Miracle-dz/UniFAR-FTUs huggingface dataset:
Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses

Background Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity. Methods Multiple technologies were used to characterize the TGF-β trap binding avidity. BA versus combinations of anti-PD-L1 and TGF-β trap or the pan-TGF-β antibody fresolimumab were compared in proliferation and two-way mixed lymphocyte reaction assays. Immunophenotyping of tumor-infiltrating lymphocytes (TILs) and RNA sequencing (RNAseq) analysis assessing stromal and immune landscape following BA or the combination therapy were performed in MC38 tumors. TGF-β and PD-L1 co-expression and their associated gene signatures in MC38 tumors and human lung carcinoma tissue were studied with single-cell RNAseq (scRNAseq) and immunostaining. BA-induced internalization, degradation, and depletion of TGF-β were investigated in vitro. Results BA and fresolimumab had comparable intrinsic binding to TGF-β1, but there was an ~80× avidity-based increase in binding affinity with BA. BA inhibited cell proliferation in TGF-β-dependent and PD-L1-expressing cells more potently than TGF-β trap or fresolimumab. Compared with the combination of anti-PD-L1 and TGF-β trap or fresolimumab, BA enhanced T cell activation in vitro and increased TILs in MC38 tumors, which correlated with efficacy. BA induced distinct gene expression in the TME compared with the combination therapy, including upregulation of immune-related gene signatures and reduced activities in TGF-β-regulated pathways, such as epithelial-mesenchymal transition, extracellular matrix deposition, and fibrosis. Regulatory T cells, macrophages, immune cells of myeloid lineage, and fibroblasts were key PD-L1/TGF-β1 co-expressing cells in the TME. scRNAseq analysis suggested BA modulation of the macrophage phenotype, which was confirmed by histological assessment. PD-L1/TGF-β1 co-expression was also seen in human tumors. Finally, BA induced TGF-β1 internalization and degradation in the lysosomes. Conclusion BA more effectively blocks TGF-β by targeting TGF-β trap to the tumor via PD-L1 binding. Such colocalized targeting elicits distinct and superior antitumor responses relative to single agent combination therapy.
A Role for Allantoate Amidohydrolase (AtAAH) in the Germination of Arabidopsis thaliana Seeds

Abstract Seed dormancy is a very complex trait controlled by interactions between genetic and environmental factors. Nitrate is inversely correlated with seed dormancy in Arabidopsis. This is explained by the fact that seed dry storage (after-ripening) reduces the need for nitrogen for germination. When nitrate is absorbed by plants, it is first reduced to nitrite and then to ammonium for incorporation into amino acids, nucleic acids and chlorophyll. Previously, we showed that ALLANTOATE AMIDOHYDROLASE (AtAAH) transcripts are up-regulated in imbibed dormant seeds compared with after-ripened seeds. AAH is an enzyme in the uric acid catabolic pathway which catalyzes the hydrolysis of allantoate to yield CO2, NH3 and S-ureidoglycine. This pathway is the final stage of purine catabolism, and functions in plants and some bacteria to provide nitrogen, particularly when other nitrogen sources are depleted. Ataah mutant seeds are more dormant and accumulate high levels of allantoate, allantoin and urea, whereas energy-related metabolites and several amino acids are lower upon seed imbibition in comparison with Columbia-0. AtAAH expression could be detected during the early stages of seed development, with a transient increase around 8 d after pollination. AtAAH expression is the highest in mature pollen. The application of exogenous potassium nitrate can partly complement the higher dormancy phenotype of the Ataah mutant seeds, whereas other nitrogen sources cannot. Our results indicate that potassium nitrate does not specifically overcome the alleviated dormancy levels in Ataah mutant seeds, but promotes germination in general. Possible pathways by which AtAAH affects seed germination are discussed.
Nomenclature for factors of the HLA system, update April, May and June 2022

