julilili42/papers huggingface dataset:
Engineered Sortases in Peptide and Protein Chemistry
2020-12-09

Abstract The transpeptidase sortase A of Staphylococcus aureus (Sa‐SrtA) is a valuable tool in protein chemistry. The native enzyme anchors surface proteins containing a highly conserved LPxTG sorting motif to a terminal glycine residue of the peptidoglycan layer in Gram‐positive bacteria. This reaction is exploited for sortase‐mediated ligation (SML), allowing the site‐specific linkage of synthetic peptides and recombinant proteins by a native peptide bond. However, the moderate catalytic efficiency and specificity of Sa‐SrtA fueled the development of new biocatalysts for SML, including the screening of sortase A variants form microorganisms other than S. aureus and the directed protein evolution of the Sa‐SrtA enzyme itself. Novel display platforms and screening formats were developed to isolate sortases with altered properties from mutant libraries. This yielded sortases with strongly enhanced catalytic activity and enzymes recognizing new sorting motifs as substrates. This minireview focuses on recent advances in the field of directed sortase evolution and applications of these tailor‐made enzymes in biochemistry.
The origins of the state: technology, cooperation and institutions
2020-12-09

Abstract We develop a theory of state formation shedding light on the rise of the first stable state institutions in Bronze Age Mesopotamia. Our analysis suggests that the mix of adverse production conditions and unforeseen innovations pushed groups favored by old technologies to establish the state by granting political and property rights to powerless individuals endowed with new and complementary skills. Through these reforms, the elite convinced the nonelite that a sufficient part of the returns on joint investments would be shared via public spending and, thus, to cooperate and accumulate a culture of cooperation. Different from the main alternative theories, we stress that: (1) group formation is heavily shaped by unforeseen shocks to the returns on both risk-sharing and innovation; (2) complementarity in group-specific skills, and not violence, is key determinant of state formation; (3) military, merchant and, especially, religious ranks favored state formation and culture accumulation.
The mineralogy and structure of use-wear polish on chert
2020-12-09

Abstract Polished edges of archaeological stone tools are commonly investigated to obtain information on the tools’ uses in prehistory. Yet to this day, it remains unclear what exactly such polishes are and how they form. Answering these questions should allow the elaboration of new interpretative methods based on objective measurements. Two major competing hypotheses of polish formation have been proposed: abrasion and the formation of a thin amorphous film on the chert or flint surface. We employ reflectance infrared spectroscopy, a technique particularly sensitive to thin amorphous films, to investigate these two hypotheses. We found no added amorphous layer that would have formed upon friction against bone, antler, ivory or wood. Our observations suggest polish formation by abrasion, notwithstanding previous claims of added amorphous surface structures. This has implications for our understanding of the physical processes taking place during friction of chert and flint against different materials. Our results also open the possibility to propose new pathways for identifying different use-wear processes, based on the degree of abrasion.
Intrinsically Self-renewing Neuroprogenitors From the A/J Mouse Spiral Ganglion as Virtually Unlimited Source of Mature Auditory Neurons
2020-12-09

Nearly 460 million individuals are affected by sensorineural hearing loss (SNHL), one of the most common human sensory disorders. In mammals, hearing loss is permanent due to the lack of efficient regenerative capacity of the sensory epithelia and spiral ganglion neurons (SGN). Sphere-forming progenitor cells can be isolated from the mammalian inner ear and give rise to inner ear specific cell types in vitro . However, the self-renewing capacities of auditory progenitor cells from the sensory and neuronal compartment are limited to few passages, even after adding powerful growth factor cocktails. Here, we provide phenotypical and functional characterization of a new pool of auditory progenitors as sustainable source for sphere-derived auditory neurons. The so-called phoenix auditory neuroprogenitors, isolated from the A/J mouse spiral ganglion, exhibit robust intrinsic self-renewal properties beyond 40 passages. At any passage or freezing–thawing cycle, phoenix spheres can be efficiently differentiated into mature spiral ganglion cells by withdrawing growth factors. The differentiated cells express both neuronal and glial cell phenotypic markers and exhibit similar functional properties as mouse spiral ganglion primary explants and human sphere-derived spiral ganglion cells. In contrast to other rodent models aiming at sustained production of auditory neurons, no genetic transformation of the progenitors is needed. Phoenix spheres therefore represent an interesting starting point to further investigate self-renewal in the mammalian inner ear, which is still far from any clinical application. In the meantime, phoenix spheres already offer an unlimited source of mammalian auditory neurons for high-throughput screens while substantially reducing the numbers of animals needed.
Short Research Report: Does Playing Apart Really Bring us Together? Investigating the Link Between Perceived Loneliness and the Use of Video Games During the COVID-19 Pandemic.
2020-12-09

