julilili42/papers huggingface dataset:
Single-Domain Antibodies for Targeting, Detection, and In Vivo Imaging of Human CD4+ Cells
2021-12-09

The advancement of new immunotherapies necessitates appropriate probes to monitor the presence and distribution of distinct immune cell populations. Considering the key role of CD4 + cells in regulating immunological processes, we generated novel single-domain antibodies [nanobodies (Nbs)] that specifically recognize human CD4. After in-depth analysis of their binding properties, recognized epitopes, and effects on T-cell proliferation, activation, and cytokine release, we selected CD4-specific Nbs that did not interfere with crucial T-cell processes in vitro and converted them into immune tracers for noninvasive molecular imaging. By optical imaging, we demonstrated the ability of a high-affinity CD4-Nb to specifically visualize CD4 + cells in vivo using a xenograft model. Furthermore, quantitative high-resolution immune positron emission tomography (immunoPET)/MR of a human CD4 knock-in mouse model showed rapid accumulation of 64 Cu-radiolabeled CD4-Nb1 in CD4 + T cell-rich tissues. We propose that the CD4-Nbs presented here could serve as versatile probes for stratifying patients and monitoring individual immune responses during personalized immunotherapy in both cancer and inflammatory diseases.
EEG-Microstates Reflect Auditory Distraction After Attentive Audiovisual Perception Recruitment of Cognitive Control Networks
2021-12-09

Processing of sensory information is embedded into ongoing neural processes which contribute to brain states. Electroencephalographic microstates are semi-stable short-lived power distributions which have been associated with subsystem activity such as auditory, visual and attention networks. Here we explore changes in electrical brain states in response to an audiovisual perception and memorization task under conditions of auditory distraction. We discovered changes in brain microstates reflecting a weakening of states representing activity of the auditory system and strengthening of salience networks, supporting the idea that salience networks are active after audiovisual encoding and during memorization to protect memories and concentrate on upcoming behavioural response.
Laminar-specific functional connectivity mapping with multi-slice line-scanning fMRI
2021-12-09

Abstract Despite extensive studies detecting laminar functional magnetic resonance imaging (fMRI) signals to illustrate the canonical microcircuit, the spatiotemporal characteristics of laminar-specific information flow across cortical regions remain to be fully investigated in both evoked and resting conditions at different brain states. Here, we developed a multislice line-scanning fMRI (MS-LS) method to detect laminar fMRI signals in adjacent cortical regions with high spatial (50 μm) and temporal resolution (100 ms) in anesthetized rats. Across different trials, we detected either laminar-specific positive or negative blood-oxygen-level-dependent (BOLD) responses in the surrounding cortical region adjacent to the most activated cortex under the evoked condition. Specifically, in contrast to typical Layer (L) 4 correlation across different regions due to the thalamocortical projections for trials with positive BOLD, a strong correlation pattern specific in L2/3 was detected for trials with negative BOLD in adjacent regions, which indicated brain state-dependent laminar-fMRI responses based on corticocortical interaction. Also, in resting-state (rs-) fMRI study, robust lag time differences in L2/3, 4, and 5 across multiple cortices represented the low-frequency rs-fMRI signal propagation from caudal to rostral slices. In summary, our study provided a unique laminar fMRI mapping scheme to better characterize trial-specific intra- and inter-laminar functional connectivity in evoked and resting-state MS-LS.
Dopamine enhances model-free credit assignment through boosting of retrospective model-based inference
2021-12-09

Dopamine is implicated in representing model-free (MF) reward prediction errors a as well as influencing model-based (MB) credit assignment and choice. Putative cooperative interactions between MB and MF systems include a guidance of MF credit assignment by MB inference. Here, we used a double-blind, placebo-controlled, within-subjects design to test an hypothesis that enhancing dopamine levels boosts the guidance of MF credit assignment by MB inference. In line with this, we found that levodopa enhanced guidance of MF credit assignment by MB inference, without impacting MF and MB influences directly. This drug effect correlated negatively with a dopamine-dependent change in purely MB credit assignment, possibly reflecting a trade-off between these two MB components of behavioural control. Our findings of a dopamine boost in MB inference guidance of MF learning highlight a novel DA influence on MB-MF cooperative interactions.
A Mutation-Agnostic Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy
2021-12-09

