julilili42/papers huggingface dataset:
Alpha-synuclein induces epigenomic dysregulation of glutamate signaling and locomotor pathways
2021-06-12

Abstract Background Mutations and multiplications in the gene encoding for alpha-synuclein are associated with Parkinson’s disease (PD). However, not all individuals with alpha-synuclein variants develop PD, suggesting that additional factors are involved. We hypothesized that increased alpha-synuclein might alter epigenetic regulation of PD pathways. Objectives To identify genome-wide DNA methylation and hydroxymethylation changes induced by overexpression of two alpha-synuclein variants in human dopaminergic neurons, and to relate these to the corresponding transcriptome. Methods We assessed DNA methylation and hydroxymethylation at &gt;850,000 CpGs using the EPIC BeadChip in LUHMES cells differentiated to dopaminergic neurons. Control LUHMES neurons, LUHMES neurons overexpressing wild type alpha-synuclein, and LUHMES neurons overexpressing A30P alpha-synuclein were compared. We used SMITE network analysis to identify functionally related genes with altered DNA methylation, DNA hydroxymethylation, and/or gene expression, incorporating LUHMES H3K4me1 ChIP-seq to delineate enhancers in addition to the default promoter and gene body regions. Results Using stringent statistical thresholds, we found that increased expression of wild type or A30P mutant alpha-synuclein induced DNA methylation changes at thousands of CpGs and DNA hydroxymethylation changes at hundreds of CpGs. Differentially methylated sites in both genotypes were enriched for several processes including movement-associated pathways and glutamate signaling. For glutamate and other signaling pathways (i.e. PDGF, insulin), this differential DNA methylation was also associated with transcriptional changes. Conclusions Our results indicated that alpha-synuclein altered the DNA methylome of dopaminergic neurons, influencing regulation of pathways involved in development, signaling, and metabolism. This supports a role for alpha-synuclein in the epigenetic etiology of PD.
The evolution and changing ecology of the African hominid oral microbiome.
2021-06-12

The oral microbiome plays key roles in human biology, health, and disease, but little is known about the global diversity, variation, or evolution of this microbial community. To better understand the evolution and changing ecology of the human oral microbiome, we analyzed 124 dental biofilm metagenomes from humans, including Neanderthals and Late Pleistocene to present-day modern humans, chimpanzees, and gorillas, as well as New World howler monkeys for comparison. We find that a core microbiome of primarily biofilm structural taxa has been maintained throughout African hominid evolution, and these microbial groups are also shared with howler monkeys, suggesting that they have been important oral members since before the catarrhine-platyrrhine split ca. 40 Mya. However, community structure and individual microbial phylogenies do not closely reflect host relationships, and the dental biofilms of Homo and chimpanzees are distinguished by major taxonomic and functional differences. Reconstructing oral metagenomes from up to 100 thousand years ago, we show that the microbial profiles of both Neanderthals and modern humans are highly similar, sharing functional adaptations in nutrient metabolism. These include an apparent Homo-specific acquisition of salivary amylase-binding capability by oral streptococci, suggesting microbial coadaptation with host diet. We additionally find evidence of shared genetic diversity in the oral bacteria of Neanderthal and Upper Paleolithic modern humans that is not observed in later modern human populations. Differences in the oral microbiomes of African hominids provide insights into human evolution, the ancestral state of the human microbiome, and a temporal framework for understanding microbial health and disease.
Genetic structure in patchy populations of a candidate foundation plant: a case study ofLeymus chinensis(Poaceae) using genetic and clonal diversity
2021-06-13

