Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection

Significance Type I interferons (IFN-I) exhibit various biological effects during viral infections, and they have been successfully used for clinical treatment of viral diseases. Humans express 12 IFNα subtypes, which strongly differ in their antiviral responses against different viruses. Here we analyzed the antiviral activity of all human IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Our data provide a systemic pattern of antiviral host effector responses mediated by high antiviral IFN-I, which could help to identify key cellular effectors targeted in novel therapeutic approaches against SARS-CoV-2 infection. Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha (α) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFNα5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2–infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2.
Modeling Bias Error in 4D Flow MRI Velocity Measurements

We present a model to estimate the bias error of 4D flow magnetic resonance imaging (MRI) velocity measurements. The local instantaneous bias error is defined as the difference between the expectation of the voxel’s measured velocity and actual velocity at the voxel center. The model accounts for bias error introduced by the intra-voxel velocity distribution and partial volume (PV) effects. We assess the intra-voxel velocity distribution using a 3D Taylor Series expansion. PV effects and numerical errors are considered using a Richardson extrapolation. The model is applied to synthetic Womersley flow and in vitro and in vivo 4D flow MRI measurements in a cerebral aneurysm. The bias error model is valid for measurements with at least 3.75 voxels across the vessel diameter and signal-to-noise ratio greater than 5. All test cases exceeded this diameter to voxel size ratio with diameters, isotropic voxel sizes, and velocity ranging from 3-15mm, 0.5-1mm, and 0-60cm/s, respectively. The model accurately estimates the bias error in voxels not affected by PV effects. In PV voxels, the bias error is an order of magnitude higher, and the accuracy of the bias error estimation in PV voxels ranges from 67.3% to 108% relative to the actual bias error. The bias error estimated for in vivo measurements increased two-fold at systole compared to diastole in partial volume and non-partial volume voxels, suggesting the bias error varies over the cardiac cycle. This bias error model quantifies 4D flow MRI measurement accuracy and can help plan 4D flow MRI scans.
Selective Activation of Retinal Ganglion Cell Subtypes Through Targeted Electrical Stimulation Parameters

To restore vision to the low vision, epiretinal implants have been developed to electrically stimulate the healthy retinal ganglion cells (RGCs) in the degenerate retina. Given the diversity of retinal ganglion cells as well as the difference in their visual function, selective activation of RGCs subtypes can significantly improve the quality of the restored vision. Our recent results demonstrated that with the proper modulation of the current amplitude, small D1-bistratified cells with the contribution to blue/yellow color opponent pathway can be selectively activated at high frequency (200 Hz). The computational results correlated with the clinical findings revealing the blue sensation of 5/7 subjects with epiretinal implants at high frequency. Here we further explored the impacts of alterations in pulse duration and interphase gap on the response of RGCs at high frequency. We used the developed RGCs, A2-monostratified and D1-bistratified, and examined their response to a range of pulse durations (0.1-1.2 ms) and interphase gaps (0-1 ms). We found that the use of short pulse durations with no interphase gap at high frequency increases the differential response of RGCs, offering better opportunities for selective activation of D1 cells. The presence of the interphase gap has shown to reduce the overall differential response of RGCs. We also explored how the low density of calcium channels enhances the responsiveness of RGCs at high frequency.
A comprehensive gene expression profile of allergic rhinitis-derived nasal fibroblasts and the potential mechanism for its phenotype

Background Allergic rhinitis (AR) is a common immunoglobulin E-mediated immune response involved various cell types, while the role of nasal fibroblasts (NFs) in the pathogenesis of AR is less understood. Purpose The study aimed to uncover the gene expression profile of AR-derived NFs and the potential mechanism for the changed phenotype of AR-NFs. Research Design The primary NFs were isolated from 3 AR patients (AR-NFs) and 3 controls (Ctrl-NFs), and the proliferation, migration and interleukins production abilities of NFs were detected respectively. RNA-sequence was used to identify differentially expressed genes (DEGs) in AR-NFs. Transcription factor (TF) regulatory network and bioinformatic analyses were both conducted to clarify the biological roles of DEGs including the TFs. The DEG with the highest validated |fold change (FC)| value, detected by qPCR, was selected for further confirmation. Results AR-NFs showed a higher proliferation and migration abilities as well as released higher levels of IL-33 and IL-6, compared to Ctrl-NFs. A total of 729 DEGs were screened out in AR-NFs. TF regulatory network indicated that BARX homeobox 1 (BARX1) and forkhead box L1 were the major node TFs. Bioinformatic analyses showed that a large number of DEGs including several target genes of BARX1 were both enriched cytokine-related GO terms, and immune- or inflammation-related pathways. BARX1 had the highest |FC| value, and silencing BARX1 in AR-NFs resulted in the significant downregulation of proliferation and migration abilities, and the production of interleukins. Conclusions Our study for the first time provided the gene expression profile of AR-derived NFs, and BARX1 could be developed as a potent target to alleviate the pathogenesis of AR.
Airway misadventures in adult critical care: a concise narrative review of managing lost or compromised artificial airways

