Copelandsnyder8709

Talking over Challenges in Diagnosing Tuberculous Meningitis and Neurosarcoidosis.

The Proline Mimetic for that Style of New Secure Extra Structures: Solvent-Dependent Amide Bond Isomerization involving (Utes)-Indoline-2-carboxylic Chemical p Derivatives.

Implementation of concurrent hospice care led to a new hybrid payment model that combines hospice payments with payments for non-hospice medical care. Little is known about the cost implications of this new hybrid payment model.

The purpose was to identify costs and compare concurrent care and standard hospice care costs by estimating the average incremental Medicaid cost of care over time.

Using national Medicaid data of 18147 hospice children and a multilevel generalized linear model, we calculated the incremental costs of receiving concurrent vs standard hospice care. We used the total cost of care over the last year of life. Increments for the analysis were hospice length of stay, stratified to 1 day, 2-14 days, and 15 + days.

Overall, compared to standard hospice care, enrollment in concurrent hospice care was significantly associated with an increase in outpatient care and prescription drug costs. For a stay of 1 day, concurrent hospice care decreased inpatient costs and increased costs of prescription drugs. For stays between 2 and 14 days, concurrent hospice decreased total costs and inpatient costs, but increased prescription drug costs. With a hospice stay of 15 + days, concurrent hospice had significantly higher costs across all measures, including total costs, inpatient costs, outpatient costs, and prescription drug costs.

This study provides critical insight into incremental costs of receiving concurrent vs standard hospice care. More research is needed to understand how concurrent hospice lengthy hospice stays are associated with increases of costs.

This study provides critical insight into incremental costs of receiving concurrent vs standard hospice care. More research is needed to understand how concurrent hospice lengthy hospice stays are associated with increases of costs.

Use of endovascular intervention (EI) for blunt cerebrovascular injury (BCVI) is without consensus guidelines. Rates of EI use and radiographic characteristics of BCVI undergoing EI nationally are unknown.

A post-hoc analysis of a prospective, observational study at 16 U.S. trauma centers from 2018 to 2020 was conducted. Internal carotid artery (ICA) BCVI was included. The primary outcome was EI use. Multivariable logistic regression was performed for predictors of EI use.

From 332 ICA BCVI included, 21 (6.3%) underwent EI. link= ABT-199 order 0/145 (0%) grade 1, 8/101 (7.9%) grade 2, 12/51 (23.5%) grade 3, and 1/20 (5.0%) grade 4 ICA BCVI underwent EI. Stroke occurred in 6/21 (28.6%) ICA BCVI undergoing EI and in 33/311 (10.6%) not undergoing EI (

= .03), with all strokes with EI use occurring prior to or at the same time as EI. Percentage of luminal stenosis (37.75 vs 20.29%,

= .01) and median pseudoaneurysm size (9.00mm vs 3.00mm,

= .01) were greater in ICA BCVI undergoing EI. On logistic regression, only pseudoaneurysm size was associated with EI (odds ratio 1.205, 95% CI 1.035-1.404,

= .02). Of the 8 grade 2 ICA BCVI undergoing EI, 3/8 were grade 2 and 5/8 were grade 3 prior to EI. Of the 12 grade 3 ICA BCVI undergoing EI, 11/12 were grade 3 and 1/12 was a grade 2 ICA BCVI prior to EI.

Pseudoaneurysm size is associated with use of EI for ICA BCVI. Stroke is more common in ICA BCVI with EI but did not occur after EI use.

Pseudoaneurysm size is associated with use of EI for ICA BCVI. Stroke is more common in ICA BCVI with EI but did not occur after EI use.This study aims to assess chemical VTE prophylactic type and timing and associated outcomes within the elderly trauma population. This is a single center study of Trauma Registry data, inclusive years July 1, 2016, to February 28, 2021. The patients were grouped based upon discharge disposition. 7261 elderly trauma patients were included in the analysis. Late administration of VTE prophylaxis was associated with a discharge disposition to hospice. Administration of unfractionated heparin was most associated with in-hospital mortality. link2 Xa inhibitors had the least impact on morbidity and mortality, with most likely associations in discharge to rehab or a skilled nursing facility. LMWH associated with a discharge to a rehab facility. The timing of administration and type of VTE prophylaxis may significantly affect the morbidity and mortality outcomes in elderly trauma.

Pathological cardiac hypertrophy is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase TRIM16 (tripartite motif-containing protein 16) has been recognized as a pivotal regulator to control cell survival, immune response, and oxidativestress. However, the role of Trim16 in cardiac hypertrophy is unknown.

We generated cardiac-specific knockout mice and adeno-associated virus serotype 9-Trim16 mice to evaluate the function of Trim16 in pathological myocardial hypertrophy. The direct effect of TRIM16 on cardiomyocyte enlargement was examined using an adenovirus system. Furthermore, we combined RNA-sequencing and interactome analysis that was followed by multiple molecular biological methodologies to identify the direct target and corresponding molecular events contributing to TRIM16 function.

We found an intimate correlation of Trim16 expression with hypertrophy-related heart failure in both human and mouse. Our functional investigations and unbiased transcriptomiing therapeutic strategy for hypertrophy-related heart failure.