During the COVID-19 pandemic, several countries implemented social distancing measures to contain virus transmission. However, these vital safety measures have the potential to impair mental health or well-being, for instance, from increased perceived loneliness. Playing social video games may offer a way to continue to socialize while adhering to social distancing measures. To examine this issue further, the present online survey investigated social gaming during the pandemic and its association to perceived loneliness within a German-speaking sample. Results indicated a small positive correlation between general gaming frequency and perceived loneliness. Detailed analysis revealed a negative association between perceived loneliness and increased social forms of video gaming. Specifically, gamers with more social motive for gaming perceived less loneliness, but gamers with a dominant escape motive demonstrated a positive link to perceived loneliness. The use of social gaming in times of social distancing seems to play a small but significant factor in perceived loneliness compared to other demographical data. The findings are discussed with respect to methodological limitations, effect sizes, and sample characteristics. The results enrich the current knowledge on video gaming and its link to social well-being and provide a more nuanced picture than simplistic investigations of screen time.
Successful long-term management of recurrent focal segmental glomerulosclerosis after kidney transplantation with costimulation blockade
2020-12-09

Abstract Recurrence of primary focal segmental glomerulosclerosis (FSGS) occurs in up to 50% of patients after kidney transplantation and is associated with poor allograft outcome. Novel therapeutic concepts directly target podocyte function via B7-1 with inconsistent response. We present the case of a 19-year-old patient with recurrent primary FSGS early after living donor kidney transplantation. Plasmapheresis and rituximab did not induce remission. Repetitive abatacept administration was able to achieve partial remission. Maintenance immunosuppression was subsequently switched to a belatacept-based calcineurin inhibitor-free immunosuppression, resulting in sustained complete remission with excellent allograft function throughout a follow-up of &amp;gt;56 months.
Pharmacogenetic considerations in the treatment of co-infections with HIV/AIDS, tuberculosis and malaria in Congolese populations of Central Africa
2020-12-09

The findings contribute to the understanding of pharmacogenetic variants involved in the metabolism of drugs used to treat HIV-infection, TB and malaria in ROC and their diversity in different populations. Such knowledge helps to predict drug efficacy, toxicity and ADRs and to inform individual and population-based decisions.
DIAproteomics: A multi-functional data analysis pipeline for data-independent-acquisition proteomics and peptidomics
2020-12-09

ABSTRACT Data-independent acquisition (DIA) is becoming a leading analysis method in biomedical mass spectrometry. Main advantages include greater reproducibility, sensitivity and dynamic range compared to data-dependent acquisition (DDA). However, data analysis is complex and often requires expert knowledge when dealing with large-scale data sets. Here we present DIAproteomics a multi-functional, automated high-throughput pipeline implemented in Nextflow that allows to easily process proteomics and peptidomics DIA datasets on diverse compute infrastructures. Central components are well-established tools such as the OpenSwathWorkflow for DIA spectral library search and PyProphet for false discovery rate assessment. In addition, it provides options to generate spectral libraries from existing DDA data and carry out retention time and chromatogram alignment. The output includes annotated tables and diagnostic visualizations from statistical post-processing and computation of fold-changes across pairwise conditions, predefined in an experimental design. DIAproteomics is open-source software and available under a permissive license to the scientific community at https://www.openms.de/diaproteomics/ .
Sensitivity of express saccades to the expected value of the target
2020-12-09

