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Demonstrations of both pro-apoptotic and pro-survival abilities of Fas (TNFRSF6/CD95/APO-1) have led to a shift from the exclusive "Fas apoptosis" to "Fas multisignals" paradigm and the acceptance that Fas-related therapies face a major challenge, as it remains unclear what determines the mode of Fas signaling. Through protein evolution analysis, which reveals unconventional substitutions of Fas tyrosine during divergent evolution, evolution-guided tyrosine-phosphorylated Fas proxy, and site-specific phosphorylation detection, we show that the Fas signaling outcome is determined by the tyrosine phosphorylation status of its death domain. The phosphorylation dominantly turns off the Fas-mediated apoptotic signal, while turning on the pro-survival signal. We show that while phosphorylations at Y232 and Y291 share some common functions, their contributions to Fas signaling differ at several levels. The findings that Fas tyrosine phosphorylation is regulated by Src family kinases (SFKs) and the phosphatase SHP-1 and that Y291 phosphorylation primes clathrin-dependent Fas endocytosis, which contributes to Fas pro-survival signaling, reveals for the first time the mechanistic link between SFK/SHP-1-dependent Fas tyrosine phosphorylation, internalization route, and signaling choice. We also demonstrate that levels of phosphorylated Y232 and Y291 differ among human cancer types and differentially respond to anticancer therapy, suggesting context-dependent involvement of Fas phosphorylation in cancer. This report provides a new insight into the control of TNF receptor multisignaling by receptor phosphorylation and its implication in cancer biology, which brings us a step closer to overcoming the challenge in handling Fas signaling in treatments of cancer as well as other pathologies such as autoimmune and degenerative diseases.

Abstract We examine the capability of Mu3e to probe light new physics scenarios that produce a prompt electron-positron resonance and demonstrate how angular observables are instrumental in enhancing the experimental sensitivity. We systematically investigate the effect of Mu3e’s expected sensitivity on the parameter space of the dark photon, as well as on axion-like particles and light scalars with couplings to muons and electrons.

ABSTRACTThe export of peptides or proteins is essential for a variety of important functions in bacteria. Among the diverse protein-translocation systems, peptidase-containing ABC transporters (PCAT) are involved in the maturation and export of quorum-sensing or antimicrobial peptides in Gram-positive bacteria and of toxins in Gram-negative organisms. In the multicellular and diazotrophic cyanobacterium Nostoc PCC 7120, the protein HetC is essential for the differentiation of functional heterocysts, which are micro-oxic and non-dividing cells specialized in atmospheric nitrogen fixation. HetC shows similarities to PCAT systems, but whether it actually acts as a peptidase-based exporter remains to be established. In this study, we show that the N-terminal part of HetC, encompassing the peptidase domain, displays a cysteine-type protease activity. The conserved catalytic residues conserved in this family of proteases are essential for the proteolytic activity of HetC and the differentiation of heterocysts. Furthermore, we show that the catalytic residue of the ATPase domain of HetC is also essential for cell differentiation. Interestingly, HetC has a cyclic nucleotide-binding domain at its N-terminus which can bind ppGpp in vitro and which is required for its function in vivo. Our results indicate that HetC is a peculiar PCAT that might be regulated by ppGpp to potentially facilitate the export of a signaling peptide essential for cell differentiation, thereby broadening the scope of PCAT role in Gram-negative bacteria.IMPORTANCEBacteria have a great capacity to adapt to various environmental and physiological conditions; it is widely accepted that their ability to produce extracellular molecules contributes greatly to their fitness. Exported molecules are used for a variety of purposes ranging from communication to adjust cellular physiology, to the production of toxins that bacteria secrete to fight for their ecological niche. They use export machineries for this purpose, the most common of which energize transport by hydrolysis of adenosine triphosphate. Here, we demonstrate that such a mechanism is involved in cell differentiation in the filamentous cyanobacterium Nostoc PCC 7120. The HetC protein belongs to the ATP-binding cassette transporter superfamily and presumably ensures the maturation of a yet unknown substrate during export. These results open interesting perspectives on cellular signaling pathways involving the export of regulatory peptides, which will broaden our knowledge of how these bacteria use two cell types to conciliate photosynthesis and nitrogen fixation.

