Biology subjects

Schmidt, L.

Publications and source records attributed to Schmidt, L..

36 records · Page 2Linked to original sources

bioRxiv2023

Fecal microbiota transplantation (FMT) from healthy and bipolar donors elicits distinct emotional behaviors and gut-brain metabolite profiles in mice

Bipolar disorder (BD) is a chronic mood disorder characterized by recurrent episodes of depression and (hypo-) mania. The gut microbiome is a potential avenue through which metabolic signaling, inflammatory pathways, environmental factors, and genetics influence BD pathogenesis via the gut-brain axis. Fecal microbiota transplantation (FMT) is a powerful translational tool for investigating the connections between the gut microbiome and BD, and there is evidence FMT can transfer affective symptoms of BD from humans to mice. In this study, we compared the behavior, gut-brain metabolomic profiles, and inflammatory marker expression in two groups of adult female C57BL/6J mice, one receiving FMT from a human donor with BD in a mixed episode ( HAM-D = 20, YMRS = 14) and another receiving FMT from a mentally healthy weight and age-matched control donor without BD (HAM-D and YMRS = 0). Here, we demonstrate that mice receiving FMT from individuals with BD had an increased abundance of Bacteroidota and decreased abundances of Parabacteroides merdae and Akkermansia muciniphila associated with altered levels of fecal metabolites, short-chain fatty acids, and related gut hormone expression relative to mice receiving control donor FMT. BD mice also exhibited differential regulation of several metabolites and inflammatory markers in the amygdala, with glycine being the most prominently affected. Furthermore, BD mice displayed increased anxiety-like behavior and decreased sociability, indicating that aspects of the behavioral phenotype of BD are transferable from humans to mice via FMT. Taken together, these findings implicate gut-brain signaling in the physiological and behavioral changes observed in our BD-FMT mouse model.

microbiology↗

bioRxiv2023

Listen to yourself: How motivational interviewing shifts food choices and craving-related brain responses to healthier options

Changing ones habits is challenging. Motivational interviewing (MI) has been proposed as a communication-based approach to overcome this challenge. Here, we tested how change and sustain talk suggestions, elicited by MI, influenced value-based dietary decision-making and responses of a recently developed neurobiological craving signature (NCS) in female adults. We found that following change talk, compared to sustain talk, participants food choices and activity in the ventromedial prefrontal cortex were more driven by the healthiness and less by the tastiness of food. These findings were paralleled by lower NCS responses to tasty food after change compared to sustain talk. Further, following change talk, participants body mass indices moderated the NCS decoding of healthy and tasty food choices. These results show that MI can shift value-based decision-making and reduce craving-related brain marker responses to highly palatable food items. The findings contribute to a better understanding of behavioral change interventions toward healthier eating.

neuroscience↗

bioRxiv2023

ARF6 as a novel activator of HIF-2alpha in pulmonary arterial hypertension

ADP-ribosylation factor 6 (ARF6), a GTPase associated with cancer metastasis, is activated in the lung endothelium in pulmonary arterial hypertension (PAH). To identify ARF6-regulated pathways relevant to PAH, we performed a state-of-the-art proteomic analysis of human pulmonary artery endothelial cells (HPAECs) overexpressing the wildtype, constitutively active, fast-cycling and dominant negative mutants of ARF6. The analysis revealed a novel link of ARF6 with hypoxia-inducible factor (HIF), in addition to endocytotic vesicle trafficking, cell proliferation, angiogenesis, oxidative stress and lipid metabolism. Active ARF6 markedly increased expression and activity of HIF-2, critical in PAH, with HIF-1 relatively unaffected. Hypoxic ARF6 activation was a prerequisite for HIF-2 activation and HIF-dependent gene expression in HPAECs, PAH blood-derived late outgrowth endothelial colony forming cells (ECFCs) and hypoxic mouse lungs in vivo. A novel ARF6 inhibitor, chlortetracycline (CTC), reduced hypoxia-induced HIF-2 activation, proliferation and angiogenesis in HPAECs and reduced HIF-2 expression in lung and heart tissues of hypoxic mice. PAH ECFCs showed elevated expression and activity of ARF6 and HIF2, which was attenuated by CTC. Oral CTC attenuated development of PH in chronically hypoxic mice. In conclusion, we are first to demonstrate a key role of ARF6 in the regulation of HIF-2 activation in vitro and in vivo and show that HIF-2, a master-regulator of vascular remodelling in PAH, can be targeted by a clinically approved antibiotic chlortetracycline.

