Neuroinflammation by cytotoxic T-lymphocytes impairs retrograde axonal transport in an oligodendrocyte mutant mouse

Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage

Ensuring affordable access to healthcare for everyone in the European Union: what gaps remain and how can the EU support Member States to overcome them?

European Union (EU) Member States have made multiple commitments to progress towards universal health coverage (UHC), so that everyone can access quality healthcare without experiencing financial hardship. Yet, significant gaps in all three dimensions of health coverage (population coverage, user charges, and benefits packages) remain. This article highlights some of these gaps, looks at how access to healthcare has been addressed through the EU’s socioeconomic governance and funding instruments, and suggests ways in which the EU can further support national progress towards UHC

Loss of RNase J leads to multi-drug tolerance and accumulation of highly structured mRNA fragments in Mycobacterium tuberculosis

Despite the existence of well-characterized, canonical mutations that confer high-level drug resistance to Mycobacterium tuberculosis (Mtb), there is evidence that drug resistance mechanisms are more complex than simple acquisition of such mutations. Recent studies have shown that Mtb can acquire non-canonical resistance-associated mutations that confer survival advantages in the presence of certain drugs, likely acting as stepping-stones for acquisition of high-level resistance. Rv2752c/rnj, encoding RNase J, is disproportionately mutated in drug-resistant clinical Mtb isolates. Here we show that deletion of rnj confers increased tolerance to lethal concentrations of several drugs. RNAseq revealed that RNase J affects expression of a subset of genes enriched for PE/PPE genes and stable RNAs and is key for proper 23S rRNA maturation. Gene expression differences implicated two sRNAs and ppe50-ppe51 as important contributors to the drug tolerance phenotype. In addition, we found that in the absence of RNase J, many short RNA fragments accumulate because they are degraded at slower rates. We show that the accumulated transcript fragments are targets of RNase J and are characterized by strong secondary structure and high G+C content, indicating that RNase J has a rate-limiting role in degradation of highly structured RNAs. Taken together, our results demonstrate that RNase J indirectly affects drug tolerance, as well as reveal the endogenous roles of RNase J in mycobacterial RNA metabolism.Fil: Martini, María Carla. Worcester Polytechnic Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hicks, Nathan D.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Xiao, Junpei. Worcester Polytechnic Institute; Estados UnidosFil: Alonso, Maria Natalia. Worcester Polytechnic Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barbier, Thibault. Harvard University. Harvard School of Public Health; Estados UnidosFil: Sixsmith, Jaimie. Harvard University. Harvard School of Public Health; Estados UnidosFil: Fortune, Sarah M.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Shell, Scarlet S.. Worcester Polytechnic Institute; Estados Unido

Holocene soil erosion in Eastern Europe-land use and/or climate controlled? The example of a catchment at the Giant Chalcolithic settlement at Maidanetske, central Ukraine

The Younger Quaternary erosion history was reconstructed in a catchment close to the Chalcolithic giant settlement Maidanetske, central Ukraine based on dated sediment sequences. Four trenches and a long percussion drill-core were analyzed in a valley grading from a Loess covered plateau towards the Talianky River. The sediments were dated by a combination of radiocarbon dating, optical stimulated luminescence (OSL) and embedded artifacts. Although there is some weakness of numerical dating so far, a non-coincidence between phases of soil erosion and the local and regional settlement history over long periods of the Holocene is indicated. This, viewed in the light of the geographical setting of the site in the climate sensitive forest-steppe borderland, suggests climatically driven erosion processes. The detected phases of erosion coincide with global (cal 27.6 ± 1.3 kyrs BP, 12.0 ± 0.4 kyrs BP), northern hemispheric (cal 8.5 ± 0.3 kyrs BP), Mediterranean (cal 3.93 ± 0.1 kyrs BP) as well as western to central European (2700 to 2000 cal BP) climate anomalies. Increased occurrences of heavy precipitation events, probably during phases of a weakened vegetation cover, could explain the observed record. Investigations at additional sites in Eastern Europe are needed to verify the representativeness of the presented record from central Ukraine at a regional level.The composition of the sediments indicates changes of the slope-channel connectivity during the deposition history. Whereas the glacial to early Holocene and modern times sediments were derived from the whole catchment area, during the mid- to late-Holocene a tendency to lower slope storage of colluvial material and valley incision is indicated

