Artemisinin and its derivatives (ARTs) are the frontline drugs against malaria, but resistance is jeopardizing their effectiveness. ART resistance is mediated by mutations in the parasite's Kelch13 ...protein, but Kelch13 function and its role in resistance remain unclear. In this study, we identified proteins located at a Kelch13-defined compartment. Inactivation of eight of these proteins, including Kelch13, rendered parasites resistant to ART, revealing a pathway critical for resistance. Functional analysis showed that these proteins are required for endocytosis of hemoglobin from the host cell. Parasites with inactivated Kelch13 or a resistance-conferring Kelch13 mutation displayed reduced hemoglobin endocytosis. ARTs are activated by degradation products of hemoglobin. Hence, reduced activity of Kelch13 and its interactors diminishes hemoglobin endocytosis and thereby ART activation, resulting in parasite resistance.
This volume addresses internationalization and internationality of adult education in two ways. On the one hand, it takes an internal perspective on the research landscape by contextualized specific ...phenomena of internationalization in adult education and learning. On the other hand, externally induced research questions are addressed from the perspective of their internationality. Both reactive and anticipatory dynamics as well as chances and limitations of internationalization become visible.
Der Band befasst sich auf zweifache Weise mit Internationalisierung und Internationalität von Erwachsenenbildung. Zum einen wird eine Binnenperspektive auf die Forschungslandschaft eingenommen, indem spezifische Internationalisierungsphänomene der Erwachsenen- und Weiterbildung eine kontextualisierte Darstellung finden. Zum anderen werden von außen induzierte Forschungsfragen unter der Perspektive ihrer Internationalität aufgegriffen und diskutiert. Die Beitragenden machen sowohl reaktive als auch antizipative Bewegungen und Dynamiken sowie Chancen und Grenzen von Internationalisierung sichtbar.
Liver fibrosis is orchestrated by a complex network of signaling pathways regulating the deposition of extracellular matrix proteins during fibrogenesis. MicroRNAs (miRNAs) represent a family of ...small noncoding RNAs controlling translation and transcription of many genes. Recently, miRNAs have been suggested to crucially modulate cellular processes in the liver such as hepatocarcinogenesis. However, their role in liver fibrosis is not well understood. We systematically analyzed the regulation of miRNAs in a mouse model of carbon tetrachloride–induced hepatic fibrogenesis (CCl4) by gene array analysis, which revealed a panel of miRNA that were specifically regulated in livers of mice undergoing hepatic fibrosis. Within those, all three members of the miR‐29‐family were significantly down‐regulated in livers of CCl4‐treated mice as well as in mice that underwent bile duct ligation. Specific regulation of miR‐29 members in murine fibrosis models correlated with lower expression of miR‐29 in livers from patients with advanced liver fibrosis. Moreover, patients with advanced liver cirrhosis showed significantly lower levels of miR‐29a in their serum when compared with healthy controls or patients with early fibrosis. On a cellular level, down‐regulation of miR‐29 in murine hepatic stellate cells (HSCs) was mediated by transforming growth factor beta (TGF‐β) as well as inflammatory signals, namely, lipopolysaccharide (LPS) and nuclear factor kappa B (NF‐κB). Furthermore, overexpression of miR‐29b in murine HSC resulted in down‐regulation of collagen expression. Conclusion: Our data indicate that miR‐29 mediates the regulation of liver fibrosis and is part of a signaling nexus involving TGF‐β‐ and NF‐κB–dependent down‐regulation of miR‐29 family members in HSC with subsequent up‐regulation of extracellular matrix genes. Thus they may represent targets for novel therapeutic strategies against hepatic fibrogenesis and also might evolve as biomarkers in the diagnosis of liver fibrosis. (HEPATOLOGY 2011.)
The clinical application of adeno-associated virus vectors (AAVs) is limited because of concerns about AAV integration-mediated tumorigenicity. We performed integration-site analysis after ...AAV1-LPL(S447X) intramuscular injection in five lipoprotein lipase-deficient subjects, revealing random nuclear integration and hotspots in mitochondria. We conclude that AAV integration is potentially safe and that vector breakage and integration may occur from each position of the vector genome. Future viral integration-site analyses should include the mitochondrial genome.