cell biology↗

bioRxiv2023

The landscape of biomedical research

The number of publications in biomedicine and life sciences has rapidly grown over the last decades, with over 1.5 million papers now being published every year. This makes it difficult to keep track of new scientific works and to have an overview of the evolution of the field as a whole. Here we present a 2D map of the entire corpus of biomedical literature, and argue that it provides a unique and useful overview of the life sciences research. We based our atlas on the abstract texts of 21 million English articles from the PubMed database. To embed the abstracts into 2D, we used the large language model PubMedBERT, combined with t-SNE tailored to handle samples of our size. We used our atlas to study the emergence of the Covid-19 literature, the evolution of the neuroscience discipline, the uptake of machine learning, the distribution of gender imbalance in academic authorship, and the distribution of retracted paper mill articles. Furthermore, we present an interactive web version of our atlas that allows easy exploration and will enable further insights and facilitate future research.

scientific communication and education↗

bioRxiv2023

Taste matters: Mapping expectancy-based appetitive placebo effects onto the brain

Expectancies, which are higher order prognostic beliefs, can have powerful effects on experiences, behavior and brain. However, it is unknown where, how, and when, in the brain, prognostic beliefs influence appetitive interoceptive experiences and related economic behavior. This study combined a placebo intervention on hunger with computational modelling and functional magnetic resonance imaging of value-based decision-making. The results show that prognostic beliefs about hunger shape hunger experiences, how much participants value food and food-value encoding in the prefrontal cortex. Computational modelling further revealed that these placebo effects were underpinned by how much and when during the decision process taste and health information are integrated into the accumulation of evidence toward a food choice. The drift weights of both sources of information further moderated ventromedial and dorsolateral prefrontal cortex interactions during choice formation. These findings provide novel insights into the neurocognitive mechanisms that translate higher order prognostic beliefs into non-aversive interoceptive sensitivity and shape decision-making.

neuroscience↗

bioRxiv2023

Deprivation of arginine and lysine interferes with growth of patient-derived tumor xenografts

In recent years, a novel treatment method for cancer emerged, which is based on the starvation of tumors of amino acids like arginine. The deprivation of arginine in serum is based on enzymatic degradation and can be realized by arginine deaminases like the L-amino acid oxidase found in the ink toxin of the sea hare Aplysia punctata. Previously isolated from the ink, the L-amino acids oxidase was described to oxidate the essential amino acid L-lysine and L-arginine to their corresponding deaminated alpha-keto acids. Here, we present the recombinant production and functionalization of amino acid oxidase Aplysia Punctata ink toxin (APIT). PEGylated APIT (APIT-PEG) increased the blood circulation time. APIT-PEG treatment of patient-derived xenografted mice shows a significant dose dependent reduction of tumor growth over time mediated by amino acid starvation of the tumor. Treatment of mice with APIT-PEG which lead to deprivation of arginine was well tolerated.

cancer biology↗

bioRxiv2022

Investigation of whether oxytocin and trust play a role in placebo effects of marketing actions

Expectations about the quality of a medical treatment influence how much an inert treatment helps to improve patient well-being. Similarly, expectations about the quality of products influence how identical goods and services are evaluated differently after their consumption. One driver for such "placebo effects" in medical treatments is social cognition in the form of trust, which may be influenced by the hormone oxytocin. An open question is whether trust and oxytocin play similar roles in marketing placebo effects. To answer this question, we combined oxytocin administration (24 IU) and trust questionnaires in a pre-registered double-blind randomized between-subjects study design (Nfood tasting task = 223; Ncognitive performance task = 202). We could not find evidence that oxytocin and trust play a role in placebo effects of marketing actions. Together with other recent null findings from oxytocin administration studies, these findings question the role trust might play in different types of placebo effects.

