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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

Numerous safe and effective coronavirus disease 2019 vaccines have been developed worldwide that use various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S as compared with vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity, and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by receptor binding domain–specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies., Science Immunology, 7 (78), ISSN:2470-9468

The secondary injury caused by RBC autolysis after intracerebral hemorrhage (ICH) can be reduced by increasing the efficiency of microglia (MG)/macrophages (Mø) phagocytizing red blood cells (RBCs). CD47 is an important regulator of MG/Mø phagocytosis. This study aims to clarify whether anti-CD47 antibody administrated into the cisterna magna after ICH can transfer to the hematoma site, promote MG/Mø gathering to phagocytize RBCs and ultimately reduce cell death.Forty male Wistar rats were divided into sham, ICH, low-dosage (group A, 0.3 μg), medium-dosage (group B, 0.9 μg) and high-dosage (group C, 1.8 μg) anti-CD47 antibody groups. For the rats in group A, B and C, anti-CD47 antibody solution was administrated into the cisterna magna at 10 min after ICH. Brain tissue was harvested 3 days after the operation. Western blotting was performed to detect the expression of Caspase-3 and Bcl-2. Immunofluorescence was performed to detect the CD68 expression. TUNEL was performed to detect the cell death.The hematoma of the ICH rats was located in the basal ganglia, with a good homogeneity of hematoma volume. Low-dosage anti-CD47 antibody in group A had no effects on the perihematomal CD68 (P = 0.338), Caspase-3 (P = 0.769), Bcl-2 (P = 0.176) expression and cell death (P = 0.698), compared with the ICH group. CD68 and Bcl-2 expression increased and Caspase-3 expression decreased significantly in group B (P0.001 for all) and group C (P0.001 for all). The increase of CD68 expression in group C was greater than that in group B (P0.01) by a large margin, while there was no difference for Bcl-2 (P = 0.908) and Caspase-3 (P = 0.913) expression between the 2 groups. Compared with the ICH group, medium-dosage of anti-CD47 antibody in group B significantly reduced the number of TUNEL-positive cells (P0.005), but not for group C (P = 0.311).The results suggested that anti-CD47 antibody administration into the cisterna magna in proper dosage (0.9 μg) can effectively reach the hematoma, induce more MG/Møs to gather around the hematoma, and reduce cell death in perihematomal brain tissue. The results of this study has provided a basic theory for improving the efficiency of MG/Mø phagocytizing RBCs and hematoma clearance after ICH by administrating anti-CD47 antibody via the cisterna magna.

To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting broadly neutralizing antibody responses to CoVs. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein with a two-shot protocol generated potent serum receptor binding domain cross-neutralizing antibody responses to both SARS-CoV-2 and SARS-CoV-1. Furthermore, responses were equally effective against most SARS-CoV-2 variants of concern (VOCs) and some were highly effective against Omicron. This result contrasts with human infection or many two-shot vaccination protocols where responses were typically more SARS-CoV-2 specific and where VOCs were less well neutralized. Structural studies showed that cloned macaque neutralizing antibodies, particularly using a given heavy chain germline gene, recognized a relatively conserved region proximal to the angiotensin converting enzyme 2 receptor binding site (RBS), whereas many frequently elicited human neutralizing antibodies targeted more variable epitopes overlapping the RBS. B cell repertoire differences between humans and macaques appeared to influence the vaccine response. The macaque neutralizing antibodies identified a pan-SARS–related virus epitope region less well targeted by human antibodies that could be exploited in rational vaccine design.

SummaryThe mammarenavirus Lymphocytic choriomeningitis virus (LCMV) is a globally distributed zoonotic pathogen that can be lethal in immunocompromised patients and cause severe birth defects if acquired during pregnancy. Despite the fundamental importance of LCMV for studying immunobiology, the structure of the trimeric surface glycoprotein, essential for entry, vaccine design and antibody neutralization, remains unknown. In this study, we present the cryoEM structure of the LCMV surface glycoprotein (GP) in its trimeric prefusion assembly both alone and in complex with a rationally engineered monoclonal neutralizing antibody termed 18.5C-M28 (M28). Additionally, we show that passive administration of M28 protects mice from LCMV clone 13 (LCMVcl13) challenge when administered as either a prophylactic or therapeutic. Our study illuminates not only the overall structural organization of LCMV GP and the mechanism for its inhibition by M28, but also presents a promising therapeutic candidate to prevent severe or fatal disease in individuals who are at risk of infection by a virus that poses a threat worldwide.HighlightsRationally-engineered antibody M28 neutralizes lymphocytic choriomeningitis virus in vitro.First high-resolution cryoEM structure of the pre-fusion trimeric lymphocytic choriomeningitis virus glycoprotein alone and in complex with M28.M28 neutralizes by bridging adjacent glycoprotein protomers and locking it in the pre-fusion state.Prophylactic and therapeutic administration of M28 protects mice from chronic lymphocytic choriomeningitis virus infection.

Immune-modulating medications for inflammatory bowel diseases (IBDs) have been associated with suboptimal vaccine responses. There are conflicting data with SARS-CoV-2 vaccination. We therefore assessed SARS-CoV-2 vaccine immunogenicity at 2 weeks after second mRNA vaccination in 29 patients with IBD compared with 12 normal healthy donors. We observed reduced humoral immunity in patients with IBD on infliximab. However, we observed no difference in humoral and cell-mediated immunity in patients with IBD on infliximab with a thiopurine or vedolizumab compared with normal healthy donors. This is the first study to demonstrate comparable cell-mediated immunity with SARS-CoV-2 vaccination in patients with IBD treated with different immune-modulating medications.

SUMMARYMultiple COVID-19 vaccines, representing diverse vaccine platforms, successfully protect against symptomatic COVID-19 cases and deaths. Head-to-head comparisons of T cell, B cell, and antibody responses to diverse vaccines in humans are likely to be informative for understanding protective immunity against COVID-19, with particular interest in immune memory. Here, SARS-CoV-2-spike—specific immune responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S and Novavax NVX-CoV2373 were examined longitudinally for 6 months. 100% of individuals made memory CD4+ T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8+ T cell frequencies, though memory CD8+ T cells were only detectable in 60-67% of subjects at 6 months. Ad26.COV2.S was not the strongest immunogen by any measurement, though the Ad26.COV2.S T cell, B cell, and antibody responses were relatively stable over 6 months. A differentiating feature of Ad26.COV2.S immunization was a high frequency of CXCR3+ memory B cells. mRNA vaccinees had substantial declines in neutralizing antibodies, while memory T cells and B cells were comparatively stable over 6 months. These results of these detailed immunological evaluations may also be relevant for vaccine design insights against other pathogens.

