In vitro anti-tumour activity of α-galactosylceramide-stimulated human invariant Vα24+NKT cells against melanoma

α-galactosylceramide (KRN 7000, α-GalCer) has shown potent in vivo anti-tumour activity in mice, including against melanoma and the highly specific effect of inducing proliferation and activation of human Vα24+NKT-cells. We hypothesized that human Vα24+NKT-cells activated by α-GalCer might exhibit anti-tumour activity against human melanoma. To investigate this, Vα24+NKT-cells were generated from the peripheral blood of patients with melanoma after stimulation with α-GalCer pulsed monocyte-derived dendritic cells (Mo-DCs). Vα24+NKT-cells did not exhibit cytolytic activity against the primary autologous or allogeneic melanoma cell lines tested. However, proliferation of the melanoma cell lines was markedly suppressed by co-culture with activated Vα24+NKT-cells (mean ± SD inhibition of proliferation 63.9 ± 1.3%). Culture supernatants of activated Vα24+NKT-cell cultures stimulated with α-GalCer pulsed Mo-DCs exhibited similar antiproliferative activities against melanoma cells, indicating that the majority of the inhibitory effects were due to soluble mediators rather than direct cell-to-cell interactions. This effect was predominantly due to release of IFN-γ, and to a lesser extent IL-12. Other cytokines, including IL-4 and IL-10, were released but these cytokines had less antiproliferative effects. These in vitro results show that Vα24+NKT-cells stimulated by α-GalCer-pulsed Mo-DCs have anti-tumour activities against human melanoma through antiproliferative effects exerted by soluble mediators rather than cytolytic effects as observed against some other tumours. Induction of local cytokine release by activated Vα24+NKT-cells may contribute to clinical anti-tumour effects of α-GalCer. © 2001 Cancer Research Campaign http://www.bjcancer.co

The input reduction principle of agroecology is wrong when it comes to mineral fertilizer use in sub-Saharan Africa

Can farmers in sub-Saharan Africa (SSA) boost crop yields and improve food availability without using more mineral fertilizer? This question has been at the center of lively debates among the civil society, policy-makers, and in academic editorials. Proponents of the “yes” answer have put forward the “input reduction” principle of agroecology, i.e. by relying on agrobiodiversity, recycling and better efficiency, agroecological practices such as the use of legumes and manure can increase crop productivity without the need for more mineral fertilizer. We reviewed decades of scientific literature on nutrient balances in SSA, biological nitrogen fixation of tropical legumes, manure production and use in smallholder farming systems, and the environmental impact of mineral fertilizer. Our analyses show that more mineral fertilizer is needed in SSA for five reasons: (i) the starting point in SSA is that agricultural production is “agroecological” by default, that is, very low mineral fertilizer use, widespread mixed crop-livestock systems and large crop diversity including legumes, but leading to poor soil fertility as a result of widespread soil nutrient mining, (ii) the nitrogen needs of crops cannot be adequately met solely through biological nitrogen fixation by legumes and recycling of animal manure, (iii) other nutrients like phosphorus and potassium need to be replaced continuously, (iv) mineral fertilizers, if used appropriately, cause little harm to the environment, and (v) reducing the use of mineral fertilizers would hamper productivity gains and contribute indirectly to agricultural expansion and to deforestation. Yet, the agroecological principles directly related to soil fertility—recycling, efficiency, diversity—remain key in improving soil health and nutrient-use efficiency, and are critical to sustaining crop productivity in the long run. We argue for a nuanced position that acknowledges the critical need for more mineral fertilizers in SSA, in combination with the use of agroecological practices and adequate policy support