The following sequences have been submitted to the Nomenclature Committee since the January, February and March 2022 nomenclature update (Marsh, 2022) and, following agreed policy, have been assigned official allele designations (Marsh et al., 2010). Full details of all sequences will be published in a forthcoming report. Below are listed the newly assigned sequences (Table 1) and confirmations of previously reported sequences (Table 2). The accession number of each sequence is given and these can be used to retrieve the sequence files from the EMBL, GenBank or DDBJ data libraries. Although accession numbers have been assigned by the data libraries and most sequences are already available, there is still the possibility that an author may not yet have allowed the sequence to be released; in such a case, you will have to contact the submitting author directly. Additional information pertaining to new sequences is often included in the publications describing these alleles; a listing of recent publications that describe new HLA sequences is given in Table 3. In addition, the sequence for the allele C*16:15:01 has been extended to become a new C*16 protein variant. The allele name C*16:15:01has been abandoned and the sequence renamedC*16:201. Furthermore, the allele DPA1*02:64 was found to have an alternative start codon, and has had theQ suffix added, to becomeDPA1*02:64Q. All new and confirmatory sequences should now be submitted directly to the WHO Nomenclature Committee for Factors of the HLA System via the IPD-IMGT/HLADatabase using the sequence submission tool provided (Robinson et al., 2020). The IPD-IMGT/HLA Databasemay be accessed via theWorldWideWeb at: www.ebi. ac.uk/ ipd/imgt/hla.
Type 1 Diabetes Hypoglycemia Prediction Algorithms: Systematic Review

Background Diabetes is a chronic condition that necessitates regular monitoring and self-management of the patient’s blood glucose levels. People with type 1 diabetes (T1D) can live a productive life if they receive proper diabetes care. Nonetheless, a loose glycemic control might increase the risk of developing hypoglycemia. This incident can occur because of a variety of causes, such as taking additional doses of insulin, skipping meals, or overexercising. Mainly, the symptoms of hypoglycemia range from mild dysphoria to more severe conditions, if not detected in a timely manner. Objective In this review, we aimed to report on innovative detection techniques and tactics for identifying and preventing hypoglycemic episodes, focusing on T1D. Methods A systematic literature search following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was performed focusing on the PubMed, Google Scholar, IEEE Xplore, and ACM Digital Library to find articles on technologies related to hypoglycemia detection in patients with T1D. Results The presented approaches have been used or devised to enhance blood glucose monitoring and boost its efficacy in forecasting future glucose levels, which could aid the prediction of future episodes of hypoglycemia. We detected 19 predictive models for hypoglycemia, specifically on T1D, using a wide range of algorithmic methodologies, spanning from statistics (1.9/19, 10%) to machine learning (9.88/19, 52%) and deep learning (7.22/19, 38%). The algorithms used most were the Kalman filtering and classification models (support vector machine, k-nearest neighbors, and random forests). The performance of the predictive models was found to be satisfactory overall, reaching accuracies between 70% and 99%, which proves that such technologies are capable of facilitating the prediction of T1D hypoglycemia. Conclusions It is evident that continuous glucose monitoring can improve glucose control in diabetes; however, predictive models for hypo- and hyperglycemia using only mainstream noninvasive sensors such as wristbands and smartwatches are foreseen to be the next step for mobile health in T1D. Prospective studies are required to demonstrate the value of such models in real-life mobile health interventions.
Geometrical Interpretation and Design of Multilayer Perceptrons