Our findings provide the first evidence supporting Trim16 as a novel suppressor of pathological cardiac hypertrophy and indicate that targeting the Trim16-Prdx1 axis represents a promising therapeutic strategy for hypertrophy-related heart failure.A mild light-driven protocol for the direct alkylation of phenols is reported. The process is driven by the photochemical activity of a halogen-bonded complex formed upon complexation of the in situ generated electron-rich phenolate anion with the α-iodosulfone. ABT-199 order The reaction proceeds rapidly (10 min) under microfluidic conditions, delivering a wide variety of ortho-alkylated products (27 examples, up to 97% yield, >201 regioselectivity, on a gram scale), including densely functionalized bioactive phenol derivatives.This report describes a copper-mediated radiocyanation of aryl halides that is applicable to complex molecules. This transformation tolerates an exceptionally wide range of functional groups, including unprotected amino acids. As such, it enables the site-specific introduction of [11C]CN into peptides at an iodophenylalanine residue. The use of a diamine-ligated copper(I) mediator is crucial for achieving high radiochemical yield under relatively mild conditions, thus limiting racemization and competing side reactions of other amino acid side chains. The reaction has been scaled and automated to deliver radiolabeled peptides, including analogues of adrenocorticotropic hormone 1-27 (ACTH) and nociceptin (NOP). For instance, this Cu-mediated radiocyanation was leveraged to prepare >40 mCi of [11C]cyano-NOP to evaluate biodistribution in a primate using positron emission tomography. This investigation provides preliminary evidence that nociceptin crosses the blood-brain barrier and shows uptake across all brain regions (SUV > 1 at 60 min post injection), consistent with the known distribution of NOP receptors in the rhesus brain.A simple and low-cost tandem sulfonylation/cyclization of 1,5-diene, aryldiazonium salt, and DABCO·(SO2)2 is disclosed. This base-promoted multicomponent reaction can provide a "green" and economic synthesis of sulfonylated pyrrolidones under transition-metal-free and moisture/oxygen-insensitive reaction conditions, thus delivering a wide range of sulfonylated pyrrolidones in moderate to high yields with excellent functional group compatibility. A plausible mechanism involving a radical process is proposed, which demonstrates highly chemoselective trapping of the aryl radical with "SO2" species, and a regioselective sulfonylation/cyclization protocol in this reaction.For fast density functional calculations, a suitable basis that can accurately represent the orbitals within a reasonable number of dimensions is essential. Here, we propose a new type of basis constructed from Tucker decomposition of a finite-difference (FD) Hamiltonian matrix, which is intended to reflect the system information implied in the Hamiltonian matrix and satisfies orthonormality and separability conditions. By introducing the system-specific separable basis, the computation time for FD density functional calculations for seven two- and three-dimensional periodic systems was reduced by a factor of 2-71 times, while the errors in both the atomization energy per atom and the band gap were limited to less than 0.1 eV. The accuracy and speed of the density functional calculations with the proposed basis can be systematically controlled by adjusting the rank size of Tucker decomposition.Bismuth ferrite-barium titanate (BF-BT) based ceramics have attracted extensive attention due to its excellent energy conversion. Recently it has been found that BF-BT based ceramics with large electrostrain are usually accompanied by a special domain configuration in which weak and strong piezoresponse domain grains coexist. In this work, we purposefully constructed the special domain configuration in the pseudocomposite ceramics of (1 - x)0.55BF-0.4BT-0.05BZN/x(0.7BF-0.3BT) (relaxor-like phase/ferroelectric phase, RE/FE) by a "two-step" method. Macroproperty characterization suggests that the critical component pseudocomposite ceramic (x = 50%) with the special domain structure can exhibit a maximum electrostrain value (S ∼ 0.28%) at 6 kV/mm, almost 3-fold to that (S ∼ 0.1%) of the two end members and 63% higher than that (S ∼ 0.17%) of the same component ceramic prepared by the "one-step" method. Further mesoscopic structure results show that the "two-phase" composite can induce the formation of grain dependent domain at nanoscale, and just this special domain conformation is conducive to a significant improvement in electrostrain. Therefore, the large strain in BF-BT-based ceramics is mainly caused by the special microstructure rather than component.Activated hypoxia-inducible factor-1alpha (HIF-1α) plays an important role in the adaptive response of tumor cells to oxygen changes through the transcriptional activation of genes that regulate important biological processes required for tumor survival and progression. In this study, we developed an ultrasensitive hypoxia sensor based on read-out with quantum dots on a gold nanodisc (quantum dot-linked immunosandwich assay, QLISA) with excellent selectivity for HIF-1α. The immunoassay platform was established by comparing the immune response results using Qdot525 as a detection nanoprobe instead of a fluorescent dye (Alexa488) (fluorescent-linked immunosandwich assay, FLISA). In addition, using three-dimensional total internal reflection fluorescence microscopy, the platform was optically sectioned along the z-axis at 10 nm intervals to compare the height difference between the nanodisc and the nanoprobe following the QLISA and FLISA procedures and to localize the target location. Here, the super-resolution QLISA (srQLISA)-based hypoxia sensor exhibited high accuracy and precision for the detection of HIF-1α-extracted samples in cancer spheroids compared with the super-resolution FLISA (srFLISA) method. The developed nanobiosensor method demonstrated a wide dynamic linear detection range of 32.2 zM-8.0 pM with a limit of detection of 16 zM under optimal experimental conditions for HIF-1α, an approximate 106-fold enhanced detection sensitivity compared with the conventional enzyme-linked immunosorbent assay method based on absorbance. The detection of HIF-1α using the newly developed srQLISA sensor allows for independently predicting tumor progression and early cancer onset increases in the microvasculature density of tumor lesions.A method for creating genuine nanopores in high area density on monolayer two-dimensional (2D) metallic oxides has been developed. By use of the strong reduction capability of hydroiodic acid, active metal ions, such as FeIII and CoIII, in 2D oxide nanosheets can be reduced to a divalent charge state (2+). The selective removal of FeO2 and CoO2 metal oxide units from the framework can be tuned to produce pores in a range of 1-4 nm. By monitoring of the redox reaction kinetics, the pore area density can be also tuned from ∼0.9 × 104 to ∼3.3 × 105 μm-2. The universality of this method to produce much smaller pores and higher area density than