The SARS-CoV-2 Omicron variant of concern comprises three sublineages designated BA.1, BA.2, and BA.3, with BA.2 steadily replacing the globally dominant BA.1. We show that the large number of BA.1 and BA.2 spike mutations severely dampen plasma neutralizing activity elicited by infection or seven clinical vaccines, with cross-neutralization of BA.2 being consistently more potent than that of BA.1, independent of the vaccine platform and number of doses. Although mRNA vaccines induced the greatest magnitude of Omicron BA.1 and BA.2 plasma neutralizing activity, administration of a booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1 and BA.2 across all vaccines evaluated. Our data suggest that although BA.1 and BA.2 evade polyclonal neutralizing antibody responses, current vaccine boosting regimens may provide sufficient protection against Omicron-induced disease.

Objective Nuclear factor-κB (NF-κB) is a critical regulator of inflammatory responses after ICH, and different subunits may have different influences on the cell death and prognosis. The aim of the present study is to clarify whether the prognosis can be influenced by inhibiting NF-κB activation and subunits expression using PDTC at different stages after ICH. Methods Rats were divided into sham group, ICH group, early interference group and late interference group. At preset time points after ICH, the ipsilateral striatum and tissue around was obtained for detection of NF-κB activation, cell death, and expression of caspase-3, bcl-2, and NF-κB subunits, to evaluate of the effect of PDTC. Results NF-κB subunit p65 mainly expressed at the early stage after ICH, and c-Rel at the late stage. NF-κB activation can be inhibited at the early stage after ICH by administrating PDTC at 10 min, 1d and 2d after ICH, and at the late stage at 6d,7d and 8d. NF-κB activation inhibition at the early stage was due to p65, and c-Rel at the late stage. Inhibiting p65 expression at the early stage after ICH can reduce the apoptotic factor caspase-3 expression and cell death, and raise the antiapoptotic factor bcl-2. Meanwhile, inhibiting c-Rel expression at the late stage after ICH can lead to the opposite result. Conclusion Measures of inhibiting NF-κB subunits can be performed to influence the secondary brain damage and prognosis of ICH. We can also speculate that early inhibition of p65 expression and late promotion of c-Rel expression may be a more efficient method to improve the prognosis of ICH.

We address whether T cell responses induced by different vaccine platforms (mRNA-1273, BNT162b2, Ad26.COV2.S, NVX-CoV2373) cross-recognize early SARS-CoV-2 variants. T cell responses to early variants were preserved across vaccine platforms. By contrast, significant overall decreases were observed for memory B cells and neutralizing antibodies. In subjects ∼6 months post-vaccination, 90% (CD4+) and 87% (CD8+) of memory T cell responses were preserved against variants on average by AIM assay, and 84% (CD4+) and 85% (CD8+) preserved against Omicron. Omicron RBD memory B cell recognition was substantially reduced to 42% compared to other variants. T cell epitope repertoire analysis revealed a median of 11 and 10 spike epitopes recognized by CD4+ and CD8+ T cells, with average preservation > 80% for Omicron. Functional preservation of the majority of T cell responses may play an important role as second-level defenses against diverse variants., Graphical Abstract, Human memory T cells induced by SARS-CoV-2 vaccines maintain the ability to recognize viral variants, including the omicron variant.

SUMMARYWe address whether T cell responses induced by different vaccine platforms (mRNA-1273, BNT162b2, Ad26.COV2.S, NVX-CoV2373) cross-recognize SARS-CoV-2 variants. Preservation of at least 83% and 85% for CD4+and CD8+T cell responses was found, respectively, regardless of vaccine platform or variants analyzed. By contrast, highly significant decreases were observed for memory B cell and neutralizing antibody recognition of variants. Bioinformatic analyses showed full conservation of 91% and 94% of class II and class I spike epitopes. For Omicron, 72% of class II and 86% of class I epitopes were fully conserved, and 84% and 85% of CD4+and CD8+T cell responses were preserved. In-depth epitope repertoire analysis showed a median of 11 and 10 spike epitopes recognized by CD4+and CD8+T cells from vaccinees. Functional preservation of the majority of the T cell responses may play an important role as a second-level defense against diverse variants.

Description, Coanchoring a SARS-CoV-2 immunogen and molecular adjuvants to alum extends vaccine kinetics and amplifies humoral immunity., There is a need for additional rapidly scalable, low-cost vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to achieve global vaccination. Aluminum hydroxide (alum) adjuvant is the most widely available vaccine adjuvant but elicits modest humoral responses. We hypothesized that phosphate-mediated coanchoring of the receptor binding domain (RBD) of SARS-CoV-2 together with molecular adjuvants on alum particles could potentiate humoral immunity by promoting extended vaccine kinetics and codelivery of vaccine components to lymph nodes. Modification of RBD immunogens with phosphoserine (pSer) peptides enabled efficient alum binding and slowed antigen clearance, leading to notable increases in germinal center responses and neutralizing antibody titers in mice. Adding phosphate-containing CpG or saponin adjuvants to pSer-RBD:alum immunizations synergistically enhanced vaccine immunogenicity in mice and rhesus macaques, inducing neutralizing responses against SARS-CoV-2 variants. Thus, phosphate-mediated coanchoring of RBD and molecular adjuvants to alum is an effective strategy to enhance the efficacy of SARS-CoV-2 subunit vaccines.

Adaptive immune responses to SARS-CoV-2 infection have been extensively characterized in blood; however, most functions of protective immunity must be accomplished in tissues. Here, we report from examination of SARS-CoV-2 seropositive organ donors (ages 10 – 74) that CD4(+) T, CD8(+) T, and B cell memory generated in response to infection is present in bone marrow, spleen, lung, and multiple lymph nodes (LNs) for up to 6 months post-infection. Lungs and lung-associated LNs were the most prevalent sites for SARS-CoV-2-specific memory T and B cells, with significant correlations between circulating and tissue-resident memory T and B cells in all sites. We further identified SARS-CoV-2-specific germinal centers in the lung-associated LNs up to 6 months post-infection. SARS-CoV-2-specific follicular helper T cells were also abundant in lung-associated LNs and lungs. Together, the results indicate local tissue coordination of cellular and humoral immune memory against SARS-CoV-2 for site-specific protection against future infectious challenges.

