bluuebunny/crossref_metadata_2025 huggingface dataset:
Justification and being in a position to know: reply to Waxman
Authors: Rosenkranz Sven
Published: May 2023

Daniel Waxman (2022a) argues that the thesis, recently advanced in Rosenkranz 2021, that one has propositional justification for φ, if and only if one is in no position to rule out that one is in a position to know φ, has clear counterexamples. However, Waxman makes controversial assumptions about the notion of being in a position to knowthat I should and coherently can reject. On the alternative construal of the notion open to me, Waxman’s strategy to produce counterexamples founders. However, this line of response has repercussions for two further theses I defend, viz.that propositional justification and its absence each are luminous. It is shown what more needs to be argued in order to avert a corresponding threat to the latter.
IndepthPathway: an integrated tool for in-depth pathway enrichment analysis based on single-cell sequencing data
Authors: Lee Sanghoon , Deng Letian , Wang Yue , Wang Kai , Sartor Maureen A , Wang Xiao-Song
Published: May 2023

Motivation

Single-cell sequencing enables exploring the pathways and processes of cells, and cell populations. However, there is a paucity of pathway enrichment methods designed to tolerate the high noise and low gene coverage of this technology. When gene expression data are noisy and signals are sparse, testing pathway enrichment based on the genes expression may not yield statistically significant results, which is particularly problematic when detecting the pathways enriched in less abundant cells that are vulnerable to disturbances.

Results

In this project, we developed a Weighted Concept Signature Enrichment Analysis specialized for pathway enrichment analysis from single-cell transcriptomics (scRNA-seq). Weighted Concept Signature Enrichment Analysis took a broader approach for assessing the functional relations of pathway gene sets to differentially expressed genes, and leverage the cumulative signature of molecular concepts characteristic of the highly differentially expressed genes, which we termed as the universal concept signature, to tolerate the high noise and low coverage of this technology. We then incorporated Weighted Concept Signature Enrichment Analysis into an R package called “IndepthPathway” for biologists to broadly leverage this method for pathway analysis based on bulk and single-cell sequencing data. Through simulating technical variability and dropouts in gene expression characteristic of scRNA-seq as well as benchmarking on a real dataset of matched single-cell and bulk RNAseq data, we demonstrate that IndepthPathway presents outstanding stability and depth in pathway enrichment results under stochasticity of the data, thus will substantially improve the scientific rigor of the pathway analysis for single-cell sequencing data.

Availability and implementation

The IndepthPathway R package is available through: https://github.com/wangxlab/IndepthPathway.
Intensity and Variable Attention: Counter Narrating ADHD, from ADHD Deficits to ADHD Difference
Authors: Bertilsdotter Rosqvist Hanna , Hultman Lill , Österborg Wiklund Sofia , Nygren Anna , Storm Palle , Sandberg Greta
Published: May 2023

Literature on attention deficit hyperactivity disorder (ADHD) has historically come from a cognitive deficit approach and lacked community authorship. In contrast, this article utilises a neurodiversity framework to explore ADHD as a cognitive difference through ADHDers’ experiences. Specifically, here we analyse collective autoethnographic writings from neurodivergent academic researchers writing to one other about their experiences of intensity and variable attention or interest-based attention. Through the process of collective writing, we started to rename and restory our experiences, which has enabled us to understand intensity and variable attention as a valuable facet of human diversity, with both strengths and challenges. This project offers an example of how community-based research can elucidate individual experiences as ADHD/AuDHD researchers, facilitate exploration of varied experiences with intensity and attention and increase self-awareness and ability to give and receive neuroaffirmative support.
Average creatinine–urea clearance: revival of an old analytical technique?
Authors: Selistre Luciano , de Souza Vandréa , Nicola Carla , Juillard Laurent , Lemoine Sandrine , Derain-Dubourg Laurence
Published: May 2023

Background

Creatinine-based equations such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) are recommended for estimating glomerular filtration rate (eGFR) in clinical practice, but have reduced performance in advanced stages of chronic kidney disease. However, only rarely studies have evaluated the performance of eGFR by measuring the average of the urinary clearances of creatinine and urea (mClUN-cr) compared with the eGFR equations.

