julilili42/papers huggingface dataset:
Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1
2020-01-09

Abstract A functional primary cilium is essential for normal and regulated signalling. Primary ciliary defects cause a group of developmental conditions known as ciliopathies, but the precise mechanisms of signal regulation by the cilium remain unclear. Previous studies have implicated the ubiquitin proteasome system (UPS) in regulation of Wnt signalling at the ciliary basal body. Here, we provide mechanistic insight into ciliary ubiquitin processing in cells and for a ciliopathy mouse model lacking the ciliary protein Mks1. In vivo loss of Mks1 sensitizes cells to proteasomal disruption, leading to abnormal accumulation of ubiquitinated proteins. To substantiate a direct link between MKS1 and the UPS, we identified UBE2E1, an E2 ubiquitin-conjugating enzyme that polyubiquitinates β-catenin, and RNF34, an E3 ligase, as novel interactants of MKS1. UBE2E1 and MKS1 colocalized, particularly during conditions of ciliary resorption, and loss of UBE2E1 recapitulates the ciliary and Wnt signalling phenotypes observed during loss of MKS1. Levels of UBE2E1 and MKS1 are co-dependent and UBE2E1 mediates both regulatory and degradative ubiquitination of MKS1. Furthermore, we demonstrate that processing of phosphorylated β-catenin occurs at the ciliary base through the functional interaction between UBE2E1 and MKS1. These observations suggest that correct β-catenin levels are tightly regulated at the primary cilium by a ciliary-specific E2 (UBE2E1) and a regulatory substrate-adaptor (MKS1), confirming the fundamental role of UPS defects in the molecular pathogenesis of ciliopathies.
Data for "Unravelling the collateral damage of antibiotics on gut bacteria"
2020-01-09

&lt;p&gt;This dataset encompasses all data needed to reproduce the analyses presented in the paper &quot;Unravelling the collateral damage of antibiotics on gut bacteria&quot;, available here:&nbsp;https://doi.org/10.1038/s41586-021-03986-2&lt;/p&gt; &lt;p&gt;You can also check the GitLab repository: https://git.embl.de/maier/abxbug/&lt;/p&gt;
Intake of dietary advanced glycation end products influences inflammatory markers, immune phenotypes, and antiradical capacity of healthy elderly in a little‐studied population
2020-01-10

Abstract Dietary advanced glycation end products (dAGE) have profound negative effects on overall health, and their intake must be assessed. In this cross‐sectional study, we investigated dAGE intake of 337 adult participants (180/157:M/F; age range 50–73 years). Data were collected on anthropometrics, body composition, dietary intake, selected blood biochemistry, immunological parameters, and antiradical capacity (50% hemolysis time; HT 50 ). From the dietary data, dAGEs and phytochemical index (PI) were calculated. Mean BMI, % body fat (%BF), and fasting plasma glucose were all within the accepted normal range. Subjects with high dAGE intake had higher %BF, higher energy intake, and lower PI. They tended to have lower CD4/CD8 ratios and higher proportions of B cells and NK cells, but had significantly higher hs‐CRP levels and lower HT 50 values. Results on HT 50 suggested that being &gt;60 years of age enhanced dAGE‐associated impairment of defense capacity in both those with low and high HT 50 compared with those &lt;60 years of age. Thus, overall dAGE consumption was high, but elderly participants had lower dAGE intake than younger adults. Indicators of nutritional status and immunological parameters of the subjects were found to be associated with dAGE intake, suggesting a potential impact on health.
Gsα stimulation of mammalian adenylate cyclases regulated by their hexahelical membrane anchors
2020-01-10

Mammalian adenylate cyclases (ACs) are pseudoheterodimers with dissimilar hexahelical membrane-anchors, isoform-specifically conserved for more than half a billion years. We exchanged both membrane anchors of the AC isoform 2 by the quorum-sensing receptor from Vibrio harveyi, CqsS, which has a ligand, Cholera-Autoinducer-1 (CAI-1). In the chimera, AC activity was stimulated by Gsα, CAI-1 had no effect. Surprisingly, CAI-1 inhibited Gsα stimulation. We report that Gsα stimulation of human AC isoforms 2, 3, 5, and 9 expressed in Sf9 cells is inhibited by serum as is AC activity in membranes isolated from rat brain cortex. AC2 activation by forskolin or forskolin/Gsα was similarly inhibited. Obviously, serum contains as yet unidentified factors affecting AC activity. The data establish a linkage in ACs, in which the membrane anchors, as receptors, transduce extracellular signals to the cytosolic catalytic dimer. A mechanistic three state model of AC regulation is presented compatible with all known regulatory inputs into mammalian ACs. The data allow designating the membrane anchors of mammalian ACs as orphan receptors, and establish a new level of AC regulation.
Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis
2020-01-10