Inbreeding (reproduction between relatives) often decreases the fitness of offspring and is thus expected to lead to the evolution of inbreeding avoidance strategies. Chimpanzees (Pan troglodytes) are expected to avoid inbreeding as they are long-lived, invest heavily in offspring and may encounter adult, opposite sex kin frequently, especially in populations where both males and females commonly remain in the group in which they were born (bisexual philopatry). However, it is unclear whether substantial bisexual philopatry has been a feature of chimpanzees' evolutionary history or whether it is a result of recent anthropogenic interference, as the only groups for which it has been documented are significantly impacted by human encroachment and experience notable rates of potentially unsustainable inbreeding. Here we use 14 years of observational data and a large genomic dataset of 256 481 loci sequenced from 459 individuals to document dispersal and inbreeding dynamics in an eastern chimpanzee (P. t. schweinfurthii) community with low levels of anthropogenic disturbance. We document the first case of substantial bisexual philopatry in a relatively undisturbed chimpanzee community and show that, despite an increased inbreeding risk incurred by females who do not disperse before reaching reproductive age, natal females were still able to avoid producing inbred offspring.

Abstract We introduce Super-Resonant Dark Matter, a model of self-interacting dark matter based on the low energy effective theory of supersymmetric QCD. The structure of the theory ensures a resonant enhancement of the self-interactions of the low energy mesons, since their mass ratio is set by the number of colors and flavors. The velocity dependence of the resonantly enhanced self-interactions allows such theories to accommodate puzzles in small scale structure that arise from dark matter halos of different sizes. The dark matter mass is then predicted to be around 3–4 MeV, with its abundance set by freeze-in via a kinetically mixed dark photon.

Advances in viral discovery techniques have led to the identification of numerous novel viruses in human samples. However, the low prevalence of certain viruses in humans raises doubts about their association with our species. To ascertain the authenticity of a virus as a genuine human-infecting agent, it can be useful to investigate the diversification of its lineage within hominines, the group encompassing humans and African great apes. Building upon this rationale, we examined the case of the New Jersey polyomavirus (NJPyV; Alphapolyomavirus terdecihominis), which has only been detected in a single patient thus far. In this study, we obtained and analyzed sequences from closely related viruses infecting all African great ape species. We show that NJPyV nests within the diversity of these viruses and that its lineage placement is compatible with an ancient origin in humans, despite its apparent rarity in human populations.

Abstract Background In the last decades, several powered ankle-foot orthoses have been developed to assist the ankle joint of their users during walking. Recent studies have shown that the effects of the assistance provided by powered ankle-foot orthoses depend on the assistive profile. In compliant actuators, the stiffness level influences the actuator’s performance. However, the effects of this parameter on the users has not been yet evaluated. The goal of this study is to assess the effects of the assistance provided by a variable stiffness ankle actuator on healthy young users. More specifically, the effect of different onset times of the push-off torque and different actuator’s stiffness levels has been investigated. Methods Eight healthy subjects walked with a unilateral powered ankle-foot orthosis in several assisted walking trials. The powered orthosis was actuated in the sagittal plane by a variable stiffness actuator. During the assisted walking trials, three different onset times of the push-off assistance and three different actuator’s stiffness levels were used. The metabolic cost of walking, lower limb muscles activation, joint kinematics, and gait parameters measured during different assisted walking trials were compared to the ones measured during normal walking and walking with the powered orthosis not providing assistance. Results This study found trends for more compliant settings of the ankle actuator resulting in bigger reductions of the metabolic cost of walking and soleus muscle activation in the stance phase during assisted walking as compared to the unassisted walking trial. In addition to this, the study found that, among the tested onset times, the earlier ones showed a trend for bigger reductions of the activation of the soleus muscle during stance, while the later ones led to a bigger reduction in the metabolic cost of walking in the assisted walking trials as compared to the unassisted condition. Conclusions This study presents a first attempt to show that, together with the assistive torque profile, also the stiffness level of a compliant ankle actuator can influence the assistive performance of a powered ankle-foot orthosis.

