julilili42/papers huggingface dataset:
Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models
2020-06-08

Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aβ, rather than dystrophic neurites, suggesting that fibrillar Aβ may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.
Graphene Field Effect Transistor Biosensors Based on Aptamer for Amyloid-βDetection
2020-06-08

The development of cost-efficient, sensitive and specific methods to detect amyloid-beta 42 ( Aβ42 ) biomarkers in cerebrospinal fluid and serum-samples is of considerable interest to enable early and reliable diagnosis of Alzheimer’s disease as a precondition for future disease-modifying therapies. This paper presents a reduced graphene oxide field effect transistor (r-GO FET) for label free ultrasensitive detection of an Aβ42 -biomarker with RNA aptamer. The channel in the device was formed by reduction of graphene oxide nanosheets by self-assembly process. As a result, the interaction between Aβ42 and RNA aptamer on the surface of r-GO channel caused a linear response in the shift of the gate voltage ( VTG ) where the minimum conductivity occurs. The r-GO FET can detect the biomarker in range of 1ng/ml to 1pg/ml at pH 7.4 with high specificity. The developed r-GO FET is a low-cost, highly sensitive and selective method for detecting tiny concentrations of Aβ42 , which would also enable measurements in serum-samples.
A Naturalistic Dynamic Monkey Head Avatar Elicits Species-Typical Reactions and Overcomes the Uncanny Valley
2020-06-08

Abstract Research on social perception in monkeys may benefit from standardized, controllable, and ethologically valid renditions of conspecifics offered by monkey avatars. However, previous work has cautioned that monkeys, like humans, show an adverse reaction toward realistic synthetic stimuli, known as the “uncanny valley” effect. We developed an improved naturalistic rhesus monkey face avatar capable of producing facial expressions (fear grin, lip smack and threat), animated by motion capture data of real monkeys. For validation, we additionally created decreasingly naturalistic avatar variants. Eight rhesus macaques were tested on the various videos and avoided looking at less naturalistic avatar variants, but not at the most naturalistic or the most unnaturalistic avatar, indicating an uncanny valley effect for the less naturalistic avatar versions. The avoidance was deepened by motion and accompanied by physiological arousal. Only the most naturalistic avatar evoked facial expressions comparable to those toward the real monkey videos. Hence, our findings demonstrate that the uncanny valley reaction in monkeys can be overcome by a highly naturalistic avatar.
Substantial decrease in paediatric lower extremity fracture rates in German hospitals in 2017 compared with 2002: an epidemiological study
2020-06-08

Abstract Background There are no recent studies on the frequency of paediatric lower extremity fractures in Germany. The aims of this study were to report fracture rates of paediatric lower extremity fractures treated in German hospitals in 2002 and 2017 and to detect changes over time as well as to evaluate the gender and age distribution for each fracture location. Methods Data from the German National Hospital Discharge Registry, which covers over 99% of all German hospitals, were used for this study. The absolute frequencies and incidence of lower extremity fractures as well as age at the time of fracture and gender were included in the data. The population was subdivided into four age groups: 0–4, 5–9, 10–14, and 15–19 years. The boy: girl ratio (BGR) for all fracture locations was calculated by dividing the absolute frequency of boys by that of girls. The fracture incidence in 2017 was compared with 2002 by calculating the incidence rate ratio (IRR). Results The total number of fractures decreased by 39.9% from 2002 to 2017. The most common fracture locations in 2002 were femoral shaft, tibial shaft, distal tibia, and lateral and medial malleolus; the absolute number of all these fractures was lower in 2017 than in 2002 in all age groups. The incidence of hip and thigh fractures, knee and lower leg fractures, and foot fractures decreased by 39.0, 41.1, and 33.3%. Proximal tibial fractures increased both in absolute numbers and in incidence in the age groups 0–4, 10–14, and 15–19 years (IRR ≥ 1.1). The overall BGR was 2.3 in 2002 and 2.0 in 2017, indicating that the number of girls relative to that of boys who suffered a lower extremity fracture was higher in 2017 than in 2002. Furthermore, the BGR of all fracture locations increased with age in both years. Conclusions The number of paediatric lower extremity fractures treated in German hospitals in 2017 was significantly lower than that in 2002. However, the fracture frequency in girls decreased to a lesser extent than that in boys. The incidence of proximal tibial fractures increased.
ParkinSong: Outcomes of a 12-Month Controlled Trial of Therapeutic Singing Groups in Parkinson’s Disease
2020-06-09

