julilili42/papers huggingface dataset:
Microvascular imaging of the unstained human superior colliculus using synchrotron-radiation phase-contrast microtomography
2022-06-02

Abstract Characterizing the microvasculature of the human brain is critical to advance understanding of brain vascular function. Most methods rely on tissue staining and microscopy in two-dimensions, which pose several challenges to visualize the three-dimensional structure of microvessels. In this study, we used an edge-based segmentation method to extract the 3D vasculature from synchrotron radiation phase-contrast microtomography (PC-μCT) of two unstained, paraffin-embedded midbrain region of the human brain stem. Vascular structures identified in PC-μCT were validated with histology of the same specimen. Using the Deriche-Canny edge detector that was sensitive to the boundary between tissue and vascular space, we could segment the vessels independent of signal variations in PC-μCT images. From the segmented volumetric vasculature, we calculated vessel diameter, vessel length and volume fraction of the vasculature in the superior colliculi. From high resolution images, we found the most frequent vessel diameter to be between 8.6–10.2 μm. Our findings are consistent with the known anatomy showing two types of vessels with distinctive morphology: peripheral collicular vessels and central collicular vessels. The proposed method opens up new possibilities for vascular research of the central nervous system using synchrotron radiation PC-μCT of unstained human tissue.
Development and chromatographic exploration of stable‐bonded cross‐linked amino silica against classical amino phases
2022-06-02

The present work reports on a novel stable‐bonded amino silica stationary phase obtained by crosslinking of surface aminopropyl moieties using triglycidyl isocyanurate. The obtained cross‐linked amido‐amino network silica material exhibited superior hydrolytic stability compared to classical 3‐aminopropyl phases and showed, inter alia, excellent separation of nine therapeutically effective sulfonamides in hydrophilic interaction/weak anion exchange chromatography elution mode. Additionally, the separation of carbohydrates was investigated under classical hydrophilic interaction chromatography conditions as well proving the suitability of the novel phase for such applications. For the evaluation of the hydrolytic stability the prepared material, as well as two commercially available benchmark columns and a set of in‐house synthesized amino‐modified materials, were exposed to harsh aqueous mobile phase conditions for in total of 50 h at elevated temperature. In this context, the materials were examined by elemental analysis, ( 13 C and 29 Si cross‐polarization/magic angle spinning) solid‐state nuclear magnetic resonance, and a chromatographic test before and subsequent to the exposure to these stress conditions. Lastly, the new stationary phase was classified in comparison to a set of commercially available stationary phases by principal component analysis of resultant retention factors gained from chromatographic standard tests.
A Fluorescence-Based Competitive Antibody Binding Assay for Kynurenine, a Potential Biomarker of Kidney Transplant Failure
2022-06-02

Kynurenine is a tryptophan metabolite linked to several inflammatory processes including transplant failure, a significant challenge in transplant medicine. The detection of small molecules such as kynurenine, however, is often complex and time consuming. Herein, we report the successful synthesis of a fluorescently labelled kynurenine derivative, showing proper fluorescence and anti-kynurenine antibody binding behavior in a magnetic bead immunoassay (MIA). The fluorescent kynurenine–rhodamine B conjugate shows a KD-value of 5.9 μM as well as IC50 values of 4.0 μM in PBS and 10.2 μM in saliva. We thus introduce a rapid test for kynurenine as a potential biomarker for kidney transplant failure.
Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency
2022-06-02

<title>Abstract</title> T-cell immunity is central for the control of COVID-19, in particular in patients incapable to mount a humoral immune response. We previously reported on the favorable safety profile and efficacy in terms of induction of SARS-CoV-2-specific T-cell responses by CoVac-1, a peptide-based T-cell activator, composed of SARS-CoV-2 T-cell epitopes derived from various viral proteins, combined with the toll-like receptor 1/2 agonist XS15<sup>1</sup>. We conducted a Phase I/II open-label trial recruiting 54 patients with congenital or acquired B-cell deficiency who received one single subcutaneous dose of CoVac-1. Immunogenicity until day 28 in terms of CoVac-1-induced T-cell responses was the primary endpoint; safety until day 56 was assessed as secondary endpoint. Neither serious nor grade 4 CoVac-1-related adverse events were observed. The expected local granuloma formation was observed in 94% of study subjects, whereas systemic reactogenicity was mostly mild or absent. SARS-CoV-2-specific Tcell responses were induced in 86% of the patients and directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4<sup>+</sup> T cells. CoVac-1-induced T-cell responses exceeded spike-specific T-cell responses after vaccination with mRNA vaccines in B-cell deficient patients and also that of immunocompetent COVID-19 convalescents with and without seroconversion. CoVac-1 induces broad and potent T-cell responses in patients with Bcell/antibody deficiency independently of current variants of concern, with a favorable safety profile. Our data warrant advancement to a pivotal Phase II/III safety and efficacy evaluation.
Exploring the ATN classification system using Brain Morphology
2022-06-02

