julilili42/papers huggingface dataset:
HBD-2 mutations are associated with childhood asthma and prophylactic hBD-2 application prevents asthma in mice
2021-09-05

<b>Background:</b> Asthma and allergies are complex diseases caused by gene-environment interplay. Human β-defensin 2 (hBD-2) is a host defense peptide secreted by epithelial cells with immunomodulatory effects and which was shown to improve asthma and IBD in mice. <b>Objectives:</b> We hypothesized that adequate hBD-2 production is crucial for prevention of asthma and allergy and that hBD-2 coding genes (<i>DEFB4A</i> and -<i>B</i>) variants could play a role in disease development. <b>Methods:</b> Single nucleotide polymorphisms (SNPs) were genotyped by MALDI-TOF MS (n=13) in 1,238 children living in rural areas from the GABRIELA Ulm cohort. Restriction assays and Sanger sequencing were performed to identify mutations, SNPs and copy number variations in <i>DEFB4A</i> and -<i>B</i> loci. To explore its prophylactic potential, mimicking a protective farm setting, we administered hBD-2 orally in mice with house dust mite (HDM)-induced asthma prior to allergy challenge. <b>Results:</b> Six asthma and atopy-associated <i>DEFB4A</i> and -<i>B</i> gene variants were detected with rs543538872 (p=2.42*10<sup>-90</sup>) being the top asthma hit. Polymorphism rs62640720 was associated with asthma, atopy, atopic asthma, and non-atopic asthma. Lack of <i>DEFB4A</i> was associated with allergy only (p=0.012). Prophylactic oral application of hBD-2 significantly reduced lung resistance and pulmonary inflammation in HDM-exposed mice. <b>Conclusions:</b> Variations in hBD-2 coding genes associate with increased asthma and allergy risk, while early hBD-2 administration hinders atopic asthma symptoms in mice. Further research is needed to evaluate if and how hBD-2 is involved in the protective farm effect against asthma and allergy.
Reduction of Phantom Limb Pain and Improved Proprioception through a TSR-Based Surgical Technique: A Case Series of Four Patients with Lower Limb Amputation
2021-09-06

Four patients underwent targeted sensory reinnervation (TSR), a surgical technique in which a defined skin area is first selectively denervated and then surgically reinnervated by another sensory nerve. In our case, either the area of the lateral femoral cutaneous nerve or the saphenous nerve was reinnervated by the sural nerve. Patients were then fitted with a special prosthetic device capable of transferring the sense of pressure from the sole of the prosthesis to the newly wired skin area. Pain reduction after TSR was highly significant in all patients. In three patients, permanent pain medication could even be discontinued, in one patient the pain medication has been significantly reduced. Two of the four patients were completely pain-free after the surgical intervention. Surgical rewiring of existing sensory nerves by TSR can provide the brain with new afferent signals seeming to originate from the missing limb. These signals help to reduce phantom limb pain and to restore a more normal body image. In combination with special prosthetic devices, the amputee can be provided with sensory feedback from the prosthesis, thus improving gait and balance.
Staphylococcus aureus Depends on Eap Proteins for Preventing Degradation of Its Phenol-Soluble Modulin Toxins by Neutrophil Serine Proteases
2021-09-06