the previously reported ones has been proven in different oxide nanosheets. To demonstrate their potential applications, ultrasmall metal organic framework particles were grown inside the pores of perforated titania oxide nanosheets. The optimized hybrid film showed ∼100% rejection of methylene blue (MB) from the water. Its water permeance reached 4260 L m-2 h-1 bar-1, which is 1-3 orders of that for reported 2D membranes with good MB rejections.The trans-tetrafluoro-λ6-sulfanyl (SF4) unit is medicinally attractive because of its high electronegativity, lipophilicity, and unique hypervalent structure. The trans-SF4 unit can characteristically connect two independent molecules linearly. However, there is no example of the use of this unit for medicinal chemistry due to difficulties in synthesis. We report the first synthesis of (ethynyl-trans-tetrafluoro-λ6-sulfanyl)pyridines (t-ethynyl-SF4-pyridines) and their use as versatile reagents for the first direct SF4-alkynylation to carbonyl compounds. The addition reaction of t-ethynyl-SF4-pyridines to the carbonyl group in the presence of MeLi smoothly afforded pyridine-SF4-propargylic tertiary and secondary alcohols in high yields.Phosphorus-carbon anode materials for alkali-metal ion storage in rechargeable batteries can simultaneously achieve high-energy density and fast charging. The P-C-bonded structure in the phosphorus-carbon materials has been observed and acknowledged to be a critical structural feature that renders improved cycling stability and rate performance. However, the underlying mechanisms, especially the role played by P-C bonds, remain elusive. By combining computational simulations and spectroscopic characterizations, we reveal that the stability of P-C bonds is critical to the electrochemical performance. In the discharge process, P-P bonds are fragile, while the bonding state of the P-C bonds is almost unchanged since electrons were mainly received by the P atoms to form lone pairs. The preserved P-C clusters can effectively serve as a reunion center for the recovery of P-P bonds in the recharging process, leading to a moderate energy change and improved cycling reversibility and structural stability of the phosphorous for electrochemical energy storage.We evaluated the effect of four different waveform profiles (Square, Sine, Triangle, and asymmetric Sawtooth) on the accuracy of collision cross section (CCS) measurements using traveling wave ion mobility spectrometry (TWIMS) separations in structures for lossless ion manipulations (SLIM). The effects of the waveform profiles on the accuracy of the CCS measurements were evaluated for four classes of compounds (lipids, peptides, steroids, and nucleosides) at different TW speeds (126-206 m/s) and amplitudes (15-89 V). For the lipids and peptides, the TWIMS-based CCS (TWCCS) deviations from the corresponding drift-tube-based CCS (DTCCS) measurements were significantly lower in experiments conducted using the Sawtooth waveform compared to the square waveform. This observation can be rationalized by the lower maximum electric field experienced by ions with a Sawtooth waveform, as compared to the other waveforms, resulting in a lower probability for significant ion heating. We also observed that given approximately comparable resolution for all four waveforms, the Sawtooth waveform resulted in lower TWCCS error and a better agreement with DTCCS values than the Square waveform. In addition, for the steroids and nucleosides, an opposite TWCCS trend was observed, with higher errors with the Sawtooth waveform and lower with the Square waveform, suggesting that these molecules tend to become slightly more compact under ion heating conditions. Under optimum conditions, all TWCCS measurements on the SLIM platform were within 0.5% of those measured in the drift tube ion mobility spectrometry.To investigate possible biochemical abnormalities associated with celiac disease (CD) antibody positivity in a primary health care setting and thereby identify predictors that could potentially reduce diagnostic delay and underdiagnosis of CD. This observational cohort study included measurements of CD antibodies in the Copenhagen Primary Care Laboratory (CopLab) database from 2000 to 2015; CD antibody positivity was defined as tissue transglutaminase antibody IgA or IgG ≥ 7 kU/L and/or deamidated gliadin peptide antibody IgG ≥ 10 kU/L. Individuals with a prior diagnosis of CD were excluded. We examined differences between individuals with positive and negative CD antibody tests regarding the results of biochemical tests performed six months before and one month after the date of the CD antibody test. We identified 76,265 measurements of CD antibodies during 2000-2015, and 57,061 individuals met the inclusion criteria (706 antibody-positive and 56,355 antibody-negative). We found lower ferritin, hemoglobin, cobalamin and folic acid levels and higher levels of transferrin, ALAT (alanine transaminase), and alkaline phosphate among individuals with a positive CD antibody test. Furthermore, we illustrated more measurements below the sex-specific reference intervals for hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), ferritin, cobalamin and folic acid among individuals with a positive CD antibody test. This study identified several biochemical abnormalities associated with CD antibody positivity among individuals referred to CD antibody testing. The pattern of abnormalities suggested that micronutrient deficiencies were prevalent among CD antibody-positive individuals, confirming malabsorption as a sign of CD. These findings illustrate the possibility of reducing diagnostic delay and underdiagnosis of CD.Pathogen adaptation to public health interventions such as vaccination may take tortuous routes and involve multiple mutations at different locations in the pathogen genome, acting on distinct phenotypic traits. Yet how these multi-locus adaptations jointly evolve is poorly understood. Here we consider the joint evolution of two adaptations pathogen escape from the vaccine-induced immune response and adjustments to pathogen virulence affecting transmission or clearance. We elucidate the role played by epistasis and recombination, with an emphasis on the different protective effects of vaccination. We show that vaccines blocking infection, reducing transmission and/or increasing clearance generate positive epistasis between the vaccine-escape and virulence alleles, favouring strains that carry both mutations, whereas vaccines reducing virulence mortality generate negative epistasis, favouring strains that carry either mutation but not both. High rates of recombination can affect these predictions. If epistasis is positive, frequent recombination can prevent the transient build-up of more virulent escape strains. If epistasis is negative, frequent recombination between loci can create an evolutionary bistability, favouring whichever adaptation is more accessible. Our work provides a timely alternative to the variant-centred perspective on pathogen adaptation and captures the effect of different types of vaccine on the interference between multiple adaptive mutations.

