julilili42/papers huggingface dataset:
A rapid and efficient strategy to identify and recover biosynthetic gene clusters from soil metagenomes
2022-04-01

Abstract Culture-independent metagenomic approaches offer a promising solution to the discovery of therapeutically relevant compounds such as antibiotics by enabling access to the hidden biosynthetic potential of microorganisms. These strategies, however, often entail laborious, multi-step, and time-consuming procedures to recover the biosynthetic gene clusters (BGCs) from soil metagenomes for subsequent heterologous expression. Here, we developed an efficient method we called single Nanopore read cluster mining (SNRCM), which enables the fast recovery of complete BGCs from a soil metagenome using long- and short-read sequencing. A metagenomic fosmid library of 83,700 clones was generated and sequenced using Nanopore as well as Illumina technologies. Hybrid assembled contigs of the sequenced fosmid library were subsequently analyzed to identify BGCs encoding secondary metabolites. Using SNRCM, we aligned the identified BGCs directly to Nanopore long-reads and were able to detect complete BGCs on single fosmids. This enabled us to select for and recover BGCs of interest for subsequent heterologous expression attempts. Additionally, the sequencing data of the fosmid library and its corresponding metagenomic DNA enabled us to assemble and recover a large nonribosomal peptide synthetase (NRPS) BGC from three different fosmids of our library and to directly amplify and recover a complete lasso peptide BGC from the high-quality metagenomic DNA. Overall, the strategies presented here provide a useful tool for accelerating and facilitating the identification and production of potentially interesting bioactive compounds from soil metagenomes. Key points • An efficient approach for the recovery of BGCs from soil metagenomes was developed to facilitate natural product discovery. • A fosmid library was constructed from soil metagenomic HMW DNA and sequenced via Illumina and Nanopore. • Nanopore long-reads enabled the direct identification and recovery of complete BGCs on single fosmids.
Modular microcircuit organization of the presubicular head-direction map
2022-04-01

Our internal sense of direction is thought to rely on the activity of head-direction (HD) neurons. We find that the mouse dorsal presubiculum (PreS), a key structure in the cortical representation of HD, displays a modular "patch-matrix" organization, which is conserved across species (including human). Calbindin-positive layer 2 neurons within the "matrix" form modular recurrent microcircuits, while inputs from the anterodorsal and laterodorsal thalamic nuclei are non-overlapping and target the "patch" and "matrix" compartments, respectively. The apical dendrites of identified HD cells are largely restricted within the "matrix," pointing to a non-random sampling of patterned inputs and to a precise structure-function architecture. Optogenetic perturbation of modular recurrent microcircuits results in a drastic tonic suppression of firing only in a subpopulation of HD neurons. Altogether, our data reveal a modular microcircuit organization of the PreS HD map and point to the existence of cell-type-specific microcircuits that support the cortical HD representation.
Real-World Therapy with Pembrolizumab: Outcomes and Surrogate Endpoints for Predicting Survival in Advanced Melanoma Patients in Germany
2022-04-01

Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman’s rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0–35.4) months, the rwPFS was 3.9 months (95%CI 3.5–4.9), the rwTtNT was 10.7 months (95%CI 9.0–12.9), and the rwToT was 6.2 months (95%CI 5.1–6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.
AI Denoising Significantly Enhances Image Quality and Diagnostic Confidence in Interventional Cone-Beam Computed Tomography
2022-04-01

(1) To investigate whether interventional cone-beam computed tomography (cbCT) could benefit from AI denoising, particularly with respect to patient body mass index (BMI); (2) From 1 January 2016 to 1 January 2022, 100 patients with liver-directed interventions and peri-procedural cbCT were included. The unenhanced mask run and the contrast-enhanced fill run of the cbCT were reconstructed using weighted filtered back projection. Additionally, each dataset was post-processed using a novel denoising software solution. Place-consistent regions of interest measured signal-to-noise ratio (SNR) per dataset. Corrected mixed-effects analysis with BMI subgroup analyses compared objective image quality. Multiple linear regression measured the contribution of “Radiation Dose”, “Body-Mass-Index”, and “Mode” to SNR. Two radiologists independently rated diagnostic confidence. Inter-rater agreement was measured using Spearman correlation (r); (3) SNR was significantly higher in the denoised datasets than in the regular datasets (p &lt; 0.001). Furthermore, BMI subgroup analysis showed significant SNR deteriorations in the regular datasets for higher patient BMI (p &lt; 0.001), but stable results for denoising (p &gt; 0.999). In regression, only denoising contributed positively towards SNR (0.6191; 95%CI 0.6096 to 0.6286; p &lt; 0.001). The denoised datasets received overall significantly higher diagnostic confidence grades (p = 0.010), with good inter-rater agreement (r ≥ 0.795, p &lt; 0.001). In a subgroup analysis, diagnostic confidence deteriorated significantly for higher patient BMI (p &lt; 0.001) in the regular datasets but was stable in the denoised datasets (p ≥ 0.103).; (4) AI denoising can significantly enhance image quality in interventional cone-beam CT and effectively mitigate diagnostic confidence deterioration for rising patient BMI.
Neural network analysis of neutron and X-ray reflectivity data: automated analysis using mlreflect, experimental errors and feature engineering
2022-04-01

