405, comprising a 1:1 mix of mRNAs encoding both Delta-derived and Omicron-derived Spike proteins. We evaluated the immunogenicity of RBMRNA-405 in BALB/c mice and compared the antibody response and prophylactic efficacy induced by monovalent Delta or Omicron-specific vaccine with the bivalent RBMRNA-405 vaccine in the SARSCoV-2 variant challenge.ResultsResults showed that the RBMRNA-405 vaccine could generate broader neutralizing antibody responses against both Wuhan-Hu-1 and other SARS-CoV-2 variants, including Delta, Omicron, Alpha, Beta, and Gamma. RBMRNA-405 efficiently blocked infectious viral replication and lung injury in both Omicron- and Delta-challenged K18-ACE2 mice.ConclusionOur data suggest that RBMRNA-405 is a promising bivalent SARS-CoV-2 vaccine with broad-spectrum efficacy for further clinical development

Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells

Transplantation of vasculogenic progenitor cells (VPC) improves neovascularization after ischemia. However, patients with type 2 diabetes mellitus show a reduced VPC number and impaired functional activity. Previously, we demonstrated that p38 kinase inhibition prevents the negative effects of glucose on VPC number by increasing proliferation and differentiation towards the endothelial lineage in vitro. Moreover, the functional capacity of progenitor cells is reduced in a mouse model of metabolic syndrome including type 2 diabetes (Lepr(db)) in vivo.The aim of this study was to elucidate the underlying signalling mechanisms in vitro and in vivo. Therefore, we performed DNA-protein binding arrays in the bone marrow of mice with metabolic syndrome, in blood-derived progenitor cells of diabetic patients as well as in VPC ex vivo treated with high levels of glucose. The transcriptional activation of ETS transcription factors was increased in all samples analyzed. Downregulation of ETS1 expression by siRNA abrogated the reduction of VPC number induced by high-glucose treatment. In addition, we observed a concomitant suppression of the non-endothelial ETS-target genes matrix metalloproteinase 9 (MMP9) and CD115 upon short term lentiviral delivery of ETS-specific shRNAs. Long term inhibition of ETS expression by lentiviral infection increased the number of cells with the endothelial markers CD144 and CD105.These data demonstrate that diabetes leads to dysregulated activation of ETS, which blocks the functional activity of progenitor cells and their commitment towards the endothelial cell lineage

Spatio-temporal divergence in the responses of Finland's boreal forests to climate variables

Spring greening in boreal forest ecosystems has been widely linked to increasing temperature, but few studies have attempted to unravel the relative effects of climate variables such as maximum temperature (TMX), minimum temperature (TMN), mean temperature (TMP), precipitation (PRE) and radiation (RAD) on vegetation growth at different stages of growing season. However, clarifying these effects is fundamental to better understand the relationship between vegetation and climate change. This study investigated spatio-temporal divergence in the responses of Finland's boreal forests to climate variables using the plant phenology index (PPI) calculated based on the latest Collection V006 MODIS BRDF-corrected surface reflectance products (MCD43C4) from 2002 to 2018, and identified the dominant climate variables controlling vegetation change during the growing season (May-September) on a monthly basis. Partial least squares (PLS) regression was used to quantify the response of PPI to climate variables and distinguish the separate impacts of different variables. The study results show the dominant effects of temperature on the PPI in May and June, with TMX, TMN and TMP being the most important explanatory variables for the variation of PPI depending on the location, respectively. Meanwhile, drought had an unexpectedly positive impact on vegetation in few areas. More than 50 % of the variation of PPI could be explained by climate variables for 68.5 % of the entire forest area in May and 87.7 % in June, respectively. During July to September, the PPI variance explained by climate and corresponding spatial extent rapidly decreased. Nevertheless, the RAD was found be the most important explanatory variable to July PPI in some areas. In contrast, the PPI in August and September was insensitive to climate in almost all of the regions studied. Our study gives useful insights on quantifying and identifying the relative importance of climate variables to boreal forest, which can be used to predict the possible response of forest under future warming.Peer reviewe