To understand the sex difference in age at adiposity rebound (AR), integrate the prevalence of early AR (EAR), and provide a quantitative association between early age at AR and overweight/obesity.

Literature review was conducted in different databases, including the Web of Science, PubMed, EMBASE, Wiley, Chinese National Knowledge Infrastructure, and ScienceDirect databases up to August 2021. Studies that reported data related to AR were considered for inclusion. Pooled effect sizes and their respective 95% confidence intervals (CIs) were calculated using random effects models, depending on the size of heterogeneity. Heterogeneity was tested by using the I

statistics.

28 studies with a combined sample size of 106,397 people were included in the final meta-analysis. Girls had a significantly earlier age of AR than boys (mean difference = 3.38 months; 95% CI 2.14-4.63). The overall prevalence of EAR was 40% (95% CI 31% to 50%), and the prevalence in girls was 5% higher than that in boys based on the definition of age at AR < 5.0-5.1 years. The overall pooled prevalence of EAR showed an increasing trend by child's birth year [1934-1973] 29% (95% CI 22% to 37%), 1991-2001 35% (95% CI 26% to 44%), and 2002-2009 52% (95% CI 40-63%). Early age at AR (age at AR < 5.0-5.1 years) was associated with a significantly increased risk of overweight/obesity (OR = 5.07; 95% CI 3.60-7.12), overweight (OR = 3.10; 95% CI 1.69-5.70), and obesity (OR = 6.97; 95% CI 4.32-11.26) from the preschool period to adulthood.

The overall prevalence of EAR is increasing, and girls experience AR earlier than boys. The early age at AR in children may be an early and effective marker of obesity.

The overall prevalence of EAR is increasing, and girls experience AR earlier than boys. The early age at AR in children may be an early and effective marker of obesity.

To develop and validate an end-to-end region-based deep convolutional neural network (R-DCNN) to jointly segment the optic disc (OD) and optic cup (OC) in retinal fundus images for precise cup-to-disc ratio (CDR) measurement and glaucoma screening.

In total, 2440 retinal fundus images were retrospectively obtained from 2033 participants. An R-DCNN was presented for joint OD and OC segmentation, where the OD and OC segmentation problems were formulated into object detection problems. We compared R-DCNN's segmentation performance on our in-house dataset with that of four ophthalmologists while performing quantitative, qualitative and generalization analyses on the publicly available both DRISHIT-GS and RIM-ONE v3 datasets. The Dice similarity coefficient (DC), Jaccard coefficient (JC), overlapping error (E), sensitivity (SE), specificity (SP) and area under the curve (AUC) were measured.

On our in-house dataset, the proposed model achieved a 98.51% DC and a 97.07% JC for OD segmentation, and a 97.63% DC and a 95.39% JC for OC segmentation, achieving a performance level comparable to that of the ophthalmologists. On the DRISHTI-GS dataset, our approach achieved 97.23% and 94.17% results in DC and JC results for OD segmentation, respectively, while it achieved a 94.56% DC and an 89.92% JC for OC segmentation. Additionally, on the RIM-ONE v3 dataset, our model generated DC and JC values of 96.89% and 91.32% on the OD segmentation task, respectively, whereas the DC and JC values acquired for OC segmentation were 88.94% and 78.21%, respectively.

The proposed approach achieved very encouraging performance on the OD and OC segmentation tasks, as well as in glaucoma screening. It has the potential to serve as a useful tool for computer-assisted glaucoma screening.

The proposed approach achieved very encouraging performance on the OD and OC segmentation tasks, as well as in glaucoma screening. It has the potential to serve as a useful tool for computer-assisted glaucoma screening.When confronted with heat stress, plants depend on the timely activation of cellular defences to survive by perceiving the rising temperature. However, how plants sense heat at the whole-plant level has remained unanswered. Here we demonstrate that shoot apical nitric oxide (NO) bursting under heat stress as a signal triggers cellular heat responses at the whole-plant level on the basis of our studies mainly using live-imaging of transgenic plants harbouring pHsfA2LUC, micrografting, NO accumulation mutants and liquid chromatography-tandem mass spectrometry analysis in Arabidopsis. Furthermore, we validate that S-nitrosylation of the trihelix transcription factor GT-1 by S-nitrosoglutathione promotes its binding to NO-responsive elements in the HsfA2 promoter and that loss of function of GT-1 disrupts the activation of HsfA2 and heat tolerance, revealing that GT-1 is the long-sought mediator linking signal perception to the activation of cellular heat responses. These findings uncover a heat-responsive mechanism that determines the timing and execution of cellular heat responses at the whole-plant level.Cycads represent one of the most ancient lineages of living seed plants. Identifying genomic features uniquely shared by cycads and other extant seed plants, but not non-seed-producing plants, may shed light on the origin of key innovations, as well as the early diversification of seed plants. Here, we report the 10.5-Gb reference genome of Cycas panzhihuaensis, complemented by the transcriptomes of 339 cycad species. Nuclear and plastid phylogenomic analyses strongly suggest that cycads and Ginkgo form a clade sister to all other living gymnosperms, in contrast to mitochondrial data, which place cycads alone in this position. We found evidence for an ancient whole-genome duplication in the common ancestor of extant gymnosperms. The Cycas genome contains four homologues of the fitD gene family that were likely acquired via horizontal gene transfer from fungi, and these genes confer herbivore resistance in cycads. The male-specific region of the Y chromosome of C. panzhihuaensis contains a MADS-box transcription factor expressed exclusively in male cones that is similar to a system reported in Ginkgo, suggesting that a sex determination mechanism controlled by MADS-box genes may have originated in the common ancestor of cycads and Ginkgo. The C. panzhihuaensis genome provides an important new resource of broad utility for biologists.

