julilili42/papers huggingface dataset:
Using the Relative Entropy of Linguistic Complexity to Assess L2 Language Proficiency Development
2021-08-20

This study applies relative entropy in naturalistic large-scale corpus to calculate the difference among L2 (second language) learners at different levels. We chose lemma, token, POS-trigram, conjunction to represent lexicon and grammar to detect the patterns of language proficiency development among different L2 groups using relative entropy. The results show that information distribution discrimination regarding lexical and grammatical differences continues to increase from L2 learners at a lower level to those at a higher level. This result is consistent with the assumption that in the course of second language acquisition, L2 learners develop towards a more complex and diverse use of language. Meanwhile, this study uses the statistics method of time series to process the data on L2 differences yielded by traditional frequency-based methods processing the same L2 corpus to compare with the results of relative entropy. However, the results from the traditional methods rarely show regularity. As compared to the algorithms in traditional approaches, relative entropy performs much better in detecting L2 proficiency development. In this sense, we have developed an effective and practical algorithm for stably detecting and predicting the developments in L2 learners’ language proficiency.
Ovarian Tissue Cryopreservation in a Patient with Breast Cancer During Pregnancy: A Case Report
2021-08-20

Abstract Background: Fertility preservation using ovarian tissue cryopreservation (OTC) in patients with certain diseases especially needing chemo- or radiotherapy is becoming a routine management in various Western countries. Our hospital is the first and until now the only center in China using this method. The question is controversial, if treatment of breast cancer during pregnancy (PrBC) should be similar like for non-pregnant young patients with breast cancer. To our knowledge this worldwide is the first report using OTC as fertility preservation for PrBC. Case presentation: During the 29th week of the pregnancy of a 24-year-old woman needle aspiration cytology of a left breast tumor showed cancer cells. The ultrasound revealed BI-RADS 4a grade. Oncologists recommended the termination of pregnancy. Cesarean section at week 32 was performed, and ovarian tissue samples were collected for OTC to preserve fertility and ovarian endocrine function. Twenty-three ovarian cortex slices were slowly programmed cryopreserved. It is estimated that 13000 follicles have been cryopreserved. Breast nodules and sentinel lymph node biopsy suggested invasive micropapillary carcinoma. Neoadjuvant chemotherapy within 1 week after diagnosis was started. After six courses of neoadjuvant chemotherapy, targeted drug therapy, and Goselin acetate, left mastectomy and left axillary lymph node dissection were performed. In total twenty-three times of radiotherapy, eight trastuzumab targeted therapy, and 17 pertuzumab + trastuzumab double targeted therapy was performed after breast cancer surgery. Until now, more than two years after delivery the ovarian function still is good. We do not see any signs of a negative impact of OTC. The injections of goserelin acetate, every 28 days, are planned to last for the next five years. In addition endocrine therapy with anastrozole, started after the breast cancer surgery, also is scheduled for five years. Conclusion: OTC for fertility preservation in patients with PrBC does not delay breast surgery, radiotherapy, or chemotherapy which is essential for an effective treatment of breast cancer. We assess this method as a promising fertility preservation method, worldwide for the first time now also used in a patient getting breast cancer in pregnancy.
Learn It First: Grounding Language in Compositional Event-Predictive Encodings
2021-08-20

While language learning in infants and toddlers progresses somewhat seamlessly, in artificial systems the grounding of language in knowledge structures that are learned from sensorimotor experiences remains a hard challenge. Here we introduce LEARNA, which learns event-characterizing abstractions to resolve natural language ambiguity. LEARNA develops knowledge structures from simulated sensorimotor experiences. Given a possibly ambiguous descriptive utterance, the learned knowledge structures enable LEARNA to infer environmental scenes, and events unfolding within, which essentially constitute plausible imaginations of the utterance's content. Similar event-predictive structures may help in developing artificial systems that can generate and comprehend descriptions of scenes and events.
Phase I Trial of a Multi-Peptide COVID-19 Vaccine for the Induction of SARS-CoV-2 T-Cell Immunity
2021-08-20