Purpose of review Loss or compromise of artificial airways in critically ill adults can lead to serious adverse events, including death. In contrast to primary emergency airway management, the optimal management of such scenarios may not be well defined or appreciated. Recent findings Endotracheal tube cuff leaks may compromise both oxygenation and ventilation, and supraglottic cuff position must first be recognized and distinguished from other reasons for gas leakage during positive pressure ventilation. Although definitive management involves tube exchange, if direct visualization is possible temporizing measures can often be considered. Unplanned extubation confers variable and context-specific risks depending on patient anatomy and physiological status. Because risk factors for unplanned extubation are well established, bundled interventions can be employed for mitigation. Tracheostomy tube dislodgement accounts for a substantial proportion of death and disability related to airway management in critical care settings. Consensus guidelines and algorithmic management of such scenarios are key elements of risk mitigation. Summary Management of lost or otherwise compromised artificial airways is a key skill set for adult critical care clinicians alongside primary emergency airway management.
ISGylation is increased in the peripheral blood mononuclear cells derived from symptomatic COVID-19 patients

Cytokine-driven hyper inflammation has been identified as a critical factor behind poor outcomes in patients severely infected with SARS-CoV-2 virus. Notably, protein ISGylation, a protein conjugated form of Type 1 IFN-inducible ubiquitin-like protein ISG15 (Interferon-Stimulated Gene 15), induces cytokine storm (CS) and augments colonic inflammation in colitis-associated colon cancers in mouse models. However, whether ISGylation is increased and causally responsible for CS and hyper inflammation in symptomatic COVID-19 patients is unknown. Here, we measured ISGylation levels in peripheral blood mononuclear cells (PBMCs) from 10 symptomatic (SARS-CoV-2-positive with symptoms) and asymptomatic (SARS-CoV-2-positive with no symptoms) COVID-19 patients, and 4 uninfected individuals (SARS-CoV-2-negative), using WesTm assay. Strikingly, we note significant increases in protein ISGylation and MX-1 (myxovirus-resistance protein-1) protein levels, both induced by type-I IFN, in symptomatic but not in asymptomatic patients and uninfected individuals. Knowing that ISGylation augments CS and intestinal inflammation in colon cancers, we propose that increased ISGylation may be an underlying cause of CS and inflammation in symptomatic patients.
Morphological correspondence between brain and endocranial surfaces in mice exposed to undernutrition during development

The morphological changes of the brain and the skull are highly integrated as a result of shared developmental pathways and different types of interactions between them. Shared developmental trajectories between these two structures might be influenced by genetic and environmental factors. Although the effect of environmental factors on neural and craniofacial traits has been extensively studied, less is known about the specific impact of stressful conditions on the coordinated variation between these structures. Here, we test the effect of early nutrient restriction on morphological correspondence between the brain and the endocast. For this purpose, mice exposed to protein or calorie‐protein restriction during gestation and lactation were compared with a control group in which dams were fed standard food ad libitum. High‐resolution images were obtained after weaning to describe brain and endocranial morphology. By magnetic resonance imaging (MRI), brain volumes were obtained and endocasts were segmented from skull reconstructions derived from micro‐computed tomography (microCT). Brain and endocranial volumes were compared to assess the correspondence in size. Shape changes were analyzed using a set of landmarks and semilandmarks on 3D surfaces. Results indicated that brain volume is relatively less affected by undernutrition during development than endocast volume. Shape covariation between the brain and the endocast was found to be quite singular for protein‐restricted animals. Procrustes distances were larger between the brain and the endocast of the same specimens than between brains or endocasts of different animals, which means that the greatest similarity is by type of structure and suggests that the use of the endocast as a direct proxy of the brain at this intraspecific scale could have some limitations. In the same line, patterns of brain shape asymmetry were not directly estimated from endocranial surfaces. In sum, our findings indicate that morphological variation and association between the brain and the endocast is modulated by environmental factors and support the idea that head morphogenesis results from complex processes that are sensitive to the pervasive influence of nutrient intake.
A STRESS-STRAIN MODEL FOR CONCRETE CYLINDERS CONFINED BY BOTH CARBON FIBER SHEETS AND HOOP REINFORCEMENT