Conflicting evidence exists regarding whether hormone therapy for prostate cancer is associated with neurotoxicity. Thus, we aim to characterize the association between different types of hormone therapy and neurocognitive impairment in a real-world pharmacovigilance database.

We queried VigiBase, the World Health Organization's international pharmacovigilance database, for reports of neurocognitive impairment among men who took hormone therapy from 1968 to 2021. We performed disproportionality analysis comparing rates of neurocognitive impairment with different types of hormone therapy versus other VigiBase drugs. Traditional hormonal therapy was defined as androgen deprivation therapy (ADT gonadotropin-releasing-hormone agonists or antagonists) or first-generation androgen receptor (AR) antagonists. Novel AR signaling inhibitors (ARSIs) were defined as ARSIs with or without ADT. Differences were assessed using reporting odds ratio (ROR) with 95% confidence intervals (CI) and Empirical Bayes Estimator (Ere exploratory in nature. The amalgamation of these and other conflicting data may contribute to clinical decision-making for men with prostate cancer eligible for treatment with these therapies, especially those with significant neurologic comorbidities.

This study demonstrates elevated odds of neurocognitive impairment with hormone therapy in a real-world data set. Neurotoxicity risk was higher with novel ARSIs than traditional agents, and higher with enzalutamide than abiraterone. Due to limitations inherent to disproportionality analysis (measuring associations, not risk) and incomplete data prohibiting the ability to control for factors such as age or use of secondary drugs (e.g., concurrent use of novel ARSIs with ADT), results are exploratory in nature. The amalgamation of these and other conflicting data may contribute to clinical decision-making for men with prostate cancer eligible for treatment with these therapies, especially those with significant neurologic comorbidities.The IMGT database profiles the TR germline alleles for all four TR loci (TRA, TRB, TRG and TRD), however, it does not comprise of the information regarding population specificity and allelic frequencies of these germline alleles. The specificity of allelic variants to different human populations can, however, be a rich source of information when studying the genetic basis of population-specific immune responses in disease and in vaccination. Therefore, we meticulously identified true germline alleles enriched with complete TR allele sequences and their frequencies across 26 different human populations, profiled by "1000 Genomes data". We identified 205 TRAV, 249 TRBV, 16 TRGV and 5 TRDV germline alleles supported by at least four haplotypes. The diversity of germline allelic variants in the TR loci is the highest in Africans, while the majority of the Non-African alleles are specific to the Asian populations, suggesting a diverse profile of TR germline alleles in different human populations. Interestingly, the alleles in the IMGT database are frequent and common across all five super-populations. We believe that this new set of germline TR sequences represents a valuable new resource which we have made available through the new population-matched TR (pmTR) database, accessible via https//pmtrig.lumc.nl/ .There is an increasing demand for supporting the adoption of rapid whole-genome sequencing (rWGS) by demonstrating its real-world value. We aimed to assess the cost-effectiveness of rWGS in critically ill pediatric patients with diseases of unknown cause. Data were collected prospectively of patients admitted to the Nicklaus Children's Hospital's intensive care units from March 2018 to September 2020, with rWGS (N = 65). Comparative data were collected in a matched retrospective cohort with standard diagnostic genetic testing. We determined total costs, diagnostic yield (DY), and incremental cost-effectiveness ratio (ICER) adjusted for selection bias and right censoring. Sensitivity analyses explored the robustness of ICER through bootstrapping. rWGS resulted in a diagnosis in 39.8% while standard testing in 13.5% (p = 0.026). rWGS resulted in a mean saving per person of $100,440 (SE = 26,497, p  less then  0.001) and a total of $6.53 M for 65 patients. rWGS in critically ill pediatric patients is cost-effective, cost-saving, shortens diagnostic odyssey, and triples the DY of traditional approaches.NIMA related Kinases (NEK7) plays an important role in spindle assembly and mitotic division of the cell. Over expression of NEK7 leads to the progression of different cancers and associated malignancies. It is becoming the next wave of targets for the development of selective and potent anti-cancerous agents. The current study is the first comprehensive computational approach to identify potent inhibitors of NEK7 protein. For this purpose, previously identified anti-inflammatory compound i.e., Phenylcarbamoylpiperidine-1,2,4-triazole amide derivatives by our own group were selected for their anti-cancer potential via detailed Computational studies. Initially, the density functional theory (DFT) calculations were carried out using Gaussian 09 software which provided information about the compounds' stability and reactivity. Furthermore, Autodock suite and Molecular Operating Environment (MOE) software's were used to dock the ligand database into the active pocket of the NEK7 protein. Both software performances were compared in terms of sampling power and scoring power. During the analysis, Autodock results were found to be more reproducible, implying that this software outperforms the MOE. The majority of the compounds, including M7, and M12 showed excellent binding energies and formed stable protein-ligand complexes with docking scores of - 29.66 kJ/mol and - 31.38 kJ/mol, respectively. The results were validated by molecular dynamics simulation studies where the stability and conformational transformation of the best protein-ligand complex