Summary: Knowledge on the population history of endangered species is critical for conservation, but whole-genome data on chimpanzees (Pan troglodytes) is geographically sparse. Here, we produced the first non-invasive geolocalized catalog of genomic diversity by capturing chromosome 21 from 828 non-invasive samples collected at 48 sampling sites across Africa. The four recognized subspecies show clear genetic differentiation correlating with known barriers, while previously undescribed genetic exchange suggests that these have been permeable on a local scale. We obtained a detailed reconstruction of population stratification and fine-scale patterns of isolation, migration, and connectivity, including a comprehensive picture of admixture with bonobos (Pan paniscus). Unlike humans, chimpanzees did not experience extended episodes of long-distance migrations, which might have limited cultural transmission. Finally, based on local rare variation, we implement a fine-grained geolocalization approach demonstrating improved precision in determining the origin of confiscated chimpanzees.

Wearable robots have become increasingly prevalent in various applications, including rehabilitation, power augmentation, and assistance. However, one of the challenges in designing wearable robots is how to attach them to the human body. The attachment method should be secure, reliable, comfortable, effective, and controlled for the user. Moreover, the attachment points should not interfere with the user’s daily activities, and the attachment process should not be time-consuming or complicated. Typical straps nowadays require a time-consuming and cumbersome donning and doffing procedure from therapists for users needing rehabilitation therapy. Therefore, we propose a novel pneumatically actuated soft strap to enclose the limb and automate part of the strapping procedure. This paper proposes a preliminary design utilizing soft bending actuators for attaching physical interfaces to humans, with integrated active elements for facilitating and automating the strapping process. Finite element analysis was conducted to assess pressure requirements, bending curvature, and geometry, with simulation results demonstrating a promising agreement, with a root mean square error (RMSE) of 3.4° in bending angle. In the future, an additional locking mechanism would be required to provide the necessary holding force and fully constrain the limb.

Prebiotic molecules, fundamental building blocks for the origin of life, have been found in carbonaceous chondrites. The exogenous delivery of these organic molecules onto the Hadean Earth could have sparked the polymerization of the first RNA molecules in Darwinian ponds during wet-dry cycles. Here, we investigate the formation of the RNA and DNA nucleobases adenine, uracil, cytosine, guanine, and thymine inside parent body planetesimals of carbonaceous chondrites. An up-to-date thermochemical equilibrium model coupled with a 1D thermodynamic planetesimal model is used to calculate the nucleobase concentrations. Different from previous studies, we assume the initial volatile concentrations more appropriate for the formation zone of carbonaceous chondrite parent bodies. This represents more accurately cosmochemical findings that these bodies have formed inside the inner, ∼2–5 au, warm region of the solar system. Due to these improvements, our model represents the concentrations of adenine and guanine measured in carbonaceous chondrites. Our model did not reproduce per se the measurements of uracil, cytosine, and thymine in these meteorites. This can be explained by transformation reactions between nucleobases and the potential decomposition of thymine. The synthesis of prebiotic organic matter in carbonaceous asteroids could be well explained by a combination of (i) radiogenic heating, (ii) aqueous chemistry involving a few key processes at a specific range of radii inside planetesimals where water can exist in the liquid phase, and (iii) a reduced initial volatile content (H _2 , CO, $\mathrm{HCN}$ , and CH _2 O) of the protoplanetary disk material in the parent body region compared to the outer region of comets.