Neutrophil granulocytes act as a first line of defense against pathogenic staphylococci. However, Staphylococcus aureus has a remarkable capacity to survive neutrophil killing, which distinguishes it from the less-pathogenic Staphylococcus epidermidis. Both species release phenol-soluble modulin (PSM) toxins, which activate the neutrophil formyl-peptide receptor 2 (FPR2) to promote neutrophil influx and phagocytosis, and which disrupt neutrophils or their phagosomal membranes at high concentrations. We show here that the neutrophil serine proteases (NSPs) neutrophil elastase, cathepsin G and proteinase 3, which are released into the extracellular space or the phagosome upon neutrophil FPR2 stimulation, effectively degrade PSMs thereby preventing their capacity to activate and destroy neutrophils. Notably, S. aureus , but not S. epidermidis , secretes potent NSP-inhibitory proteins, Eap, EapH1, EapH2, which prevented the degradation of PSMs by NSPs. Accordingly, a S. aureus mutant lacking all three NSP inhibitory proteins was less effective in activating and destroying neutrophils and it survived less well in the presence of neutrophils than the parental strain. We show that Eap proteins promote pathology via PSM-mediated FPR2 activation since murine intraperitoneal infection with the S. aureus parental but not with the NSP inhibitors mutant strain, led to a significantly higher bacterial load in the peritoneum and kidneys of mFpr2 -/- compared to wild-type mice. These data demonstrate that NSPs can very effectively detoxify some of the most potent staphylococcal toxins and that the prominent human pathogen S. aureus has developed efficient inhibitors to preserve PSM functions. Preventing PSM degradation during infection represents an important survival strategy to ensure FPR2 activation.
Mindful of personality trait change: Are treatment effects on personality trait change ephemeral and attributable to changes in states?
2021-09-06

Abstract Objective Are treatment effects on personality trait change ephemeral and attributable to change in clinical states? Data of an intervention study were used to examine if change in clinical states (e.g., stress or depression) accounts for change in personality traits and to test whether both changes in traits and clinical states were independently associated with substance use. Method Seventy‐nine substance use patients ( M age = 25.3, SD = 2.7; 35% female) took part at a 4‐week intervention and completed a total of 15 bi‐monthly assessments across 28 weeks to measure change in traits and states during and after treatment. Results The results suggest that participants showed large trait and state changes over time, which happened rapidly with the majority occurring during the first four weeks. Trait and state changes were highly correlated, but not perfectly redundant. Significant variance in personality trait change remained after controlling for change in clinical states. Moreover, both trait and state change independently predicted substance use. Conclusion Personality trait change occurred relatively fast and was maintained until the last follow‐up assessment six months after the end of the intervention. Also, the findings point to the notion that the conceptual distinction between traits and states may not be as important as originally thought.
How Many Classes and Students Should Ideally be Sampled When Assessing the Role of Classroom Climate via Student Ratings on a Limited Budget? An Optimal Design Perspective
2021-09-06

Abstract A central question in educational research is how classroom climate variables, such as teaching quality, goal structures, or interpersonal teacher behavior, are related to critical student outcomes, such as students’ achievement and motivation. Student ratings are frequently used to measure classroom climate. When using student ratings to assess classroom climate, researchers first ask students to rate classroom climate characteristics and then aggregate the ratings on the class level. Multilevel latent variable modeling is then used to determine whether class-mean ratings of classroom climate are predictive of student outcomes and to correct for unreliability so that the relations can be estimated without bias. In this article, we adopt an optimal design perspective on this specific strategy. Specifically, after briefly recapping a prominent model in climate research, we show and explain (a) how statistical power can be maximized by choosing optimal numbers of classes and students per class given a fixed budget for conducting a study and (b) how the budget required to achieve a prespecified level of power can be minimized. Moreover, we present an example from research on teaching quality to illustrate the procedures and to provide guidance to researchers who are interested in studying the role of classroom climate. Also, we present a Shiny App that can be used to help find optimal designs for classroom climate studies. The app can be accessed at https://psychtools.shinyapps.io/optimalDesignsClassroomClimate
Bruton’s Tyrosine Kinase-Mediated Signaling in Myeloid Cells Is Required for Protective Innate Immunity During Pneumococcal Pneumonia
2021-09-06