neuroscience↗

bioRxiv2022

Direct observation of motor protein stepping in living cells using MINFLUX

Dynamic measurements of molecular machines can provide invaluable insights into their mechanism, but have been challenging in living cells. Here, we developed live-cell tracking of single fluorophores with nanometer spatial and millisecond temporal resolution in 2D and 3D using the recently introduced super-resolution technique MINFLUX. This allowed us to resolve the precise stepping motion of the motor protein kinesin-1 as it walks on microtubules in living cells. In addition, nanoscopic tracking of motors on microtubule of fixed cells enabled us to resolve their spatial organization with protofilament resolution. Our approach will enable future in vivo studies of motor protein kinetics in complex environments and super-resolution mapping of dense microtubule arrays, and pave the way towards monitoring functional conformational changes of protein machines at high spatiotemporal resolution in living systems.

biophysics↗

bioRxiv2022

Delineating organizational principles of the endogenous L-A virus by cryo-EM and computational analysis of native cell extracts

The high abundance of most viruses in infected host cells benefits their structural characterization; endogenous viruses are present in low copy numbers, however, and are therefore challenging to investigate. Here, we retrieve cell extracts enriched with an endogenous virus, the yeast L-A virus. The determined cryo-EM structure discloses capsid-stabilizing cation-{pi} stacking and an interplay of non-covalent interactions from ten distinct capsomere interfaces. The capsid-embedded mRNA decapping active site trench is supported by a constricting movement of two opposite-facing loops. tRNA-loaded polysomes and other biomacromolecules, presumably mRNA, are found in virus proximity while stacked dsRNA bundles and the sub-stoichiometric polymerase localize underneath the capsid surface. Mature viruses participate in larger viral communities resembling their rare in-cell equivalents in terms of size, composition, and inter-virus distances. Our results collectively describe a 3D-architecture of a viral milieu, opening the door to cellextract-based high-resolution structural virology.

biochemistry↗

bioRxiv2022

Evidence of active oviposition avoidance to systemically applied imidacloprid in the Colorado Potato Beetle (Leptinotarsa decemlineata)

Agricultural pests can develop behavioral resistance to insecticides via choosing to feed or oviposit on non-toxic hosts. As young larvae have relatively low mobility, oviposition preferences from female adults may play a critical role in shaping the evolutionary trajectory of pest populations. While oviposition avoidance of toxic hosts was found in different agriculture pests, it remains unclear whether such preferences can be learned from female adults. To address this question, we investigated feeding and oviposition preferences to imidacloprid in the Colorado Potato Beetle (CPB, Leptinotarsa decemlineata), a major potato pest. We first identified two CPB strains that have different levels of resistance to imidacloprid. Then, we performed choice assays in the two strains and found that both strains did not have an innate feeding avoidance to systemically applied imidacloprid at both larval and adult stages. Further oviposition choice assays showed that the susceptible strain preferred to lay eggs on insecticide-free plants while the resistant strain did not. Analysing moving patterns of the two strains suggested that the oviposition preference is likely due to active learning by the female adults. Together, these results indicate that CPB can have active oviposition avoidance, which might have contributed to the rapid global invasion of this agricultural pest.

animal behavior and cognition↗

bioRxiv2020

The brain's hedonic valuation system's resting-state connectivity predicts weight loss and correlates with leptin