Metachromatic leukodystrophy (MLD) is a rare genetic disorder caused by mutations in the <i>Arylsulfatase-A</i> (<i>ARSA</i>) gene. The enzyme plays a key role in sulfatide metabolism in brain cells, and its deficiency leads to neurodegeneration. The clinical manifestations of MLD include stagnation and decline of motor and cognitive function, leading to premature death with limited standard treatment options. Here, we describe a mutation-agnostic hematopoietic stem and progenitor cell (HSPC) gene therapy using CRISPR-Cas9 and AAV6 repair template as a prospective treatment option for MLD. Our strategy achieved efficient insertions and deletions (>87%) and a high level of gene integration (>47%) at the <i>ARSA</i> locus in human bone marrow-derived HSPCs, with no detectable off-target editing. As a proof of concept, we tested our mutation-agnostic therapy in HSPCs derived from two MLD patients with distinct mutations and demonstrated restoration of ARSA enzyme activity (>30-fold improvement) equivalent to healthy adults. In summary, our investigation enabled a mutation-agnostic therapy for MLD patients with proven efficacy and strong potential for clinical translation.
Functionally Active Antibodies to the Angiotensin II Type 1-Receptor Measured by a Luminometric Bioassay Do Not Correlate With Clinical Manifestations in Systemic Sclerosis: A Comparison With Antibodies to Vascular Receptors and Topoisomerase I Detected by ELISA
2021-12-09

Objectives 1) To detect functionally active antibodies(abs) to the angiotensin II type-1-receptor (AT 1 R) by a novel luminometric assay. 2) To assess their prevalence in systemic sclerosis (SSc), other collagen disorders, as well as in further chronic inflammatory disorders including autoimmune, toxic and chronic viral diseases. 3) To compare these abs with anti-AT1R antibodies by ELISA as well as with antibodies to endothelin-type-A receptors (ET A 1) and to topoisomerase I (topo-I) with respect to their specificity and clinical relevance. Methods Sera from 98 SSc-patients, 110 patients with other chronic inflammatory rheumatic disorders, 97 patients with autoimmune liver diseases, 57 patients with toxic or chronic viral liver diseases and 36 healthy controls were analyzed. A luminometric bioassay was established with Huh-7-cells constitutively expressing the AT 1 R. Patients’ sera were also tested by commercially available ELISA for anti-AT 1 R, -ET A 1- and by an in-house ELISA for anti–topo-I-abs. Results Fifty-two percent of the SSc-patients had functionally active anti-AT 1 R-abs with stimulatory (34%) or inhibitory capacity (18%). They were present also in up to 59% of patients with other rheumatic diseases but only 22% of healthy individuals (sensitivity 52%, specificity 53%). The functionally active antibodies detected by the luminometric assay did not correlate with anti-AT 1 R-, -ET A 1- or -topo-I-abs measured by ELISA, but there was a strong correlation between anti-topo-I-, AT 1 R-, and -ET A 1-ab reactivity measured by ELISA. Sensitivities of 55%, 28% and 47% and specificities of 66%, 87%, and 99% were calculated for these anti-AT 1 R-, -ET A 1-, and anti-topo-I-abs, respectively. Functionally active abs did not correlate with disease severity or any organ manifestation. In contrast, abs to topo-I, AT 1 R, and ET A 1 were associated with digital ulcers, pulmonary- and esophageal manifestation. Conclusions Functionally active anti-AT 1 R-abs can be detected in SSc-patients but do not correlate with disease activity. They are not specific for this disease and occur also in other autoimmune disorders and even viral or toxic diseases. Also, the vascular antibodies detected by ELISA are not SSc-specific but correlated with disease manifestations. In contrast, anti-topo-I-abs were confirmed to be a highly specific biomarker for both, diagnosis and organ manifestations of SSc.
Evaluation of Geum urbanum L. Extracts with Respect to Their Antimicrobial Potential
2021-12-09