This paper details a high-resolution record of French Atlantic coast extreme wave events using a multi-proxy analysis of dated sedimentary deposits. Two lagoons 1) the Petite Mer de Gâvres and 2) the ...Traicts du Croisic were chosen to identify damaging storm events from the last 300 years with Beeker sampling, 210Pb and 137Cs dating and sedimentary analysis. Using two new geochemical proxies in the French Atlantic coast, Sr/Fe and Ca/Ti, shows that several storminess events are reported in the nine cores drilled. By correlation with historical archives, seven major storms are confirmed: 1924 CE, 1940 CE, 1972 CE, 1977 CE, 1990 CE, 1999 CE, and an 1896 CE highly damaging event. Four other XIXth and XVIIIth century extreme wave event correlations are also proposed from this multi-proxy analysis: 1775 CE, 1811 CE, 1838 CE and 1876 CE. Societal and natural impacts caused by these coastal floods are revealed using our dense and varied historical archives.
•Good sedimentological and historical correlation for the last three centuries•Sr/Fe and Ca/Ti are two proxies useful for detecting recent washover in the French Atlantic coast•Eleven extreme events recorded in French Atlantic coast sediments
Nucleoid-associated proteins (NAPs) are global regulators of gene expression in Escherichia coli, which affect DNA conformation by bending, wrapping and bridging the DNA. Two of these--H-NS and ...Fis--bind to specific DNA sequences and structures. Because of their importance to global gene expression, the binding of these NAPs to the DNA was previously investigated on a genome-wide scale using ChIP-chip. However, variation in their binding profiles across the growth phase and the genome-scale nature of their impact on gene expression remain poorly understood. Here, we present a genome-scale investigation of H-NS and Fis binding to the E. coli chromosome using chromatin immunoprecipitation combined with high-throughput sequencing (ChIP-seq). By performing our experiments under multiple time-points during growth in rich media, we show that the binding regions of the two proteins are mutually exclusive under our experimental conditions. H-NS binds to significantly longer tracts of DNA than Fis, consistent with the linear spread of H-NS binding from high- to surrounding lower-affinity sites; the length of binding regions is associated with the degree of transcriptional repression imposed by H-NS. For Fis, a majority of binding events do not lead to differential expression of the proximal gene; however, it has a significant indirect effect on gene expression partly through its effects on the expression of other transcription factors. We propose that direct transcriptional regulation by Fis is associated with the interaction of tandem arrays of Fis molecules to the DNA and possible DNA bending, particularly at operon-upstream regions. Our study serves as a proof-of-principle for the use of ChIP-seq for global DNA-binding proteins in bacteria, which should become significantly more economical and feasible with the development of multiplexing techniques.
Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Dominant mutations in NOTCH3 cause cerebral autosomal dominant ...arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic archetype of cerebral ischemic SVD. Progress toward understanding the pathogenesis of this disease and developing effective therapies has been hampered by the lack of a good animal model. Here, we report the development of a mouse model for CADASIL via the introduction of a CADASIL-causing Notch3 point mutation into a large P1-derived artificial chromosome (PAC). In vivo expression of the mutated PAC transgene in the mouse reproduced the endogenous Notch3 expression pattern and main pathological features of CADASIL, including Notch3 extracellular domain aggregates and granular osmiophilic material (GOM) deposits in brain vessels, progressive white matter damage, and reduced cerebral blood flow. Mutant mice displayed attenuated myogenic responses and reduced caliber of brain arteries as well as impaired cerebrovascular autoregulation and functional hyperemia. Further, we identified a substantial reduction of white matter capillary density. These neuropathological changes occurred in the absence of either histologically detectable alterations in cerebral artery structure or blood-brain barrier breakdown. These studies provide in vivo evidence for cerebrovascular dysfunction and microcirculatory failure as key contributors to hypoperfusion and white matter damage in this genetic model of ischemic SVD.