Methods

This cross-sectional study evaluated the usefulness of mClUN-cr in a population of 855 participants who performed a GFR measurement by urinary inulin clearance. The performance of mClUN-cr was compared with those of CKD-EPI 2009 and CKD-EPI 2021, considering three criteria: bias, precision and accuracy.

Results

In the whole sample, the mClUN-cr performed similarly to CKD-EPI equations (2009 and 2021) [precision: 11.5 (95% CI 10.5; 12.5) vs 19.0 (95% CI 17.2; 20.1) and 19.1 (95% CI 17.4; 20.4), and accuracy P30: 97.0 (95% CI 95.8; 98.0) vs 82.0 (95% CI 79.2; 84.4) and 77.2 (95% CI 74.5; 80.0)]. The CKD-EPI equations (2009 and 2021) had the best performance when mGFR was >60 mL/min/1.73 m2. In contrast, the mClUN-cr performed better than others with lowest mGFR values, more noticeable when mGFR was <60 mL/min/1.73 m2.

Conclusions

The study described the best performance of mClUN-cr at GFR levels below 60 mL/min/1.73 m2 and a satisfactory result in the overall cohort. The findings point to a role of this tool, especially for estimating GFR in chronic kidney disease patients in developing countries, when reference measurement of GFR is not available.
Influenza vaccination is associated with lower risk of renal cell carcinoma among chronic kidney disease patients: a population-based cohort study
Authors: Lin Chia-Wei , Zheng Jing-Quan , Tzou Kai-Yi , Fang Yu-Ann , Kao Wei-Tang , Lin Hsin-Ting , Liu Ju-Chi , Huang Yu-Han , Lin Yuh-Feng , Lu Kuo-Cheng , Dong Shao-Wei , Zheng Cai-Mei , Wu Chia-Chang
Published: May 2023

Background

Chronic kidney disease (CKD) patients possess a higher risk for renal cell carcinoma (RCC) possibly because of related underlying inflammation and immune dysregulation. In the current population-based cohort study, we evaluate the effects of influenza vaccination on RCC among CKD patients.

Methods

We analysed the vaccinated and unvaccinated CKD patients (≥55 years of age) identified from the Taiwan National Health Insurance Database. Propensity score matching was used to reduce the selection bias. Subgroup analyses based on comorbid conditions, dialysis status and vaccinated dosages were also conducted.

Results

The incidence of RCC decreased significantly in the vaccinated compared with unvaccinated group {unadjusted hazard ratio [HR] 0.50 [95% confidence interval (CI) 0.31–0.81], P < .01; adjusted HR 0.46 [95% CI 0.28–0.75], P < .01}. Such protective effects of influenza vaccination were noted significantly among those ≥75 years of age [unadjusted HR 0.29 (95% CI 0.12–0.74), P < .01; adjusted HR 0.22 (95% CI 0.08–0.58), P < .01]. A reverse association was noted between the total number of vaccinations and RCC events in both unadjusted and adjusted models. The Kaplan–Meier estimates of the RCC events showed significantly higher free survival rates in the vaccinated as compared with the unvaccinated patients (logrank P = .005).

Conclusion

This population-based cohort study found a significant inverse relationship between influenza vaccination and the risk of RCC in CKD patients and the protective effects were more prominent in patients >75 years of age. A possible relation exists between the total number of vaccinations and RCC events. Future randomized clinical and basic studies will be needed to prove these findings and underlying pathophysiological mechanisms.
Relationship of serum lipid parameters with kidney function decline accompanied by systemic arterial stiffness: a retrospective cohort study
Authors: Nagayama Daiji , Watanabe Yasuhiro , Yamaguchi Takashi , Fujishiro Kentaro , Suzuki Kenji , Shirai Kohji , Saiki Atsuhito
Published: May 2023

Background

Dyslipidemia is associated with kidney function decline (KFD), although the non-linear relationship of lipid parameters to KFD has not been fully elucidated. We aimed to determine the detailed relationship of baseline lipid parameters with KFD, considering the mediation of arterial stiffness.