Editorial: Genomic selection: Lessons learned and perspectives

Genomic selection (GS) has been one of the most prominent Research Topics in breeding science in the last two decades after the milestone paper by Meuwissen et al. (2001). Its huge potential for increasing the efficiency of breeding programs attracted scientific curiosity and research funding. Many different statistical prediction methods have been tested, and different use cases have been explored. We organized this Research Topic to look both back and forward. The objectives were to review the developments of the last 20 years, to provide a snapshot of current hot topics, and potentially also to define areas on which more (or less) focus should be put in the future, thereby supporting readers with formulating and prioritizing their ideas for future research. Several questions were brought up when organizing this Research Topic including: How did GS change breeding schemes? Which impact did GS have on realized selection gain? What, considering the context of particularities of different crops, may be optimal breeding schemes to leverage the full potential of GS? What has been the impact of and what is the potential of hybrid prediction, statistical epistasis models, deep learning and other methods? What are the long-term effects of GS? Can predictive breeding approaches also be used to harness genetic resources from germplasm banks in a more efficient way

Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts

BACKGROUND: Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-O-sulfation state. HSPGs bind to numerous growth factor ligands including fibroblast growth factors (FGF), epidermal growth factors (EGF), and vascular endothelial growth factors (VEGF), and are critically important in the context of cancer cell growth, invasion, and metastasis. We hypothesized that sulfatase activity in the tumor microenvironment would regulate tumor growth in vivo. METHODS: We established a model of stable expression of sulfatases in the human breast cancer cell line MDA-MB-231 and purified recombinant human Sulfatase 2 (rhSulf2) for exogenous administration. In vitro studies were performed to measure effects on breast cancer cell invasion and proliferation, and groups were statistically compared using Student's t-test. The effects of hSulf2 on tumor progression were tested using in vivo xenografts with two methods. First, MDA-MB-231 cells stably expressing hSulf1, hSulf2, or both hSulf1/hSulf2 were grown as xenografts and the resulting tumor growth and vascularization was compared to controls. Secondly, wild type MDA-MB-231 xenografts were treated by short-term intratumoral injection with rhSulf2 or vehicle during tumor growth. Ultrasound analysis was also used to complement caliper measurement to monitor tumor growth. In vivo studies were statistically analyzed using Student's t test. RESULTS: In vitro, stable expression of hSulf2 or administration of rhSulf2 in breast cancer cells decreased cell proliferation and invasion, corresponding to an inhibition of ERK activation. Stable expression of the sulfatases in xenografts significantly suppressed tumor growth, with complete regression of tumors expressing both hSulf1 and hSulf2 and significantly smaller tumor volumes in groups expressing hSulf1 or hSulf2 compared to control xenografts. Despite significant suppression of tumor volume, sulfatases did not affect vascular density within the tumors. By contrast, transient exogenous treatment of MDA-MB-231 xenografts with rhSulf2 was not sufficient to inhibit or reverse tumor growth. CONCLUSION: These data indicate that in vivo progression of human breast cancer xenografts can be inhibited with sulfatase expression, and therapeutic effect requires constant delivery at the tumor site. Our results support a direct effect of sulfatases on tumor growth or invasion, rather than an effect in the stromal compartment

Direct and indirect control of the initiation of meiotic recombination by DNA damage checkpoint mechanisms in budding yeast