The multilayer perceptron (MLP) neural network is interpreted from the geometrical viewpoint in this work, that is, an MLP partition an input feature space into multiple nonoverlapping subspaces using a set of hyperplanes, where the great majority of samples in a subspace belongs to one object class. Based on this high-level idea, we propose a three-layer feedforward MLP (FF-MLP) architecture for its implementation. In the first layer, the input feature space is split into multiple subspaces by a set of partitioning hyperplanes and rectified linear unit (ReLU) activation, which is implemented by the classical two-class linear discriminant analysis (LDA). In the second layer, each neuron activates one of the subspaces formed by the partitioning hyperplanes with specially designed weights. In the third layer, all subspaces of the same class are connected to an output node that represents the object class. The proposed design determines all MLP parameters in a feedforward one-pass fashion analytically without backpropagation. Experiments are conducted to compare the performance of the traditional backpropagation-based MLP (BP-MLP) and the new FF-MLP. It is observed that the FF-MLP outperforms the BP-MLP in terms of design time, training time, and classification performance in several benchmarking datasets. Our source code is available at https://colab.research. google.com/drive/1Gz0L8AnT4ijrUchrhEXXsnaacrFdenn? usp = sharing.
Reduction of metal artifacts in x-ray CT images using a convolutional neural network

Patients usually contain various metallic implants (e.g. dental fillings, prostheses), causing severe artifacts in the x-ray CT images. Although a large number of metal artifact reduction (MAR) methods have been proposed in the past four decades, MAR is still one of the major problems in clinical x-ray CT. In this work, we develop a convolutional neural network (CNN) based MAR framework, which combines the information from the original and corrected images to suppress artifacts. Before the MAR, we generate a group of data and train a CNN. First, we numerically simulate various metal artifacts cases and build a dataset, which includes metal-free images (used as references), metal-inserted images and various MAR methods corrected images. Then, ten thousands patches are extracted from the databased to train the metal artifact reduction CNN. In the MAR stage, the original image and two corrected images are stacked as a three-channel input image for CNN, and a CNN image is generated with less artifacts. The water equivalent regions in the CNN image are set to a uniform value to yield a CNN prior, whose forward projections are used to replace the metal affected projections, followed by the FBP reconstruction. Experimental results demonstrate the superior metal artifact reduction capability of the proposed method to its competitors.
Postoperative Opioid Use and Prescribing Patterns among Patients Undergoing Cervical Laminectomy with Instrumented Fusion versus Cervical Laminoplasty with Reconstruction

Study Design Retrospective cohort study. Objective To compare patterns in opioid usage and prescriptions between patients who undergo cervical laminectomy with instrumented fusion (LF) vs cervical laminoplasty with reconstruction (LP) within single surgeon and national database cohorts. Methods We identified patients with cervical myelopathy undergoing primary LF or LP in both a single-surgeon series cohort (2004-2018) and a nationally representative cohort drawn from the IBM® Marketscan® database (2014-2016). We recorded opioid usage within 6 months of surgery and identified differences in unadjusted opioid use rates between LF and LP patients. Multivariable logistic regression was used to evaluate the association between procedure type and postoperative opioid use. Results Without adjusting for covariates, LF patients had a higher rate of 6-month opioid use in the single-surgeon cohort (15.7% vs 5.1%, P = .02). After adjusting for covariates, LF patients had higher odds of 6-month postoperative opioid use (OR 2.8 [95% CI 1.0-7.7], P = .04). In the national cohort, without adjusting for covariates, there was no significant difference in 6-month opioid use between LF and LP patients. Even after adjusting for covariates, we found no significant difference in odds. Conclusions Findings from a single-surgeon cohort reveal that LF is associated with a higher rate of 6-month opioid use than LP. This is at odds with findings from a national database cohort, which suggested that LP and LF patients have similar rates of opioid usage at 6-months postoperatively. To prevent overuse of narcotics, surgeons must consider the distinct pain requirements associated with different procedures even in treatment of the same condition.
Transcutaneous Vagus Nerve Stimulation Ameliorates the Phenotype of Heart Failure With Preserved Ejection Fraction Through Its Anti-Inflammatory Effects