The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in three NF2-associated and five sporadically operated recurrent VS after primary irradiation. We compared these findings with 49 non-irradiated (36 sporadic and 13 NF2-associated) VS through gene-expression profiling and pathway analysis. Furthermore, we stained the key molecules of the distinct pathway by immunohistochemistry. A total of 195 differentially expressed genes in sporadic and NF2-related comparisons showed significant differences based on the criteria of p value &lt; 0.05 and a two-fold change. These genes were involved in pathways that are known to be altered upon irradiation (e.g., mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF) signaling). We observed a combined downregulation of PTEN signaling and an upregulation of mTOR signaling in progressive NF2-associated VS after irradiation. Immunostainings with mTOR and PTEN antibodies confirmed the respective molecular alterations. Taken together, mTOR inhibition might be a promising therapeutic strategy in NF2-associated VS progress after irradiation.
Bilingual and multilingual mental lexicon: a modeling study with Linear Discriminative Learning
2020-01-10

This study addresses the question of whether there is anything special about learning a third language, as compared to learning a second language, just by virtue of the third language being the third language acquired, and independently of the specific properties of the third language. We used computational modeling to explore this question for the learning of a small vocabulary of some 400 words, with English as L1, German or Mandarin as L2, and Mandarin and alternatively Dutch, as L3. For computational modeling, we made use of the mathematical framework of linear discriminative learning, which we extended with the learning rule of Widrow-Hoff to enable the modeling of incremental learning of the mappings between form and meaning when words' meanings are represented by vectors of real numbers (embeddings) rather than by abstract symbolic units. A series of simulation experiments covering single-language learning, bilingual learning, and finally trilingual learning, clarified that within the framework of discrimination learning, within-language homophones give rise to frailty in comprehension that in turn for production gives rise to semantic errors in L1, and language intrusions in L2 and L3. Our model correctly predicts production to lag behind comprehension in learning, and it clarified that, within the boundaries of discrimination learning, the properties of the L3 crucially determine whether L3 learning appears to involve a language that is `dormant' with respect to L1 and L2. Qualitatively surprisingly different patterns of acquisition of the L3, and its interactions with L1 and L2, can arise in our simulations without any changes in the mathematics driving learning. Our simulations also show that when words' forms incorporate not only segmental but also suprasegmental information, the nature of errors that arise in production changes. In the general discussion, we reflect on the implications of our findings for the question of what is special about multilingualism.
Building Forcello: Etruscan wattle‐and‐daub technique in the Po Plain (Bagnolo San Vito, Mantua, northern Italy)
2020-01-10

The study analyses through an interdisciplinary approach the wattle‐and‐daub building technique used on the Po Plain of northern Italy, focusing on the archaeological evidence from the Etruscan site of Forcello, near Bagnolo San Vito (Mantua) (540–375 bce ). Wattle and daub is widespread across different times and periods, and is particularly common in regions such as the Po Plain, where stone sources for construction are not immediately available. Thanks to a combined archaeometric, geological and anthracological study, the paper provides new insights on a fifth‐century bce building structure from Forcello. The findings reveal information on the life history of this feature, including its construction, maintenance and final destruction. The research also sheds a new light on the wattle‐and‐daub technique and on the interaction between people and the Po Plain Etruscan palaeoenvironment.
Phosphoglycerol-type wall- and lipoteichoic acids are enantiomeric polymers differentially cleaved by the stereospecific glycerophosphodiesterase GlpQ
2020-01-10