Abstract T-cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T-cell epitopes derived from various viral proteins, combined with the toll-like receptor 1/2 agonist XS15 emulsified in Montanide TM ISA51 VG, aiming to induce superior SARS-CoV-2 T-cell immunity to combat COVID-19. We conducted a Phase I open-label trial, including 36 participants aged 18 to 80 years, who received one single subcutaneous CoVAC-1 vaccination. The primary endpoint was safety analyzed until day 56. Immunogenicity in terms of CoVac-1-induced T-cell response was analyzed as main secondary endpoint until day 28. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study subjects, while systemic reactogenicity was absent or mild. SARS-CoV-2-specific T-cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T-helper 1 CD4 + and CD8 + T cells. CoVac-1-induced interferon-γ T-cell responses by far surpassed those detected in COVID-19 convalescents and were unaffected by current SARS-CoV-2 variants of concern (VOC). Together, CoVac-1 showed a favorable safety profile and induced broad, potent, and VOC-independent T-cell responses, supporting the presently ongoing evaluation in a Phase II trial for patients with B-cell/antibody deficiency. Funded by the Ministry of Science, Research and the Arts Baden-Württemberg, Germany; ClinicalTrials.gov number, NCT04546841.
Organ Preservation Strategies in Laryngeal Chondrosarcoma
2021-08-21

Objectives/Hypothesis Laryngeal chondrosarcoma (LC) is a rare, slowly growing malignancy. The preferred treatment is laryngeal preservation surgery (LPS). Some patients may require multiple interventions or total laryngectomy (TL). We investigated risk factors for retreatment and TL, and assessed the impact of LPS on oncological and functional outcomes. Study Design Case series Methods We searched our institution database for LC. Tumor grading, localization, and margin status were tested as predictors of recurrence and organ preservation. Results We included 21 patients (seven females, mean age 58 ± 12 years). LPS was applied in 20 (95.2%) of them as a primary procedure. Six patients were treated by transoral approach and 14 received “open‐neck” LPS. Fifteen (71.4%) were operated only once, while six patients underwent a total of 15 adjunctive procedures. Additional operations were always performed for recurrence of tumors localized within the cricoid plate. The histological grading was G1 in 81% and G2 in 19%. However, two patients with a primary G1 LC showed a G2 recurrence. Reoperations for recurrence were more frequent among patients with G2 in respect to G1 histology (83% vs. 7%, P &lt; .001). Fifty percent of G2 LC and 8% of G1 underwent TL ( P &lt; .05). Margin status had no influence on recurrence rate. Conclusions Patients with G2 LC have more recurrences requiring surgery and a higher incidence of TL. Cricoid plate localization is relevant for organ preservation. Margin status signals possible disease persistence, without influencing the need for future surgeries. Need for reoperation entails a risk of not being able to maintain organ functionality. Level of Evidence 4 Laryngoscope , 132:838–843, 2022
Rapid enantioselective amino acid analysis by ultra-high performance liquid chromatography-mass spectrometry combining 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate derivatization with core-shell quinine carbamate anion exchanger separation
2021-08-21