Bruton’s tyrosine kinase (Btk) is a cytoplasmic kinase expressed in B cells and myeloid cells. It is essential for B cell development and natural antibody-mediated host defense against bacteria in humans and mice, but little is known about the role of Btk in innate host defense in vivo . Previous studies have indicated that lack of (natural) antibodies is paramount for impaired host defense against Streptococcus (S.) pneumoniae in patients and mice with a deficiency in functional Btk. In the present study, we re-examined the role of Btk in B cells and myeloid cells during pneumococcal pneumonia and sepsis in mice. The antibacterial defense of Btk -/- mice was severely impaired during pneumococcal pneumosepsis and restoration of natural antibody production in Btk -/- mice by transgenic expression of Btk specifically in B cells did not suffice to protect against infection. Btk -/- mice with reinforced Btk expression in MhcII + cells, including B cells, dendritic cells and macrophages, showed improved antibacterial defense as compared to Btk -/- mice. Bacterial outgrowth in Lysmcre-Btk fl /Y mice was unaltered despite a reduced capacity of Btk-deficient alveolar macrophages to respond to pneumococci. Mrp8cre-Btk fl /Y mice with a neutrophil specific paucity in Btk expression, however, demonstrated impaired antibacterial defense. Neutrophils of Mrp8cre-Btk fl /Y mice displayed reduced release of granule content after pulmonary installation of lipoteichoic acid, a gram-positive bacterial cell wall component relevant for pneumococci. Moreover, Btk deficient neutrophils showed impaired degranulation and phagocytosis upon incubation with pneumococci ex vivo . Taken together, the results of our study indicate that besides regulating B cell-mediated immunity, Btk is critical for regulation of myeloid cell-mediated, and particularly neutrophil-mediated, innate host defense against S. pneumoniae in vivo .
Using Primary Reinforcement to Enhance Translatability of a Human Affect and Decision-Making Judgment Bias Task
2021-09-06

Abstract Good translatability of behavioral measures of affect (emotion) between human and nonhuman animals is core to comparative studies. The judgment bias (JB) task, which measures “optimistic” and “pessimistic” decision-making under ambiguity as indicators of positive and negative affective valence, has been used in both human and nonhuman animals. However, one key disparity between human and nonhuman studies is that the former typically use secondary reinforcers (e.g., money) whereas the latter typically use primary reinforcers (e.g., food). To address this deficiency and shed further light on JB as a measure of affect, we developed a novel version of a JB task for humans using primary reinforcers. Data on decision-making and reported affective state during the JB task were analyzed using computational modeling. Overall, participants grasped the task well, and as anticipated, their reported affective valence correlated with trial-by-trial variation in offered volume of juice. In addition, previous findings from monetary versions of the task were replicated: More positive prediction errors were associated with more positive affective valence, a higher lapse rate was associated with lower affective arousal, and affective arousal decreased as a function of number of trials completed. There was no evidence that more positive valence was associated with greater “optimism,” but instead, there was evidence that affective valence influenced the participants' decision stochasticity, whereas affective arousal tended to influence their propensity for errors. This novel version of the JB task provides a useful tool for investigation of the links between primary reward and punisher experience, affect, and decision-making, especially from a comparative perspective.
Behavioral state tunes mouse vision to ethological features through pupil dilation
2021-09-06

Sensory processing changes with behavioral context to increase computational flexibility. In the visual system, active behavioral states enhance sensory responses but typically leave the preferred stimuli of neurons unchanged. Here we find that behavioral state does modulate stimulus selectivity in mouse visual cortex in the context of colored natural scenes. Using population imaging, behavior, pharmacology, and deep neural networks, we identified a shift of color selectivity towards ultraviolet stimuli exclusively caused by pupil dilation, resulting in a dynamic switch from rod to cone photoreceptors, extending their role beyond night and day vision. This facilitated the detection of ethological stimuli, such as aerial predators against the twilight sky. In contrast to previous studies that have used pupil dilation as an indirect measure of brain state, our results suggest that the brain uses pupil dilation itself to differentially recruit rods and cones on short timescales to tune visual representations to behavioral demands.
Shared Task on the Disambiguation of German Verbal Idioms at KONVENS 2021
2021-09-06