Abstract Preparations derived from roots and rhizomes of Geum urbanum L. are traditionally used for the treatment of ulcers and irritations of mucous membranes of the mouth, stomach, and intestinal tract. In complementary medicine, fermentation is one of the methods applied to recover plant extracts used for the production of such pharmaceutical preparations. The present study was performed to characterize the secondary metabolites and to evaluate the antimicrobial potential of different G. urbanum root and rhizome extracts. For this purpose, individual metabolites of fresh and fermented G. urbanum root and rhizome extracts were analyzed by HPLC‐DAD‐MS n and GC/MS. Among others, rare ellagitannin‐sulfates could be characterized by LC/MS n . In addition, the antibacterial activity of various extracts of fresh and dried G. urbanum roots and rhizomes against Staphylococcus aureus (ATCC 6538) and Cutibacterium acnes (CP033842.1; FDAARGOS 503 chromosome) were assessed and compared to that of G. rivale . Furthermore, low‐ and high‐molecular tannins were fractionated by column chromatography, demonstrating the latter to exhibit highest antibacterial activity.
Dual-energy CT based monitoring of treatment-induced bone marrow changes in lung cancer patients: preliminary results
2021-12-09

Both highly myelotoxic as well as-to a smaller degree-less myelotoxic systemic therapy led to a significant drop in bone marrow attenuation with no significant tendency towards subsequent elevation irrespective of the treatment's degree of toxicity or the presence of myelosuppression and not even under hematological supportive therapy. The results suggest that in this clinical setting an increase in bone marrow attenuation should be regarded as suspicious for tumor infiltration.
Pullback and forward dynamics of nonautonomous Laplacian lattice systems on weighted spaces
2021-12-09

&lt;p style='text-indent:20px;'&gt;A nonautonomous lattice system with discrete Laplacian operator is revisited in the weighted space of infinite sequences &lt;inline-formula&gt;&lt;tex-math id="M1"&gt;\\begin{document} \\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;. First the existence of a pullback attractor in &lt;inline-formula&gt;&lt;tex-math id="M2"&gt;\\begin{document} \\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt; is established by utilizing the dense inclusion of &lt;inline-formula&gt;&lt;tex-math id="M3"&gt;\\begin{document} \\end{document}&lt;/tex-math&gt;&lt;/inline-formula&gt;. Moreover, the pullback attractor is shown to consist of a singleton trajectory when the lattice system is uniformly strictly contracting. Then forward dynamics is investigated in terms of the existence of a nonempty compact forward omega limit set. A general class of weights for the sequence space are adopted, instead of particular types of weights often used in the literature. The analysis presented in this work is more direct compare with previous studies.&lt;/p&gt;
Influence of bulky substituents on single-molecule SERS sensitivity
2021-12-09

The surface-enhanced Raman spectroscopy (SERS) detection limit strongly depends on the molecular structure, which we demonstrate for a family of tert-butyl-substituted porphycenes. Even though the investigated species present very similar photophysical properties, the ratio between the SERS signal and fluorescence background depends on the number of bulky tert-butyl groups. Moreover, the probability of single molecule detection systematically drops with the number of the moieties attached to the pyrrole ring. As steric hindrance is the only significantly changing feature among the studied chromophores, we attribute the observed phenomena to the spatial structure. We also show that the sensitivity of the SERS technique can be improved by lowering the temperature. We managed to observe single-molecule spectra for derivatives for which this was unattainable at room temperature.
The bronze cup from Dohnsen in the light of old and new evidence
2021-12-09

Abstract The bronze cup found in Dohnsen (Lower Saxony, Northern Germany) in the 1950s is an enigmatic artefact that bears striking similarities with the metalwork of the Late Aegean Bronze Age. We provide an accurate review of the primary sources of information on the cup's find history and context, and present the results of previously unpublished chemical and Pb isotope analyses. The latter suggest that the vessel might have been produced from Central European ores, but it represents the metalworking skills of a travelling smith with knowledge of foreign shapes and styles.
Genome Sequence of Lysobacter sp. Strain BMK333-48F3, the Producer Strain of Potent Lipopeptide Antibiotics of the Tripropeptin Family
2021-12-09