Express saccades are the fastest visually driven way of shifting gaze to targets of interest. We examined whether the pathway underlying these saccades has access to information on the value of saccade targets. We found that not only regular saccades but also express saccades occur earlier in case of higher expectations of reward. Yet, the sensitivity of express saccades to reward decreases linearly when approaching the earliest possible reaction time.
A plant surface receptor for sensing insect herbivory
2020-12-09

Micro-nano plastics originating from the prevalent usage of plastics have raised increasingly alarming concerns worldwide. However, there remains a fundamental knowledge gap in nanoplastics because of the lack of effective analytical ...Plastics are now omnipresent in our daily lives. The existence of microplastics (1 μm to 5 mm in length) and possibly even nanoplastics (<1 μm) has recently raised health concerns. In particular, nanoplastics are believed to be more toxic since their ...
Binding and Perspective Taking as Inference in a Generative Neural\\n Network Model
2020-12-09

The ability to flexibly bind features into coherent wholes from different\\nperspectives is a hallmark of cognition and intelligence. Importantly, the\\nbinding problem is not only relevant for vision but also for general\\nintelligence, sensorimotor integration, event processing, and language. Various\\nartificial neural network models have tackled this problem with dynamic neural\\nfields and related approaches. Here we focus on a generative encoder-decoder\\narchitecture that adapts its perspective and binds features by means of\\nretrospective inference. We first train a model to learn sufficiently accurate\\ngenerative models of dynamic biological motion or other harmonic motion\\npatterns, such as a pendulum. We then scramble the input to a certain extent,\\npossibly vary the perspective onto it, and propagate the prediction error back\\nonto a binding matrix, that is, hidden neural states that determine feature\\nbinding. Moreover, we propagate the error further back onto perspective taking\\nneurons, which rotate and translate the input features onto a known frame of\\nreference. Evaluations show that the resulting gradient-based inference process\\nsolves the perspective taking and binding problem for known biological motion\\npatterns, essentially yielding a Gestalt perception mechanism. In addition,\\nredundant feature properties and population encodings are shown to be highly\\nuseful. While we evaluate the algorithm on biological motion patterns, the\\nprincipled approach should be applicable to binding and Gestalt perception\\nproblems in other domains.\\n
Genome-wide CRISPR and small-molecule screens uncover targetable dependencies in ATRT
2020-12-09

Summary Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Concepts for molecular-driven therapies in ATRTs lag behind, mainly due to the absence of actionable genetic alterations. We performed genome-wide CRISPR/Cas9 knockout screens in six human ATRT cell lines and identified a total of 671 context-specific essential genes. Based on these genetic dependencies, we constructed a library of small-molecule inhibitors that we found to preferentially inhibit growth of ATRT cells. CDK4/6 inhibitors, among the most potent drugs in our library, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on CDK4 or CDK6 . These distinct dependencies drive heterogeneity in response to CDK4/6 inhibitors in ATRTs. Our approach might serve as a blueprint for fostering the identification of functionally-instructed therapeutic strategies in other incurable diseases beyond ATRT, whose genomic profiles also lack actionable alterations so far.
Increasing Reliability Using Adaptive Cross-Layer Techniques in DRPs: Just-Safe-Enough Responses to Reliability Threats
2020-12-09

Abstract The developments in the semiconductor industry as predicted by institutions such as the ITRS present a difficult question to hardware and software developers alike: How to implement increasingly complex, power hungry, and critical applications reliably in today’s and tomorrow’s semiconductor technology? The present trend of semiconductor technology is characterized by a sharp increase in complexity, cost, and delicacy. Also, it does not scale along the demands which are still based on and often exceed Moore’s Law. In this chapter, we propose to exploit the architectural redundancies provided by potent, yet energy efficient massively parallel architectures, modeled using Dynamically Reconfigurable Processors (DRP). Using DRPs, we built an extensive cross-layer approach, offering different levels of reliability measures to operating system (OS) and software developers through low-cost hardware redundancy schemes and appropriate physical operating condition tuning. On the hardware side, online testing schemes and error detection are deployed to trigger dynamic remapping to avoid the usage of faulty components. This approach is further complemented through hardware health monitoring that can detect reliability issues such as negative bias temperature instability (NBTI) or hot carrier injection (HCI) before they surface as an error as well as further tuning of operating conditions to delay such phenomena from surfacing.
Antenatally diagnosed renal tumor: Questions
2020-12-09