The Python package mlreflect is demonstrated, which implements an optimized pipeline for the automated analysis of reflectometry data using machine learning. The package combines several training and data treatment techniques discussed in previous publications. The predictions made by the neural network are accurate and robust enough to serve as good starting parameters for an optional subsequent least-mean-squares (LMS) fit of the data. For a large data set of 242 reflectivity curves of various thin films on silicon substrates, the pipeline reliably finds an LMS minimum very close to a fit produced by a human researcher with the application of physical knowledge and carefully chosen boundary conditions. The differences between simulated and experimental data and their implications for the training and performance of neural networks are discussed. The experimental test set is used to determine the optimal noise level during training. The extremely fast prediction times of the neural network are leveraged to compensate for systematic errors by sampling slight variations in the data.
Stick to it! Mechanical performance tests to explore the resilience of prehistoric glues in hafting
2022-04-01

Abstract Known preserved glue remains are relatively rare, but they witness a broad range in glue types that may have existed in the past, varying in terms of the main component and additives. However, archaeological experimentation rarely mirrors that variety, leading to a certain lack of information on the behaviour and interest of several traditional glues, notably animal‐based glues. Through mechanical bench testing (shear–compression), this paper aims to document the resilience of 11 different glues and mixtures in combination with three different organic substrates and flint, in order to reproduce a realistic hafting system. Results highlight that glue performance depends on the hafting materials used, thereby demonstrating that the choice of an appropriate glue depends on the hafting arrangement envisaged. The results also indicate that no glue outperforms all others or witnesses universal applicability. We therefore argue that glue use and performance should be evaluated from the perspective of the complete tool within a particular use context and environment. Only such an integrated perspective permits to reflect on the role of glue in past tool technologies, including its manufacture, composition and use, and on the significance of glue with regard to human behaviour and its evolution.
Aspects of Pelvic Floor Protection in Spontaneous Delivery – a Review
2022-04-01

Abstract The necessity of increasingly addressing aspects of pelvic floor protection, i.e., prevention of the most frequent female pelvic floor disorders, such as urinary incontinence, faecal incontinence and pelvic organ prolapse, is the result of the steadily improving understanding of the association of pregnancy and delivery with the prevalence of these disorders. About a quarter of all women experience one or more such symptoms during their life. Apart from age and weight, pregnancies and births play an important part. While initial discussion of pelvic floor protection often focused very rapidly on the mode of delivery and elective caesarean section as a possible protective intervention, it has become apparent in the last few decades how varied and wide-ranging the options are that can be used to protect against pelvic floor disorders. The mode of delivery as such is “only” one element among numerous other considerations and has diminished markedly in importance. Interprofessionality and interdisciplinarity undoubtedly represent an important development as resulting recommendations must always be incorporated in an overall context that considers mother and child at the same time. Considering the pelvic floor only certainly does not make sense. This review article will analyze in greater detail important pre-, intra- and postpartum aspects that in their entirety can provide insight into the various aspects of pelvic floor protection. The authors regard the following article as an additional basis for discussion on achieving a sustained reduction in the incidence and prevalence of female pelvic floor disorders.
Plasma autoantibodies to glial fibrillary acidic protein (GFAP) react with brain areas according to Braak staging of Parkinson’s disease
2022-04-01