Methods

A total of 27 864 urban residents with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 at baseline, who participated in a median of three (range two to eight) consecutive annual health examinations were studied. Arterial stiffness was assessed by cardio-ankle vascular index (CAVI). KFD was defined as development of eGFR <60 mL/min/1.73 m2.

Results

During the study period, 1837 participants (6.6%) developed KFD. Receiver operating characteristic analysis determined that the cutoff values independently associated with KFD are 123 mg/dL for low-density lipoprotein cholesterol (LDL-C) [area under the curve (95% confidence interval) 0.570 (0.557–0.583)], 65 mg/dL for high-density lipoprotein cholesterol (HDL-C) [0.552 (0.539–0.566)], 82 mg/dL for triglycerides (TG) [0.606 (0.593–0.618)] and 1.28 for TG/HDL-C ratio [0.600 (0.587–0.612)]. These cut-offs were independently associated with KFD in Cox analysis. Regarding the contribution of each lipid parameter to KFD, a linear relationship was observed for both TG and TG/HDL-C, and a U-shaped relationship for HDL-C. A adjusted mediating effect of CAVI on the relationship of TG or TG/HDL-C ratio with KFD was observed (mediating rate: 2.9% in TG, 2.5% in TG/HDL-C ratio). Regarding the association to KFD, a linear relationship was observed for both TG and TG/HDL-C, and a U-shaped relationship for HDL-C. A mediating effect of CAVI on the relationship of TG or TG/HDL-C ratio with KFD was observed after adjustment for confounders.

Conclusions

TG and TG/HDL-C ratio related linearly to KFD and this was partially mediated by CAVI. A U-shaped relationship was observed between HDL-C and KFD risk. LDL-C showed no significant association. Further study should investigate whether intensive TG-lowering treatment prevents KFD via decreasing CAVI.
Hypergraphx: a library for higher-order network analysis
Authors: Lotito Quintino Francesco , Contisciani Martina , De Bacco Caterina , Di Gaetano Leonardo , Gallo Luca , Montresor Alberto , Musciotto Federico , Ruggeri Nicolò , Battiston Federico
Published: May 2023

From social to biological systems, many real-world systems are characterized by higher-order, non-dyadic interactions. Such systems are conveniently described by hypergraphs, where hyperedges encode interactions among an arbitrary number of units. Here, we present an open-source python library, hypergraphx (HGX), providing a comprehensive collection of algorithms and functions for the analysis of higher-order networks. These include different ways to convert data across distinct higher-order representations, a large variety of measures of higher-order organization at the local and the mesoscale, statistical filters to sparsify higher-order data, a wide array of static and dynamic generative models, and an implementation of different dynamical processes with higher-order interactions. Our computational framework is general, and allows to analyse hypergraphs with weighted, directed, signed, temporal and multiplex group interactions. We provide visual insights on higher-order data through a variety of different visualization tools. We accompany our code with an extended higher-order data repository and demonstrate the ability of HGX to analyse real-world systems through a systematic analysis of a social network with higher-order interactions. The library is conceived as an evolving, community-based effort, which will further extend its functionalities over the years. Our software is available at https://github.com/HGX-Team/hypergraphx.
Normative cut-offs for polycystic ovary syndrome diagnostic features in adolescents using cluster analysis
Authors: Kiconco Sylvia , Earnest Arul , Enticott Joanne , Hart Roger , Mori Trevor A , Hickey Martha , Teede Helena J , Joham Anju E
Published: May 2023

Objective

The diagnosis of polycystic ovary syndrome (PCOS) remains challenging with international guidelines prioritising accurate cut-offs for individual diagnostic features. These diagnostic cut-offs are currently based on arbitrary percentiles, often from poorly characterised cohorts, and are dependent on variable laboratory ranges defined by assay manufacturers, limiting diagnostic accuracy. Cluster analysis is the recommended approach for defining normative cut-offs within populations for clinical syndromes. Few PCOS adult studies have applied cluster analysis, with no studies in adolescents. We aimed to define normative cut-offs for individual PCOS diagnostic features in a community-based population of adolescents using cluster analysis.

Design

This analysis utilised data from the Menstruation in Teenagers Study, a subgroup of the Raine Study, which is a population based prospective cohort of 244 adolescents whose mean age at PCOS assessment was 15.2 years.