A unique dataset of turbidity from 7 years of continuous monitoring at six stations, distributed evenly along a 62-km long transect, is presented to discuss, for the first time, the present-day ...dynamics of the turbidity maximum zone (TMZ) in the Loire Estuary. This system is considered one of the largest macrotidal, hyper-turbid estuaries of the European coast, mainly as the result of intense engineering works in the last two centuries. Besides accurate TMZ tracking, from tidal to multi-annual time scales, the high temporal and spatial resolution of measurements allows us to address TMZ aspects scarcely reported in the literature on estuarine sedimentary dynamics. In the Loire Estuary, TMZ moves upstream during periods of low discharge and its upstream boundary may reach up to 62km from the mouth. The TMZ displacement is faster during its downstream flushing by river floods than during its upstream migration by tidal pumping (respectively 1.6kmday−1 and 0.9kmday−1 during 2011). However, the expulsion of the TMZ from the upper reaches requires higher discharge levels than its installation (respective discharge thresholds of 497–1034m3s−1 and 300–360m3s−1). This is due to the presence of mobile mud remaining after the TMZ presence, as confirmed by clockwise turbidity-discharge hysteresis patterns. While the installation threshold barely varies over years, the expulsion threshold is higher during years with a more concentrated and persistent TMZ. The interannual variability of the TMZ concentration and persistence is explained by the water volume transported during the previous high discharge period and the duration of the low discharge period, respectively, as recently shown for the Gironde Estuary, leading to a better understanding of TMZ features in macrotidal estuaries. The summer-averaged river flow is introduced as a hydrological indicator of the upstream boundary of the TMZ. In the context of global change, these three discharge-based indicators of TMZ behavior provide powerful tools to assess future scenarios.
•Original set of 7-years of high-frequency records of turbidity in the Loire Estuary.•TMZ dynamics in the Loire Estuary are investigated for the first time.•Interannual variability of TMZ (persistence, concentration, position) is detailed.•TMZ shifts are analyzed in terms of concentration, velocities and water thresholds.•New hydrological indicators of TMZ features are defined.
Sublacustrine landslide stratigraphy is considered useful for quantitative paleoseismology in low-seismicity settings. However, as the recharging of underwater slopes with sediments is one of the ...factors that governs the recurrence of slope failures, it is not clear if landslide deposits can provide continuous paleoseismic records in settings of frequent strong shaking. To test this, we selected three lakes in south-central Alaska that experienced a strong historical megathrust earthquake (the 1964 Mw9.2 Great Alaska Earthquake) and exhibit high sedimentation rates in their main basins (0.2cmyr−1–1.0cmyr−1). We present high-resolution reflection seismic data (3.5kHz) and radionuclide data from sediment cores in order to investigate factors that control the establishment of a reliable landslide record. Seismic stratigraphy analysis reveals the presence of several landslide deposits in the lacustrine sedimentary infill. Most of these landslide deposits can be attributed to specific landslide events, as multiple landslide deposits sourced from different lacustrine slopes occur on a single stratigraphic horizon. We identify numerous events in the lakes: Eklutna Lake proximal basin (14 events), Eklutna Lake distal basin (8 events), Skilak Lake (7 events) and Kenai Lake (7 events). The most recent event in each basin corresponds to the historic 1964 megathrust earthquake. All events are characterized by multiple landslide deposits, which hints at a regional trigger mechanism, such as an earthquake (the synchronicity criterion). This means that the landslide record in each basin represents a record of past seismic events. Based on extrapolation of sedimentation rates derived from radionuclide dating, we roughly estimate a mean recurrence interval in the Eklutna Lake proximal basin, Eklutna Lake distal basin, Skilak Lake and Kenai Lake, at ~250yrs., ~450yrs., ~900yrs. and ~450yrs., respectively. This distinct difference in recording can be explained by variations in preconditioning factors like slope angle, slope recharging (sedimentation rate) and the sediment source area: faster slope recharging and a predominance of delta and alluvial fan failures, increase the sensitivity and lower the intensity threshold for slope instability. Also, the seismotectonic setting of the lakes has to be taken into account. This study demonstrates that sublacustrine landslides in several Alaskan lakes can be used as reliable recorders of strong earthquake shaking, when a multi-lake approach is used, and can enhance the temporal and spatial resolution of the paleoseismic record of south-central Alaska.
•The 1964 Alaska earthquake produced numerous sublacustrine slope failures.•The landslide record is dependent on the slope angle and sedimentation rate.•Delta/alluvial fan failures can be useful for establishing paleoseismic histories.•Multi-lake landslide records provide continuous and sensitive paleoseismic records.
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