Amino acid analysis (AAA) is of central importance for the characterization of the amino acid composition of proteins, peptides, pharmaceutical formulations, dietary supplements, in bioanalysis and metabolomics. Common methodologies are based on achiral assays and hence do not consider distinction of D and L-amino acid enantiomers. This may be misleading in many instances, because therapeutic peptides and natural peptides synthesized by non-ribosomal peptide synthetases (NRPSs) frequently contain D-amino acids to achieve proteolytic stability. Furthermore, stereochemical integrity control of peptides made from L-amino acids also need stereoselective assays, and racemization in natural products (proteins, peptides, amino acids) have shown to be useful biomarkers of disease and require assays, which can provide information about the individual stereoisomers. Hence, rapid enantioselective amino acid analysis (ReAAA) is of utmost importance. However, currently employed enantioselective assays are often only focusing on a limited number of amino acids or require long analysis times making them incompatible for high-throughput sample analysis. Here, we present an ReAAA assay, which is based on a fast UHPLC enantiomer separation using a short QN-AX core-shell particle column (2.7 μm) coupled to electrospray ionization quadrupole time of flight mass spectrometric (ESI-QTOF-MS) detection. Amino acid samples are mixed with a [u-13C15N]-labelled L- or DL-amino acid standard mixture, precolumn derivatized with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) reagent and subjected to UHPLC-ESI-MS analysis. A number of chromatographic variables have been optimized (buffer additives and concentration, water content, flow rate and temperature) to achieve the goal of simultaneous amino acid enantiomer separation of all proteinogenic amino acids within the shortest possible analysis time. A mobile phase consisting of 50 mM NH4FA, 50 mM FA and 0.5% H2O in MeOH combined with a flow rate of 1 mL/min and a column temperature of 30 °C has been identified as optimal. With these conditions, all of the proteinogenic DL-enantiomers (except for Arg) can be separated in less than 2.5 min. If D-Arg and distinction between D-Leu/D-Ile is of concern, a second-tier method can accomplish this goal. The method can be very useful for ReAAA when high sample throughput is a major demand. Its utility was demonstrated by ReAAA of a lipopeptide hydrolysate which contained several D-amino acids and of an amino acid supplement in which minor D-amino acid impurities could be detected.
A Protein-Based Biosensor for Detecting Calcium by Magnetic Resonance Imaging
2021-08-22

Calcium-responsive contrast agents for magnetic resonance imaging (MRI) offer a promising approach for noninvasive brain-wide monitoring of neural activity at any arbitrary depth. Current examples of MRI-based calcium probes involve synthetic molecules and nanoparticles, which cannot be used to examine calcium signaling in a genetically encoded form. Here, we describe a new MRI sensor for calcium, based entirely on a naturally occurring calcium-binding protein known as calprotectin. Calcium-binding causes calprotectin to sequester manganese ions, thereby limiting Mn<sup>2+</sup> enhanced paramagnetic relaxation of nearby water molecules. We demonstrate that this mechanism allows calprotectin to alter T<sub>1</sub> and T<sub>2</sub> based MRI signals in response to biologically relevant calcium concentrations. The resulting response amplitude, i.e., change in relaxation time, is comparable to existing MRI-based calcium sensors as well as other reported protein-based MRI sensors. As a preliminary demonstration of its biological applicability, we used calprotectin to detect calcium in a lysed hippocampal cell preparation as well as in intact Chinese hamster ovary cells treated with a calcium ionophore. Calprotectin thus represents a promising path toward noninvasive imaging of calcium signaling by combining the molecular and cellular specificity of genetically encodable tools with the ability of MRI to image through scattering tissue of any size and depth.
COVID-19 patient serum less potently inhibits ACE2-RBD binding for various SARS-CoV-2 RBD mutants
2021-08-22

Abstract As global vaccination campaigns against SARS-CoV-2 proceed, there is particular interest in the longevity of immune protection, especially with regard to increasingly infectious virus variants. Neutralizing antibodies (Nabs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are promising correlates of protective immunity and have been successfully used for prevention and therapy. As SARS-CoV-2 variants of concern (VOCs) are known to affect binding to the ACE2 receptor and by extension neutralizing activity, we developed a bead-based multiplex ACE2-RBD inhibition assay (RBDCoV-ACE2) as a highly scalable, time-, cost-, and material-saving alternative to infectious live-virus neutralization tests. By mimicking the interaction between ACE2 and the RBD, this serological multiplex assay allows the simultaneous analysis of ACE2 binding inhibition to the RBDs of all SARS-CoV-2 VOCs and variants of interest (VOIs) in a single well. Following validation against a classical virus neutralization test and comparison of performance against a commercially available assay, we analyzed 266 serum samples from 168 COVID-19 patients of varying severity. ACE2 binding inhibition was reduced for ten out of eleven variants examined compared to wild-type, especially for those displaying the E484K mutation such as VOCs beta and gamma. ACE2 binding inhibition, while highly individualistic, positively correlated with IgG levels. ACE2 binding inhibition also correlated with disease severity up to WHO grade 7, after which it reduced.
Social mindfulness and prosociality vary across the globe
2021-08-23