Methods

K-means cluster analysis and receiver operating characteristics curves were used to define normative cut-offs for modified Ferriman–Gallwey (mFG) score, free testosterone (free T), free androgen index (FAI), and menstrual cycle length.

Results

Normative cut-offs for mFG, free T, FAI, and menstrual cycle lengths were 1.0, 23.4 pmol/L, 3.6, and 29 days, respectively. These corresponded to the 65th, 71st, 70th, and 59th population percentiles, respectively.

Conclusion

In this novel study, we define the normative diagnostic criteria cut-offs in this unselected adolescent population and show that these cut-offs correspond to lower percentiles than conventional cut-offs. These findings highlight the pertinent need to re-define PCOS diagnostic cut-offs in adolescents. Validation is required in larger, multi-ethnic, and well-characterised adolescent cohorts.
A high order unfitted hybridizable discontinuous Galerkin method for linear elasticity
Authors: Cárdenas Juan Manuel , Solano Manuel
Published: May 2023

This work analyses a high-order hybridizable discontinuous Galerkin (HDG) method for the linear elasticity problem in a domain not necessarily polyhedral. The domain is approximated by a polyhedral computational domain where the HDG solution can be computed. The introduction of the rotation as one of the unknowns allows us to use the gradient of the displacements to obtain an explicit representation of the boundary data in the computational domain. The boundary data is transferred from the true boundary to the computational boundary by line integrals, where the integrand depends on the Cauchy stress tensor and the rotation. Under closeness assumptions between the computational and true boundaries, the scheme is shown to be well-posed and optimal error estimates are provided even in the nearly incompressible case. Numerical experiments in two dimensions are presented.
Comparative Study of Continuous Wavelet Transform and Multivariate Calibration for the Simultaneous Spectrophotometric Determination of Tamsulosin and Solifenacin in Pharmaceutical Formulation and Biological Sample
Authors: Ashrafi Nazanin , Sohrabi Mahmoud Reza , Saber Tehrani Mandana
Published: May 2023

Background

Spectrophotometry alone is not applicable for the simultaneous determination of drugs in a multicomponent pharmaceutical formulation owing to their overlap.

Objective

In this study, the combination of UV-Vis spectrophotometry and chemometric methods, including continuous wavelet transform (CWT) and partial least-squares (PLS) was presented for the simultaneous estimation of tamsulosin (TAM) and solifenacin (SOL) in synthetic mixtures, commercial formulations, and a biological sample.

Methods

The simultaneous spectrophotometric determination of TAM and SOL in binary mixtures, a real sample, and a biological sample was performed by applying CWT and PLS approaches.

Results

In the CWT method, two various wavelet families named Daubechies (db2) at wavelength 223 nm and Biorthogonal (bior1.3) at wavelength 227 nm based on the appropriate zero-crossing point were selected for TAM and SOL, respectively. The linear ranges of TAM and SOL were 0.25–4 μg/mL and 10–30 μg/mL, respectively. The LODs were 0.0459 μg/mL and 0.2085 μg/mL, while the LOQs were 0.3208 μg/mL and 0.6495 μg/mL for TAM and SOL, respectively. The average recovery values of 18 mixtures were 98.28% and 97.79% for TAM and SOL, respectively. Also, the root mean square error (RMSE) of both components was lower than 2.3. Based on the k-fold cross-validation in the PLS approach, the optimum number of components related to TAM and SOL were 9 and 5 with a mean square error prediction (MSEP) of 0.0153 and 0.0370, respectively. The mean recovery values of the test set were found to be 100.09% for TAM and 99.95% for SOL where RMSE values were 0.0064 and 0.0169 for TAM and SOL, respectively.

Conclusion

Analysis of variance (ANOVA) was applied to the results of the real sample and there was no significant difference between the proposed methods and HPLC as a reference technique. The result obtained revealed that the proposed methods were found to be fast, facile, economical, and precise, and provide a suitable alternative to the HPLC technique for the concurrent determination of TAM and SOL in QC laboratories.

