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"Schmidt, Sabine"
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A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites
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.
Journal Article
A largely random AAV integration profile after LPLD gene therapy
An adeno-associated virus (AAV) vector encoding a variant of human lipoprotein lipase was recently approved in Europe as the first gene therapy for the treatment of LPL deficiency. Here Manfred Schmidt and his colleagues report their analysis of AAV integration sites after injection of the gene therapy construct in LPL-deficient patients and in mice.
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.
Journal Article
Relationship between intramuscular fat content in longissimus thoracis and hair fatty acids in finishing crossbred bulls
Intramuscular fat (IMF) content below 6% in live cattle is difficult to estimate accurately. Therefore, this study tested whether fatty acids in the IMF of LT and hair correlate to each other, and whether fatty acids can be used to predict IMF. Forty-four finishing crossbred bulls from two farms were examined. Each bull had a hair sample collected before slaughter, and two days post-slaughter, LT muscle samples were collected to assess IMF (range: 2.3–6.6%) and fatty acids. Predictions of IMF from hair fatty acids were developed using linear, non-linear and non-parametric approaches. Nineteen congruent fatty acids could be detected in hair and LT. Although proportions varied, lauric and oleic acids showed positive correlations between LT and hair (
r
= 0.48–0.49;
P
≤ 0.001). Lauric acid in hair showed also a consistently prediction of IMF and moderate rank-based association between predicted and observed IMF across all tested prediction models. For the first time, the study presents evidence that hair fatty acids taken shortly before slaughter provide significant information about the IMF in bulls. To use this information for breeding or feeding strategies, it would be necessary to extend hair sampling by testing earlier stages in life.
Journal Article
Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease
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.
Journal Article
Sediment discharge from Greenland’s marine-terminating glaciers is linked with surface melt
Sediment discharged from the Greenland Ice Sheet delivers nutrients to marine ecosystems around Greenland and shapes seafloor habitats. Current estimates of the total sediment flux are constrained by observations from land-terminating glaciers only. Addressing this gap, our study presents a budget derived from observations at 30 marine-margin locations. Analyzing sediment cores from nine glaciated fjords, we assess spatial deposition since 1950. A significant correlation is established between mass accumulation rates, normalized by surface runoff, and distance down-fjord. This enables calculating annual sediment flux at any fjord point based on nearby marine-terminating outlet glacier melt data. Findings reveal a total annual sediment flux of 1.324 + /− 0.79 Gt yr-1 over the period 2010-2020 from all marine-terminating glaciers to the fjords. These estimates are valuable for studies aiming to understand the basal ice sheet conditions and for studies predicting ecosystem changes in Greenland’s fjords and offshore areas as the ice sheet melts and sediment discharge increase.
As Greenland’s huge calving glaciers melt, they pump sediment deep into biologically rich fjords. In this study, the quantity and path of this sediment is tracked and an empirical relationship is found between sediment and the amount of surface melt on the glacier.
Journal Article
The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites
Single amino acid changes in the parasite protein Kelch13 (K13) result in reduced susceptibility of P . falciparum parasites to artemisinin and its derivatives (ART). Recent work indicated that K13 and other proteins co-localising with K13 (K13 compartment proteins) are involved in the endocytic uptake of host cell cytosol (HCCU) and that a reduction in HCCU results in reduced susceptibility to ART. HCCU is critical for parasite survival but is poorly understood, with the K13 compartment proteins among the few proteins so far functionally linked to this process. Here we further defined the composition of the K13 compartment by analysing more hits from a previous BioID, showing that MyoF and MCA2 as well as Kelch13 interaction candidate (KIC) 11 and 12 are found at this site. Functional analyses, tests for ART susceptibility as well as comparisons of structural similarities using AlphaFold2 predictions of these and previously identified proteins showed that vesicle trafficking and endocytosis domains were frequent in proteins involved in resistance or endocytosis (or both), comprising one group of K13 compartment proteins. While this strengthened the link of the K13 compartment to endocytosis, many proteins of this group showed unusual domain combinations and large parasite-specific regions, indicating a high level of taxon-specific adaptation of this process. Another group of K13 compartment proteins did not influence endocytosis or ART susceptibility and lacked detectable vesicle trafficking domains. We here identified the first protein of this group that is important for asexual blood stage development and showed that it likely is involved in invasion. Overall, this work identified novel proteins functioning in endocytosis and at the K13 compartment. Together with comparisons of structural predictions it provides a repertoire of functional domains at the K13 compartment that indicate a high level of adaption of endocytosis in malaria parasites.
Journal Article
Transcriptome Complexity in a Genome-Reduced Bacterium
To study basic principles of transcriptome organization in bacteria, we analyzed one of the smallest self-replicating organisms, Mycoplasma pneumoniae. We combined strand-specific tiling arrays, complemented by transcriptome sequencing, with more than 252 spotted arrays. We detected 117 previously undescribed, mostly noncoding transcripts, 89 of them in antisense configuration to known genes. We identified 341 operons, of which 139 are polycistronic; almost half of the latter show decaying expression in a staircase-like manner. Under various conditions, operons could be divided into 447 smaller transcriptional units, resulting in many alternative transcripts. Frequent antisense transcripts, alternative transcripts, and multiple regulators per gene imply a highly dynamic transcriptome, more similar to that of eukaryotes than previously thought.
Journal Article
Longer operative times but equally safe - a propensity score-matched analysis for laparoscopic procedures in women with early-stage (r-ASRM I-II) endometriosis performed by gynecology residents compared to attending surgeons
Introduction
Surgery for endometriosis is usually performed through minimally invasive surgery, either by experienced endometriosis surgeons or by supervised gynecology residents during their surgical training. This trial aimed to assess the influence of surgical experience on the efficiency and safety of minimally invasive surgery treatment for early-stage endometriosis.
Material and Methods
Post- and introperative complications rates and length of stay of patients with stage I and II (revised American Society of Reproductive Medicine stage (rASRM)) endometriosis undergoing laparoscopic surgery at the University Hospital Mainz, Germany, between 2018 and 2022 were evaluated in a propensity score-matched analysis based on the experience of the primary surgeon (resident/fellow vs. attending). Linear and logistic regression models were used on the matched data set to calculate the treatment effect on the treated.
Results
580 patients were included in the final data set. Of those, 339 were operated on by 11 attending surgeons and 241 by 22 residents/fellows. The matched dataset showed a mean difference of 0.02 in propensity scores after full propensity score-matching. Compared to surgical procedures performed by experienced surgeons, prolonged operating times were found for surgeries performed by residents/fellows (5.27 min in the whole data set (SE 1.36),
p
< 0.001), and 9.54 min (SE 3.57,
p
= 0.007) when analyzing only rASRM stage II endometriosis. The need for revision surgery was reduced in the resident/fellow group, but did not reach statistical significance (0.56 (95%CI: 0.301-0.1.02),
p
= 0.06). No significant differences were found for intra- or postoperative complications and length of hospital stay.
Conclusions
Gynecology residents and fellows trained on the patient can safely perform surgery for early-stage endometriosis at the cost of increased operative times. Additional training options, such as surgical simulation training, should be explored to shorten learning curves, reduce the financial burden on hospitals due to prolonged operative times and counter the impending reduction in intraoperative training possibilities for residents.
Journal Article