were justified on the basis of RMSD and RMSF trajectory analysis. The drug likeness properties and toxicity profile of all compounds were determined by ADMETlab 2.0. Furthermore, the anticancer potential of the potent compounds were confirmed by cell viability (MTT) assay. This study suggested that selected compounds can be further investigated at molecular level and evaluated for cancer treatment and associated malignancies.Nuclear transcription factor Mesenchyme Homeobox 2 (MEOX2) is a homeobox gene that is originally discovered to suppress the growth of vascular smooth muscle and endothelial cells. However, whether or not it is connected to cancer is yet unknown. Here, we report that MEOX2 functions as a tumor-initiating element in glioma. Bioinformatic analyses of public databases and investigation of MEOX2 expression in patients with glioma demonstrated that MEOX2 was abundant at both mRNA and protein levels in glioma. MEOX2 expression was shown to be inversely linked with the prognosis of glioma patients. MEOX2 inhibition changed the morphology of glioma cells, inhibited cell proliferation and motility, whereas had no effect on cell apoptosis. Besides, silencing MEOX2 also hampered the epithelial-mesenchymal transition (EMT), focal adhesion formation, and F-actin assembly. Overexpression of MEOX2 exhibited opposite effects. Importantly, RNA-sequencing, ChIP-qPCR assay, and luciferase reporter assay revealed Cathepsin S (CTSS) as a novel transcriptional target of MEOX2 in glioma cells. Consistently, MEOX2 causes glioma tumor development in mice and greatly lowers the survival period of tumor-bearing mice. Our findings indicate that MEOX2 promotes tumorigenesis and progression of glioma partially through the regulation of CTSS. Targeting MEOX2-CTSS axis might be a promising alternative for the treatment of glioma.Properly responding to DNA damage is vital for eukaryotic cells, including the induction of DNA repair, growth arrest and, as a last resort to prevent neoplastic transformation, cell death. Besides being crucial for ensuring homeostasis, the same pathways and mechanisms are at the basis of chemoradiotherapy in cancer treatment, which involves therapeutic induction of DNA damage by chemical or physical (radiological) measures. Apart from typical DNA damage response mediators, the relevance of cell-intrinsic antiviral signaling pathways in response to DNA breaks has recently emerged. Originally known for combatting viruses via expression of antiviral factors including interferons (IFNs) and establishing of an antiviral state, RIG-I-like receptors (RLRs) were found to be critical for adequate induction of cell death upon the introduction of DNA double-strand breaks. We here show that presence of IRF3 is crucial in this process, most likely through direct activation of pro-apoptotic factors rather than transcriptional induction of canonical downstream components, such as IFNs. Investigating genes reported to be involved in both DNA damage response and antiviral signaling, we demonstrate that IRF1 is an obligatory factor for DNA damage-induced cell death. Interestingly, its regulation does not require activation of RLR signaling, but rather sensing of DNA double-strand breaks by ATM and ATR. Hence, even though independently regulated, both RLR signaling and IRF1 are essential for full-fledged induction/execution of DNA damage-mediated cell death programs. Our results not only support more broadly developing IRF1 as a biomarker predictive for the effectiveness of chemoradiotherapy, but also suggest investigating a combined pharmacological stimulation of RLR and IRF1 signaling as a potential adjuvant regimen in tumor therapy.Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 subunit of gamma-aminobutyric acid A receptor (GABAAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAAR γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia.Inosine triphosphate pyrophosphatases (ITPases) are ubiquitous house-cleaning enzymes that specifically recognize deaminated purine nucleotides and catalyze their hydrolytic cleavage. In this work, we have characterized the Trypanosoma brucei ITPase ortholog (TbITPA). Recombinant TbITPA efficiently hydrolyzes (deoxy)ITP and XTP nucleotides into their respective monophosphate form. Immunolocalization analysis performed in bloodstream forms suggests that the primary role of TbITPA is the exclusion of deaminated purines from the cytosolic nucleoside triphosphate pools. Even though ITPA-knockout bloodstream parasites are viable, they are more sensitive to inhibition of IMP dehydrogenase with mycophenolic acid, likely due to an expansion of IMP, the ITP precursor. On the other hand, TbITPA can also hydrolyze the activated form of the antiviral ribavirin although in this case, the absence of ITPase activity in the cell confers protection against this nucleoside analog. This unexpected phenotype is dependant on purine availability and can be explained by the fact that ribavirin monophosphate, the reaction product generated by TbITPA, is a potent inhibitor of trypanosomal IMP dehydrogenase and GMP reductase. In summary, the present study constitutes the first report on a protozoan inosine triphosphate pyrophosphatase involved in the removal of harmful deaminated nucleotides from the cytosolic pool.Retinal ganglion cells (RGCs) axons are the signal carriers of visual information between retina and brain. Therefore, they play one of the important roles affected in many optic neurodegenerative diseases like glaucoma. Among the genetic risks associated with glaucoma, the E50K mutation in the Optineurin (OPTN) gene are known to result in glaucoma in the absence of increased intraocular pressure (IOP), whereas the relevant pathological mechanism and neurological issues remain to be further investigated. link2 In this study, the OPTN (E50K) mutant mouse model was established through CRISPR/Cas9-mediated genome editing, and aging-related RGCs loss and the visual dysfunction were identified. In