Highlights

UV-Vis spectrophotometry combined with CWT and PLS was developed. Simultaneous analysis of TAM and SOL was performed using the proposed approaches. These methods were implemented on synthetic mixtures, commercial formulations, and a biological sample. ANOVA test was used to compare the suggested methods and the HPLC technique.
Bee–plant interaction and community response along an urbanization gradient
Authors: Ayers Anthony C , Rehan Sandra M
Published: May 2023

Elucidating bee response to urbanization is essential to promoting pollinator diversity in cities especially considering such landscapes are projected to expand to support future global populations. To determine how bee community composition and plant–pollinator interactions respond to urbanization, 29 sites representing three urban categories (high, medium and low urbanization) were monitored biweekly from May through early October in Toronto, Canada. Bees were collected passively using pan and blue vane traps as well as actively using aerial nets and vacuums to compare community structure and plant–pollinator networks among urban categories. Functional traits such as dietary breadth, behaviour, nesting substrate and native or non-native status were also examined to determine how landscape influences bee community assemblages. In total, 5477 bees, comprising 26 genera and 164 species, were represented in this study. The urban landscape was largely supportive of species within the family Apidae and Halictidae as well as ground nesting, native and generalist species. Overall, community composition was affected by urban landscape characteristics such as percent tree cover and impervious (i.e. paved and built) surface surrounding sites; however, bee richness and abundance were significantly influenced by plant richness and not by landscape variables. A total of 3267 interactions were observed throughout the study region with characteristics of plant–pollinator networks remaining consistent along the urban gradient with a few floral host plants such as Solidago dominating interactions in certain urban contexts. These results provide important land use and floral host information for targeting pollinator conservation and habitat restoration.
Broad-band spectro-temporal investigation of neutron star low-mass X-ray binary GX 349+2
Authors: Kashyap Unnati , Chakraborty Manoneeta , Bhattacharyya Sudip , Ram Biki
Published: May 2023

We report a broad-band investigation of the Z-type neutron star (NS) low mass X-ray binary (LMXB) GX 349+2 using AstroSat and Neutron star Interior Composition Explorer (NICER). AstroSat observed the source exhibiting large scale variability in its normal branch (NB)/flaring branch (FB) vertex and FB and a moderate evolution during NICER observations. The power spectra exhibit very low-frequency noise (VLFN) and low-frequency noise (LFN)/FB noise, described by a power law (PL) and an evolving Lorentzian. We investigate the energy dependence of variability components and their correlation with the spectral state to probe their origin. The joint spectra of GX 349+2 are modeled by two thermal and one non-thermal component. The source moves along the Z track, with the increasing accretion rate, further heating of the NS boundary layer (BL), and increasing temperature/radius of the brightened hotspot at the disc-BL interface/NS surface. A PL well represents the hard non-thermal coronal emission. As predicted by the gravitational redshift, we find a correlation between the line energy detected in NICER spectra and the inner disc radius with the Spearman rank correlation coefficient of 1. Using this correlation, we demonstrate the potential of a method to constrain the accreting compact object properties, including evolving continuum and line spectroscopy. We report the first detection of hard lag providing evidence of the VLFN originating from the accretion disc in NS LMXBs, representing fluctuation of propagation through the disc.
Physician approval for pregnancy in patients with systemic lupus erythematosus showing only serological activity: A vignette survey study
Authors: Isojima Sakiko , Yajima Nobuyuki , Yanai Ryo , Miura Yoko , Fukuma Shingo , Kaneko Kayoko , Fujio Keishi , Oku Kenji , Matsushita Masakazu , Miyamae Takako , Wada Takashi , Tanaka Yoshiya , Kaneko Yuko , Nakajima Ayako , Murashima Atsuko
Published: May 2023

Objective

The European League Against Rheumatism recommends that the disease activity of systemic lupus erythematosus should be stable before pregnancy because complications and disease flares increase if pregnancy occurs while disease activity is high. However, some patients have ongoing serological activity even after treatment. Herein, we investigated how physicians decide on the acceptability of pregnancy in patients showing only serological activity.

Methods

A questionnaire was administered from December 2020 to January 2021. It included the characteristics of physicians, facilities, and the allowance for pregnancies of patients using vignette scenarios.