Human motion intention detection is an essential part of the control of upper-body exoskeletons. While surface electromyography (sEMG)-based systems may be able to provide anticipatory control, they typically require exact placement of the electrodes on the muscle bodies which limits the practical use and donning of the technology. In this study, we propose a novel physical interface for exoskeletons with integrated sEMG- and pressure sensors. The sensors are 3D-printed with flexible, conductive materials and allow multi-modal information to be obtained during operation. A K-Nearest Neighbours classifier is implemented in an off-line manner to detect reaching movements and lifting tasks that represent daily activities of industrial workers. The performance of the classifier is validated through repeated experiments and compared to a unimodal EMG-based classifier. The results indicate that excellent prediction performance can be obtained, even with a minimal amount of sEMG electrodes and without specific placement of the electrode.

Approximating quantiles and distributions over streaming data has been studied for roughly two decades now. Recently, Karnin, Lang, and Liberty proposed the first asymptotically optimal algorithm for doing so. This manuscript complements their theoretical result by providing a practical variants of their algorithm with improved constants. For a given sketch size, our techniques provably reduce the upper bound on the sketch error by a factor of two. These improvements are verified experimentally. Our modified quantile sketch improves the latency as well by reducing the worst-case update time from O(1ε) down to O(log1ε).

Das Thüringer Kompetenznetzwerk Forschungsdatenmanagement stellt seinen kampagnenbasierten Ansatz zur Kommunikation des Themas Forschungsdatenmanagement und der landesweiten FDM-Aktivitäten vor. Die Strategie zielt auf eine regelmäßige Kommunikation mit allen Adressaten des Netzwerks ab, die in Inhalt und Frequenz den jeweiligen Zielgruppen angepasst ist. Dem Gedanken der Nachhaltigkeit folgend, werden ausschließlich Materialien, die noch nicht anderweitig in ähnlicher Form bestehen, selbst gestaltet und zur Nachnutzung zur Verfügung gestellt. Wo angemessen, wird auf bestehende Angebote der FDM-Community aufgebaut.

The origin of life might be sparked by the polymerization of the first RNA molecules in Darwinian ponds during wet-dry cycles. The key life-building block ribose was found in carbonaceous chondrites. Its exogenous delivery onto the Hadean Earth could be a crucial step toward the emergence of the RNA world. Here, we investigate the formation of ribose through a simplified version of the formose reaction inside carbonaceous chondrite parent bodies. Following up on our previous studies regarding nucleobases with the same coupled physico-chemical model, we calculate the abundance of ribose within planetesimals of different sizes and heating histories. We perform laboratory experiments using catalysts present in carbonaceous chondrites to infer the yield of ribose among all pentoses (5Cs) forming during the formose reaction. These laboratory yields are used to tune our theoretical model that can only predict the total abundance of 5Cs. We found that the calculated abundances of ribose were similar to the ones measured in carbonaceous chondrites. We discuss the possibilities of chemical decomposition and preservation of ribose and derived constraints on time and location in planetesimals. In conclusion, the aqueous formose reaction might produce most of the ribose in carbonaceous chondrites. Together with our previous studies on nucleobases, we found that life-building blocks of the RNA world could be synthesized inside parent bodies and later delivered onto the early Earth.

With the growing popularity of Human–Robot Interactions, a series of robotic assistive devices have been created over the last decades. However, due to the lack of easily integrable resources, the development of these custom made devices turns out to be long and expensive. Therefore, the SMARCOS, a novel off-the-shelf Smart Variable Stiffness Actuator for human-centered robotic applications is proposed in this paper. This modular actuator combines compliant elements and sensors as well as low-level controller and high-bandwidth communication. The characterisation of the actuator is presented in this manuscript, followed by two use-cases wherein the benefits of such technology can be truly exploited. The actuator provides a lightweight design that can serve as the building blocks to facilitate the development of robotic applications.