ABSTRACT PREMISE The distribution of genetic diversity on the landscape has critical ecological and evolutionary implications. This may be especially the case on a local scale for foundation plant species since they create and define ecological communities, contributing disproportionately to ecosystem function. METHODS We examined the distribution of genetic diversity and clones, which we defined first as unique multi-locus genotypes (MLG), and then by grouping similar MLGs into multi-locus lineages (MLL). We used 186 markers from inter-simple sequence repeats (ISSR) across 358 ramets from 13 patches of the foundation grass Leymus chinensis . We examined the relationship between genetic and clonal diversities, their variation with patch-size, and the effect of the number of markers used to evaluate genetic diversity and structure in this species. RESULTS Every ramet had a unique MLG. Almost all patches consisted of individuals belonging to a single MLL. We confirmed this with a clustering algorithm to group related genotypes. The predominance of a single lineage within each patch could be the result of the accumulation of somatic mutations, limited dispersal, some sexual reproduction with partners mainly restricted to the same patch, or a combination of all three. CONCLUSIONS We found strong genetic structure among patches of L. chinensis . Consistent with previous work on the species, the clustering of similar genotypes within patches suggests that clonal reproduction combined with somatic mutation, limited dispersal, and some degree of sexual reproduction among neighbors causes individuals within a patch to be more closely related than among patches.
Two-Loop ${\\cal O}((\\alpha_t+\\alpha_\\lambda+\\alpha_\\kappa)^2)$ Corrections to the Higgs Boson Masses in the CP-Violating NMSSM
2021-06-13

We present our computation of the two-loop corrections to the Higgs boson masses of the CP-violating Next-to-Minimal Supersymmetric Standard Model (NMSSM) using the Feynman-diagrammatic approach in the gaugeless limit at vanishing external momentum. We choose a mixed -on-shell (OS) renormalisation scheme for the Higgs sector and apply both and OS renormalisation in the top/stop sector. For the treatment of the infrared divergences we apply and compare three different regularisation methods: the introduction of a regulator mass, the application of a small momentum expansion, and the inclusion of the full momentum dependence. Our new corrections have been implemented in the Fortran code NMSSMCALC that computes the Higgs mass spectrum of the CP-conserving and CP-violating NMSSM as well as the Higgs boson decays including the state-of-the-art higher-order corrections. Our numerical analysis shows that the newly computed corrections increase with rising and , remaining overall below about 3\\% compared to our previously computed corrections, in the region compatible with perturbativity below the GUT scale. The renormalisation scheme and scale dependence is of typical two-loop order. The impact of the CP-violating phases in the new corrections is small. We furthermore show that the Goldstone Boson Catastrophe due to the infrared divergences can be treated in a numerically efficient way by introducing a regulator mass that approximates the momentum-dependent results best for squared mass values in the permille range of the squared renormalisation scale. Our results mark another step forward in the program of increasing the precision in the NMSSM Higgs boson observables.
55. Rights for rivers
2021-06-13

For some years now, a growing environmental movement has been demanding that rivers be given rights or the status of legal persons. Proponents argue that this approach would better protect river ecosystems. In addition, it resonates with calls to give indigenous peoples more say in the management of their livelihoods. Various countries (e.g. New Zealand or Colombia) have already created corresponding legal frameworks. This paper will first deal with inherent tensions between ethical justifications of rights for rivers (ecocentrism vs corrective justice). Second, it will look at the case of the Whanganui River (NZ) which has the most elaborated legal framework of a river right. Concludingly, it argues that the case for rights of rivers raise challenging questions for various domains of applied ethics (such as agriculture, food or conservation ethics).
17. A water culture perspective for food security
2021-06-13

The changing climate is disrupting freshwater infrastructures and this affects food security. Dominant technocratic systems of knowledge and practice supporting water infrastructures are being undermined by rapid changes, which introduce new uncertainties and contest old securities. Novel ways of mobilising knowledge and practice for water infrastructures are needed that readmit communities' diverse cultural interactions with water and promote adaptive decision-making. The paper introduces the project 'Changing Water Cultures' (CANALS) claiming: (1) that current understandings of water, climate and infrastructures struggle to address emerging uncertainties due to climate change; (2) that a proper regard for water cultures is needed to overcome these obstacles; particularly by (3) extending the 'peer communities' of diverse knowledge-holders. The paper's water culture perspective understands cultures as both practices and systems of symbols and meanings. It recognises the hybrid character of water, which exists independently of humans and at the same time is culturally enacted through human practices. From this perspective, the paper looks beyond infrastructures physical manifestation to include the social practices connecting people and objects in the world in socio-material relations. A water-cultural perspective thus better captures the complex processes around water infrastructures and food in the context of challenges posed by climate change. The paper first argues for a novel way of analysing water infrastructures and second explains its relevance for understanding food security in a changing climate.
Human Platelets Take up Anti-VEGF Agents
2021-06-14