Results

The questionnaire was distributed to 4946 physicians, and 9.4% responded. The median age of respondents was 46 years, and 85% were rheumatologists. Pregnancy allowance was significantly affected by the duration of the stable period and status of serological activity [duration: proportion difference 11.8 percentage points (p.p.), P < .001; mild activity: proportion difference −25.8 p.p., P < .001; high activity: proportion difference −65.6 p.p., P < .001]. For patients with high-level serological activity, 20.5% of physicians allowed pregnancy if there were no clinical symptoms for 6 months.

Conclusions

Serological activity had a significant effect on the acceptability of pregnancy. However, some physicians allowed patients with serological activity alone to become pregnant. Further observational studies are required to clarify such prognoses.
Dual-center validation of using magnetic resonance imaging radiomics to predict stereotactic radiosurgery outcomes
Authors: DeVries David A , Tang Terence , Alqaidy Ghada , Albweady Ali , Leung Andrew , Laba Joanna , Lagerwaard Frank , Zindler Jaap , Hajdok George , Ward Aaron D
Published: May 2023

Background

MRI radiomic features and machine learning have been used to predict brain metastasis (BM) stereotactic radiosurgery (SRS) outcomes. Previous studies used only single-center datasets, representing a significant barrier to clinical translation and further research. This study, therefore, presents the first dual-center validation of these techniques.

Methods

SRS datasets were acquired from 2 centers (n = 123 BMs and n = 117 BMs). Each dataset contained 8 clinical features, 107 pretreatment T1w contrast-enhanced MRI radiomic features, and post-SRS BM progression endpoints determined from follow-up MRI. Random decision forest models were used with clinical and/or radiomic features to predict progression. 250 bootstrap repetitions were used for single-center experiments.

Results

Training a model with one center’s dataset and testing it with the other center’s dataset required using a set of features important for outcome prediction at both centers, and achieved area under the receiver operating characteristic curve (AUC) values up to 0.70. A model training methodology developed using the first center’s dataset was locked and externally validated with the second center’s dataset, achieving a bootstrap-corrected AUC of 0.80. Lastly, models trained on pooled data from both centers offered balanced accuracy across centers with an overall bootstrap-corrected AUC of 0.78.

Conclusions

Using the presented validated methodology, radiomic models trained at a single center can be used externally, though they must utilize features important across all centers. These models’ accuracies are inferior to those of models trained using each individual center’s data. Pooling data across centers shows accurate and balanced performance, though further validation is required.
WSD-0922, a novel brain-penetrant inhibitor of epidermal growth factor receptor, promotes survival in glioblastoma mouse models
Authors: Conage-Pough Jason E , Stopka Sylwia A , Oh Ju-Hee , Mladek Ann C , Burgenske Danielle M , Regan Michael S , Baquer Gerard , Decker Paul A , Carlson Brett L , Bakken Katrina K , Zhang Jinqiang , Liu Lily , Sun Claire , Mu Zhihua , Zhong Wei , Tran Nhan L , Elmquist William F , Agar Nathalie Y R , Sarkaria Jann N , White Forest M
Published: May 2023

Background

Although the epidermal growth factor receptor (EGFR) is a frequent oncogenic driver in glioblastoma (GBM), efforts to therapeutically target this protein have been largely unsuccessful. The present preclinical study evaluated the novel EGFR inhibitor WSD-0922.

Methods

We employed flank and orthotopic patient-derived xenograft models to characterize WSD-0922 and compare its efficacy to erlotinib, a potent EGFR inhibitor that failed to provide benefit for GBM patients. We performed long-term survival studies and collected short-term tumor, plasma, and whole-brain samples from mice treated with each drug. We utilized mass spectrometry to measure drug concentrations and spatial distribution and to assess the impact of each drug on receptor activity and cellular signaling networks.

Results

WSD-0922 inhibited EGFR signaling as effectively as erlotinib in in vitro and in vivo models. While WSD-0922 was more CNS penetrant than erlotinib in terms of total concentration, comparable concentrations of both drugs were measured at the tumor site in orthotopic models, and the concentration of free WSD-0922 in the brain was significantly less than the concentration of free erlotinib. WSD-0922 treatment provided a clear survival advantage compared to erlotinib in the GBM39 model, with marked suppression of tumor growth and most mice surviving until the end of the study. WSD-0922 treatment preferentially inhibited phosphorylation of several proteins, including those associated with EGFR inhibitor resistance and cell metabolism.