ABSTRACT The microbiome is important to all animals, including poultry, playing a critical role in health and performance. Low-dose antibiotics have historically been used to modulate food production animals and their microbiome. Identifying alternatives to antibiotics conferring similar modulatory properties has been elusive. The purpose of this study was to determine if a host-tailored probiotic could recapitulate effects of a low-dose antibiotic on host response and the developing microbiome. Over 13 days of life, turkey poults were supplemented continuously with a low-dose antibiotic or oral supplementation of a prebiotic with or without two different probiotics (8 cage units, n = 80 per group). Gastrointestinal bacterial and fungal communities of poults were characterized by 16S rRNA gene and ITS2 amplicon sequencing. Localized and systemic host gene expression was assessed using transcriptome sequencing (RNA-Seq), kinase activity was assessed by avian-specific kinome peptide arrays, and performance parameters were assessed. We found that development of the early-life microbiome of turkey poults was tightly ordered in a tissue- and time-specific manner. Low-dose antibiotic and turkey-tailored probiotic supplementation, but not nontailored probiotic supplementation, elicited similar shifts in overall microbiome composition during development compared to controls. Treatment-induced bacterial changes were accompanied by parallel shifts in the fungal community and host gene expression and enhanced performance metrics. These results were validated in pen trials that identified further additive effects of the turkey-tailored probiotic combined with different prebiotics. Alternative approaches to low-dose antibiotic use in poultry are feasible and can be optimized utilizing the indigenous poultry microbiome. Similar approaches may also be beneficial for humans. IMPORTANCE Alternative approaches are greatly needed to reduce the need for antibiotic use in food animal production. This study utilized a pipeline for the development of a host-tailored probiotic to enhance performance in commercial turkeys and modulate their microbiota, similar to the effects of low-dose antibiotic administration. We determined that a host-tailored probiotic, developed in the context of the commercial turkey gut microbiome, was more effective at modulating these parameters than a nontailored probiotic cocktail. Furthermore, the host-tailored probiotic mimicked many of the effects of a low-dose antibiotic growth promoter. Surprisingly, the effects of the antibiotic growth promoter and host-tailored probiotic were observed across kingdoms, illustrating the coordinated interkingdom effects of these approaches. This work suggests that tailored approaches to probiotic development hold promise for modulating the avian host and its microbiota.

Sensing pressure at the physical interface between the robot and the human has important implications for wearable robots. On the one hand, monitoring pressure distribution can give valuable benefits on the aspects of comfortability and safety of such devices. Additionally, on the other hand, they can be used as a rich sensory input to high level interaction controllers. However, a problem is that the commercial availability of this technology is mostly limited to either low-cost solutions with poor performance or expensive options, limiting the possibilities for iterative designs. As an alternative, in this manuscript we present a three-dimensional (3D) printed flexible capacitive pressure sensor that allows seamless integration for wearable robotic applications. The sensors are manufactured using additive manufacturing techniques, which provides benefits in terms of versatility of design and implementation. In this study, a characterization of the 3D printed sensors in a test-bench is presented after which the sensors are integrated in an upper arm interface. A human-in-the-loop calibration of the sensors is then shown, allowing to estimate the external force and pressure distribution that is acting on the upper arm of seven human subjects while performing a dynamic task. The validation of the method is achieved by means of a collaborative robot for precise force interaction measurements. The results indicate that the proposed sensors are a potential solution for further implementation in human–robot interfaces.

Slot Filling, a subtask of Relation Extraction, represents a key aspect for building structured knowledge bases usable for semantic-based information retrieval. In this work, we present a machine learning filter whose aim is to enhance the precision of relation extractors while minimizing the impact on the recall. Our approach consists in the filtering of relation extractors’ output using a binary classifier. This classifier is based on a wide array of features including syntactic, semantic and statistical features such as the most frequent part-of-speech patterns or the syntactic dependencies between entities. We experimented the classifier on the 18 participating systems in the TAC KBP 2013 English Slot Filling track. The TAC KBP English Slot Filling track is an evaluation campaign that targets the extraction of 41 pre-identified relations (e.g., title, date of birth, countries of residence, etc.) related to specific named entities (persons and organizations). Our results show that the classifier is able to improve the global precision of the best 2013 system by 20.5% and improve the F1-score for 20 relations out of 33 considered.