A smaller-dose jab does the job Low-dose messenger RNA (mRNA) vaccines potentially allow health providers to administer more doses from a limited vaccine supply and can be less reactogenic. Whether low-dose COVID-19 mRNA vaccines generate immune responses comparable to currently approved doses remains an open question, however. Mateus et al . report the results of a clinical trial comparing patients who received a 25-μg mRNA-1273 (Moderna) COVID-19 vaccine to 100-μg mRNA-1273 COVID-19 vaccinees and severe acute respiratory syndrome coronavirus 2–infected individuals. The low-dose Moderna vaccine generated long-lived T cell immunity that was equivalent between younger and older patients and that could be enhanced by the presence of cross-reactive T cells. Moreover, antibody and T cell responses induced by the low-dose vaccine were comparable to natural infection and about half as strong as those seen with high-dose vaccination. —STS

Understanding human immune responses to SARS-CoV-2 RNA vaccines is of interest for a panoply of reasons. Here we examined vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25 μg Moderna mRNA-1273 vaccine over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing crossreactive T cell memory impacts vaccine-generated immunity. Low dose (25 μg) mRNA-1273 elicited durable Spike binding antibodies comparable to that of convalescent COVID-19 cases. Vaccine-generated Spike memory CD4+ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of TFH cells and IFNγ-expressing cells. Spike CD8+ T cells were generated in 88% of subjects, with equivalent percentages of CD8+ T cell memory responders at 6 months post-boost compared to COVID-19 cases. Lastly, subjects with pre-existing crossreactive CD4+ T cell memory had increased CD4+ T cell and antibody responses to the vaccine, demonstrating a biological relevance of SARS-CoV-2 crossreactive CD4+ T cells.One-Sentence SummaryThe mRNA-1273 vaccine induces a durable and functional T cell and antibody response comparable to natural infection.

The imbalance between mitochondrial fusion and fission has been implicated in cerebral ischemia and several neurodegenerative diseases. However, the role of mitochondrial fission in traumatic brain injury (TBI) remains poorly understood. Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in the nervous system. In the present study, we investigated the changes in Drp1 expression in the ipsilateral hippocampus of rats after TBI and the effects of Mdivi-1 (a selective inhibitor of Drp1) as a post-insult treatment for TBI. Our findings showed that the protein levels of Drp1 were increased at 6 h and peaked at 12 h post-TBI, but we did not observe Drp1 phosphorylation at Ser616, Ser637, Ser40 or Ser44 during this process. We examined the effect of Mdivi-1 on trauma-induced brain damage in both vitro and vivo. In cells, Mdivi-1 significantly attenuated H2O2-induced mitochondrial membrane potential (MMP) dissipation in PC-12 cells. Three days of Mdivi-1 treatment significantly reduced the cortical lesion volume, blood-brain barrier permeability, brain edema and oxidative stress. Mdivi-1 reduced activated caspase-3 release in the cortical border zone and hippocampal dentate gyrus three days after TBI. Furthermore, treatment with Mdivi-1 for 4 weeks rescued neurogenesis in DG and attenuated hippocampal atrophy. Regarding behavioral outcomes, Mdivi-1-treated TBI rats showed a significant improvement in water maze acquisition and retention compared with the saline-treated TBI rats. Moreover, Mdivi-1 treatment reduced anxiety-like behavior in an open-field test. Our results support the notion that Mdivi-1 provides brain protection and improves the behavioral performance in TBI rats.

Objective: The exact role of nuclear factor-kappaB (NF-κB) in intracerebral hemorrhage (ICH) is still unclear to date. The aim of the present study is to clarify the activation of NF-κB and the role of its subunits in inflammatory response and cell death after ICH. Methods: The model of ICH rats was made, and at preset time points after operation, as well as rats in the control and sham groups, the ipsilateral striatum and tissue around was obtained for detection of NF-κB activation, cell death, and expression of interleukin-1β, tumor necrosis factor-α, Caspase-3, Bcl-2, and NF-κB subunits. Results: There were 2 peaks of NF-κB activation (2 days and 10 days) after ICH. The expression of p50 and p65 reached the peak at 1 day and 2 day, leading to the first peak of NF-κB activation, and that of c-Rel at 10 day, leading to the second. The peak of cell death and caspase-3 expression, and the nadir of bcl-2 expression appeared to be synchronizing with or right after the first peak of NF-κB activation. Then, at the second peak of NF-κB activation, cell death, and caspase-3 expression decreased and the bcl-2 expression returned to the normal level. Conclusions: NF-κB activation showed a bimodal distribution mode after ICH. We can speculate that p50 and p65 may promote the inflammatory response and apoptosis, and c-Rel may play the opposite role. Measures might be performed at the different phases to reduce the brain injury in the early stage and promote the brain recovery in the late stage after ICH.

The recommendation algorithm is attracting increasing attention in analyzing big data. Matrix factorization (MF) is one of the recommendation methods and Singular Value Decomposition (SVD) is the most popular matrix factorization method. However, the existing SVD methods usually initialize user and item feature randomly, not fully utilize the information of the data, so require plenty of experiments to determine feature matrix dimension, with low convergence efficiency and low accuracy. This paper presents a hybrid initialization method based on attribute mapping and autoencoder neural network to solve these problems, which consists of three parts: (1) use the number of item attribute types to determine feature matrix dimension in order to avoid multiple experiments to select the optimal dimension value; (2) use items’ attributes to initialize the item feature matrix in SVD＋＋, and use an attribute mapping mechanism to get an item feature vector by fitting the rating matrix to accelerate the convergence; (3) adopt the autoencoder neural network to reduce feature dimension and obtain item latent features for initializing SVD＋＋. The experimental results show that our methods achieve better performance than SVD＋＋ random initialization and also be adopted to other matrix factorization methods.