Purpose. Growing evidence suggests different systemic exposure of anti-vascular endothelial growth factor (anti-VEGF) agents with repeated intravitreal application. Since the penetration of anti-VEGF agents through vascular barrier was reported, the interaction of anti-VEGF with nonresident platelets has become a topic of interest. The purpose of this study was to evaluate, with the help of visualization techniques, whether platelets take up the anti-VEGF agents ranibizumab, aflibercept, and bevacizumab. Methods. The uptake of anti-VEGF agents with or without VEGF treatment was investigated using immunofluorescence and immunogold staining in human platelets. The role of actin filaments and clathrin-coated vesicles in the transport of ranibizumab, aflibercept, and bevacizumab was evaluated by two pharmacologic inhibitors: staurosporine (protein kinase C inhibitor) and cytochalasin D. Results. All three anti-VEGF agents were taken up by platelets and colocalized with VEGF. Ranibizumab and aflibercept were mainly detected in alpha-granules; however, bevacizumab was equally localized in alpha-granules and in platelet vesicles. Both staurosporine and cytochalasin D completely inhibited the uptake of aflibercept into platelets. Both pharmacological inhibitors also decreased the transport of ranibizumab and bevacizumab into platelets. Bevacizumab was significantly more frequently colocalized within clathrin-coated vesicles than ranibizumab and aflibercept. Conclusion. All three anti-VEGF agents are taken up by platelets and internalized in alpha-granules, which may result in a higher local exposure of anti-VEGF after the activation of platelets, potentially contributing to arterial thromboembolic events. Clathrin-coated vesicles seem to be more prominent in the transport of bevacizumab than ranibizumab and aflibercept. Nevertheless, whether the different localization and transport of bevacizumab are truly related to specific differences of receptor-mediated endocytosis has to be revealed by further research.
Novel Techniques to Improve Precise Cell Injection
2021-06-14

We noted recently that the injection of cells with a needle through a cystoscope in the urethral sphincter muscle of pigs failed to deposit them nearby or at the intended target position in about 50% of all animals investigated (n &gt; 100). Increasing the chance for precise cell injection by shotgun approaches employing several circumferential injections into the sphincter muscle bears the risk of tissue injury. In this study, we developed and tested a novel needle-free technique to precisely inject cells in the urethral sphincter tissue, or other tissues, using a water-jet system. This system was designed to fit in the working channels of endoscopes and cystoscopes, allowing a wide range of minimally invasive applications. We analyze key features, including the physical parameters of the injector design, pressure ranges applicable for tissue penetration and cell injections and biochemical parameters, such as different compositions of injection media. Our results present settings that enable the high viability of cells post-injection. Lastly, the method is suitable to inject cells in the superficial tissue layer and in deeper layers, required when the submucosa or the sphincter muscle of the urethra is targeted.
Pharmacological inhibition of the VCP/proteasome axis rescues photoreceptor degeneration in RHOP23H rat retinal explants
2021-06-14

1. Abstract Rhodopsin ( RHO ) misfolding mutations are a common cause of the blinding disease autosomal dominant retinitis pigmentosa (adRP). The most prevalent mutation, RHO P23H , results in its misfolding and retention in the Endoplasmic Reticulum (ER). Under homeostatic conditions, misfolded proteins are selectively identified, retained at the ER, and cleared via ER-associated degradation (ERAD) and/or autophagy. Overload of these degradation processes for a prolonged period leads to imbalanced proteostasis and may eventually result in cell death. ERAD of misfolded proteins like RHO P23H includes the subsequent steps of protein recognition, targeting for ERAD, retrotranslocation, and proteasomal degradation. In the present study, we investigated and compared pharmacological modulation of ERAD at these four different major steps. We show that inhibition of the VCP/proteasome activity favors cell survival and suppresses P23H-mediated retinal degeneration in RHO P23H rat retinal explants. We suggest targeting this activity as a therapeutic approach for patients with currently untreatable adRP.
Faculty Opinions recommendation of An aged immune system drives senescence and ageing of solid organs.
2021-06-14