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

Several human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome

Rapid Dissemination of SIV Follows Multisite Entry after Rectal Inoculation

Receptive ano-rectal intercourse is a major cause of HIV infection in men having sex with men and in heterosexuals. Current knowledge of the mechanisms of entry and dissemination during HIV rectal transmission is scarce and does not allow the development of preventive strategies. We investigated the early steps of rectal infection in rhesus macaques inoculated with the pathogenic isolate SIVmac251 and necropsied four hours to nine days later. All macaques were positive for SIV. Control macaques inoculated with heat-inactivated virus were consistently negative for SIV. SIV DNA was detected in the rectum as early as four hours post infection by nested PCR for gag in many laser-microdissected samples of lymphoid aggregates and lamina propria but never in follicle-associated epithelium. Scarce SIV antigen positive cells were observed by immunohistofluorescence in the rectum, among intraepithelial and lamina propria cells as well as in clusters in lymphoid aggregates, four hours post infection and onwards. These cells were T cells and non-T cells that were not epithelial cells, CD68+ macrophages, DC-SIGN+ cells or fascin+ dendritic cells. DC-SIGN+ cells carried infectious virus. Detection of Env singly spliced mRNA in the mucosa by nested RT-PCR indicated ongoing viral replication. Strikingly, four hours post infection colic lymph nodes were also infected in all macaques as either SIV DNA or infectious virus was recovered. Rapid SIV entry and dissemination is consistent with trans-epithelial transport. Virions appear to cross the follicle-associated epithelium, and also the digestive epithelium. Viral replication could however be more efficient in lymphoid aggregates. The initial sequence of events differs from both vaginal and oral infections, which implies that prevention strategies for rectal transmission will have to be specific. Microbicides will need to protect both digestive and follicle-associated epithelia. Vaccines will need to induce immunity in lymph nodes as well as in the rectum

Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir

Using a repeat-exposure macaque model, Walid Heneine and colleagues find that pre-exposure prophylaxis with combination antiretroviral drugs provides protection against rectal challenge with a SHIV virus

Human Natural Killer T Cells Are Heterogeneous in Their Capacity to Reprogram Their Effector Functions

BACKGROUND: Natural killer T (NKT) cells are a subset of T cells that help potentiate and regulate immune responses. Although human NKT cell subsets with distinct effector functions have been identified, it is unclear whether the effector functions of these subsets are imprinted during development or can be selectively reprogrammed in the periphery. RESULTS: We found that neonatal NKT cells are predominantly CD4+ and express higher levels of CCR7 and CD62L and lower levels of CD94 and CD161 than adult CD4+ or CD4− NKT cell subsets. Accordingly, neonatal NKT cells were more flexible than adult CD4+ NKT cells in their capacity to acquire Th1- or Th2-like functions upon either cytokine-mediated polarization or ectopic expression of the Th1 or Th2 transcription factors T-bet and GATA-3, respectively. Consistent with their more differentiated phenotype, CD4- NKT cells were predominantly resistant to functional reprogramming and displayed higher cytotoxic function. In contrast to conventional T cells, neither the expression of CXCR3 nor the cytotoxic capacity of neonatal NKT cells could be reprogrammed. CONCLUSIONS AND SIGNIFICANCE: Together, these results suggest that neonatal CD4+, adult CD4+, and adult CD4− NKT may represent unique states of maturation and that some functions of human NKT cells may be developmentally imprinted, while others are acquired similar to conventional T cell subsets during peripheral maturation and differentiation. Given the potent immuno-regulatory functions of NKT cells, these findings have important implications for the development of novel NKT cell-based therapeutics and vaccines

Characterisation of a high-pressure direct-current magnetron discharge used for tungsten nanoparticle production

International audienc

Characterisation of a high-pressure direct-current magnetron discharge used for tungsten nanoparticle production

International audienc

On the long-waves dispersion in Yukawa systems

International audienceA useful simplification of the quasilocalized charge approximations (QLCA) method to calculate the dispersion relations in strongly coupled Yukawa fluids is discussed. In this simplified version, a simplest possible model radial distribution function, properly related to the thermodynamic properties of the system, is used. The approach demonstrates good agreement with the dispersion relations obtained using the molecular dynamics simulations and the original QLCA in the long-wavelength regime. (C) 2016 AIP Publishing LLC

Forces applied to nanoparticles in magnetron discharges and the resulting size segregation

International audienceTwo-dimensional measurements of magnetron discharge plasma parameters are used to calculate the forces applied to an isolated nanoparticle in conditions where nanoparticles are produced from cathode sputtering. Plasma spatial inhomogeneities, which are specific to magnetron discharges, also induce inhomogeneities in the charging mechanism and applied forces. It is shown that the nanoparticle transport is due to electric, thermophoretic and ion drag forces, and that the dominant one proportional to the nanoparticle size varies according to position. For a given plasma, these spatial differences explain the segregation of size in the nanoparticle deposits, which are observed inside the device