E50K mice 16 months old, the axonal transport decreased comparing to wild-type (WT) mice at the same age. Furthermore, results of electron microscopy demonstrated significant morphological anomaly of mitochondria in RGCs axons of young E50K mice 3 months old, and these changes were aggravated with age. These indicated that the damaged mitochondria-associated dysfunction of RGCs axon should play an etiological role in glaucoma as an age-related outcome of OPTN (E50K) mutation. The findings of this study have potential implications for the targeted prevention and treatment of NTG.RecQ helicases-also known as the "guardians of the genome"-play crucial roles in genome integrity maintenance through their involvement in various DNA metabolic pathways. Aside from being conserved from bacteria to vertebrates, their importance is also reflected in the fact that in humans impaired function of multiple RecQ helicase orthologs are known to cause severe sets of problems, including Bloom, Werner, or Rothmund-Thomson syndromes. Our aim was to create and characterize a zebrafish (Danio rerio) disease model for Bloom syndrome, a recessive autosomal disorder. In humans, this syndrome is characterized by short stature, skin rashes, reduced fertility, increased risk of carcinogenesis, and shortened life expectancy brought on by genomic instability. We show that zebrafish blm mutants recapitulate major hallmarks of the human disease, such as shortened lifespan and reduced fertility. Moreover, similarly to other factors involved in DNA repair, some functions of zebrafish Blm bear additional importance in germ line development, and consequently in sex differentiation. Unlike fanc genes and rad51, however, blm appears to affect its function independent of tp53. Therefore, our model will be a valuable tool for further understanding the developmental and molecular attributes of this rare disease, along with providing novel insights into the role of genome maintenance proteins in somatic DNA repair and fertility.Identifying the mechanism of glioma progression is critical for diagnosis and treatment. Although studies have shown that guanylate-binding protein 2(GBP2) has critical roles in various cancers, its function in glioma is unclear. In this work, we demonstrate that GBP2 has high expression levels in glioma tissues. In glioma cells, depletion of GBP2 impairs proliferation and migration, whereas overexpression of GBP2 enhances proliferation and migration. Regarding the mechanism, we clarify that epidermal growth factor receptor (EGFR) signaling is regulated by GBP2, and also demonstrate that GBP2 interacts directly with kinesin family member 22(KIF22) and regulates glioma progression through KIF22/EGFR signaling in vitro and in vivo. Therefore, our study provides new insight into glioma progression and paves the way for advances in glioma treatment.Penetration of immune cells into tumor cells was believed to be immune-suppressive via cell-in-cell (CIC) mediated death of the internalized immune cells. We unexpectedly found that CIC formation largely led to the death of the host tumor cells, but not the internalized immune cells, manifesting typical features of death executed by NK cells; we named this "in-cell killing" which displays the efficacy superior to the canonical way of "kiss-killing" from outside. By profiling isogenic cells, CD44 on tumor cells was identified as a negative regulator of "in-cell killing" via inhibiting CIC formation. link3 CD44 functions to antagonize NK cell internalization by reducing N-cadherin-mediated intercellular adhesion and by enhancing Rho GTPase-regulated cellular stiffness as well. Remarkably, antibody-mediated blockade of CD44 signaling potentiated the suppressive effects of NK cells on tumor growth associated with increased heterotypic CIC formation. Together, we identified CIC-mediated "in-cell killing" as a promising strategy for cancer immunotherapy.Papillary thyroid cancer (PTC) is a common endocrine system malignancy all over the world. Aberrant expression of six transmembrane epithelial antigen of the prostate 2 (STEAP2) has been functionally associated with cancer progression in many cancers. Nevertheless, its biological function in PTC is still unclear. Here, we found that PTC tissues had preferentially downregulated STEAP2 as compared with noncancerous tissues. Low STEAP2 expression correlated with aggressive clinicopathological characteristics and dismal prognosis in patients with PTC. We performed gain- and loss-of-function experiments, including cell proliferation assay (Cell Counting Kit-8 assay), EdU (5-ethynyl-2'-deoxyuridine) and colony formation assays, transwell migration, and invasion assays, and constructed a nude mouse xenograft tumor model. The results demonstrated that STEAP2 overexpression inhibited PTC cell proliferation, migration, and invasion in vitro and inhibited lung metastasis and tumorigenicity in vivo. Conversely, silencing STEAP2 yielded the opposite results in vitro. Mechanistically, bioinformatics analysis combined with validation experiments identified STEAP2 as the downstream target of methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification. METTL3 stabilized STEAP2 mRNA and regulated STEAP2 expression positively in an m6A-dependent manner. We also showed that m6A-mediated STEAP2 mRNA translation initiation relied on a pathway dependent on the m6A reader protein YTHDF1. Rescue experiments revealed that silencing STEAP2 partially rescued the tumor-suppressive phenotype induced by METTL3 overexpression. Lastly, we verified that the METTL3-STEAP2 axis functions as an inhibitor in PTC by suppressing epithelial-mesenchymal transition and the Hedgehog signaling pathway. Taken together, these findings strongly suggest that METTL3-mediated STEAP2 m6A modification plays a critical tumor-suppressive role in PTC progression. The METTL3-STEAP2 axis may be a potential therapeutic molecular target against PTC.Variants of concern (VOCs) like Delta and Omicron, harbor