既存の鉄筋コンクリート橋脚のじん性を向上させる目的で炭素繊維シート (以下, CFSと呼ぶ) を巻いて補強しようとすると, 不十分とはいえ橋脚には既に帯鉄筋が存在しているため, 橋脚にはCFSと帯鉄筋との両者による横拘束が作用することになる. したがって, CFSによる横拘束効果を地震時保有水平耐力法に基づいた鉄筋コンクリート橋脚の耐震補強設計に反映させるには, 両者による横拘束の共同作用を評価する必要がある. 本研究では, CFSと帯鉄筋の両者で拘束したコンクリート柱の一軸圧縮試験結果に, これまでの著者らの実験データを加えた合計46体の結果に基づいて, CFSと帯鉄筋の両者で拘束したコンクリート柱の応力度～ひずみに影響を与える要因を検討し, さらに, その関係を定式化した.
Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues

ABSTRACT Introduction Nucleoside analogues represent a cornerstone of achievement in drug discovery, rising to prominence particularly in the fields of antiviral and anticancer discovery over the last 60 years. Traditionally accessed using chemical synthesis, a paradigm shift to include the use of biocatalytic synthesis is now apparent. Areas covered Herein, the authors discuss the recent advances using this technology to access nucleoside analogues. Two key aspects are covered, the first surrounding methodology concepts, effectively using enzymes to access diverse nucleoside analogue space and also for producing key building blocks. The second focuses on the use of biocatalytic cascades for de novo syntheses of nucleoside analogue drugs. Finally, recent advances in technologies for effecting enzymatic nucleoside synthesis are considered, chiefly immobilization and flow. Expert opinion Enzymatic synthesis of nucleoside analogues is maturing but has yet to usurp chemical synthesis as a first-hand synthesis technology, with scalability and substrate modification primary issues. Moving forward, tandem approaches that harness expertise across molecular microbiology and chemical synthesis will be vital to unlocking the potential of next generation nucleoside analogue drug discovery.
A Learning Robust and Discriminative Shape Descriptor for Plant Species Identification

Plant identification based on leaf images is a widely concerned application field in artificial intelligence and botany. The key problem is extracting robust discriminative features from leaf images and assigning a measure of similarity. This study proposes an effective, robust shape descriptor to identify plant species from images of their leaves, which we call the high-level triangle shape descriptor (HTSD). First, we extract a leaf image’s external contour and internal salient point information. We then use triangle features to describe the leaf contour, which we call the contour point based on triangle features (CPTFs). The internal information of the leaf image is based on salient point triangle features (SPTFs). The third step is to apply the Fisher vector to encode the two kinds of point-based local triangle features into the HTSD. Finally, we employ the simple euclidean distance to calculate the dissimilarities between the HTSD characteristics of leaf images. We have extensively evaluated the proposed approach on several public leaf datasets successfully. Experimental results show that our method has superior recognition accuracy, outperforming current state-of-the-art shape-based and deep-learning plant identification approaches.
Lactobacillus rhamnosus CNCM I-3690 decreases subjective academic stress in healthy adults: a randomized placebo-controlled trial

ABSTRACT Psychological stress negatively affects the intestinal barrier function in animals and humans. We aimed to study the effect of Lactobacillus rhamnosus CNCM I-3690 on intestinal permeability and stress-markers during public speech. Healthy students were randomized to L. rhamnosus-containing (test) or acidified (placebo) milk consumed twice daily for 4 weeks, with 46 subjects per treatment group. Small intestinal permeability was quantified by a 2 h urinary lactulose–mannitol ratio (LMR, primary outcome), fractional excretion of lactulose (FEL) and mannitol (FEM). Salivary cortisol, State-Trait Anxiety Inventory (STAI) and Perceived Stress scores (PSS) were collected. No between-treatment differences were found for LMR (p = .71), FEL or FEM. Within-treatment analyses showed similar LMR and FEL but a stress-induced increase of FEM with the placebo (p < .05) but not test product. Despite a similar increase in salivary cortisol, the stress-induced increase in STAI was significantly lower with the test product vs. placebo (p = .01). Moreover, a stress-preventative effect of the probiotic was found for PSS and more pronounced in subjects with high stress-induced cortisol (p = .01). While increased FEM was mediated by salivary cortisol levels, the effect of the test product on subjective stress was not mediated by changes in FEM. No serious adverse events occurred. In conclusion, we demonstrated that L. rhamnosus CNCM I-3690 prevented stress-induced hyperpermeability to mannitol. Subjective but not objective stress-markers were reduced with L. rhamnosus vs. placebo, suggesting anxiolytic effects, which were independent of barrier stabilization and attractive for the reduction of stress in both health and disease. Clinicaltrials.gov, number NCT03408691.
CITEMOXMBD: A flexible single-cell multimodal omics analysis framework to reveal the heterogeneity of immune cells