This 12-month controlled clinical trial of ParkinSong demonstrated improvements in speech loudness and voice-related QoL for participants with PD, and enhanced wellbeing for both caregivers and care recipients. No adverse effects were reported over 12 months and improvements were sustained.
YycH and YycI Regulate Expression of Staphylococcus aureus Autolysins by Activation of WalRK Phosphorylation
2020-06-09

Staphylococcus aureus is a facultative pathogen that can encode numerous antibiotic resistance and immune evasion genes and can cause severe infections. Reduced susceptibility to last resort antibiotics such as vancomycin and daptomycin is often associated with mutations in walRK, an essential two-component regulatory system (TCS). This study focuses on the WalK accessory membrane proteins YycH and YycI and their influence on WalRK phosphorylation. Depletion of YycH and YycI by antisense RNA caused an impaired autolysis, indicating a positive regulatory function on WalK as has been previously described. Phosphorylation assays with full-length recombinant proteins in phospholipid liposomes showed that YycH and YycI stimulate WalK activity and that both regulatory proteins are needed for full activation of the WalK kinase. This was validated in vivo through examining the phosphorylation status of WalR using Phos-tag SDS-PAGE with a yycHI deletion mutant exhibiting reduced levels of phosphorylated WalR. In the yycHI knockdown strain, muropeptide composition of the cell wall was not affected, however, the wall teichoic acid content was increased. In conclusion, a direct modulation of WalRK phosphorylation activity by the accessory proteins YycH and YycI is reported both in vitro and in vivo. Taken together, our results show that YycH and YycI are important in the direct regulation of WalRK-dependent cell wall metabolism.
Relationship of Weather Types on the Seasonal and Spatial Variability of Rainfall, Runoff, and Sediment Yield in the Western Mediterranean Basin
2020-06-09

Rainfall is the key factor to understand soil erosion processes, mechanisms, and rates. Most research was conducted to determine rainfall characteristics and their relationship with soil erosion (erosivity) but there is little information about how atmospheric patterns control soil losses, and this is important to enable sustainable environmental planning and risk prevention. We investigated the temporal and spatial variability of the relationships of rainfall, runoff, and sediment yield with atmospheric patterns (weather types, WTs) in the western Mediterranean basin. For this purpose, we analyzed a large database of rainfall events collected between 1985 and 2015 in 46 experimental plots and catchments with the aim to: (i) evaluate seasonal differences in the contribution of rainfall, runoff, and sediment yield produced by the WTs; and (ii) to analyze the seasonal efficiency of the different WTs (relation frequency and magnitude) related to rainfall, runoff, and sediment yield. The results indicate two different temporal patterns: the first weather type exhibits (during the cold period: autumn and winter) westerly flows that produce the highest rainfall, runoff, and sediment yield values throughout the territory; the second weather type exhibits easterly flows that predominate during the warm period (spring and summer) and it is located on the Mediterranean coast of the Iberian Peninsula. However, the cyclonic situations present high frequency throughout the whole year with a large influence extended around the western Mediterranean basin. Contrary, the anticyclonic situations, despite of its high frequency, do not contribute significantly to the total rainfall, runoff, and sediment (showing the lowest efficiency) because of atmospheric stability that currently characterize this atmospheric pattern. Our approach helps to better understand the relationship of WTs on the seasonal and spatial variability of rainfall, runoff and sediment yield with a regional scale based on the large dataset and number of soil erosion experimental stations.
Immune Signatures and Survival of Patients With Metastatic Melanoma, Renal Cancer, and Breast Cancer
2020-06-09