Abstract Background The NIA-AA proposed Amyloid-Tau-Neurodegeneration (ATN) as a classification system for AD biomarkers. The Amyloid Cascade Hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-→A+T-N-→A+T+N-→A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (Amyloid-conversion first, Tau-conversion second, N-conversion last) and alternative progressions using Voxel-based Morphometry (VBM) in a large cross-sectional MRI cohort. Methods We used baseline data of the DELCODE cohort of 437 subjects (127 Controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning and neuropsychological assessment. ATN classification was performed using CSF-Aβ42/Aβ40 (A+/-), CSF-phospho-Tau (T+/-), and adjusted hippocampal volume or CSF-total-Tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-→A+T-N-→A+T+N-→A+T+N+ was compared against biologically less plausible (permuted) sequences among AD-continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N-towards A+T+N+ including also non-AD-continuum ATN groups. Results The ACH-based progression A-T-N-→A+T-N-→A+T+N-→A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects e.g. due to brain-reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e. ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by Tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak-stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF-total-Tau for N instead. Conclusion Using the ATN classification system, early Amyloid status conversion (before Tau and Neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy. DRKS00007966, 04/05/2015, retrospectively registered
Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in a renal transplant recipient case report
2022-06-02

Abstract Thrombotic microangiopathies are disorders characterized by nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and multi-systemic failure. They are classified as thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome, and typical hemolytic uremic syndrome. The latter is associated with intestinal infections by Shiga toxin-producing bacteria. Typical hemolytic uremic syndrome in adults is an extremely rare condition, characterized by high morbidity and mortality. It has been seldom described in solid organ transplant recipients. Here is presented the case of a kidney transplant recipient who had typical hemolytic uremic syndrome with multisystem commitment, refractory to management and with a fatal outcome.
Image Quality and Radiation Dose of Contrast-Enhanced Chest-CT Acquired on a Clinical Photon-Counting Detector CT vs. Second-Generation Dual-Source CT in an Oncologic Cohort: Preliminary Results
2022-06-03

Our aim was to compare the image quality and patient dose of contrast-enhanced oncologic chest-CT of a first-generation photon-counting detector (PCD-CT) and a second-generation dual-source dual-energy CT (DSCT). For this reason, one hundred consecutive oncologic patients (63 male, 65 ± 11 years, BMI: 16–42 kg/m2) were prospectively enrolled and evaluated. Clinically indicated contrast-enhanced chest-CT were obtained with PCD-CT and compared to previously obtained chest-DSCT in the same individuals. The median time interval between the scans was three months. The same contrast media protocol was used for both scans. PCD-CT was performed in QuantumPlus mode (obtaining full spectral information) at 120 kVp. DSCT was performed using 100 kV for Tube A and 140 kV for Tube B. “T3D” PCD-CT images were evaluated, which emulate conventional 120 keV polychromatic images. For DSCT, the convolution algorithm was set at I31f with class 1 iterative reconstruction, whereas comparable Br40 kernel and iterative reconstruction strengths (Q1 and Q3) were applied for PCD-CT. Two radiologists assessed image quality using a five-point Likert scale and performed measurements of vessels and lung parenchyma for signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and in the case of pulmonary metastases tumor-to-lung parenchyma contrast ratio. PCD-CT CNRvessel was significantly higher than DSCT CNRvessel (all, p &lt; 0.05). Readers rated image contrast of mediastinum, vessels, and lung parenchyma significantly higher in PCD-CT than DSCT images (p &lt; 0.001). Q3 PCD-CT CNRlung_parenchyma was significantly higher than DSCT CNRlung_parenchyma and Q1 PCD-CT CNRlung_parenchyma (p &lt; 0.01). The tumor-to-lung parenchyma contrast ratio was significantly higher on PCD-CT than DSCT images (0.08 ± 0.04 vs. 0.03 ± 0.02, p &lt; 0.001). CTDI, DLP, SSDE mean values for PCD-CT and DSCT were 4.17 ± 1.29 mGy vs. 7.21 ± 0.49 mGy, 151.01 ± 48.56 mGy * cm vs. 288.64 ± 31.17 mGy * cm and 4.23 ± 0.97 vs. 7.48 ± 1.09, respectively. PCD-CT enables oncologic chest-CT with a significantly reduced dose while maintaining image quality similar to a second-generation DSCT for comparable protocol settings.
Event‐based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross‐sectional data
2022-06-03