The emergence of SARS-CoV-2 variants raises concerns about the efficacy of COVID-19 vaccines to induce an immune response capable of recognizing upcoming variants. While there are multiple studies detailing the impact of SARS-CoV-2 variants on neutralizing antibodies, there is relatively little information on the effect of variant mutations on CD4 and CD8 T cell recognition. We will present the results of our ongoing study on the effects on T cell reactivity to a comprehensive panel of variants circulating globally (B.1.617.2 [delta], P.1 [gamma], B.1.617.1 [kappa], C.37 [lambda], R.1, B.1.1.7 [alpha], B.1.351 [beta], B.1.1.519, B.1.525 [eta], B.1.526 [iota], B.1.427/9 [epsilon], B.1.526.1 and B.1.621 [mu] comparing it with the most recent B.1.1.529 [omicron] variant. The results will span from bioinformatics analyses addressing the effect of SARS-CoV-2 mutations of known epitopes in the Immune Epitope Database (IEDB, https://www.iedb.org/) to the experimental evaluation of the T cell responses specific to each SARS-CoV-2 Spike variant in individuals immunized with several vaccine platforms and at multiple timepoints after vaccination. Parallel experiments will also determine the epitope repertoire in specific donors and dissect the impact of SARS-CoV-2 variant associated mutations on the recognition of each CD4 and CD8 T cell epitope. Finally, the capability of T cell cross-recognition will be compared with breakthrough infection and with or without booster vaccination. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.S. and Contract No. 75N9301900065 to A.S, D.W.

Human SERINC5 (SER5) protein is a recently described restriction factor against human immunodeficiency virus-1 (HIV-1), which is antagonized by HIV-1 Nef protein. Other retroviral accessory proteins such as the glycosylated Gag (glycoGag) from the murine leukemia virus (MLV) can also antagonize SER5. In addition, some viruses escape SER5 restriction by expressing a SER5-insensitive envelope (Env) glycoprotein. Here, we studied the activity of human and feline SER5 on HIV-1 and on the two pathogenic retroviruses in cats, feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV). HIV-1 in absence of Nef is restricted by SER5 from domestic cats and protected by its Nef protein. The sensitivity of feline retroviruses FIV and FeLV to human and feline SER5 is considerably different: FIV is sensitive to feline and human SER5 and lacks an obvious mechanism to counteract SER5 activity, while FeLV is relatively resistant to SER5 inhibition. We speculated that similar to MLV, FeLV-A or FeLV-B express glycoGag proteins and investigated their function against human and feline SER5 in wild type and envelope deficient virus variants. We found that the endogenous FeLV recombinant virus, FeLV-B but not wild type exogenous FeLV-A envelope mediates a strong resistance against human and feline SER5. GlycoGag has an additional but moderate role to enhance viral infectivity in the presence of SER5 that seems to be dependent on the FeLV envelope. These findings may explain, why in vivo FeLV-B has a selective advantage and causes higher FeLV levels in infected cats compared to infections of FeLV-A only.

Pandemic human immunodeficiency virus type 1 (HIV-1) is the result of the zoonotic transmission of simian immunodeficiency virus (SIV) from the chimpanzee subspecies Pan troglodytes troglodytes (SIVcpzPtt). The related subspecies Pan troglodytes schweinfurthii is the host of a similar virus, SIVcpzPts, which did not spread to humans. We tested these viruses with small-molecule capsid inhibitors (PF57, PF74, and GS-CA1) that interact with a binding groove in the capsid that is also used by CPSF6. While HIV-1 was sensitive to capsid inhibitors in cell lines, human macrophages, and peripheral blood mononuclear cells (PBMCs), SIVcpzPtt was resistant in rhesus FRhL-2 cells and human PBMCs but was sensitive to PF74 in human HOS and HeLa cells. SIVcpzPts was insensitive to PF74 in FRhL-2 cells, HeLa cells, PBMCs, and macrophages but was inhibited by PF74 in HOS cells. A truncated version of CPSF6 (CPSF6-358) inhibited SIVcpzPtt and HIV-1, while in contrast, SIVcpzPts was resistant to CPSF6-358. Homology modeling of HIV-1, SIVcpzPtt, and SIVcpzPts capsids and binding energy estimates suggest that these three viruses bind similarly to the host proteins cyclophilin A (CYPA) and CPSF6 as well as the capsid inhibitor PF74. Cyclosporine treatment, mutation of the CYPA-binding loop in the capsid, or CYPA knockout eliminated the resistance of SIVcpzPts to PF74 in HeLa cells. These experiments revealed that the antiviral capacity of PF74 is controlled by CYPA in a virus- and cell type-specific manner. Our data indicate that SIVcpz viruses can use infection pathways that escape the antiviral activity of PF74. We further suggest that the antiviral activity of PF74 capsid inhibitors depends on cellular cofactors. IMPORTANCE HIV-1 originated from SIVcpzPtt but not from the related virus SIVcpzPts, and thus, it is important to describe molecular infection by SIVcpzPts in human cells to understand the zoonosis of SIVs. Pharmacological HIV-1 capsid inhibitors (e.g., PF74) bind a capsid groove that is also a binding site for the cellular protein CPSF6. SIVcpzPts was resistant to PF74 in HeLa cells but sensitive in HOS cells, thus indicating cell line-specific resistance. Both SIVcpz viruses showed resistance to PF74 in human PBMCs. Modulating the presence of cyclophilin A or its binding to capsid in HeLa cells overcame SIVcpzPts resistance to PF74. These results indicate that early cytoplasmic infection events of SIVcpzPts may differ between cell types and affect, in an unknown manner, the antiviral activity of capsid inhibitors. Thus, capsid inhibitors depend on the activity or interaction of currently uncharacterized cellular factors.

The family of human APOBEC3 (A3) restriction factors is formed by seven different proteins, A3A-D and A3F-H. Among these A3s, A3B harbors strong restriction activity against several retroviruses, such as SIV, and MLV. How lentiviruses and other retroviruses, prevalent in many primate species, counteract A3B is poorly understood. In this study, we found that A3B strongly inhibited SIVmac and HIV-2 infectivity, which was antagonized by their Vif proteins. Both SIVmac and HIV-2 Vifs diminished the protein level of A3B in viral producer cells, and hindered A3B incorporation into viral particles. We observed that HIV-2 Vif binds A3B and induces its degradation by assembly of an A3-Vif-CUL5-ElonginB/C E3-ligase complex. A3B and HIV-2 Vif localize and interact in the nucleus. In addition, we also found that the accessory protein Bet of prototype foamy virus (PFV) significantly antagonized the anti-SIVmac activity of A3B. Like Vif, Bet prevented the incorporation of A3B into viral particles. However, in contrast to Vif Bet did not induce the degradation of A3B. Rather, Bet binds A3B to block formation of high molecular weight A3B complexes and induces A3B cytoplasmic trapping. In summary, these findings indicate that A3B is recognized by diverse retroviruses and counteracted by virus-specific pathways that could be targeted to inhibit A3B mutating activity in cancers.