Background!#!Approximately 20% of antibody-mediated rejection (ABMR) episodes in the absence of donor-specific antibodies against human leucocyte antigens (HLA-DSA) in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, antibodies against the angiotensin type 1 receptor (AT!##!Case!#!We report on a male patient with kidney failure in infancy due to obstructive uropathy who had lost his first kidney transplant due to AT!##!Conclusion!#!This case highlights the difficulty of persistently decreasing elevated AT
Antenatally diagnosed kidney tumor: Answers
2020-12-09

Background!#!Approximately 20% of antibody-mediated rejection (ABMR) episodes in the absence of donor-specific antibodies against human leucocyte antigens (HLA-DSA) in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, antibodies against the angiotensin type 1 receptor (AT!##!Case!#!We report on a male patient with kidney failure in infancy due to obstructive uropathy who had lost his first kidney transplant due to AT!##!Conclusion!#!This case highlights the difficulty of persistently decreasing elevated AT
NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients
2020-12-10

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.
Performance of Breast Cancer Polygenic Risk Scores in 760 FemaleCHEK2Germline Mutation Carriers
2020-12-10

Abstract Background Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies–independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2. Methods A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided. Results Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P &amp;lt; 2.20 × 10−16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10−6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26). Conclusions PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.
Incidental Attitude Formation via the Surveillance Task: A Preregistered Replication of the Olson and Fazio (2001) Study
2020-12-10

Evaluative conditioning is one of the most widely studied procedures for establishing and changing attitudes. The surveillance task is a highly cited evaluative-conditioning paradigm and one that is claimed to generate attitudes without awareness. The potential for evaluative-conditioning effects to occur without awareness continues to fuel conceptual, theoretical, and applied developments. Yet few published studies have used this task, and most are characterized by small samples and small effect sizes. We conducted a high-powered ( N = 1,478 adult participants), preregistered close replication of the original surveillance-task study (Olson &amp; Fazio, 2001). We obtained evidence for a small evaluative-conditioning effect when “aware” participants were excluded using the original criterion—therefore replicating the original effect. However, no such effect emerged when three other awareness criteria were used. We suggest that there is a need for caution when using evidence from the surveillance-task effect to make theoretical and practical claims about “unaware” evaluative-conditioning effects.
Sirolimus in renal transplant recipients with malignancies in Germany
2020-12-10

Abstract Background Renal transplant recipients have an increased cancer risk. The mammalian target of rapamycin inhibitor sirolimus (SRL) has immunosuppressive and antitumour activities but knowledge about its use in recipients with cancer is limited. Methods We retrospectively analysed 726 renal allograft recipients converted to SRL from 10 German transplant centres. Patient and graft survival were analysed depending on malignancy status prior to conversion and tumour entity. Results Malignancy before conversion to SRL was reported in 230 patients, with 137 patients having skin cancers and 101 having solid cancers. Cancer occurred 4.6 ± 9.4 (median 3.0) years after transplantation. Basal cell carcinoma, squamous cell carcinoma and Bowen’s disease were the most prevalent skin cancers, while carcinomas of the kidney, colon and breast were the most prevalent solid cancers before conversion. Patients with prior malignancy were older and had better renal function at conversion compared with patients without a history of cancer. After conversion to SRL, cancer incidence rates (IRs) of all tumours were lower compared with rates before conversion. Cancer IRs after conversion were higher in patients with malignancy before conversion compared with those without. Patient survival was worse in patients with solid cancers compared with patients with skin cancers or without malignancies. Biopsy-proven acute rejections in the first year after conversion were less frequent in patients with malignancy compared with those without. Graft survival and renal function in all cancer types were better than in patients converted to SRL without cancers. Conclusions Conversion to SRL in patients with a history of cancer is safe regarding renal function and graft survival, while patient survival is largely dependent on tumour entity.