Abstract Objective Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross‐sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE‐HS) correlate with clinical features. Methods We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1‐weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA‐Epilepsy consortium, comprising 804 people with MTLE‐HS and 1625 healthy controls from 25 centers. Features with a moderate case–control effect size (Cohen d ≥ .5) were used to train an event‐based model (EBM), which estimates a sequence of disease‐specific biomarker changes from cross‐sectional data and assigns a biomarker‐based fine‐grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. Results In MTLE‐HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10 −16 ), age at onset ( ρ = −.18, p = 9.82 × 10 −7 ), and ASM resistance (area under the curve = .59, p = .043, Mann–Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE‐HS with mild or nondetectable abnormality on T1W MRI. Significance From cross‐sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE‐HS subjects in other cohorts and help establish connections between imaging‐based progression staging and clinical features.
Constraints on the magnetic field structure in accreting compact objects from aperiodic variability
2022-06-03

We investigate the aperiodic variability for a relatively large sample of accreting neutron stars and intermediate polars, focusing on the properties of the characteristic break commonly observed in power spectra of accreting objects. In particular, we investigate the relation of the break frequency and the magnetic field strength, both of which are connected to the size of the magnetosphere. We find that for the majority of objects in our sample the measured break frequency values indeed agree with estimated inner radii of the accretion disc, which allows to use observed break frequencies to independently assess the magnetic field strength and structure in accreting compact objects. As a special case, we focus on Hercules X-1 which is a persistent, medium-luminosity X-ray pulsar accreting from its low-mass companion. In the literature, it has been suggested that the complex pulse profiles, the spin-up behaviour and the luminosity-correlation of the cyclotron energy seen in Her X-1 can be explained with a complex magnetic field structure of the neutron star. Here, we connect the measured break frequency to the magnetospheric radius and show that the magnetic field strength derived assuming a dipole configuration is nearly an order of magnitude smaller than the magnetic field strength corresponding to the cyclotron energy. Accordingly, this discrepancy can be explained with the magnetic field having strong multipole components. The multipolar structure would also increase the accreting area on the neutron star surface, explaining why the critical luminosity for accretion column formation is puzzlingly high in this source.
Hydrological Perturbations Facilitated Phyllosphere Denitrification of an Urban Greening Tree
2022-06-03

In urban ecosystems, nutrient stocks, such as carbon (C), nitrogen (N), and phosphorus (P), are anthropogenically being enriched for material and energy supply. The overloaded nutrients have adverse ecological consequences, such as causing eutrophication of waters and soil in urban areas. Studying the ecophysiology of nutrient-cycling microbes in urban areas is the foundation to explore strategies for removing such excessive nutrients. The phyllosphere is an understudied microbial habitat for examining how the urban microbiome responds to common environmental changes, such as hydrological perturbations. Here, we investigated how successive rainy–sunny cycles within a season affect the genetic potential (gene abundances) for leaf nutrient cycling and particularly the functional potential (enzyme activities) for leaf denitrification of the greening tree Photinia fraseri. Of 41 detected C, N, P, and sulfur (S) cycling genes using high-throughput quantitative polymerase chain reaction, rainfalls only significantly (p < 0.05) increased the abundances of denitrification marker genes nirK and nirS and one C-fixation gene on the phyllosphere while having no significant impacts on other nutrient-cycling genes. The nirK and nirS genes encode nitrite reductases, which catalyze the hallmark step of the denitrification process. Further, a denitrification enzyme activity assay of phyllosphere microbiota showed that, in comparison to sunny weather, rainfalls significantly promoted nitrate reduction (5.48 μmol of NO3– g–1 h–1; p < 0.001) and N2O production (2.07 nmol of N2O g–1 h–1; p < 0.05) rates, respectively. Together, this study revealed that hydrological perturbations can affect tree phyllosphere denitrification. Understating the ecophysiology of urban phyllosphere denitrifying microbes might be important for developing suitable phylloremediation strategies to attenuate urban N inputs.
The Minus-End-Directed Kinesin OsDLK Shuttles to the Nucleus and Modulates the Expression of Cold-Box Factor 4
2022-06-03