Abstract Idiopathic Parkinson’s disease (PD) is characterized by a progredient degeneration of the brain, starting at deep subcortical areas such as the dorsal motor nucleus of the glossopharyngeal and vagal nerves (DM) (stage 1), followed by the coeruleus–subcoeruleus complex; (stage 2), the substantia nigra (SN) (stage 3), the anteromedial temporal mesocortex (MC) (stage 4), high-order sensory association areas and prefrontal fields (HC) (stage 5) and finally first-order sensory association areas, premotor areas, as well as primary sensory and motor field (FC) (stage 6). Autoimmunity might play a role in PD pathogenesis. Here we analyzed whether anti-brain autoantibodies differentially recognize different human brain areas and identified autoantigens that correlate with the above-described dissemination of PD pathology in the brain. Brain tissue was obtained from deceased individuals with no history of neurological or psychiatric disease and no neuropathological abnormalities. Tissue homogenates from different brain regions (DM, SN, MC, HC, FC) were subjected to SDS-PAGE and Western blot. Blots were incubated with plasma samples from 30 PD patients and 30 control subjects and stained with anti-IgG antibodies to detect anti-brain autoantibodies. Signals were quantified. Prominent autoantigens were identified by 2D-gel-coupled mass spectrometry sequencing. Anti-brain autoantibodies are frequent and occur both in healthy controls and individuals with PD. Glial fibrillary acidic protein (GFAP) was identified as a prominent autoantigen recognized in all plasma samples. GFAP immunoreactivity was highest in DM areas and lowest in FC areas with no significant differences in anti-GFAP autoantibody titers between healthy controls and individuals with PD. The anti-GFAP autoimmunoreactivity of different brain areas correlates with the dissemination of histopathological neurodegeneration in PD. We hypothesize that GFAP autoantibodies are physiological but might be involved as a cofactor in PD pathogenesis secondary to a leakage of the blood–brain barrier.
Biomarker clustering in autosomal dominant Alzheimer's disease
2022-04-01

Abstract INTRODUCTION As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS We used hierarchical clustering to group 19 cross‐sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.
Spatial preferences account for inter-animal variability during the continual learning of a dynamic cognitive task
2022-04-01

Understanding the complexities of behavior is necessary to interpret neurophysiological data and establish animal models of neuropsychiatric disease. This understanding requires knowledge of the underlying information-processing structure-something often hidden from direct observation. Commonly, one assumes that behavior is solely governed by the experimenter-controlled rules that determine tasks. For example, differences in tasks that require memory of past actions are often interpreted as exclusively resulting from differences in memory. However, such assumptions are seldom tested. Here, we provide a comprehensive examination of multiple processes that contribute to behavior in a prevalent experimental paradigm. Using a combination of behavioral automation, hypothesis-driven trial design, and reinforcement learning modeling, we show that rats learn a spatial alternation task consistent with their drawing upon spatial preferences in addition to memory. Our approach also distinguishes learning based on established preferences from generalization of task structure, providing further insights into learning dynamics.
Effect of Two Different Training Interventions on Cycling Performance in Mountain Bike Cross-Country Olympic Athletes
2022-04-01

To improve performance in endurance sports, it is important to include both high-intensity and low-intensity training, but there is neither a universally accepted practice nor clear scientific evidence that allows reliable statements about the predominance of a specific training method. This randomized controlled trial compared the effects of a polarized training model (POL) to a low-intensity training model (LIT) on physiological parameters and mountain bike cross-country Olympic (XCO) race performance in eighteen competitive XCO athletes (17.9 ± 3.6 years). The superiority of one of the two methods could not be shown in this study. The results did not show statistically significant differences between POL and LIT, as both interventions led to slight improvements. However, a small tendency toward better effects for POL was seen for cycling power output during the race (4.4% vs. –2.2%), at the 4 mmol/L (6.1% vs. 2.8%) and individual anaerobic lactate threshold (5.1% vs. 2.3%), and for maximal aerobic performance (4.4% vs. 2.6%), but not for maximal efforts lasting 10 to 300 s. Despite the lack of significant superiority in this and some other studies, many athletes and coaches prefer POL because it produces at least equivalent effects and requires less training time.
Sprachliche Komplexität im Unterricht
2022-04-01