Lysobacter sp. strain BMK333-48F3 is known primarily for its production of the antibiotically active tripropeptins. Here, we report its draft genome sequence, which will give insight into the biosynthesis of tripropeptins and enable genome mining for further secondary metabolites.
Neutrons on Rails: Transregional Monitoring of Soil Moisture and Snow Water Equivalent
2021-12-10

Abstract Large‐scale measurements of the spatial distribution of water content in soils and snow are challenging for state‐of‐the‐art hydrogeophysical methods. Cosmic‐ray neutron sensing (CRNS) is a noninvasive technology that has the potential to bridge the scale gap between conventional in situ sensors and remote sensing products in both, horizontal and vertical domains. In this study, we explore the feasibility and potential of estimating water content in soils and snow with neutron detectors in moving trains. Theoretical considerations quantify the stochastic measurement uncertainty as a function of water content, altitude, resolution, and detector efficiency. Numerical experiments demonstrate that the sensitivity of measured water content is almost unperturbed by train materials. Finally, three distinct real‐world experiments provide a proof of concept on short and long‐range tracks. With our results a transregional observational soil moisture product becomes a realistic vision within the next years.
Early knapping techniques do not necessitate cultural transmission
2021-12-10

Early stone tools are claimed to be the earliest evidence for the cultural transmission of toolmaking techniques, and with it, cumulative culture. This claim has ostensibly been supported by experimental studies wherein modern humans learned stone tool production (knapping) in conditions that provided opportunities for cultural transmission. However, alternative hypotheses propose that individual learning was sufficient for the expression of early knapping techniques. In order to evaluate this possibility, the capacities of individuals to independently re-innovate early knapping techniques need to be determined. For this, individuals must be tested in cultural isolation, i.e., in a test condition in which knapping techniques cannot be culturally transmitted via demonstrations or reverse engineering. Here, we report on the results of this test condition with human participants (N = 28). Naïve individuals spontaneously re-innovated various early knapping techniques, resulting in products resembling the earliest core and flake technologies. These results contradict previous hypotheses and conclusions of earlier experiments that explicitly implicated cultural transmission in Oldowan stone tool production. They suggest instead that knapping techniques among pre-modern hominins could have been individually derived rather than necessitating cultural transmission.
Generation of ENSEMBL-based proteogenomics databases boosts the identification of non-canonical peptides
2021-12-10

Abstract Summary We have implemented the pypgatk package and the pgdb workflow to create proteogenomics databases based on ENSEMBL resources. The tools allow the generation of protein sequences from novel protein-coding transcripts by performing a three-frame translation of pseudogenes, lncRNAs and other non-canonical transcripts, such as those produced by alternative splicing events. It also includes exonic out-of-frame translation from otherwise canonical protein-coding mRNAs. Moreover, the tool enables the generation of variant protein sequences from multiple sources of genomic variants including COSMIC, cBioportal, gnomAD and mutations detected from sequencing of patient samples. pypgatk and pgdb provide multiple functionalities for database handling including optimized target/decoy generation by the algorithm DecoyPyrat. Finally, we have reanalyzed six public datasets in PRIDE by generating cell-type specific databases for 65 cell lines using the pypgatk and pgdb workflow, revealing a wealth of non-canonical or cryptic peptides amounting to &amp;gt;5% of the total number of peptides identified. Availability and implementation The software is freely available. pypgatk: https://github.com/bigbio/py-pgatk/ and pgdb: https://nf-co.re/pgdb. Supplementary information Supplementary data are available at Bioinformatics online.
"All mimsy were the borogoves” – A discriminative learning model of morphological knowledge in pseudo-word inflection
2021-12-10

Grammatical knowledge of native speakers has often been investigated in so-called wug tests, in which participants have to inflect pseudo-word forms (wugs). Typically it has been argued that in inflecting these pseudo-words, speakers apply their knowledge of word formation processes. However, it remains unclear what exactly this knowledge is and how it is learned.According to one theory, the knowledge is best characterized as abstractions and rules that specify how units can be combined. Another theory maintains that it is best characterized by analogy. In both cases the knowledge is learned by association based on positive evidence alone.In this paper, we model the classification of pseudo-words to Maltese plural classes on the basis of phonetic input using a shallow neural network trained with an error-driven learning algorithm. We demonstrate that the classification patterns mirror those of Maltese native speakers in a wug test. Our results indicate that speakers rely on gradient knowledge of a relation between the phonetics of whole words and plural classes, which is learned in an error-driven way.
Quality of Life of Patients with Head and Neck Cancer Receiving Cetuximab, Fluorouracil, Cisplatin Comparing to Cetuximab, Fluorouracil, Cisplatin, and Docetaxel within the CEFCID Trial
2021-12-10