Weight gain is often associated with the pleasure of eating foods rich in calories and lack of willpower to reduce such food cravings, but empirical evidence is sparse. Here we investigated the role that connectivity within the brains hedonic valuation system (BVS, the ventral striatum and the ventromedial prefrontal cortex) at rest plays (1) to predict weight gain or loss over time and (2) for homeostatic hormone regulation. We found that intrinsic connectivity within the BVS at rest (RSC) predicted out-of-sample weight changes over time in lean and obese participants. Counterintuitively, such BVS RSC was higher in lean versus obese participants before the obese participants underwent a drastic weight loss intervention (Roux-en-Y gastric bypass surgery, RYGB). The RYGB surgery increased BVS RSC in the obese after surgery. The obese participants increase in BVS RSC correlated with decreases in fasting state systemic leptin, a homeostatic hormone signalling satiety that has been previously linked to dopamine functioning. Taken together, our results indicate a first link between brain connectivity in reward circuits in a more tonic state at rest, homeostatic hormone regulation involved in dopamine functioning and ability to lose weight. Significance statementWith obesity rates on the rise, advancing our understanding of what factors drive peoples ability to lose and gain weight is crucial. This research is the first to link what we know about the brains hedonic valuation system (BVS) to weight loss and homeostatic hormone regulation. We found that connectivity at rest (RSC) within the BVS system predicted changes in weight, differentiated between lean and obese participants, and increased after a weight loss intervention (gastric bypass surgery). Interestingly, the extent to which BVS RSC improved after surgery correlated to decreases in circulating levels of the satiety hormone leptin. These findings are the first to reveal the neural and hormonal determinants of weight loss, combining hedonic and homeostatic drivers of (over-)eating.

neuroscience↗

bioRxiv2019

2.7 A cryo-EM structure of vitrified M. musculus H-chain apoferritin from 200 keV \"screening microscope\"

Here we present the structure of mouse H-chain apoferritin at 2.7 [A] (FSC=0.143) solved by single particle cryogenic electron microscopy (cryo-EM) using a 200 kV device. Data were collected using a compact, two-lens illumination system with a constant power objective lens, without the use of energy filters or aberration correctors. Coulomb potential maps reveal clear densities for main chain carbonyl oxygens, residue side chains (including alternative conformations) and bound solvent molecules. We argue that the advantages offered by (a) the high electronic and mechanical stability of the microscope, (b) the high emission stability and low beam energy spread of the high brightness Field Emission Gun (x-FEG), (c) direct electron detection technology and (d) particle-based Contrast Transfer Function (CTF) refinement have contributed to achieving resolution close to the Rayleigh limit. Overall, we show that basic electron optical settings for automated cryo-electron microscopy imaging, widely thought of as a "screening cryo-microscope", can be used to determine structures approaching atomic resolution. HighlightsO_LIThe 2.7 [A] structure of mouse apoferritin was solved using a 200 keV screening cryo-microscope C_LIO_LIThe apoferritin reconstruction was resolved without an energy filter, aberration correctors, or constant-power condenser lenses C_LIO_LIComparison to available crystallographic and cryo-EM structures from high-end cryo-microscopes demonstrates consistency in resolved water molecules, metals and side chain orientations C_LIO_LIAlthough radiation damage is more prominent at 200 keV compared to 300 keV, this type of instrumentation is more accessible to research laboratories due to its compactness and simplicity C_LI

biophysics↗

bioRxiv2019

Macrophage-specific NF-kappa B activation dynamics can segregate inflammatory bowel disease patients

The heterogeneous nature of inflammatory bowel disease (IBD) presents challenges, particularly when choosing therapy. Activation of the NF-{kappa}B transcription factor is a highly-regulated, dynamic event in IBD pathogenesis. We expressed the human NF-{kappa}B/p65 subunit in blood-derived macrophages, using lentivirus. Confocal imaging of p65 activation revealed that a higher proportion of macrophages from Crohns patients responded to lipid-A compared to controls. In contrast, cells from ulcerative colitis (UC) patients exhibited a shorter duration of p65 nuclear localisation compared to healthy controls and Crohns donors. Using a similar lentivirus approach, NF-{kappa}B-regulated luciferase was expressed in patient macrophages, isolated from frozen peripheral blood mononuclear cell samples. Following activation, samples could be segregated into three clusters based on the NF-{kappa}B-regulated luciferase response. The majority of UC samples appeared in hypo-responsive cluster 1, with Crohns patients representing the majority of hyper-responsive cluster 3. A positive correlation was seen between NF-{kappa}B-induced luciferase activity and cytokine levels released to medium from stimulated macrophages, but not in serum or biopsy. Analysis of macrophage cytokine responses and patient metadata revealed a strong correlation between Crohns patients who smoked and hyper-activation of p65. These in vitro dynamic assays of NF-{kappa}B activation in blood-derived macrophages segregate IBD patients into groups with different phenotypes and therefore may help determine response to therapy. Significance statementThis manuscript describes two dynamic assays of NF-{kappa}B activation in blood-derived macrophages that can segregate IBD patients into groups with different phenotypes. For the first time we introduce the use of dynamic measurements of a transcription factor activation as a method to stratify patients and we are confident that our approach will lead in future to early patient stratification and prediction of treatment outcome.