Background: A systemic proinflammatory state plays a central role in the development of heart failure with preserved ejection fraction (HFpEF). Low-level transcutaneous vagus nerve stimulation (LLTS) suppresses inflammation in animals and humans, mediated by an α7nAchR (alpha7 nicotinic acetylcholine receptor)-dependent pathway. We examined the effects of LLTS on cardiac function, inflammation, and fibrosis in the presence of α7nAchR pharmacological blockade in a rat model of HFpEF. Methods: Dahl salt-sensitive rats at 7 weeks of age were treated with high-salt diet for 6 weeks to induce HFpEF, followed by 4 weeks of (1) LLTS, (2) LLTS with the α7nAchR blocker methyllycaconitine, (3) sham, and (4) olmesartan. Blood pressure, cardiac function by echocardiography, heart rate variability, and serum cytokines were measured at 13 and 17 weeks of age. Cardiac fibrosis, inflammatory cell infiltration, and gene expression were determined at 17 weeks. Results: LLTS attenuated the increase in blood pressure; improved cardiac function; decreased inflammatory cytokines, macrophage infiltration, and fibrosis; and improved survival compared with other groups. Methyllycaconitine attenuated these effects, whereas olmesartan did not improve cardiac function or fibrosis despite maintaining similar blood pressure as LLTS. Heart rate variability was similarly improved in the LLTS and LLTS plus methyllycaconitine groups but remained low in the other groups. LLTS reversed the dysregulated inflammatory signaling pathways in HFpEF hearts. Conclusions: Neuromodulation with LLTS improved cardiac function in a rat model of HFpEF through its anti-inflammatory and antifibrotic effects. These results provide the basis for further clinical trials in humans.
Identifying Business Schools’ Business Behaviors- employing the perspectives of Corporate Ethos

Employing business schools and their MBA programs as an example in the broadest context of higher education programs, this study visualizes and reflects theoretical issues of academic capitalism and the commercialization of higher education programs. By probing, illustrating and documenting empirical business practices and assessing the degree to which business schools commercialize their education programs, this study also advances our understanding of commercialization practices of higher education programs. The findings attest to the theoretical issues of commercialization that higher education programs, in the context of business schools are highly engaged in commercial activities and are competing with the private sector for customers in the MBA industry. The findings also illustrate that business schools from many perspectives treat their students as consumers and therefore commercialize their academic programs and operations in ways that can strengthen their capabilities to attract and recruit more consumers, and to compete for reputation as well as maintain exceptional relationships and fulfill consumers’ needs. This study suggests that issues such as monitoring mechanisms for commercial behaviors, balancing the advantages and disadvantages of pursuing commercial behaviors as well as how commercialization influences faculty and students in terms of the experience of teaching and learning should be scrutinized.
Synthesis of an Atom‐Specifically 2H/13C‐Labeled Uridine Ribonucleoside Phosphoramidite

A combined enzymatic and chemical synthesis of a 2′‐O‐cyanoethoxymethyl (CEM) protected [1′,6‐13C2, 5‐2H]‐uridine phosphoramidite is described herein. This is the first report of an atom‐specific nucleobase and ribose labeled 2′‐O‐CEM protected ribonucleoside phosphoramidite. Importantly, the CEM 2′‐OH protecting group permits the efficient solid‐phase synthesis of large (>60 nucleotides) RNAs with good yield and purity. The new isotope‐labeled phosphoramidite can therefore be applied to nuclear magnetic resonance (NMR) spectroscopy studies. Specifically, the [1′,6‐13C2, 5‐2H]‐uridine phosphoramidite can be used to make position‐specifically labeled RNAs for NMR analysis without complications from resonance overlap and scalar and dipolar couplings. © 2022 Wiley Periodicals LLC.
Happy Alone? Motivational Profiles of Solitude and Well-Being Among Senior Living Residents

Research on solitude in older adulthood is scarce, and findings are mixed on whether time alone at this age is risky or beneficial. A mixed-method study was conducted to examine patterns of motivations for solitude among senior living residents (N = 397, Mage = 83) and associations with well-being. Cluster analyses identified four motivational profiles: Low, Positive, Negative, and Dual. Overall, those with Low and Positive motivations for solitude displayed greater levels of well-being on both hedonic (e.g., life satisfaction) and eudaimonic (e.g., personal growth) measures; in particular, the Positive profile showed significantly higher levels of psychological richness. Themes drawn from responses to open-ended survey questions asking about the benefits and challenges of both socializing and being alone are discussed in light of the four motivational profiles, and implications for aging services are discussed.
Commissioning an Exradin W2 plastic scintillation detector for clinical use in small radiation fields