Significance Cooperation is key to well-functioning groups and societies. Rather than addressing high-cost cooperation involving giving money or time and effort, we examine social mindfulness—a form of interpersonal benevolence that requires basic perspective-taking and is aimed at leaving choice for others. Do societies differ in social mindfulness, and if so, does it matter? Here, we find not only considerable variation across 31 nations and regions but also an association between social mindfulness and countries’ performance on environmental protection. We conclude that something as small and concrete as interpersonal benevolence can be entwined with current and future issues of global importance.
Human versus Bovine Serum Albumin: A Subtle Difference in Hydrophobicity Leads to Large Differences in Bulk and Interface Behavior
2021-08-23

The protein human serum albumin (HSA) is able to readily crystallize in the presence of trivalent cations, whereas this is not the case for the homologous protein in cattle, bovine serum albumin (BSA), although both have analogous functions as well as similar physicochemical properties. To understand the underlying interactions and mechanisms, we investigated their bulk phase behavior with CeCl3 by visual inspection, optical microscopy, and small-angle X-ray scattering (SAXS). The results reveal that both proteins undergo reentrant condensation and liquid–liquid phase separation (LLPS). However, the LLPS binodal for HSA shifts toward lower protein concentrations than that for BSA, indicating a stronger intermolecular attraction in HSA solutions at the same compositions, consistent with SAXS measurements. Moreover, crystallization occurs within the condensed regime of HSA, but no crystallization was observed for BSA. Adsorption studies at a hydrophilic SiO2 surface demonstrate that both systems show reentrant adsorption with a higher amount of adsorbed BSA, likely due to enhanced cation-mediated interactions and/or hydrogen bonds. We conclude that the higher surface hydrophobicity of HSA could explain the experimental observations. These additional hydrophobic interactions not only strengthen the attraction between the proteins but also provide directional and specific protein–protein contacts, which are favored for protein crystallization. This work further demonstrates the sensitivity and complexity of protein interactions in solution: subtle differences in molecular structure lead to a dramatic change in their phase behavior. Generalization of these findings can pave the way toward, e.g., better drug design and improve medical treatment.
The Potential of Shear Wave Elastography to Reduce Unnecessary Biopsies in Breast Cancer Diagnosis: An International, Diagnostic, Multicenter Trial
2021-08-23

Abstract Purpose In this prospective, multicenter trial we evaluated whether additional shear wave elastography (SWE) for patients with BI-RADS 3 or 4 lesions on breast ultrasound could further refine the assessment with B-mode breast ultrasound for breast cancer diagnosis. Materials and Methods We analyzed prospective, multicenter, international data from 1288 women with breast lesions rated by conventional 2 D B-mode ultrasound as BI-RADS 3 to 4c and undergoing 2D-SWE. After reclassification with SWE the proportion of undetected malignancies should be &lt; 2 %. All patients underwent histopathologic evaluation (reference standard). Results Histopathologic evaluation showed malignancy in 368 of 1288 lesions (28.6 %). The assessment with B-mode breast ultrasound resulted in 1.39 % (6 of 431) undetected malignancies (malignant lesions in BI-RADS 3) and 53.80 % (495 of 920) unnecessary biopsies (biopsies in benign lesions). Re-classifying BI-RADS 4a patients with a SWE cutoff of 2.55 m/s resulted in 1.98 % (11 of 556) undetected malignancies and a reduction of 24.24 % (375 vs. 495) of unnecessary biopsies. Conclusion A SWE value below 2.55 m/s for BI-RADS 4a lesions could be used to downstage these lesions to follow-up, and therefore reduce the number of unnecessary biopsies by 24.24 %. However, this would come at the expense of some additionally missed cancers compared to B-mode breast ultrasound (rate of undetected malignancies 1.98 %, 11 of 556, versus 1.39 %, 6 of 431) which would, however, still be in line with the ACR BI-RADS 3 definition (&lt; 2 % of undetected malignancies).
Oscillatory Microrheology, Creep Compliance and Stress Relaxation of Biological Cells Reveal Strong Correlations as Probed by Atomic Force Microscopy
2021-08-23