INTRODUCTION Nuclear factor-kB (NF-kB) is a critical regulator of inflammatory responses following intracerebral haemorrhage (ICH). According to our previous study, inhibiting the p65 subunit at an early stage after ICH can reduce cell death, while inhibiting c-Rel at a late stage can lead to the opposite result. The aim of this study is to clarify whether patient prognosis can be improved by inhibiting p65 at the early stage and promoting c-Rel at the late stage. MATERIAL AND METHODS Rats were divided into a sham group, ICH group, early NF-kB-inhibiting group using ammonium pyrrolidinedithiocarbamate (PDTC; group A, p65 subunit was dominant and inhibited at the early stage), late NF-kB-activating group using phorbol myristate acetate (PMA; group B, c-Rel was dominant and promoted at the late stage), and early NF-kB-inhibiting and late-activating group (group C, p65 subunit was inhibited at the early stage and c-Rel was promoted at the late stage). At preset time points after ICH, perihematomal tissue was obtained for detection of NF-kB activation, cell death, and expression of caspase-3, Bcl-2, and NF-kB subunits, to evaluate of the effect of PDTC and PMA. RESULTS At four days after ICH, p65 expression (p < 0.01) and the number of TUNEL-positive cells (p < 0.01) in group A were significantly lower than in the ICH group. At 10 days after ICH, c-Rel expression in groups B and C was significantly higher than in other groups (p < 0.01 for all). TUNEL-positive cell numbers in groups A and B were significantly lower than in the ICH group, though more numerous than in group C (p < 0.01 for all). CONCLUSIONS Administration of both PDTC at the early stage and PMA at the late stage reduced perihematomal cell death after ICH, and using the two reagents together had a stronger anti-apoptotic effect than separate usage.

APOBEC3 deaminases (A3s) provide mammals with an anti-retroviral barrier by catalyzing dC-to-dU deamination on viral ssDNA. Within primates, A3s have evolved diversely via gene duplications and fusions. Human APOBEC3C (hA3C) efficiently restricts the replication of viral infectivity factor (vif)-deficient Simian immunodeficiency virus (SIVΔvif), but for unknown reasons, it inhibits HIV-1Δvif weakly. In catarrhines (Old World monkeys and apes), the A3C loop 1 displays the conserved amino acid pair WE, while the corresponding consensus sequence in A3F and A3D is the largely divergent pair RK, which is also the inferred ancestral sequence for the last common ancestor of A3C|D|F in primates. Here, we report that modifying the WE residues in hA3C loop 1 to RK leads to stronger interactions with ssDNA substrate, facilitating catalytic function, which resulted in a drastic increase in both deamination activity and the ability to restrict HIV-1 and LINE-1 replication. Conversely, the modification hA3F_WE resulted only in a marginal decrease in HIV-1Δvif inhibition. The two series of ancestral gene duplications that generated A3C, A3D-CTD and A3F-CTD allowed neo/subfunctionalization: A3F-CTD maintained the ancestral RK residues in loop 1, while strong evolutionary pressure selected for the RK→WE modification in catarrhines A3C, possibly allowing for novel substrate specificity and function.AUTHOR SUMMARYThe restriction factors of the APOBEC3 (A3) family of cytidine deaminases inhibit the replication of Vif-deficient retroviruses mainly by mutating their viral genomes. While there are seven A3 proteins (A3A-A3H) found in humans only A3G and A3F potently inhibit HIV-1 replication. A3C in general and its retroviral restriction capacity have not been widely studied probably due to its weak anti-HIV-1 activity, however, it displays a strong antiviral effect against SIV. Understanding the role of A3C is important because it is highly expressed in CD4+ T cells, is upregulated upon HIV-1 infection, and is distributed cell-wide. In this study, we report that replacing two residues in loop 1 of A3C protein with conserved positively-charged amino acids enhance the substrate DNA binding, which markedly facilitates its deamination-dependent antiviral activity against HIV-1 as well as increasing the restriction of LINE-1 retroelements. Furthermore, our evolutionary analysis demonstrates that the pressure that caused the loss of potential loop 1 residues occurred only in A3C but not in primate homologues. Overall, our study highlights the possibility of A3C acting as a super restriction factor, however, this was likely evolutionarily selected against to achieve a balance between anti-viral/anti-LINE-1 activity and genotoxicity.

In this paper, we focus on the problem of context-aware recommendation using tensor factorization. Traditional tensor-based models in context-aware recommendation scenario only consider user-item-context interactions. In this paper, we argue that rating can't be totally explained by the interactions and the rating also influenced by the combined impact of overall mean, user bias, item bias and context bias. Based on this hypothesis, we propose a novel context-aware recommendation model named Bias Tensor Factorization, which take all this factors into account. Additionally, traditional context-aware recommenders with tensor factorization still have three main drawbacks: (1) the model complexity of those models increase exponentially with the number of context features, (2) those models can only handle context features with categorical values and (3) the models fail to select effective features from available context features. To address those problems, we propose a context features auto-encoding algorithm based on regression tree which can both handle numerical features and select effective features. Then we integrate this algorithm with Bias Tensor Factorization. Experiments on a real world contextual dataset and Movielens show that our proposed algorithms outperform the state-of-art context-aware recommendation algorithms, namely tensor factorization and factorization machine.