Conclusions

WSD-0922 is a highly potent inhibitor of EGFR in GBM, and warrants further evaluation in clinical studies.
Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness
Authors: Koessinger Dominik , Novo David , Koessinger Anna , Campos America , Peters Jasmine , Dutton Louise , Paschke Peggy , Zerbst Désirée , Moore Madeleine , Mitchell Louise , Neilson Matthew , Stevenson Katrina , Chalmers Anthony , Tait Stephen , Birch Joanna , Norman Jim
Published: May 2023

Background

Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo-, and radiotherapy. A deeper understanding of the mechanisms invoked by GBM to infiltrate the brain is needed to develop approaches to contain the disease and reduce recurrence. The aim of this study was to discover mechanisms through which extracellular vesicles (EVs) released by GBM influence the brain microenvironment to facilitate infiltration, and to determine how altered extracellular matrix (ECM) deposition by glial cells might contribute to this.

Methods

CRISPR was used to delete genes, previously established to drive carcinoma invasiveness and EV production, from patient-derived primary and GBM cell lines. We purified and characterized EVs released by these cells, assessed their capacity to foster pro-migratory microenvironments in mouse brain slices, and evaluated the contribution made by astrocyte-derived ECM to this. Finally, we determined how CRISPR-mediated deletion of genes, which we had found to control EV-mediated communication between GBM cells and astrocytes, influenced GBM infiltration when orthotopically injected into CD1-nude mice.

Results

GBM cells expressing a p53 mutant (p53R273H) with established pro-invasive gain-of-function release EVs containing a sialomucin, podocalyxin (PODXL), which encourages astrocytes to deposit ECM with increased levels of hyaluronic acid (HA). This HA-rich ECM, in turn, promotes migration of GBM cells. Consistently, CRISPR-mediated deletion of PODXL opposes infiltration of GBM in vivo.

Conclusions

This work describes several key components of an EV-mediated mechanism though which GBM cells educate astrocytes to support infiltration of the surrounding healthy brain tissue.
Assessing bird diversity in Neotropical rainforests: A comparative study of camera traps and mist nets reveals complementary sampling approaches
Authors: Vargas-Daza Angela M , Betancurt-Grisales Juan F , Cardona-Salazar Leydy J , Benavides-Ossa Yeny A , Fontúrbel Francisco E , Castaño-Villa Gabriel J
Published: May 2023

Different sampling methods are used to study bird diversity in the tropics, mist nets being one of the most common approaches. However, camera traps have been used for this purpose in the last 20 years. We compared the performance of mist nets and camera traps in sampling the diversity of understory and sub-canopy birds in a Neotropical rainforest. Given its high biodiversity, obtaining accurate bird diversity estimates in these forests is a challenging task. We sampled secondary forest patches in the Colombian central Andes between 2019 and 2021. We compared the effectiveness of both methods based on six comparison criteria (body size, foraging stratum, detection difficulty, habitat specialization, population trend, and migratory status). We recorded a total of 99 bird species: 92 species were captured using mist nets and 37 species using camera traps; 30 species were detected using both methods (mainly generalist and abundant birds). Mist net’s effectiveness was 83%, while camera trap effectiveness was 68%. Differences in sampling effectiveness were mainly determined by body size, as small birds were captured using mist nets, while camera traps often recorded large birds. However, detection difficulty and habitat specialization were also relevant. Camera traps effectively recorded ground-dwelling species that were not captured in mist nets. In contrast, those birds that forage in the sub-canopy stratum were mainly captured in the mist nets but not detected in camera traps. Although both methods detected different species, we found similar patterns regarding estimated species richness among different categories of body size, detection difficulty, population trend, and behavior, but not for habitat specialization. As both methods have advantages and limitations, using mist nets and camera traps together would improve bird diversity estimations. We urge investigators to explore canopy ecology with camera traps, as they provide long-term information that cannot be obtained with other methods.
Glutamine Metabolism, Sensing and Signaling in Plants
Authors: Lee Kim-Teng , Liao Hong-Sheng , Hsieh Ming-Hsiun
Published: May 2023