The mechanical properties of cells are important for many biological processes, including wound healing, cancers, and embryogenesis. Currently, our understanding of cell mechanical properties remains incomplete. Different techniques have been used to probe different aspects of the mechanical properties of cells, among them microplate rheology, optical tweezers, micropipette aspiration, and magnetic twisting cytometry. These techniques have given rise to different theoretical descriptions, reaching from simple Kelvin-Voigt or Maxwell models to fractional such as power law models, and their combinations. Atomic force microscopy (AFM) is a flexible technique that enables global and local probing of adherent cells. Here, using an AFM, we indented single retinal pigmented epithelium cells adhering to the bottom of a culture dish. The indentation was performed at two locations: above the nucleus, and towards the periphery of the cell. We applied creep compliance, stress relaxation, and oscillatory rheological tests to wild type and drug modified cells. Considering known fractional and semi-fractional descriptions, we found the extracted parameters to correlate. Moreover, the Young’s modulus as obtained from the initial indentation strongly correlated with all of the parameters from the applied power-law descriptions. Our study shows that the results from different rheological tests are directly comparable. This can be used in the future, for example, to reduce the number of measurements in planned experiments. Apparently, under these experimental conditions, the cells possess a limited number of degrees of freedom as their rheological properties change.
Historic nucleic acids isolated by Friedrich Miescher contain RNA besides DNA
2021-08-23

Abstract One hundred fifty years ago, Friedrich Miescher discovered DNA when he isolated “Nuclein”—as he named it—from nuclei of human pus cells. Miescher recognized his isolate as a new type of molecule equal in importance to proteins. He realised that it is an acid of large molecular weight and high phosphorus content. Subsequently, he discovered Nuclein also in the nuclei of other cell types, realised that it chemically defines the nucleus, and speculated on its role in proliferation, heredity and fertilisation. While now universally recognised as the discoverer of DNA, whether Miescher also discovered RNA has not yet been addressed. To determine whether his isolation also yielded RNA, we first reproduced his historic protocols. Our resulting modern Nuclein contained a significant percentage of RNA. Encouraged by this result, we then analysed a sample of Nuclein isolated by Miescher from salmon sperm. Assuming that the RNA present in this sample had degraded to nucleobases, we tested for the presence of uracil in the historic Nuclein. Detection of significant levels of uracil by LC-UV-MS demonstrates that Miescher isolated both forms of nucleic acid—DNA and RNA—and underlines the fundamental nature of his discovery for the field of molecular genetics.
SARS‐CoV‐2‐reactive T‐cell receptors isolated from convalescent COVID‐19 patients confer potent T‐cell effector function
2021-08-23

Abstract Both B cells and T cells are involved in an effective immune response to SARS‐CoV‐2, the disease‐causing virus of COVID‐19. While B cells—with the indispensable help of CD4 + T cells—are essential to generate neutralizing antibodies, T cells on their own have been recognized as another major player in effective anti‐SARS‐CoV‐2 immunity. In this report, we provide insights into the characteristics of individual HLA‐A*02:01‐ and HLA‐A*24:02‐restricted SARS‐CoV‐2‐reactive TCRs, isolated from convalescent COVID‐19 patients. We observed that SARS‐CoV‐2‐reactive T‐cell populations were clearly detectable in convalescent samples and that TCRs isolated from these T cell clones were highly functional upon ectopic re‐expression. The SARS‐CoV‐2‐reactive TCRs described in this report mediated potent TCR signaling in reporter assays with low nanomolar EC50 values. We further demonstrate that these SARS‐CoV‐2‐reactive TCRs conferred powerful T‐cell effector function to primary CD8 + T cells as evident by a robust anti‐SARS‐CoV‐2 IFN‐γ response and in vitro cytotoxicity. We also provide an example of a long‐lasting anti‐SARS‐CoV‐2 memory response by reisolation of one of the retrieved TCRs 5 months after initial sampling. Taken together, these findings contribute to a better understanding of anti‐SARS‐CoV‐2 T‐cell immunity and may contribute to paving the way toward immunotherapeutics approaches targeting SARS‐CoV‐2.