The adoption of unrelated orphaned infants is something chimpanzees and humans have in common. Providing parental care has fitness implications for both the adopter and orphan, and cases of adoption have thus been cited as evidence for a shared origin of an altruistic behaviour. We provide new data on adoptions in the free-living Sonso chimpanzee community in Uganda, together with an analysis of published data from other long-term field sites. As a default pattern, we find that orphan chimpanzees do not become adopted by adult group members but wherever possible associate with each other, usually as maternal sibling pairs. This occurs even if both partners are still immature, with older individuals effectively becoming 'child household heads'. Adoption of orphans by unrelated individuals does occur but usually only if no maternal siblings or other relatives are present and only after significant delays. In conclusion, following the loss of their mother, orphaned chimpanzees preferentially associate along pre-existing social bonds, which are typically strongest amongst maternal siblings.

In long-lived social mammals such as primates, individuals can benefit from social bonds with close kin, including their mothers. In the patrilocal chimpanzee (Pan troglodytes spp.) and bonobo (Pan paniscus), sexually mature males reside and reproduce in their natal groups and can retain post-dependency bonds with their mothers, while immatures of both sexes might also have their paternal grandmothers available. However, quantitative information on the proportion of males and immatures that co-reside with both types of these close female relatives is limited for both species. Combining genetic parentage determination and group composition data from five communities of wild chimpanzees and three communities of wild bonobos, we estimated the frequency of co-residence between (1) mature males and their mothers, and (2) immature males and females and their paternal grandmothers. We found that adult males resided twice as frequently with their mothers in bonobos than in chimpanzees, and that immature bonobos were three times more likely to possess a living paternal grandmother than were immature chimpanzees. Patterns of female and male survivorship from studbook records of captive individuals of both species suggest that mature bonobo females survive longer than their chimpanzee counterparts, possibly contributing to the differences observed in mother-son and grandmother-immature co-residency levels. Taking into account reports of bonobo mothers supporting their sons' mating efforts and females sharing food with immatures other than their own offspring, our findings suggest that life history traits may facilitate maternal and grandmaternal support more in bonobos than in chimpanzees.

BACKGROUND: Many group-living species display strong sex biases in dispersal tendencies. However, gene flow mediated by apparently philopatric sex may still occur and potentially alters population structure. In our closest living evolutionary relatives, dispersal of adult males seems to be precluded by high levels of territoriality between males of different groups in chimpanzees, and has only been observed once in bonobos. Still, male-mediated gene flow might occur through rare events such as extra-group matings leading to extra-group paternity (EGP) and female secondary dispersal with offspring, but the extent of this gene flow has not yet been assessed. METHODOLOGY/PRINCIPAL FINDINGS: Using autosomal microsatellite genotyping of samples from multiple groups of wild western chimpanzees (Pan troglodytes verus) and bonobos (Pan paniscus), we found low genetic differentiation among groups for both males and females. Characterization of Y-chromosome microsatellites revealed levels of genetic differentiation between groups in bonobos almost as high as those reported previously in eastern chimpanzees, but lower levels of differentiation in western chimpanzees. By using simulations to evaluate the patterns of Y-chromosomal variation expected under realistic assumptions of group size, mutation rate and reproductive skew, we demonstrate that the observed presence of multiple and highly divergent Y-haplotypes within western chimpanzee and bonobo groups is best explained by successful male-mediated gene flow. CONCLUSIONS/SIGNIFICANCE: The similarity of inferred rates of male-mediated gene flow and published rates of EGP in western chimpanzees suggests this is the most likely mechanism of male-mediated gene flow in this subspecies. In bonobos more data are needed to refine the estimated rate of gene flow. Our findings suggest that dispersal patterns in these closely related species, and particularly for the chimpanzee subspecies, are more variable than previously appreciated. This is consistent with growing recognition of extensive behavioral variation in chimpanzees and bonobos.