Abstract Purpose The purpose of this work is to evaluate the Standard Imaging Exradin W2 plastic scintillation detector (W2) for use in the types of fields used for stereotactic radiosurgery. Methods Prior to testing the W2 in small fields, the W2 was evaluated in standard large field conditions to ensure good detector performance. These tests included energy dependence, short‐term repeatability, dose‐response linearity, angular dependence, temperature dependence, and dose rate dependence. Next, scan settings and calibration of the W2 were optimized to ensure high quality data acquisition. Profiles of small fields shaped by cones and multi‐leaf collimator (MLCs) were measured using the W2 and IBA RAZOR diode in a scanning water tank. Output factors for cones (4–17.5 mm) and MLC fields (1, 2, 3 cm) were acquired with both detectors. Finally, the dose at isocenter for seven radiosurgery plans was measured with the W2 detector. Results W2 exhibited acceptable warm‐up behavior, short‐term reproducibility, axial angular dependence, dose‐rate linearity, and dose linearity. The detector exhibits a dependence upon energy, polar angle, and temperature. Scanning measurements taken with the W2 and RAZOR were in good agreement, with full‐width half‐maximum and penumbra widths agreeing to within 0.1 mm. The output factors measured by the W2 and RAZOR exhibited a maximum difference of 1.8%. For the seven point‐dose measurements of radiosurgery plans, the W2 agreed well with our treatment planning system with a maximum deviation of 2.2%. The Čerenkov light ratio calibration method did not significantly impact the measurement of relative profiles, output factors, or point dose measurements. Conclusion The W2 demonstrated dosimetric characteristics that are suitable for radiosurgery field measurements. The detector agreed well with the RAZOR diode for output factors and scanned profiles and showed good agreement with the treatment planning system in measurements of clinical treatment plans.
Beneficial role of naringin against methotrexate-induced injury to rat testes: biochemical and ultrastructural analyses

ABSTRACT Background Methotrexate (MTX) is a commonly used chemotherapeutic drug that has adverse toxic effects on germ cells. Naringin (NG) is a natural flavanone glycoside, with different phytotherapeutic applications, and its possible protective effects against MTX-induced testicular tissue damage were investigated in this study. Methods Low and high doses of NG (40 and 80 mg/kg/day) were given for 10 days by intraperitoneal (i.p.) injection and MTX (20 mg/kg i.p.) was given at the 4th day of the experiment, with or without NG in rats. Results The obtained results showed that exposure to MTX increased malondialdehyde (MDA) levels and nitric oxide (NO) production compared with the control. In the meantime, MTX depleted catalse (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), and reduced glutathione (GSH) in the testicular tissue. Further, serum testosterone levels were significantly decreased in the MTX group. NG significantly counteracted the aforementioned effects of MTX; however, NG80 was more effective in restoring SOD, GR, MDA and NO. Interestingly, NG80 achieved a better improvement in the ultrastructural pattern of the testicular cells in MTX-exposed rats. Conclusion These results indicated, for the first time, that NG could be a potential candidate therapy against MTX-reprotoxic impacts.
Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR‐Driven Lung Cancer

Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR‐driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single‐cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8+ T cell and CD4+ Th1 cell infiltration, while EVax elicits robust Th1 cell‐mediated immune responses and protects mice against EGFRL858R mutation‐driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic‐ and granulocytic‐myeloid‐derived suppressor cells, regulatory T cells, and pro‐tumor CD4+ Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory‐like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR‐driven lung tumorigenesis and promotes an adaptive T cell‐mediated tumor‐specific immune response that enhances the efficacy of EVax.