Despite remarkable recent progress in treating solid cancers, especially the success of immunomodulatory antibody therapies for numerous different cancer types, it remains the case that many patients fail to respond to treatment. It is therefore of immense importance to identify biomarkers predicting clinical responses to treatment and patient survival, which would not only assist in targeting treatments to patients most likely to benefit, but might also provide mechanistic insights into the reasons for success or failure of the therapy. Several peripheral blood or tumor tissue diagnostic and predictive biomarkers known to be informative for cancer patient survival may be applicable for this purpose. The use of peripheral blood ("liquid biopsy") offers numerous advantages not only for predicting treatment responses at baseline but also for monitoring patients on-therapy. Assessment of the tumor microenvironment and infiltrating immune cells also delivers important information on cancer-host interactions but the requirement for tumor tissues makes this more challenging, especially for monitoring sequential changes in the individual patient. In this contribution, we will review our findings on immune signatures potentially informative for clinical outcome in melanoma, breast cancer and renal cell carcinoma, particularly the outcome of checkpoint blockade, by applying multiparametric flow cytometry and mass cytometry, routine clinical monitoring and functional testing for predicting and following individual patient responses to therapy.
Adverse Drug Reactions in the Emergency Department: Is There a Role for Pharmacogenomic Profiles at Risk?—Results from the ADRED Study
2020-06-09

Individual differences in required drug dosages exist based on the pharmacogenomic (PGx) profiles. This study aimed to assess associations between PGx profiles and adverse drug reactions (ADR) that lead to admissions to the emergency department (ED). ADR cases of the prospective multi-center observational trial in EDs (ADRED study) were analyzed (n = 776) together with the relevant PGx phenotypes of the enzymes CYP2D6, CYP2C19, CYP2C9, and VKORC1. Overall, the allele frequency distribution in this cohort did not differ from the population frequencies. We compared the frequencies of phenotypes in the subgroups with the drugs suspected of certain ADR, in the remaining cases. The frequency distribution of CYP2C19 differed for the ADR bleeding cases suspected of clopidogrel (p = 0.020). In a logistic regression analysis, higher CYP2C19 activity (OR (95% CI): 4.97 (1.73−14.27)), together with age (1.05 (1.02−1.08)), showed an impact on the clopidogrel-suspecting ADRs, when adjusting for the clinical parameters. There was a trend for an association of phenprocoumon-risk profiles (low VKORC1 or CYP2C9 activity) with phenprocoumon-suspecting ADRs (p = 0.052). The PGx impact on serious ADRs might be highest in drugs that cannot be easily monitored or those that do not provoke mild ADR symptoms very quickly. Therefore, patients that require the intake of those drugs with PGx variability such as clopidogrel, might benefit from PGx testing.
An ECF-type transporter scavenges heme to overcome iron-limitation in Staphylococcus lugdunensis
2020-06-09

Energy-coupling factor type transporters (ECF) represent trace nutrient acquisition systems. Substrate binding components of ECF-transporters are membrane proteins with extraordinary affinity, allowing them to scavenge trace amounts of ligand. A number of molecules have been described as substrates of ECF-transporters, but an involvement in iron-acquisition is unknown. Host-induced iron limitation during infection represents an effective mechanism to limit bacterial proliferation. We identified the iron-regulated ECF-transporter Lha in the opportunistic bacterial pathogen Staphylococcus lugdunensis and show that the transporter is specific for heme. The recombinant substrate-specific subunit LhaS accepted heme from diverse host-derived hemoproteins. Using isogenic mutants and recombinant expression of Lha, we demonstrate that its function is independent of the canonical heme acquisition system Isd and allows proliferation on human cells as sources of nutrient iron. Our findings reveal a unique strategy of nutritional heme acquisition and provide the first example of an ECF-transporter involved in overcoming host-induced nutritional limitation.
Structural basis of client specificity in mitochondrial membrane-protein chaperones
2020-06-09