Feline immunodeficiency virus (FIV) Vif protein counteracts feline APOBEC3s (FcaA3s) restriction factors by inducing their proteasomal degradation. The functional domains in FIV Vif for interaction with FcaA3s are poorly understood. Here, we have identified several motifs in FIV Vif that are important for selective degradation of different FcaA3s. Cats ( Felis catus ) express three types of A3s: single-domain A3Z2, single-domain A3Z3, and double-domain A3Z2Z3. We proposed that FIV Vif would selectively interact with the Z2 and the Z3 A3s. Indeed, we identified two N-terminal Vif motifs (12LF13 and 18GG19) that specifically interacted with the FcaA3Z2 protein but not with A3Z3. In contrast, the exclusive degradation of FcaA3Z3 was regulated by a region of three residues (M24, L25, and I27). Only a FIV Vif carrying a combination of mutations from both interaction sites lost the capacity to degrade and counteract FcaA3Z2Z3. However, alterations in the specific A3s interaction sites did not affect the cellular localization of the FIV Vif protein and binding to feline A3s. Pulldown experiments demonstrated that the A3 binding region localized to FIV Vif residues 50 to 80, outside the specific A3 interaction domain. Finally, we found that the Vif sites specific to individual A3s are conserved in several FIV lineages of domestic cat and nondomestic cats, while being absent in the FIV Vif of pumas. Our data support a complex model of multiple Vif-A3 interactions in which the specific region for selective A3 counteraction is discrete from a general A3 binding domain. IMPORTANCE Both human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV) Vif proteins counteract their host's APOBEC3 restriction factors. However, these two Vif proteins have limited sequence homology. The molecular interaction between FIV Vif and feline APOBEC3s are not well understood. Here, we identified N-terminal FIV Vif sites that regulate the selective interaction of Vif with either feline APOBEC3Z2 or APOBEC3Z3. These specific Vif sites are conserved in several FIV lineages of domestic cat and nondomestic cats, while being absent in FIV Vif from puma. Our findings provide important insights for future experiments describing the FIV Vif interaction with feline APOBEC3s and also indicate that the conserved feline APOBEC3s interaction sites of FIV Vif allow FIV transmissions in Felidae .

Gag intracellular assembly and export are very important processes for lentiviruses replication. Previous studies have demonstrated that equine infectious anemia virus (EIAV) matrix (MA) possesses distinct phosphoinositide affinity compared with HIV-1 MA and that phosphoinositide-mediated targeting to peripheral and internal membranes is a critical factor in EIAV assembly and release. In this study, we compared the cellular assembly sites of EIAV and HIV-1. We observed that the assembly of EIAV particles occurred on interior cellular membranes, while HIV-1 was targeted to the plasma membrane (PM) for assembly. Then, we determined that W7 and K9 in the EIAV MA N terminus were essential for Gag assembly and release but did not affect the cellular distribution of Gag. The replacement of EIAV MA with HIV-1 MA directed chimeric Gag to the PM but severely impaired Gag release. MA structural analysis indicated that the EIAV and HIV-1 MAs had similar spatial structures but that helix 1 of the EIAV MA was closer to loop 2. Further investigation indicated that EIAV Gag accumulated in the trans -Golgi network (TGN) but not the early and late endosomes. The 9 N-terminal amino acids of EIAV MA harbored the signal that directed Gag to the TGN membrane system. Additionally, we demonstrated that EIAV particles were transported to the extracellular space by the cellular vesicle system. This type of EIAV export was not associated with multivesicular bodies or microtubule depolymerization but could be inhibited by the actin-depolymerizing drug cytochalasin D, suggesting that dynamic actin depolymerization may be associated with EIAV production. IMPORTANCE In previous studies, EIAV Gag was reported to localize to both the cell interior and the plasma membrane. Here, we demonstrate that EIAV likely uses the TGN as the assembly site in contrast to HIV-1, which is targeted to the PM for assembly. These distinct assembly features are determined by the MA domain. We also identified two sites in the N terminus of EIAV MA that were important for Gag assembly and release. Furthermore, the observation of EIAV transport by cellular vesicles but not by multivesicular bodies sheds light on the mechanisms underlying EIAV cellular replication.

Human myxovirus resistance protein B (hMXB) is a restriction factor of HIV-1 that also inhibits a variety of retroviruses. However, hMXB is not antiviral against equine infectious anemia virus (EIAV). We show here that equine MX2 (eMX2) potently restricts EIAV in vitro. Additionally, eMX2 inhibits HIV-1 and other lentiviruses, including murine leukemia virus. Previously, it was reported that hMXB repression is reduced in hMXB Δ1-25, but not in GTP-binding mutant K131A and GTP-hydrolysis mutant T151A. In contrast to this phenomenon, our study indicates that eMX2 restriction is not diminished in eMX2 Δ1-25, but is in eMX2 K127A and T147A, which correspond to hMXB K131A and T151A, respectively. Thus, eMX2 may inhibit retroviral replication by a novel mechanism that differs from that of hMXB.

Digital potentiometer is another form of DAC circuit, which has been widely applied in the measurement and control (MAC). However, the common use of digital potentiometer resistance value is limited to 10k?, 50k?, 100k?, 200k?, and its change of resistance is linear. This is often not suited to the needs of the measurement and control. And digital potentiometer chip is an imported product, thus, it is hard to buy with high cost. While 51 MCU is cheap, and its P0 port has no pull-up resistors. By connecting power resistor, simple digital potentiometer can be emulated. And the use of other parallel ports along with analog switch CC4066 can simulate digital potentiometer. And the resistance can be chosen according to various needs.