a high number of mutations, which aid these viruses in escaping a majority of known SARS-CoV-2 neutralizing antibodies (NAbs). In this study, Rhesus macaques immunized with 2-dose inactivated vaccines (Coronavac) were boosted with an additional dose of homologous vaccine or an RBD-subunit vaccine, or a bivalent inactivated vaccine (Beta and Delta) to determine the effectiveness of sequential immunization. The booster vaccination significantly enhanced the duration and levels of neutralizing antibody titers against wild-type, Beta, Delta, and Omicron. Animals administered with an indicated booster dose and subsequently challenged with Delta or Omicron variants showed markedly reduced viral loads and improved histopathological profiles compared to control animals, indicating that sequential immunization could protect primates against Omicron. link3 These results suggest that sequential immunization of inactivated vaccines or polyvalent vaccines could be a potentially effective countermeasure against newly emerging variants.In the tumor microenvironment, cancer cells experience hypoxia resulting in the accumulation of misfolded/unfolded proteins largely in the endoplasmic reticulum (ER). Consequently, ER proteotoxicity elicits unfolded protein response (UPR) as an adaptive mechanism to resolve ER stress. In addition to canonical UPR, proteotoxicity also stimulates the selective, autophagy-dependent, removal of discrete ER domains loaded with misfolded proteins to further alleviate ER stress. These mechanisms can favor cancer cell growth, metastasis, and long-term survival. Our investigations reveal that during hypoxia-induced ER stress, the ER-phagy receptor FAM134B targets damaged portions of ER into autophagosomes to restore ER homeostasis in cancer cells. Loss of FAM134B in breast cancer cells results in increased ER stress and reduced cell proliferation. Mechanistically, upon sensing hypoxia-induced proteotoxic stress, the ER chaperone BiP forms a complex with FAM134B and promotes ER-phagy. To prove the translational implication of our mechanistic findings, we identified vitexin as a pharmacological agent that disrupts FAM134B-BiP complex, inhibits ER-phagy, and potently suppresses breast cancer progression in vivo.Nonalcoholic fatty liver disease (NAFLD) is an ubiquitous disease that exists across a wide spectrum ranging from steatosis, steatohepatitis, advanced fibrosis, and liver cirrhosis. Hallmarks of NAFLD are lipid accumulation, insulin resistance, and chronic low-grade inflammation. However, there currently are no medications approved for NAFLD. B-cell lymphoma 6 (BCL6) is a transcriptional inhibitor that is vital for germinal center B-cell formation. Our study identified BCL6 as a critical modulator of hepatic lipid metabolism and appears to contribute to the initiation and progression of NAFLD. In our research, we induced hepatic BCL6 overexpression using adeno-associated virus (AAV), as well as conditional liver-specific BCL6 knockout mice (BCL6-CKO). With these models, we noted that BCL6 overexpression improved insulin resistance and hepatic steatosis in mice models maintained on a HFD diet. Conversely, these parameters worsened in the livers of mice with downregulated BCL6 levels. Mechanistically, the translocase fatty acid CD36 was determined to be a transcriptional target of BCL6 that influences its role in hepatic steatosis. BCL6 bound directly to the CD36 promoter region, restraining CD36 transcription under physiological conditions. We conclude that the hepatocyte BCL6 inhibits the NAFLD progression in mice, including deranged lipid accumulation and glucose metabolism, through a CD36-dependent manner. These results indicate that BCL6 may potentially be targeted in NAFLD treatment.Extensive changes of circRNA expression underscore their essential contributions to multiple hallmarks of cancers; however, their functions and mechanisms of action in esophageal squamous cell carcinoma (ESCC) remain undetermined. Here, we adopted a three-stage approach by first screening for significantly differentially expressed circRNAs in ESCC and performing an external validation study, followed by the functional analyses. The properties of circRNAs were evaluated using Sanger sequencing, RNase R digestion, actinomycin D treatment, subcellular localization analysis, and fluorescence in situ hybridization. Target transcripts were predicted using online tools and verified by dual-luciferase, RNA immunoprecipitation, qRT-PCR, and western blot. Biotin-labeled RNA-protein pull-down, mass spectrometry, and RNA immunoprecipitation were employed to identify proteins interacting with circRNAs. Gain- and loss-of-function experiments were performed to uncover the roles of circRNAs, their target genes, and binding pidate therapeutic target.Mesenchymal stem cells (MSCs) are a type of immunosuppressive stromal cell found in multiple tissues and organs. ABT-199 order However, whether MSCs possess immunosupportive characteristics remains unclear. In this study, we showed that the lymph nodes contain immunosupportive MSCs. They produce and secrete a high level of MCP-1 to promote T-cell proliferation and differentiation, in contrast to bone marrow MSCs (BMMSCs), which repress T-cell activation. Unlike BMMSCs, lymph node MSCs (LNMSCs) fail to respond to activated T-cell-induced production of PD-L1 to induce T-cell apoptosis. Mechanistically, MCP-1 activates phospho-Erk to sustain T-cell proliferation and activation while it represses NF-κB/PD-L1 pathway to avoid induction of T-cell apoptosis. Interestingly, inflammatory lymph node-derived LNMSCs abolish their immunosupportive function due to reduction of MCP-1 expression. Finally, we show that systemic infusion of LNMSCs rescues immunosuppression in cytoxan (CTX)-treated mice. This study reveals a previously unrecognized mechanism underlying MSC-based immunoregulation using the MCP-1/PD-L1 axis to energize T cells and suggests a potential to use MSCs to treat immunosuppressive disorders.