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing. PMID: 33981041 Funding information This work was supported by: NIA NIH HHS, United States Grant ID: R01 AG044376 NIA NIH HHS, United States Grant ID: R56 AG058543 NIA NIH HHS, United States Grant ID: P01 AG062413 NIA NIH HHS, United States Grant ID: U19 AG056278 NIA NIH HHS, United States Grant ID: R56 AG059676 NIA NIH HHS, United States Grant ID: R01 AG063543 NIA NIH HHS, United States Grant ID: P01 AG043376 More Less keyboard_arrow_down
Central Insulin Modulates Dopamine Signaling in the Human Striatum
2021-06-15

Abstract Objective Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin-resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive. Research Design and Methods We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrid scanner, we simultaneously performed [11C]-raclopride-PET and resting-state functional MRI in 10 healthy normal-weight men after application of intranasal insulin or placebo on 2 separate days in a randomized, placebo-controlled, blinded, crossover trial. Results In response to central insulin compared with placebo administration, we observed greater [11C]-raclopride binding potential in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 minutes after nasal insulin compared with placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 minutes after intranasal insulin. Conclusions This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.
Unveiling ecological assembly rules from commonalities in trait distributions
2021-06-15

Abstract Deciphering the effect of neutral and deterministic processes on community assembly is critical to understand and predict diversity patterns. The information held in community trait distributions is commonly assumed as a signature of these processes, but empirical and modelling attempts have most often failed to untangle their confounding, sometimes opposing, impacts. Here, we simulated the assembly of trait distributions through stochastic (dispersal limitation) and/or deterministic scenarios (environmental filtering and niche differentiation). We characterized the shape of trait distributions using the skewness–kurtosis relationship. We identified commonalities in the co‐variation between the skewness and the kurtosis of trait distributions with a unique signature for each simulated assembly scenario. Our findings were robust to variation in the composition of regional species pools, dispersal limitation and environmental conditions. While ecological communities can exhibit a high degree of idiosyncrasy, identification of commonalities across multiple communities can help to unveil ecological assembly rules in real‐world ecosystems.
Medical education in times of COVID-19: survey on teachers' perspectives from a German medical faculty
2021-06-15

Background: Clinicians in their role as teachers and medical faculties were struggling to address the medical students’ needs regarding their medical education in times of COVID-19. They were especially confronted with several challenges regarding what medical training should look like and how to transfer medical training to integrate relevant skills like interpersonal or practical competencies. This study aimed to investigate the teachers’ perspectives on medical education and COVID-19 in general, including their distress level. Methods: This quantitative questionnaire study was distributed online among responsible lecturers of medical training at the Medical Faculty of Tuebingen. Teachers answered questions about the medical training, COVID-19 in general (on a seven point- Likert scale from “not at all” to “completely”) and their mental well-being (STAI). Descriptive data analysis and t-tests were performed. Results: The teachers reported being significantly (p
Under Threat, Weaker Evidence Is Required to Reach Undesirable Conclusions
2021-06-15

Critical decisions, such as in domains ranging from medicine to finance, are often made under threatening circumstances that elicit stress and anxiety. The negative effects of such reactions on learning and decision-making have been repeatedly underscored. In contrast, here we show that perceived threat alters the process by which evidence is accumulated in a way that may be adaptive. Participants (<i>n</i> = 91) completed a sequential evidence sampling task in which they were incentivized to accurately judge whether they were in a desirable state, which was associated with greater rewards than losses, or an undesirable state, which was associated with greater losses than rewards. Before the task participants in the "threat group" experienced a social-threat manipulation. Results show that perceived threat led to a reduction in the strength of evidence required to reach an undesirable judgment. Computational modeling revealed this was because of an increase in the relative rate by which negative information was accumulated. The effect of the threat manipulation was global, as the alteration to evidence accumulation was observed for information which was not directly related to the cause of the threat. Requiring weaker evidence to reach undesirable conclusions in threatening environments may be adaptive as it can lead to increased precautionary action.<b>SIGNIFICANCE STATEMENT</b> To make good judgments, people gather information. As information is often unlimited, a decision has to be made as to when the data are sufficiently strong to reach a conclusion. Here, we show that this decision is significantly influenced by perceived threat. In particular, under threat, the rate of negative information accumulation increased, such that weaker evidence was required to reach an undesirable conclusion. Such modulation could be adaptive as it can result in enhanced cautious behavior in dangerous environments.