ABSTRACT The cell envelope of Gram-positive bacteria generally comprises two types of polyanionic polymers, either linked to peptidoglycan, wall teichoic acids (WTA), or to membrane glycolipids, lipoteichoic acids (LTA). In some bacteria, including Bacillus subtilis strain 168, WTA and LTA both are glycerolphosphate polymers, yet are synthesized by different pathways and have distinct, although not entirely understood morphogenetic functions during cell elongation and division. We show here that the exo-lytic sn -glycerol-3-phosphodiesterase GlpQ can discriminate between B. subtilis WTA and LTA polymers. GlpQ completely degrades WTA, lacking modifications at the glycerol residues, by sequentially removing glycerolphosphates from the free end of the polymer up to the peptidoglycan linker. In contrast, GlpQ is unable to cleave unmodified LTA. LTA can only be hydrolyzed by GlpQ when the polymer is partially pre-cleaved, thereby allowing GlpQ to get access to the end of the polymer that is usually protected by a connection to the lipid anchor. This indicates that WTA and LTA are enantiomeric polymers: WTA is made of sn -glycerol-3-phosphate and LTA is made of sn -glycerol-1-phosphate. Differences in stereochemistry between WTA and LTA were assumed based on differences in biosynthesis precursors and chemical degradation products, but so far had not been demonstrated directly by differential, enantioselective cleavage of isolated polymers. The discriminative stereochemistry impacts the dissimilar physiological and immunogenic properties of WTA and LTA and enables independent degradation of the polymers, while appearing in the same location; e.g. under phosphate limitation, B. subtilis 168 specifically hydrolyzes WTA and synthesizes phosphate-free teichuronic acids in exchange.
How the Probabilistic Structure of Grammatical Context Shapes Speech
2020-01-11

Does systematic covariation in the usage patterns of forms shape the sublexical variance observed in conversational speech? We address this question in terms of a recently proposed discriminative theory of human communication that argues that the distribution of events in communicative contexts should maintain mutual predictability between language users, present evidence that the distributions of words in the empirical contexts in which they are learned and used are geometric, and thus support this. Here, we extend this analysis to a corpus of conversational English, showing that the distribution of grammatical regularities and the sub-distributions of tokens discriminated by them are also geometric. Further analyses reveal a range of structural differences in the distribution of types in parts of speech categories that further support the suggestion that linguistic distributions (and codes) are subcategorized by context at multiple levels of abstraction. Finally, a series of analyses of the variation in spoken language reveals that quantifiable differences in the structure of lexical subcategories appears in turn to systematically shape sublexical variation in speech signal.
Raw EEG-EOG data used in the publication "Auditory Electrooculogram-based Communication System for ALS Patients in Transition from Locked-in to Complete Locked-in State"
2020-01-12

&lt;p&gt;The dataset includes raw EEG and EOG recordings during BCI experiments for three patients: p11, p13, p15, and p16. The structure of the dataset is the following: patient/visit/day.&lt;/p&gt;\\n\\n&lt;p&gt;The experiment is described in detail in the publication "Auditory Electrooculogram-based Communication System for ALS Patients in Transition from Locked-in to Complete Locked-in State". The correspondence between raw file and BCI session is reported in the attached pdf file "Supplementary Table S5 Session to Raw File Recordings Correspondence".&lt;/p&gt;\\n\\n&lt;p&gt;The datasets include EEG and EOG channels. The data are raw (i.e. non filtered and non processed). Data have been acquired with a sampling rate of 500Hz using active electrodes and the amplifier V-Amp DC (Brain Products, Germany). EOG channels are labeled EOGU, EOGD, EOGR, EOGL namely for EOG up, down, right, left; the location in the 10-20 system are respectively SO1, IO1, LO1, LO2.&lt;/p&gt;\\n\\n&lt;p&gt;The data are marked with triggers: for each session two markers indicate start and end of the session; for each trial markers indicate start of baseline, start of presentation of question, start of response time, start of feedback. Each trial was marked in a different way if it was a yes trial belonging to a training or feedback session, a no trial belonging to a training or feedback session, or a trial belonging to a speller session. The markers that have been used are the following:&lt;br&gt;\\n&lt;strong&gt;start&lt;/strong&gt; 9&lt;br&gt;\\n&lt;em&gt; yes no speller&lt;/em&gt;&lt;br&gt;\\n&lt;strong&gt;baseline&lt;/strong&gt; 10 11 12&lt;br&gt;\\n&lt;strong&gt;presentation&lt;/strong&gt; 5 6 7&lt;br&gt;\\n&lt;strong&gt;response&lt;/strong&gt; 4 8 13&lt;br&gt;\\n&lt;strong&gt;feedback&lt;/strong&gt; 1 2 3&lt;/p&gt;\\n\\n&lt;p&gt;&lt;strong&gt;end&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt; 15&lt;/p&gt;
Dysfunction of Oskyddad causes Harlequin-type ichthyosis-like defects in Drosophila melanogaster
2020-01-13