Lentiviruses have evolved the Vif protein to counteract APOBEC3 (A3) restriction factors by targeting them for proteasomal degradation. Previous studies have identified important residues in the interface of human immunodeficiency virus type 1 (HIV-1) Vif and human APOBEC3C (hA3C) or human APOBEC3F (hA3F). However, the interaction between primate A3C proteins and HIV-1 Vif or natural HIV-1 Vif variants is still poorly understood. Here, we report that HIV-1 Vif is inactive against A3Cs of rhesus macaques (rhA3C), sooty mangabey monkeys (smmA3C), and African green monkeys (agmA3C), while HIV-2, African green monkey simian immunodeficiency virus (SIVagm), and SIVmac Vif proteins efficiently mediate the depletion of all tested A3Cs. We identified that residues N/H130 and Q133 in rhA3C and smmA3C are determinants for this HIV-1 Vif-triggered counteraction. We also found that the HIV-1 Vif interaction sites in helix 4 of hA3C and hA3F differ. Vif alleles from diverse HIV-1 subtypes were tested for degradation activities related to hA3C. The subtype F-1 Vif was identified to be inactive for degradation of hA3C and hA3F. The residues that determined F-1 Vif inactivity in the degradation of A3C/A3F were located in the C-terminal region (K167 and D182). Structural analysis of F-1 Vif revealed that impairing the internal salt bridge of E171-K167 restored reduction capacities to A3C/A3F. Furthermore, we found that D101 could also form an internal interaction with K167. Replacing D101 with glycine and R167 with lysine in NL4-3 Vif impaired its counteractivity to A3F and A3C. This finding indicates that internal interactions outside the A3 binding region in HIV-1 Vif influence the capacity to induce degradation of A3C/A3F. IMPORTANCE The APOBEC3 restriction factors can serve as potential barriers to lentiviral cross-species transmissions. Vif proteins from lentiviruses counteract APOBEC3 by proteasomal degradation. In this study, we found that monkey-derived A3C, rhA3C and smmA3C, were resistant to HIV-1 Vif. This was determined by A3C residues N/H130 and Q133. However, HIV-2, SIVagm, and SIVmac Vif proteins were found to be able to mediate the depletion of all tested primate A3C proteins. In addition, we identified a natural HIV-1 Vif (F-1 Vif) that was inactive in the degradation of hA3C/hA3F. Here, we provide for the first time a model that explains how an internal salt bridge of E171-K167-D101 influences Vif-mediated degradation of hA3C/hA3F. This finding provides a novel way to develop HIV-1 inhibitors by targeting the internal interactions of the Vif protein.

Rev, an important accessory protein of equine infectious anaemia virus (EIAV), induces the nuclear export of incompletely spliced viral mRNAs. Rev is translated from the tat-rev mRNA through leaky scanning of the tat CUG. In this study, the function of the Kozak sequence at the beginning of the rev ORF was investigated. Deletion or attenuation of the Kozak sequence resulted in expression of an N-terminal 11 aa-truncated Rev in addition to WT Rev. Truncated Rev displayed weaker promotion of Gag expression and processing than WT Rev. Furthermore, EIAV rescued from an infectious molecular clone (pEIAVUK3) with Kozak attenuation exhibited decreased viral replication in host cells in vitro. These results provide a new understanding of the relationship between EIAV Rev expression and viral replication.

Additional file 1: Figure S1 . Cellular localization of feline A3s and FIV Vif. HOS cells were transfected with FcaA3Z2b, FcaA3Z3, or FcaA3Z2Z3 (all with HA-tag), together with FIV Vif-TLQAAA. To detect A3 (green) immunofluorescence, staining was performed with an anti-HA antibody. To detect FIV Vif (red) immunofluorescence, staining was performed with an anti-V5 antibody. Nuclei (blue) were visualized by DAPI staining. Figure S2. Comparison of protein sequences of A3s and Vif. (A, B) The sequence alignment of (A) FcaA3Z2 (FcaA3Z2b), (B) FcaA3Z3 and big cat A3 proteins. The D165-H166 and L40-I41 + A65 domains that are essential for FIV Vif induced degradation are marked by red boxes. (C) Sequence alignment of domestic cat FIV Vif (FIVfca subtype 34TF10) and lion FIV (FIVple subtype E) Vif. The C187 and C190 that are essential for induced FcaA3s degradation and marked the presumed BC box (TLQ/SLQ) marked by red boxes. (D) Sequence alignment of HIV-1 (strain NL4-3) and HIV-2 (strain RodA) Vif. The CUL5 box (HCCH) and BC box (SLQ) were marked by red boxes. Pti, Ple, Lly and Pco represent Panthera tigris corbetti; Panthera leo bleyenberghi; Lynx lynx; Puma concolor. Figure S3. Evolutionary supernetwork of A3 sequences retrieved from carnivores. The network was constructed with SplitsTree_v4 using 1,000 maximum likelihood bootstrapped trees created with RAxML_v8.2. Scale bar is given in substitutions per site. The approximate position of the root obtained using maximum likelihood inference with all A3Z1, A3Z2 and A3Z3 sequences from carnivores is indicated in grey. (A) The evolutionary distances among A3Z3 sequences within the two in-paralogs within Caniformia (upper branches and left branch) and within Feliformia (right branches) are indicated as overall average pairwise nucleotide distance ± bootstrap standard error estimate. For each tip, the actual sequence orthologous to positions 38-44 in the F. catus A3Z3 gene are given in parentheses. The inset displays the evolutionary relationships among the Carnivora species for which we have identified A3Z3 paralogs. (B) The evolutionary distances among A3Z2 sequences within Caniformia (upper branches) and within Feliformia (lower branches) are indicated as overall average pairwise nucleotide distance ± bootstrap standard error estimate. For each tip, the actual sequence orthologous to positions 165-170 in the F. catus A3Z2 genes are given in parentheses. Figure S4. The mutations in FcaA3 that cause resistance to FIV Vif do not alter the cellular distribution of FcaA3s. HOS cells were transfected with FcaA3Z2 (FcaA3Z2b), FcaA3Z2.DH-YN, FcaA3Z3, FcaA3Z3.A65I + LI-AA, FcaA3Z2Z3 or FcaA3Z2Z3-M (all with HA-tag). To detect A3 (green) immunofluorescence, staining was performed with an anti-HA antibody. Nuclei (blue) were visualized by DAPI staining. Figure S5. Sequence alignment of feline APOBEC3. Sequence alignment of feline A3Z2Z3 and human A3G as generated by the TopModel approach. The Z2 and Z3 domains are underlined in yellow and blue, respectively. The sequence of the linker domain is underlined in magenta. Helical regions and β-strands are depicted as red helices and green arrows, respectively. In addition, the alignments of three template structures used to model the structure of the linker domain are given (PDB IDs 2YS9, 2DA4, 2MMB). Figure S6. Expression of CD4 and CCR5 receptors on the surface of HOS (red) and HOS.CD4.CCR5 cells (blue) expressing feline A3Z2Z3 or A3Z2Z3-M. CD4 and CCR5 were detected by flow cytometry and anti-CD4 and anti-CCR5 antibodies. Numbers indicate the percentage of positive cells. HOS cells served as background control. Figure S7. The mutated FcaA3s are encapsidated and inhibit FIV by cytidine deamination. (A) The mutated FcaA3s can inhibit the infectivity of FIVΔvif reporter viruses. 293T cells were co-transfected with plasmids for FIVΔvif luciferase together with FcaA3s. 48 h later, supernatant normalized for reverse transcriptase activity was used to transduce 293T cells. Luciferase activity was determined two days post transduction. Asterisks represent statistically significant differences: ***, p 0.05 [Dunnett t test]. (B) Immunoblot of FIV producer cells and VLPs used for (A). Encapsidation of wild-type and mutated feline A3s into FIVΔvif virus like particles (VLPs), A3 proteins were detected by anti-HA antibody. Tubulin detection for equal loading of cell lysate was done using anti-tubulin, for demonstration of equal loading of FIV VLPs VSV-G and FIV p24 proteins were detected by anti-VSV-G and anti-FIV p24 antibodies separately. (C) Encapsidated wild-type and mutated FcaA3s deaminate cytidines FIV genomes. FIVΔvif was produced in the absence and presence of wild-type and mutant FcaA3s (FcaA3Z3, FcaA3Z3.A65I + LI-AA, FcaA3Z2Z3, FcaA3Z2Z3-M) or HsaA3G. The vector particles were used to infect 293T cells. 12 h later, the total cellular DNA was extracted and differential DNA denaturation PCR (3D-PCR) was performed. Td: denaturing temperature. Figure S8. Vif titration on FcaA3 linker mutants. Co-transfection of increasing amounts of expression plasmids for (A) HIV-2 Vif and (B) SIVmac Vif with constant amounts of the indicated A3 expression plasmids. The expression of FcaA3s and Vifs were analyzed by anti-HA and anti-V5 antibodies, respectively. Cell lysates were also analyzed for equal amounts of total proteins using anti-tubulin antibody. Figure S9. Expression and encapsidation of feline A3 linker mutants using (A) FIVΔvif and (B) SIVmacΔvif. Immunoblots of corresponding experiments shown in Fig. 10C and 10D. Immunoblots of lysates of virus producer cells (cell) and virus particles (VLP). A3s were detected by anti-HA antibodies, cell lysates were also analyzed for equal amounts of total proteins using anti-tubulin antibody and VLP lysates using anti-VSV-G antibody. Figure S10. HIV-1 Vif cannot target the “YYFWDPN/DY” domain in FcaA3. (A) CO-IP of feline A3Z2Z3 (HA tag) with either HIV-1 Vif (V5 tag) or FIV Vif (TLQAAA mutant, V5 tag). A3Z2Z3 immune precipitated and detected by anti-HA antibody, co-precipitated Vif was detected by anti-V5 antibody. (B) Comparison of the “YYFWDPN/DY” domain in HsaA3G and FcaA3Z2Z3 and derived mutations generated in FcaA3Z2Z3, the mutated residues shown in bold. (C) FcaA3Z2Z3 mutants were investigated for being sensitive for degradation by HIV-1 Vif. Expression plasmids of FcaA3Z2Z3 mutants of HsaA3G were co-transfected together with HIV-1 Vif into 293T cells. 48 h later, Cell lysates were used to detect the expression of FcaA3Z2Z3 and HIV-1 Vif by anti-HA and anti-V5 antibodies, respectively. Cell lysates were also analyzed for equal amounts of total proteins using anti-tubulin antibody.