ABSTRACT Simultaneous measurement of multiple modalities in single-cell analysis, represented by CITE-seq, is a promising approach to link transcriptional changes to cellular phenotype and function, requiring new computational methods to define cellular subtypes and states based on multiple data types. Here, we design a flexible single-cell multimodal analysis framework, called CITEMO, to integrate the transcriptome and antibody-derived tags (ADT) data to capture cell heterogeneity from the multi omics perspective. CITEMO uses Principal Component Analysis (PCA) to obtain a low-dimensional representation of the transcriptome and ADT, respectively, and then employs PCA again to integrate these low-dimensional multimodal data for downstream analysis. To investigate the effectiveness of the CITEMO framework, we apply CITEMO to analyse the cell subtypes of Cord Blood Mononuclear Cells (CBMC) samples. Results show that the CITEMO framework can comprehensively analyse single-cell multimodal samples and accurately identify cell subtypes. Besides, we find some specific immune cells that co-express multiple ADT markers. To better describe the co-expression phenomenon, we introduce the co-expression entropy to measure the heterogeneous distribution of the ADT combinations. To further validate the robustness of the CITEMO framework, we analyse Human Bone Marrow Cell (HBMC) samples and identify different states of the same cell type. CITEMO has an excellent performance in identifying cell subtypes and states for multimodal omics data. We suggest that the flexible design idea of CITEMO can be an inspiration for other single-cell multimodal tasks. The complete source code and dataset of the CITEMO framework can be obtained from https://github.com/studentiz/CITEMO.
The effect of lactate dehydrogenase-A inhibition on intracellular nucleotides and mitochondrial respiration in pancreatic cancer cells

Abstract Pancreatic cancer (PC) is one of the most lethal malignancies. PC is characterized by a high expression of the glucose transporter GLUT-1 and of lactate dehydrogenase A (LDH-A). The novel LDH-A inhibitor NHI-Glc-2 was designed for a better uptake via GLUT-1 and was shown to be cytotoxic against the PC cell line PANC-1. Using RP-HPLC we investigated its effect on adenine nucleotides and NADH/NAD+, while the Seahorse analyzer was used to determine its effect on glycolysis and mitochondrial function. A 24 hour exposure to 10 µM NHI-Glc-2 (around the IC50) decreased the ATP concentration by about 10%, but at 25 µM this decrease was 38%, while NAD+ decreased by 26%, associated with a 35% decrease in the NADH/NAD+ ratio. A 10 µM NHI-Glc-2 decreased extracellular acidification and oxygen consumption (about 75%), as well as the mitochondrial respiration parameters by 50%. In conclusion, LDH-A inhibition markedly affected the energy supply of PANC-1 cells. The respiration data indicated a dependency of the cells on glycolysis and fatty acid oxidation. Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2022. 2031215 .
HY5 inhibits in vitro shoot stem cell niches initiation via directly repressing pluripotency and cytokinin pathways.

The efficiency of plant regeneration from explants is influenced by phytohormones and environmental conditions. Light has a particularly marked effect on in vitro shoot regeneration, and some light signaling factors are involved in shoot regeneration, while the underlying molecular mechanism remains elusive. Here, ELONGATED HYPOCOTYL5 (HY5), as the key transcription factor of light signaling, was found to inhibit shoot regeneration under a range of light conditions. The heightened shoot regeneration capacity of the hy5-215 mutant was less marked in the dark than in the light, showing that HY5-mediated inhibition of shoot regeneration is partly light-dependent. The co-localization of WUSCHEL (WUS) and CLAVATA3 (CLV3) expressions was found to coincide with the initiation of stem cell niches in root explants during shoot regeneration. HY5 could directly repress CLV3 and WUS expression by binding to their respective promoters. In parallel, HY5 indirectly repressed CLV3 and WUS by binding to the ARABIDOPSIS RESPONSE REGULATOR12 (ARR12) promoter. The resulting dual regulation exerted by HY5 on WUS and CLV3 impeded the initiation of shoot stem cell niches. A HY5-mediated inhibitory pathway was identified which links cytokinin signaling and the pluripotency pathway during shoot regeneration.