immunology↗

bioRxiv2018

Silencing cuticular pigmentation genes enables RNA FISH in intact chemosensory appendages

Optical imaging of gene expression by RNA-fluorescent in situ hybridisation (FISH) in whole-mount sensory appendages of insects is often impeded by their highly pigmented cuticle. Since most chemical bleaching agents are incompatible with imaging fluorescent-labelled nucleotides, we developed a RNA interference-based method for clearing cuticular pigmentation that allows imaging of fluorescent mRNA in whole-mount appendages of insects. Silencing key genes of the tyrosine-derived pigmentation pathway by injecting dsRNA of laccase2 or tyrosine hydroxylase in two leaf beetles species (Chrysomela populi, Phaedon cochleariae) resulted in clearance of the highly pigmented cuticle and in significant decreased light absorbance. Intact chemosensory appendages (palps, antennae and legs) from RNAi-cleared individuals were used to image expression and spatial distribution of antisense mRNA of two chemosensory genes (gustatory receptor, odorant-binding protein) via RNA FISH and confocal laser scanning microscopy. Imaging of these genes did neither work for RNAi-controls (dsGfp) due to retained pigmentation, nor for FISH-controls using sense mRNA. Furthermore, we show that several chemical bleaching agents are not feasible with FISH, either due to significant degradation of polynucleotides, lack of clearing efficacy or long incubation times. Overall, silencing pigmentation genes is a significant improvement over bleaching agents allowing fluorescence imaging in whole-mount appendages and organs.

molecular biology↗

bioRxiv2018

Multiple brain networks mediating stimulus-pain relationships in humans

The brain transforms nociceptive input into a complex pain experience comprised of sensory, affective, motivational, and cognitive components. However, it is still unclear how pain arises from nociceptive input, and which brain networks coordinate to generate pain experiences. We introduce a new high-dimensional mediation analysis technique to estimate distributed, network-level patterns mediating the relationship between stimulus intensity and pain. In a large-scale analysis of functional magnetic resonance imaging data (N=284), we identify both traditional mediators in somatosensory brain regions and additional mediators located in prefrontal, midbrain, striatal, and default-mode regions unrelated to nociception in standard analyses. The whole brain mediators are specific for pain vs. aversive sounds and are organized in five functional networks. Brain mediators explain 32% more within-subject variance of single-trial pain ratings than previous brain-based models. Our results provide a new, broader view of the networks underlying pain experience, as well as distinct targets for interventions.