Chaperones are essential for assisting protein folding, and for transferring poorly soluble proteins to their functional locations within cells. Hydrophobic interactions drive promiscuous chaperone–client binding, but our understanding how additional interactions enable client specificity is sparse. Here we decipher what determines binding of two chaperones (TIM8·13, TIM9·10) to different integral membrane proteins, the alltransmembrane mitochondrial carrier Ggc1, and Tim23 which has an additional disordered hydrophilic domain. Combining NMR, SAXS and molecular dynamics simulations, we determine the structures of Tim23/TIM8·13 and Tim23/TIM9·10 complexes. TIM8·13 uses transient salt bridges to interact with the hydrophilic part of its client, but its interactions to the trans-membrane part are weaker than in TIM9·10. Consequently, TIM9·10 is outcompeting TIM8·13 in binding hydrophobic clients, while TIM8·13 is tuned to few clients with both hydrophilic and hydrophobic parts. Our study exemplifies how chaperones fine-tune the balance of promiscuity vs . specificity.
Oral intake of lipopolysaccharide regulates toll-like receptor 4-dependent granulopoiesis
2020-06-09

While neutrophil production in emergency states has been extensively studied, regulation of neutrophil homeostasis in the steady-state remained incompletely understood. We have shown that innate immune receptor toll-like receptor (TLR)4 and downstream TIR-domain-containing adapter-inducing interferon-β (TRIF) are indispensable for the generation of a granulocyte-colony stimulating factor (G-CSF)-dependent regulatory feedback loop upon antibody-induced neutropenia. These findings demonstrated that steady-state granulopoiesis is a demand-driven process, which may rely on differential triggering of innate immune receptors by microbial cell wall constituents such as lipopolysaccharide. Herein, we present further evidence on underlying mechanisms: oral intake of highly endotoxic lipopolysaccharide, but not TLR-antagonistic lipopolysaccharide derived from Rhodobacter sphaeroides, induces hematopoietic stem and progenitor cell fate decisions toward the neutrophil lineage independent of G-CSF. TLR4 has been identified as the indispensable sensor for oral lipopolysaccharide-modulated steady-state granulopoiesis. These results have important implications: food lipopolysaccharide content or the composition of the gastrointestinal microbiome may be strongly underrated as determinants of peripheral blood neutrophil levels. Both neutrophilia and neutropenia are associated with drastically worse outcomes in epidemiological studies of the general population as well as in diseased states. Impact statement In our present study, we investigated the impact of LPS on neutrophil homeostasis and found that oral intake is sufficient to induce hematopoietic stem and progenitor cell fate decisions towards the neutrophil lineage independent of G-CSF. In addition, TLR4 has been identified as the indispensable sensor for oral LPS-modulated steady-state granulopoiesis. We provide evidence that the gastrointestinal microbiome is critical for neutrophil homeostasis, which has implications for patients being treated with chemotherapy or antimicrobial therapy, since both are significantly influencing the composition of the intestinal microbiome.
Shakespeare and the Present: History and Mediality in Richard III
2020-06-09

In Tyrant: Shakespeare on Power Stephen Greenblatt employs a presentist mode of reading when he highlights how certain aspects of the play resonate with the current US presidency. The book rekindled debates about historicist versus presentist modes of reading Shakespeare. Neither Greenblatt nor his critics noted, however, that at the very centre of Richard III – the central play in Tyrant – Shakespeare inserted a dialogue on the very questions of whether historical documents give later generations access to the past, and how these documents should be interpreted. In this article I demonstrate that Richard III develops an idea of history that speaks to the question of historicism versus presentism by pointing towards the mediality of historical knowledge. I argue that, considered from a presentist perspective, the play's reflections on orality and literacy in a culture turning from an oral to a literate culture speak more specifically to our political present than does Greenblatt's character criticism of Richard.
The Basis of Theory Building in Biology Lies in the Organism Concept – A Historical Perspective on the Shoulders of Three Giants
2020-06-09