&lt;p&gt;The processing of multiword expressions (MWEs) has gained a lot of attention in recent years. Not least thanks to the shared tasks on verbal MWE identification organized by the PARSEME network. A phenomenon that because of its inherently rare nature is quite infrequent in datasets such as the PARSEME corpus are literal readings of verbal idioms (VIDs). This makes it difficult to efficiently train systems capable of identifying them. To alleviate this issue for German we built a VID corpus with a higher than usual number of literal readings. Together with the SemEval 2013 Task 5b dataset this formed the corpus for the Shared Task on the Disambiguation of German Verbal Idioms at KONVENS 2021. This paper describes the organization of the competition as well as the results of the participating systems.&lt;/p&gt;
Mapping of a N-terminal α-helix domain required for human PINK1 stabilisation, Serine228 autophosphorylation and activation in cells
2021-09-06

Abstract Human autosomal recessive mutations in the PINK1 gene are causal for Parkinson’s disease (PD). PINK1 encodes a mitochondrial localised protein kinase that is a master-regulator of mitochondrial quality control pathways. Structural studies to date have elaborated the mechanism of how mutations located within the kinase domain disrupt PINK1 function, however, the molecular mechanism of PINK1 mutations located upstream and downstream of the kinase domain are unknown. We have employed mutagenesis studies of human PINK1 in cells to define the minimal region of PINK1, required for optimal ubiquitin phosphorylation, beginning at residue Ile111. Bioinformatic analysis of the region spanning Ile111 to the kinase domain and inspection of the AlphaFold human PINK1 structure model predicts a conserved N-terminal α-helical domain extension (NTE domain) within this region corroborated by hydrogen/deuterium exchange mass spectrometry (HDX-MS) of recombinant insect PINK1 protein. The AlphaFold structure also predicts the NTE domain forms an intramolecular interaction with the C-terminal extension (CTE). Cell-based analysis of human PINK1 reveals that PD-associated mutations (e.g. Q126P), located within the NTE:CTE interface, markedly inhibit stabilization of PINK1; autophosphorylation at Serine228 (Ser228); and Ubiquitin Serine65 (Ser65) phosphorylation. Furthermore, we provide evidence that NTE domain mutants do not affect intrinsic catalytic kinase activity but do disrupt PINK1 stabilisation at the mitochondrial Translocase of outer membrane (TOM) complex. The clinical relevance of our findings is supported by the demonstration of defective stabilization and activation of endogenous PINK1 in human fibroblasts of a patient with early-onset PD due to homozygous PINK1 Q126P mutations. Overall, we define a functional role of the NTE:CTE interface towards PINK1 stabilisation and activation and show that loss of NTE:CTE interactions is a major mechanism of PINK1-associated mutations linked to PD.
Gravitational-wave glitches: Resonant islands and frequency jumps in nonintegrable extreme-mass-ratio inspirals
2021-09-07

The detection of gravitational waves from extreme-mass-ratio inspirals with upcoming space-borne detectors will allow for unprecedented tests of general relativity in the strong-field regime. Aside from assessing whether black holes are unequivocally described by the Kerr metric, such detections may place constraints on the degree of spacetime symmetry. In particular, depending on exactly how a hypothetical departure from the Kerr metric manifests, the Carter symmetry, which implies the integrability of the geodesic equations, may be broken. Here, we examine the gravitational waveforms associated with non-integrable extreme-mass-ratio inspirals involving a small-mass companion and a supermassive compact object of general relativity, namely the Manko-Novikov spacetime. We show that the waveforms displays sudden frequency jumps, when the companion transverses resonant islands. These findings demonstrate that such abrupt manifestations in the gravitational-wave frequencies are generic, have a genuine astrophysical origin and function as a distinctive signature of chaotic phenomena in extreme-mass-ratio binaries.
RAP Extensions for the Hybrid Configuration Model
2021-09-07