Abstract We investigate the linguistic complexity of oral classroom interactions in late primary and early secondary school across German school types. The goal is to explore whether teachers and students align in terms of their use of the academic language register. We empirically base this investigation on transcriptions of teacher and student contributions during content matter lessons on the vaporisation and condensation of water. Across school types and grade levels, we compare the extent to which teachers offer language that is adaptively rich in linguistic constructs commonly associated with academic language, such as deagentivation, nominal style, and cohesive devices. Putting this in relation to the developing academic language competence of the students, we then compare the language offered by the teachers to the use of these academic language constructs in the students’ spoken language contributions. We discuss the methodological challenges arising from analyzing oral classroom interactions and from applying automatic linguistic complexity analyses to such data.
Teachers and trainers in adult education–Investigating the dimensionality of their knowledge about methods and concepts of teaching and learning
2022-04-01

Abstract Knowledge about methods and concepts of teaching and learning is considered an important aspect of the pedagogical-psychological knowledge (PPK) of teachers in adult and continuing education (ACE) for designing helpful situations of teaching and learning. The article poses the theoretical-conceptual and empirical question of the dimensionality of this knowledge using a sample of N = 212 ACE teachers. The results point to the multidimensionality of this knowledge in the ACE field. The findings are critically discussed in terms of their robustness and scope, as well as possibilities for the further development of the test.
P14: DREAMM-9: PHASE I STUDY OF BELANTAMAB MAFODOTIN PLUS STANDARD OF CARE IN PATIENTS WITH TRANSPLANT-INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA
2022-04-01

Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a SoC for NDMM. Belamaf, a B-cell maturation antigen (BCMA)–targeting antibody-drug conjugate, demonstrated durable responses in patients with relapsed/refractory multiple myeloma. Preclinical studies of belamaf in combination with bortezomib/lenalidomide suggest enhanced antimyeloma activity. We report preliminary findings of belamaf + VRd for patients with TI NDMM. Materials and Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open label, randomized, dose and schedule evaluation trial. Adults with TI NDMM and ECOG status 0–2 are eligible. VRd is administered Q3W until Cycle 8, followed by lenalidomide + dexamethasone (Rd) Q4W. Belamaf + VRd is administered until Cycle 8, and with Rd thereafter. The currently evaluated belamaf dose cohorts are: Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: Overall 36 patients were treated across the 5 cohorts. The median (range) age was 74.0 (63–80) years; 56% patients were male, 17 (47%) had stage 2 disease, 3 (8%) had extramedullary disease, 6 (17%) patients had high risk cytogenetic abnormalities; the median number of belamaf cycles ranged from 1–9. No new safety signals were observed. Across Cohorts 1–5, all patients experienced AEs related to study treatment; 1 patient in Cohort 1 died due to COVID-19 infection. The most common AEs leading to dose modification were thrombocytopenia, neutropenia, and corneal events. Patients in Cohort 2 and 3 had the lowest number of Grade ≥3 corneal events (3 and 2 events, respectively). All 12 patients in Cohort 1, all 6 in Cohorts 3 and 5, and 5/6 patients in Cohorts 2 and 4 have responded to the treatment; ≥half of patients in each cohort achieved very good partial response or better. As of data cut-off, 3/12 patients in Cohort 1, 2/6 in Cohort 4, and 1/6 patients each in Cohorts 3 and 5 remained in complete response. Belamaf PK profile was similar to that observed in patients with RRMM taking into consideration baseline patients characteristics. Conclusions: Preliminary data suggest addition of belamaf to VRd did not reveal new safety signals and demonstrates high response rates, albeit with short follow-up. The trial is ongoing to confirm safety and evaluate the efficacy of belamaf + VRd. Funding: GSK (Study 209664); drug linker technology licensed from Seagen Inc; mAb produced using POTELLIGENT Technology licensed from BioWa. Encore statement: Previously presented as Poster 2738 at the American Society of Hematology Annual Meeting, 11–14 December 2021; submitted with permission and on behalf of the original authors.
The a-theory of time, temporal passage, and comprehensiveness
2022-04-01

Abstract It has been argued recently that one major difficulty facing the A-theory of time consists in the view’s failure to provide a satisfactory account of the passage of time. Critics have objected that this particular charge is premised on an unduly strong conception of temporal passage, and that the argument does not go through on alternative, less demanding conceptions of passage. The resulting dialectical stalemate threatens to prove intractable, given the notorious elusiveness of the notion of temporal passage. Here I argue that there is progress to be made in this regard. The argument from passage takes issue with a certain feature of the standard versions of the A-theory that is in fact problematic independently of worries about temporal passage. To illustrate this, I present a new argument, the argument from comprehensiveness, which demonstrates that the standard A-theoretic account of temporal reality is inadequate, even if it is granted that it can accommodate passage.