The rise of molecular biology went hand in hand with a marginalization of the integrative unit in biology – the organism. Although the new methodological approaches contributed to eminent progress in many fields, the often assumed sufficiency of restricting the focus to molecules is problematic. This was already clear to the founders of theoretical biology (Schaxel, Bertalanffy, and others). Although theories have long played a role in biology and can be traced back to antiquity, the field of theoretical biology was first established only in the early 20th century. Theoretical biology needs to take into account the specific features in living nature that are not tackled by other disciplines. Unsurprisingly, the organization of parts and processes together with the organism concept play a central role for such theoretical considerations. The phenomena shown by living beings cannot be traced back – in a mere “atomistic” way – to the behaviour of singled out parts alone. There are different kinds of interactions among all levels of organization in an organism, and they have to be grasped practically and theoretically. Microdeterminism, which refers to the idea that macroscopic phenomena are determined solely by events on the micro- or molecular level, must be complemented by macrodeterminacy (Weiss), which works in the diametrically opposite direction. The present paper underlines the key role of theoretical biology and its connection to the organism concept by examining their common historical development based on the contributions of Paul A. Weiss, Ludwig von Bertalanffy, and Rupert Riedl.
A novel epitope tagging system to visualize and monitor antigens in live cells with chromobodies
2020-06-09

Summary Epitope tagging is a versatile approach to study different proteins using a well-defined and established methodology. To date, most epitope tags such as myc, HA, V5 and FLAG tags are recognized by antibodies which limits their application to fixed cells, tissues or protein samples. Here we introduce a broadly applicable tagging strategy utilizing a short peptide tag/chromobody (PepTag/PepCB) system. The addition of the small PepTag does not interfere with the examined structures in different cellular compartments and its detection with the fluorescently labeled Pep-chromobody (PepCB) enables optical antigen tracing in real time. By employing the phenomenon of antigen-mediated chromobody stabilization (AMCBS) using a turnover-accelerated PepCB we demonstrated that the system is suitable to visualize and quantify changes in Pep-tagged antigen concentration by quantitative live-cell imaging. We expect that this novel tagging strategy offers new opportunities to study the dynamic regulation of proteins, e.g. during cellular signaling, cell differentiation, or upon drug action.
Orf Virus-Based Vaccine Vector D1701-V Induces Strong CD8+ T Cell Response against the Transgene but Not against ORFV-Derived Epitopes
2020-06-10

The potency of viral vector-based vaccines depends on their ability to induce strong transgene-specific immune response without triggering anti-vector immunity. Previously, Orf virus (ORFV, Parapoxvirus) strain D1701-V was reported as a novel vector mediating protection against viral infections. The short-lived ORFV-specific immune response and the absence of virus neutralizing antibodies enables repeated immunizations and enhancement of humoral immune responses against the inserted antigens. However, only limited information exists about the D1701-V induced cellular immunity. In this study we employed major histocompatibility complex (MHC) ligandomics and immunogenicity analysis to identify ORFV-specific epitopes. Using liquid chromatography-tandem mass spectrometry we detected 36 ORFV-derived MHC I peptides, originating from various proteins. Stimulated splenocytes from ORFV-immunized mice did not exhibit specific CD8+ T cell responses against the tested peptides. In contrast, immunization with ovalbumin-expressing ORFV recombinant elicited strong SIINFEKL-specific CD8+ T lymphocyte response. In conclusion, our data indicate that cellular immunity to the ORFV vector is negligible, while strong CD8+ T cell response is induced against the inserted transgene. These results further emphasize the ORFV strain D1701-V as an attractive vector for vaccine development. Moreover, the presented experiments describe prerequisites for the selection of T cell epitopes exploitable for generation of ORFV-based vaccines by reverse genetics.