Modern applications in industrial automation rely on a deterministic network service, i.e., low latency, high reliability, and network convergence. Therefore, the IEEE 802.1 TSN Task Group introduces Time-Sensitive Networking (TSN). Besides mechanisms for traffic shaping, time synchronization, and reliability, TSN introduces three different configuration models for resource reservation: the fully distributed, the fully centralized, and the centralized network/distributed (hybrid) user model. Furthermore, IEEE P802.1Qdd specifies the Resource Allocation Protocol (RAP) to enable resource reservation for TSN streams in the fully distributed model. In this paper, we give an introduction to RAP, and propose extensions to RAP for the use in the hybrid configuration model. Additionally, we implement a prototype which is published under an open-source license.
Detection of mobile elements insertions for routine clinical diagnostics in targeted sequencing data
2021-09-07

Abstract Background Targeted sequencing approaches such as gene panel or exome sequencing have become standard of care for the diagnosis of rare and common genetic disease. The detection and interpretation of point mutations, small insertions and deletions, and even exon‐level copy number variants are well established in clinical genetic testing. Other types of genetic variation such as mobile elements insertions (MEIs) are technically difficult to detect. In addition, their downstream clinical interpretation is more complex compared to point mutations due to a larger genomic footprint that can not only predict a clear loss of protein function but might disturb gene regulation and splicing even when located within the non‐coding regions. As a consequence, the contribution of MEIs to disease and tumor development remains largely unexplored in routine diagnostics. Methods In this study, we investigated the occurrence of MEIs in 7,693 exome datasets from individuals with rare diseases and healthy relatives as well as 788 cancer patients analyzed by panel sequencing. Results We present several exemplary cases highlighting the diagnostic value of MEIs and propose a strategy for the detection, prioritization, and clinical interpretation of MEIs in routine clinical diagnostics. Conclusion In this paper, we state that detection and interpretation of MEIs in clinical practice in targeted NGS data can be performed relatively easy despite the fact that MEIs very rarely occur in coding parts of the human genome. Large scale reanalysis of MEIs in existing cohorts may solve otherwise unsolvable cases.
Adaptive capacity and flexibility of the Neanderthals at Heidenschmiede (Swabian Jura) with regard to core reduction strategies
2021-09-07

The branched reduction system at the Heidenschmiede described here is hitherto exceptional for the Middle Paleolithic of the Swabian Jura. By means of refits and supporting objects, we are able to describe a superordinate reduction system that combines several individual reduction concepts, such as Levallois and blade production, within one volume. In the Middle Paleolithic of the Swabian Jura, blade technology has thus far played a rather minor role. On the one hand, it is possible to split a selected volume (nodule) into three parts, which are reduced separately according to individual concepts. On the other hand, it is also possible to reduce parts of a volume with one concept first and then with another. The hypothetical reduction system can be branched or linear, thus emphasizing the technological flexibility in core reduction, which requires a high degree of cognitive skills of three-dimensional imagination.
Healthcare for Trans*gender People in Germany: Gaps, Challenges, and Perspectives
2021-09-07

People whose gender does not correspond to the binary gender system, i.e., trans ∗ gender people, face two main problems when it comes to healthcare in Germany: (1) They often suffer from general psychiatric comorbidities as well as specific and significant mental distress due to gender dysphoria, and (2) the German healthcare system lacks sufficiently educated and clinically experienced medical personnel who are able to provide specialized healthcare. Aside from transition, it often is extremely difficult for trans ∗ gender people to get access to and be integrated into the medical system. Stigmatization and pathologization in treatment are widespread, as are long waiting times for specialized healthcare providers who are often only accessible to those trans ∗ gender people willing to travel long distances. Frequently, trans ∗ gender people face further difficulties and barriers after transition, as some healthcare professionals fail to provide suitable care (e.g., gynecological consultation for transmen). The ICD-11 German Modification (ICD-11-GM), which should be routinely used by 2022, implements a depathologization of trans ∗ gender people in the medical system. This paper compares the issues related to health and healthcare of trans ∗ gender people in Germany with those in other European countries. We review the care offered by specialized centers with regard to treatment of and support for trans ∗ gender people. We conclude with specific proposals that may contribute to establish an improved, up-to-date, gender-sensitive healthcare system.