neuroscience↗

bioRxiv2018

Open access policies of high impact medical journals: a cross-sectional study

ObjectivesAcademic and not-for-profit research funders are increasingly requiring that the research they fund must be published open access, with some insisting on publishing with a Creative Commons Attribution (CC BY) licence to allow the broadest possible use. We set out to clarify the open access variants provided by leading medical journals for research in general and industry-funded research in particular, and record the availability of the CC BY licence for commercially funded research.\n\nMethodsWe identified medical journals with a 2015 impact factor of at least 15.0 on 24 May 2017, then excluded from the analysis journals that only publish review articles. Between 29 June 2017 and 26 July 2017, we collected information about each journals open access policies from their websites and/or by email contact. We contacted the journals by email again between 6 December 2017 and 2 January 2018 to confirm our findings.\n\nResultsThirty-five medical journals publishing original research from 13 publishers were included in the analysis. All 35 journals offered some form of open access with varying embargo periods of up to 12 months. Of these journals, 21 (60%) provided immediate open access with a CC BY licence under certain circumstances (e.g. to specific research funders). Of these 21, 20 only offered a CC BY licence to authors funded by non-commercial organizations and one offered this option to funders who required it.\n\nConclusionsMost leading medical journals do not offer to authors reporting commercially funded research an open access licence that allows unrestricted sharing and adaptation of the published material. The journals policies are therefore not aligned with open access declarations and guidelines. Commercial research funders lag behind academic funders in the development of mandatory open access policies, and it is time for them to work with publishers to advance the dissemination of the research they fund.\n\nStrengths and limitations of this studyO_LIThis manuscript includes a systematic analysis of open access policies of journals with a high impact factor, including society-owned journals, from multiple publishers.\nC_LIO_LIThe open access policies of all journals analysed were clarified, and confirmation of our findings was received by email from 97% of the contacted journals.\nC_LIO_LIOpen access policies of the journals and publishers analysed are subject to change, so the information presented here may not be current.\nC_LIO_LIBy selecting journals with a high impact factor, our analysis does not include prestigious journals from specialized therapy areas and regional or non-English language journals, which may have lower impact factors.\nC_LIO_LIAlthough our study covers only a small number of journals, extending such a manual analysis to a greater number of journals without loss of detail and verification of all results would be cumbersome and inefficient by relying on traditional analysis tools.\nC_LI

scientific communication and education↗

bioRxiv2017

Red Bull Gives You Incentive Motivation: Understanding Placebo Effects of Energy Drinks on Human Cognitive Performance

The consumption of cognitive enhancers like energy drinks (EnD) is on the rise, but do they really improve cognitive performance, and, if yes, why? We examined two novel psychological mechanisms. First, we dissociated the role of expectations and actual consumption by crossing what people consumed--Red Bull Silver Edition or a similar-tasting Sprite soda--and what they thought they consumed. We found that participants performed better in a numerical Stroop task when they believed that they had consumed an EnD, irrespective of what they had actually consume, Second, we investigated the role of motivation for such a placebo effect of EnD. We found that expected, but not actual, consumption of EnD increased the effects of incentives on cognitive performance. Our results suggest that believing that one consumes an EnD increased participants motivation to perform and thus enhanced their performance.\n\nSignificance statementAcademic doping has become increasingly popular on campuses around the globe over the last years. However, it remains unknown if and how commercially available cognitive enhancers such as energy drinks (EnD) impact cognitive performance. We varied actual and believed consumption of an EnD and measured cognitive performance and its allocation according to the magnitude of points to earn. We found that the belief that one has consumed an EnD but not its actual consumption, increased cognitive performance specifically in high point trials compared to low point trials. These findings provide novel insights into motivational processes underpinning marketing-led expectancy effects, and contribute to the current public policy debate on the use and abuse of increased alertness and concentration claims for EnD.

neuroscience↗

bioRxiv2017

How context alters value: Price information recruits the brain’s valuation and affective regulation system for shaping experienced taste pleasantness

Informational cues such as the price of a wine can trigger expectations about its taste quality and thereby modulate the sensory experience on a reported and neural level. Yet it is unclear how the brain translates such expectations into sensory pleasantness. We used multilevel mediation analysis of neural and behavioral data obtained in participants who tasted identical wines cued with different prices. We found that the brain's valuation system (BVS) in concert with the anterior prefrontal cortex explained the effect of price cues on taste pleasantness ratings. The sensitivity of the BVS to rewards outside the taste domain moderated the strength of these effects. Moreover, brain mediators of price cue effects overlapped with brain regions previously found to be involved in placebo analgesia. These findings provide novel evidence for the fundamental role that neural pathways linked to motivation and affective regulation play for the effect of informational cues on sensory experiences.

neuroscience↗