Meiotic recombination plays an essential role in the proper segregation of chromosomes at meiosis I in many sexually reproducing organisms. Meiotic recombination is initiated by the scheduled formation of genome-wide DNA double-strand breaks (DSBs). The timing of DSB formation is strictly controlled because unscheduled DSB formation is detrimental to genome integrity. Here, we investigated the role of DNA damage checkpoint mechanisms in the control of meiotic DSB formation using budding yeast. By using recombination defective mutants in which meiotic DSBs are not repaired, the effect of DNA damage checkpoint mutations on DSB formation was evaluated. The Tel1 (ATM) pathway mainly responds to unresected DSB ends, thus the sae2 mutant background in which DSB ends remain intact was employed. On the other hand, the Mec1 (ATR) pathway is primarily used when DSB ends are resected, thus the rad51 dmc1 double mutant background was employed in which highly resected DSBs accumulate. In order to separate the effect caused by unscheduled cell cycle progression, which is often associated with DNA damage checkpoint defects, we also employed the ndt80 mutation which permanently arrests the meiotic cell cycle at prophase I. In the absence of Tel1, DSB formation was reduced in larger chromosomes (IV, VII, II and XI) whereas no significant reduction was found in smaller chromosomes (III and VI). On the other hand, the absence of Rad17 (a critical component of the ATR pathway) lead to an increase in DSB formation (chromosomes VII and II were tested). We propose that, within prophase I, the Tel1 pathway facilitates DSB formation, especially in bigger chromosomes, while the Mec1 pathway negatively regulates DSB formation. We also identified prophase I exit, which is under the control of the DNA damage checkpoint machinery, to be a critical event associated with down-regulating meiotic DSB formation

Differential activation of nuclear inositide-dependent signalling pathways during erythropoiesis and myelopoiesis induced by lenalidomide and azacitidine in myelodysplastic syndromes (MDS)

Inositide-dependent signalling pathways regulated by phosphoinositide-specific phospholi- pase C (PI-PLC) beta1 have been demonstrated to play important roles in MDS pathogenesis and in cell differentiation (1). Moreover, the MDS therapy aims at inducing myeloid and/or erythroid differentiation of MDS stem cells. Indeed, azacitidine is a demethylating agent that can induce myeloid differentiation. On the other hand, lenalidomide may restore a normal erythropoiesis. The exact molecular mechanisms underlying the effect of azacitidine and lenalidomide in MDS cells are still unclear, although it is clear that these therapies regulate stem cell proliferation, differentiation and apoptosis (2). The combination of azacitidine and lenalidomide in MDS therapy is now under considera- tion, given the capability of both drugs to balance proliferation and differentiation processes (3). In this study we analyzed the molecular effect of this combination therapy on PI-PLC isoenzymes, not only studying PI-PLCbeta1, but also PI-PLCgamma1, that can be associated with erythropoiesis. We analyzed 44 patients diagnosed with high-risk MDS who were given azacitidine and lenalidomide. Given the limited number of cells, we quantified the expression of these molecules by Real-Time PCR analyses and immunocytochemical experiments. Moreover, we carried out cell cycle analyses and studied both PI-PLCbeta1 methylation status and the expression of Globin genes. In our case series, 28/44 patients were evaluable, with an overall response rate of 78.6% (22/28 cases). At a molecular level, a significant increase of PI-PLCbeta1 and/or PI-PLCgamma1 expression was associated with a favourable clinical response to the combination therapy. Responder cases also showed an increase of Beta-globin expression, hinting at a specific contri- bution of lenalidomide on erythroid activation, whilst the frequent demethylation of PI-PLCbeta1 promoter could be specifically linked to azacitidine. Taken together, our results show that the combination of azacitidine and lenalidomide can be important for activating PI-PLC isoenzymes, therefore regulating myeloid and erythroid dif- ferentiation in MDS cells

Fermenting Feminism

"Fermenting Feminism brings together artists whose work responds to what it means to bring fermentation and feminism into the same critical space. These are works that approach fermentation through intersectional and trans-inclusive feminist frameworks, and works that approach feminisms through the metaphor and material practice of fermentation. As both a metaphor and a physical process, fermentation embodies bioavailability and accessibility, preservation and transformation, inter-species symbiosis and coevolution, biodiversity and futurity, harm reduction and care." -- p. [1]