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The present paper studies questions of the use of space in various ways on the basis of data obtained from a site at Sormás-Török-földek. The significance of this site lies in the fact that two enclosures were excavated here which differ in character, but which are in a close relationship physically and chronologically. They demonstrate precisely the radical change, which took place in the mode of space-use, representing two important stages of the progression as a result of which the separation of territories used for domestic and ritual activities were physically manifested.

The rondels – circular earthworks of late Neolithic Europe – have a repeated form highly suggestive of deliberate design and symbolism. The concentric ditches are cut by two, three or most often four causeways at right angles. Here the authors investigate the orientation of the causeways in 51 rondels belonging to the Lengyel culture and conclude that they correlate well with the sunrise. The idea of a solar cult receives some corroboration from patterns on contemporary pottery.

In European Neolithic populations, the arrival of farmers prompted admixture with local hunter-gatherers over many centuries, resulting in distinct signatures in each region due to a complex series of interactions. Early European union of farmers David Reich and colleagues analyse genome-wide data from 180 individuals from the Neolithic and Chalcolithic periods of Hungary, Germany and Spain to study the population dynamics of Neolithization in European prehistory. They examine how gene flow reshaped European populations during the Neolithic period, including pervasive admixture—the interbreeding between previously isolated populations—between groups with different ancestry profiles. In each region, they find that the arrival of farmers prompted admixture with local hunter-gatherers, over the course of 3,000 years. Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 who received a limited amount of admixture from resident hunter-gatherers 3 , 4 , 5 , 9 . Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000–2900 bc , n  = 100), Germany (5500–3000 bc , n  = 42) and Spain (5500–2200 bc , n  = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions.

The questions of socio-historical circumstances in South-Western Hungary based on observations made mainly at sites in Zala county during Post-LBK times are discussed below. This time period corresponds to the turn of the Middle and Late Neolithic in Western-Hungary which is, at the same time, the beginning of the emergence of the Lengyel culture. It has previously been accepted that there was genetic continuity between the LBK and the Lengyel cultures. The formation process of the Lengyel culture in Hungary has recently been reviewed. The role of the Sopot culture turned out to be more significant than it formerly had been conceived. The emergence of the Lengyel culture has been reconsidered also in other territories, e.g. in Slovakia, where a great cultural and historical break from the preceding LBK (Zeliezovce Group) was proved. Climatic changes are hypothesized in the background of the changes. According to former theories the genesis of the Lengyel culture was considered as a process taking place on the multicultural substrate of the LBK groups in which the Sopot culture played a catalyser role causing and inspiring the transformations. On the other hand, essential details of this time period, among them the factual character of the changes, were not clarified. A fair number of new data resulted from lately excavated sites of the Sopot culture, e.g. Becsehely-Bükkaljai-dulo, Petrivente-Újkúti-dulo, Sormás-Török-földek, and Sormás-Mántai-dulo have broadened our knowledge significantly on the turn of the Middle and Late Neolithic. By the end of the Middle Neolithic a high concentration of Late LBK and Sopot settlements developed in South-Western-Transdanubia. In the territory considered earlier as a periphery compared to the Sopot central core area a secondary settlement block was formed, which consisted of a close chain of extended and enclosed settlements (e.g. the sites mentioned above). The nature of Post-LBK times are mainly discussed on detailed analyses of two sites from the study area. A multicultural site at Sormás-Török-földek represents settlements of the Sopot and Lengyel cultures. Beyond substantial new relative chronological data several absolute chronological radiocarbon data are also available both from Sopot and formative Lengyel contexts from the site. The site at Esztergályhorváti provided a unique feature; a mass grave containing skeletal remains exclusively of male individuals. The Esztergályhorváti find assemblage is dated by 14C to the same period as Sormás-Török-földek. The comparative review of these two sites aims to clarify whether Post-LBK times in South-Western-Hungary were calm, peaceful terms generating prosperous and continuous development of local communities or should it rather be interpreted as a wartime, fraught with danger and violence? The author sets out arguments in favour of the peaceful nature of this time period.