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; CeFCiD was a multicenter phase II study comparing the efficacy of cetuximab (C), 5-flourouracil, and cisplatin with the same regimen adding docetaxel (D) in recurrent/metastatic head and neck cancer. The primary analysis trial did not demonstrate survival benefit from therapy intensification in first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The current analysis of the trial assessed the impact of treatment on quality of life (QoL). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; The European Organization for Research and Treatment of Cancer Quality of life Questionnaire QLQ-C30 and the tumor-specific module for head and neck cancer (QLQ-H&amp;amp;N35) were used to assess QoL at baseline (visit 1), after 2 (visit 3), 4 (visit 5), and 6 (visit 7) cycles of chemotherapy. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Of 180 patients included in this study, 86 patients (47.8%) completed the questionnaires at baseline. Considering selected scores over treatment time, there was no difference in global QoL, dyspnea, swallowing, and speech between the treatment arms in the course. For fatigue, a significant increase from baseline to visit 3 (&lt;i&gt;p&lt;/i&gt; = 0.02), visit 5 (&lt;i&gt;p&lt;/i&gt; = 0.002), and to visit 7 (&lt;i&gt;p&lt;/i&gt; = 0.003) was observed for patients receiving D, cisplatin or carboplatin (P), 5-fluorouracil (F), and C. At the end of chemotherapy, the manifestation of fatigue was similar compared in the 2 treatment arms. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; Therapy intensification not adversely affects selected scores of QoL of patients with recurrent and/or metastatic SCCHN. Nevertheless, fatigue seems to be pronounced in patients treated with D.
Characterization of Genetic Heterogeneity in Recurrent Metastases of Renal Cell Carcinoma
2021-12-10

Metastatic renal cell carcinoma (RCC) exhibits poor prognosis. Better knowledge of distant metastases is crucial to foster personalized treatment strategies. Here, we aimed to investigate the genetic landscape of metastases, including synchronous and/or recurrent metastases to elucidate potential drug target genes and clinically relevant mutations in a real-world setting of patients. We assessed 81 metastases from 56 RCC patients, including synchronous and/or recurrent metastases of 19 patients. Samples were analysed through next-generation sequencing with a high coverage (~1000× mean coverage). We therefore established a novel sequencing panel comprising 32 genes with impact on RCC development. We observed a high frequency of mutations in known RCC driver genes (e.g., &gt;40% carriers of VHL and PBRM1 mutations) in metastases irrespective of the metastatic site. The somatic mutational composition was significantly associated with cancer-specific survival (p(logrank) = 0.03). Moreover, we identified in 34 patients at least one drug target gene as well as clinically relevant mutations listed in the VICC Meta-Knowledgebase in 7%. In addition to significantly higher mutational burden in recurrent metastases compared to earlier ones, synchronous and/or recurrent metastases of individual patients, even after a time-period &gt;2 yrs, shared a high proportion of somatic events. Our data demonstrate the importance of somatic profiling in metastases for precision medicine in RCC.
Division, Syllogistic, and Science in Prior Analytics I.31
2021-12-10

In the first book of the Prior Analytics, Aristotle sets out, for the first time in Greek philosophy, a logical system. After this, Aristotle compares this method with Plato’s method of division, a procedure designed to find essences of natural kinds through systematic classification. This critical comparison in APr I.31 raises an interpretive puzzle: how can Aristotle reasonably juxtapose two methods that differ so much in their aims and approach? What can be gained by doing so? Previous interpreters have failed to show how this comparison is legitimate or what important point Aristotle is making. The goal of this paper is to resolve the puzzle. In resolving this puzzle we not only learn more about the relationship between division and the syllogistic in Aristotle. We will also learn something about the motivation for the syllogistic itself, by seeing the role that it plays in his philosophy of science.