Prevention of desiccation is a constant challenge for terrestrial organisms. Land insects have an extracellular coat, the cuticle, that plays a major role in protection against exaggerated water loss. Here, we report that the ABC transporter Oskyddad (Osy)-a human ABCA12 paralog-contributes to the waterproof barrier function of the cuticle in the fruit fly Drosophila melanogaster. We show that the reduction or elimination of Osy function provokes rapid desiccation. Osy is also involved in defining the inward barrier against xenobiotics penetration. Consistently, the amounts of cuticular hydrocarbons that are involved in cuticle impermeability decrease markedly when Osy activity is reduced. GFP-tagged Osy localises to membrane nano-protrusions within the cuticle, likely pore canals. This suggests that Osy is mediating the transport of cuticular hydrocarbons (CHC) through the pore canals to the cuticle surface. The envelope, which is the outermost cuticle layer constituting the main barrier, is unaffected in osy mutant larvae. This contrasts with the function of Snu, another ABC transporter needed for the construction of the cuticular inward and outward barriers, that nevertheless is implicated in CHC deposition. Hence, Osy and Snu have overlapping and independent roles to establish cuticular resistance against transpiration and xenobiotic penetration. The osy deficient phenotype parallels the phenotype of Harlequin ichthyosis caused by mutations in the human abca12 gene. Thus, it seems that the cellular and molecular mechanisms of lipid barrier assembly in the skin are conserved during evolution.
Ultra-High Field MRI in Alzheimer’s Disease: Effective Transverse Relaxation Rate and Quantitative Susceptibility Mapping of Human Brain In Vivo and Ex Vivo compared to Histology
2020-01-13

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo. Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R 2 *) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo. Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R 2 * maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively.
Exploring early interprofessional socialization: a pilot study of student’s experiences in medical history taking
2020-01-13

Traditional hierarchies and structures in healthcare, as well as traditional professional socialization practices, continue to create barriers to effective interprofessional collaboration. Nevertheless, some studies indicate that early socialization with other health professionals can build bridges and improve understanding of each other's roles and contributions to patient care. This pilot study aimed to gain insights into the nursing and medical students' experiences of interprofessional medical history taking during a collective learning activity. A descriptive case study was conducted using modified interviews based on the speed-dating (SD) technique to explore participants' reasons for the choice of profession (SD1) and experiences of interprofessional history taking (SD2). Data were digitally captured using audio-recordings. An inductive-deductive approach to qualitative content analysis of transcribed responses was undertaken. Eighteen students (medicine n = 6; nursing n = 12) participated. Two main categories with sub-themes emerged from the inductive SD1 analysis: (a) reasons for choosing a career and (b) knowledge about professions. The SD2 deductive analysis identified three major categories with sub-themes: (a) breaking down barriers, (b) interprofessional role learning - interprofessional collaboration and (c) dual-identity development. Our findings showed that early interprofessional socialization of students supported their learning about the complementary roles of doctors and nurses and enabled them to gain early experiences of interprofessional teamwork.
Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia
2020-01-14

Background There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, –61.3 to 54.6), MAPT mutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions Raised GFAP concentrations appear to be unique to GRN -related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.
Guidance Document: Validation of a High-Performance Liquid Chromatography-Tandem Mass Spectrometry Immunopeptidomics Assay for the Identification of HLA Class I Ligands Suitable for Pharmaceutical Therapies
2020-01-14

For more than two decades naturally presented, human leukocyte antigen (HLA)-restricted peptides (immunopeptidome) have been eluted and sequenced using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Since, identified disease-associated HLA ligands have been characterized and evaluated as potential active substances. Treatments based on HLA-presented peptides have shown promising results in clinical application as personalized T cell-based immunotherapy. Peptide vaccination cocktails are produced as investigational medicinal products under GMP conditions. To support clinical trials based on HLA-presented tumor-associated antigens, in this study the sensitive LC-MS/MS HLA class I antigen identification pipeline was fully validated for our technical equipment according to the current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines.The immunopeptidomes of JY cells with or without spiked-in, isotope labeled peptides, of peripheral blood mononuclear cells of healthy volunteers as well as a chronic lymphocytic leukemia and a bladder cancer sample were reliably identified using a data-dependent acquisition method. As the LC-MS/MS pipeline is used for identification purposes, the validation parameters include accuracy, precision, specificity, limit of detection and robustness.