The questions of socio-historical circumstances in South-Western Hungary based on observations made mainly at sites in Zala county during Post-LBK times are discussed below. This time period corresponds to the turn of the Middle and Late Neolithic in Western-Hungary which is, at the same time, the beginning of the emergence of the Lengyel culture. It has previously been accepted that there was genetic continuity between the LBK and the Lengyel cultures. The formation process of the Lengyel culture in Hungary has recently been reviewed. The role of the Sopot culture turned out to be more significant than it formerly had been conceived. The emergence of the Lengyel culture has been reconsidered also in other territories, e.g. in Slovakia, where a great cultural and historical break from the preceding LBK (Želiezovce Group) was proved. Climatic changes are hypothesized in the background of the changes. According to former theories the genesis of the Lengyel culture was considered as a process taking place on the multicultural substrate of the LBK groups in which the Sopot culture played a catalyser role causing and inspiring the transformations. On the other hand, essential details of this time period, among them the factual character of the changes, were not clarified. A fair number of new data resulted from lately excavated sites of the Sopot culture, e.g. Becsehely-Bükkaljai-dűlő, Petrivente-Újkúti-dűlő, Sormás-Török-földek, and Sormás-Mántai-dűlő have broadened our knowledge significantly on the turn of the Middle and Late Neolithic. By the end of the Middle Neolithic a high concentration of Late LBK and Sopot settlements developed in South-Western-Transdanubia. In the territory considered earlier as a periphery compared to the Sopot central core area a secondary settlement block was formed, which consisted of a close chain of extended and enclosed settlements (e.g. the sites mentioned above). The nature of Post-LBK times are mainly discussed on detailed analyses of two sites from the study area. A multicultural site at Sormás-Török-földek represents settlements of the Sopot and Lengyel cultures. Beyond substantial new relative chronological data several absolute chronological radiocarbon data are also available both from Sopot and formative Lengyel contexts from the site. The site at Esztergalyhorvati provided a unique feature; a mass grave containing skeletal remains exclusively of male individuals. The Esztergalyhorvati find assemblage is dated by14C to the same period as Sormas-Török-földek. The comparative review of these two sites aims to clarify whether Post-LBK times in South-Western-Hungary were calm, peaceful terms generating prosperous and continuous development of local communities or should it rather be interpreted as a wartime, fraught with danger and violence? The author sets out arguments in favour of the peaceful nature of this time period.

Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants1–8 who received a limited amount of admixture from resident hunter-gatherers3–5,9. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Using the highest-resolution genome-wide ancient DNA data set assembled to date—a total of 180 samples, 130 newly reported here, from the Neolithic and Chalcolithic of Hungary (6000–2900 BCE, n = 100), Germany (5500–3000 BCE, n = 42), and Spain (5500–2200 BCE, n = 38)—we investigate the population dynamics of Neolithization across Europe. We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways that gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modeling approaches to elucidate multiple dimensions of historical population interactions.

Ancient DNA studies have established that European Neolithic populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Using the highest-resolution genome-wide ancient DNA data set assembled to date --- a total of 177 samples, 127 newly reported here, from the Neolithic and Chalcolithic of Hungary (6000-2900 BCE, n = 98), Germany (5500-3000 BCE, n = 42), and Spain (5500-2200 BCE, n = 37) --- we investigate the population dynamics of Neolithization across Europe. We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways that gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modeling approaches to elucidate multiple dimensions of historical population interactions.

Am Südostrand des Verbreitungsgebiets befinden wir uns zwar geografisch gesehen in einer Rand lage, doch was Entstehung und Entwicklung der Kreisgrabenanlagen angeht, handelt es sich keineswegs um die Peripherie, wie ungarische Forschungen zeigen.

Background Hypertriglyceridemia is closely linked to atherosclerosis related inflammatory processes and blood–brain barrier (BBB) dysfunction. Using apolipoprotein B-100 (APOB-100) transgenic mice, an animal model of chronic hypertriglyceridemia, we analyzed BBB function and morphology in vitro and ex vivo. Our objective was to determine which BBB characteristics are produced mainly by interleukin (IL)-6, an atherosclerosis promoting cytokine, and whether these actions can be antagonized by IL-10, an anti-inflammatory cytokine. Methods Brain endothelial and glial cell cultures and brain microvessels were isolated from wild type (WT) and APOB-100 transgenic mice and were treated with IL-6, IL-10 and their combination. First, IL-6 and IL-10 production was measured in WT and APOB-100 microvessels using qPCR. Then functional parameters of endothelial cell cultures were analyzed and immunocytochemistry for key BBB proteins was performed. Results IL-6 mRNA levels were higher in brain microvessels than in brain parenchyma of APOB-100 transgenic mice. Transendothelial electric resistance and P-glycoprotein activity were lower, and paracellular permeability was higher in cultured APOB-100 brain endothelial cells. These features were sensitive to both IL-6 and IL-10 treatments. A decreased P-glycoprotein immunostaining was measured in transgenic endothelial cells under control conditions and in WT cells after treating them with IL-6. This effect was antagonized by IL-10. Changes in immunostaining for tight junction proteins were observed after IL-6 exposure, which were in part antagonized by IL-10. In glial cell cultures an increase in aquaporin-4 immunolabeling in the transgenic group and an increase in microglia cell density in WT glia cultures was detected after IL-6 treatment, which was antagonized by IL-10. In isolated brain microvessels a decrease in P-glycoprotein immunolabeled area fraction was measured in APOB-100 microvessels under control conditions and in WT microvessels after every cytokine treatment. ZO-1 immunolabeling showed characteristics similar to that of P-glycoprotein. No change was seen in claudin-5 and occludin immunoreactive area fractions in microvessels. A decrease in aquaporin-4 immunoreactivity was measured in WT microvessels treated by IL-6, which was antagonized by IL-10. Conclusion IL-6 produced in microvessels contributes to BBB impairment observed in the APOB-100 mice. We showed that IL-10 partly antagonizes the effects of IL-6 at the BBB.

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.