To explore the clinical characteristics, efficacy and prognosis of primary extradural meningiomas (PEMs) in head.A total of 19 treated surgically case of PEMs at Qilu Hospital, Shandong University between May 1994 and December 2012 were analyzed retrospectively with respects to their demographic features, presenting symptomsduration, tumor locationtype, imaging features, surgical results, pathological grade, histological subtype and follow-up outcomes.PEMs in head accounted for 1.2% of all meningiomas in this group. The male-to-female ratio was 1: 0.7. The mean age was 36.6 years with a bimodal distribution of age. The common presenting symptoms included nasal obstruction and a painless and gradually expanding mass in the region of lesion. The average duration of symptom was 3.07 years. The skull convexities, paranasal sinuses and nasal cavity, orbit and epidural space were common tumor sites. The most common type was typeII. The rate of total tumor removal was 100%. And no perioperative mortality occurred in this series. Benign and atypical meningiomas accounted for 94.7% and 6.3% respectively. Meningothelial and psammomatous meningiomas were common histopathological subtypes. There was one case of tumoral recurrence. And no mortality was reported during a mean follow-up period of 2.43 (0.25-8.5) years.PEMs in head have some marked clinical characteristics compared with primary intradural meningiomas. Total tumor removal together with a wide excision of all involved tissue followed by the reconstruction of tissue defects is the best surgical option. The prognosis is excellent in most cases after complete resection.

Nuclear factor-κB (NF-κB) plays an important role in secondary damage after intracerebral hemorrhage (ICH). We explored NF-κB activation and the relationship between NF-κB and cell death in the perihematomal brain tissue of patients after ICH. According to the interval between onset of hemorrhage and specimen collection, 53 cases of patients with basal ganglia hemorrhage were divided into six experimental groups: 0–6, 7–12, 13–24, 25–48, 49–96, and >96 h group. Brain tissues of the experimental groups and control group were collected. IL-1β, TNF-α, and NF-κB p65 expressions at the protein level were detected by immunohistochemistry. Cell death was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. All of the detection items of immunohistochemistry and TUNEL showed significant differences between the experimental groups and control group. At the protein level, nuclear NF-κB p65, IL-1β, and TNF-α achieved maximum values at 13–48, 0–24, and 13–48 h, respectively. Maximum cell death was reached at 13–48 h. NF-κB activation increased dramatically in perihematomal brain tissue after ICH. NF-κB activation was closely related with cell death and had an important function in secondary brain damage after ICH in patients.

This study investigated the therapeutic effect of neural stem cells transplanted via the carotid artery at different times after intracerebral hemorrhage. A great number of 5-bromo-2-deoxyuridine-positive cells were observed surviving and distributed evenly in the perihematoma areas. Phenotypes of grafted cells depended upon time of transplantation, and the later the cells were transplanted, the larger the percentage of cells that differentiated into neurons. Animals treated at 7 and 14 days after injury exhibited the most significant improvements in behavioral tests. Therefore,intracarotid injection allows efficient delivery of cells to the injured hemisphere, especially during the period 7-14 days after injury, and may potentially be applicable in humans.