The transition to terrestrial plants was accompanied by a progressive loss of microtubule minus-end-directed dynein motors. Instead, the minus-end-directed class-XIV kinesins expanded considerably, likely related to novel functions. One of these motors, OsDLK (Dual Localisation Kinesin from rice), decorates cortical microtubules but moves into the nucleus in response to cold stress. This analysis of loss-of-function mutants in rice indicates that OsDLK participates in cell elongation during development. Since OsDLK harbours both a nuclear localisation signal and a putative leucin zipper, we asked whether the cold-induced import of OsDLK into the nucleus might correlate with specific DNA binding. Conducting a DPI-ELISA screen with recombinant OsDLKT (lacking the motor domain), we identified the Opaque2 motif as the most promising candidate. This motif is present in the promoter of NtAvr9/Cf9, the tobacco homologue of Cold-Box Factor 4, a transcription factor involved in cold adaptation. A comparative study revealed that the cold-induced accumulation of NtAvr9/Cfp9 was specifically quelled in transgenic BY−2 cells overexpressing OsDLK-GFP. These findings are discussed as a working model, where, in response to cold stress, OsDLK partitions from cortical microtubules at the plasma membrane into the nucleus and specifically modulates the expression of genes involved in cold adaptation.
Determination of muscle strength and function in plesiosaur limbs: finite element structural analyses ofCryptoclidus eurymerushumerus and femur
2022-06-03

Background The Plesiosauria (Sauropterygia) are secondary marine diapsids. They are the only tetrapods to have evolved hydrofoil fore- and hindflippers. Once this specialization of locomotion had evolved, it remained essentially unchanged for 135 Ma. It is still controversial whether plesiosaurs flew underwater, rowed, or used a mixture of the two modes of locomotion. The long bones of Tetrapoda are functionally loaded by torsion, bending, compression, and tension during locomotion. Superposition of load cases shows that the bones are loaded mainly by compressive stresses. Therefore, it is possible to use finite element structure analysis (FESA) as a test environment for loading hypotheses. These include muscle reconstructions and muscle lines of action (LOA) when the goal is to obtain a homogeneous compressive stress distribution and to minimize bending in the model. Myological reconstruction revealed a muscle-powered flipper twisting mechanism. The flippers of plesiosaurs were twisted along the flipper length axis by extensors and flexors that originated from the humerus and femur as well as further distal locations. Methods To investigate locomotion in plesiosaurs, the humerus and femur of a mounted skeleton of Cryptoclidus eurymerus (Middle Jurassic Oxford Clay Formation from Britain) were analyzed using FE methods based on the concept of optimization of loading by compression. After limb muscle reconstructions including the flipper twisting muscles, LOA were derived for all humerus and femur muscles of Cryptoclidus by stretching cords along casts of the fore- and hindflippers of the mounted skeleton. LOA and muscle attachments were added to meshed volumetric models of the humerus and femur derived from micro-CT scans. Muscle forces were approximated by stochastic iteration and the compressive stress distribution for the two load cases, “downstroke” and “upstroke”, for each bone were calculated by aiming at a homogeneous compressive stress distribution. Results Humeral and femoral depressors and retractors, which drive underwater flight rather than rowing, were found to exert higher muscle forces than the elevators and protractors. Furthermore, extensors and flexors exert high muscle forces compared to Cheloniidae. This confirms a convergently evolved myological mechanism of flipper twisting in plesiosaurs and complements hydrodynamic studies that showed flipper twisting is critical for efficient plesiosaur underwater flight.
Small Molecule Thioesters as SARS-CoV-2 Main Protease inhibitors: Enzyme inhibition and mechanism, structure-activity relationship, antiviral activity, and X-ray structure determination
2022-06-03

Those files comprise trajectories of MD simulations of Mpro dimers in presence of covalently bound ligands of interest. We also provide the data for the simulation interactions and RMSD/RMSF as raw data here enclosed. Methods and ligand specifications are provided in the respective manuscript.Trajectories were generated in Desmond and are provided in this format, alternative formats or specific frames are available upon request. Numbering goes as follow 967- cov1 MPRO, PDB ID: 7LMJ (Chains C and D) apostructure - ionization HID41<br> 968- cov1 MPRO, PDB ID: 7LMJ (Chains C and D) LN5516- ionization HID41 991- cov1 PDB ID: 7LMJ (Chains C and D) LN5519- ionization HID41 972- mers MPRO PDB ID: 4YLU (Chains A and B) apostructure - ionization HID41<br> 973- mers MPRO PDB ID:4YLU (Chains A and B) LN5516 - ionization HID41 992- mers MPRO PDB ID:4YLU (Chains A and B) LN5519 - ionization HID41