Glutamine (Gln) is the first amino acid synthesized in nitrogen (N) assimilation in plants. Gln synthetase (GS), converting glutamate (Glu) and NH4+ into Gln at the expense of ATP, is one of the oldest enzymes in all life domains. Plants have multiple GS isoenzymes that work individually or cooperatively to ensure that the Gln supply is sufficient for plant growth and development under various conditions. Gln is a building block for protein synthesis and an N-donor for the biosynthesis of amino acids, nucleic acids, amino sugars and vitamin B coenzymes. Most reactions using Gln as an N-donor are catalyzed by Gln amidotransferase (GAT) that hydrolyzes Gln to Glu and transfers the amido group of Gln to an acceptor substrate. Several GAT domain–containing proteins of unknown function in the reference plant Arabidopsis thaliana suggest that some metabolic fates of Gln have yet to be identified in plants. In addition to metabolism, Gln signaling has emerged in recent years. The N regulatory protein PII senses Gln to regulate arginine biosynthesis in plants. Gln promotes somatic embryogenesis and shoot organogenesis with unknown mechanisms. Exogenous Gln has been implicated in activating stress and defense responses in plants. Likely, Gln signaling is responsible for some of the new Gln functions in plants.
Revisiting Atiyah–Hitchin manifold in the generalized Legendre transform
Authors: Arai Masato , Baba Kurando , Ionaş Radu A
Published: May 2023

We revisit construction of the Atiyah–Hitchin manifold in the generalized Legendre transform approach. This was originally studied by Ivanov and Roček [I. T. Ivanov, M. Roček, Commun. Math. Phys. 182, 291 (1996)] and subsequently investigated more by Ionas [R. A. Ionas, arXiv:0712.3598] , in the latter of which the explicit forms of the Kähler potential and the Kähler metric are calculated. There is a difference between the former and the latter. In the generalized Legendre transform approach, a Kähler potential is constructed from the contour integration of one function with holomorphic coordinates. The choice of the contour in the latter is different from that in the former; this difference may yield a discrepancy in the Kähler potential and eventually in the Kähler metric. We show that the former only gives the real Kähler potential, which is consistent with its definition, while the latter yields the complex one. We derive the Kähler potential and the metric for the Atiyah–Hitchin manifold in terms of holomorphic coordinates for the contour considered by Ivanov and Roček for the first time.
Effect of lactation and nursery diets supplemented with a feed flavor on sow feed intake and lactation performance and subsequent weaned pig nursery performance
Authors: Spinler Mikayla S , Gebhardt Jordan T , Tokach Mike D , Goodband Robert D , DeRouchey Joel M , Kyle Josh M , Woodworth Jason C
Published: May 2023

A total of 105 sows (Line 241, DNA, Columbus, NE) were used across four batch farrowing groups to evaluate the effects of feeding a feed flavor in lactation diets on sow and litter performance. Sow groups 1 and 2 farrowed in an old farrowing facility during the summer months and groups 3 and 4 farrowed in a new farrowing facility during the winter months. Sows were blocked by body weight (BW) within parity on days 110 of gestation and allotted to 1 of 2 dietary treatments. Dietary treatments were a standard corn–soy-based lactation diet (control) or the control diet with the addition of a feed flavor at 0.05% of diet (Krave AP, Adisseo, Alpharetta, GA, USA). Farrowing facility environment had a large impact and resulted in many interactions with the feed flavor treatment. From farrowing to weaning, sows fed the feed flavor in the old farrowing house tended to have a higher (P = 0.058) lactation feed intake, while no difference in average daily feed intake (ADFI) was observed in the new farrowing house. Pigs weaned from sows fed with the feed flavor in the old farrowing facility had a higher (P = 0.026) BW at weaning and piglet average daily gain (ADG) from day 2 to weaning (P = 0.001) compared to piglets from sows not fed with the feed flavor; whereas the opposite occurred in the new farrowing house. Progeny from one farrowing group in the old farrowing facility was followed into the nursery. A total of 360 weaned pigs (DNA 241 × 600: initially 5.7 kg) were used in a 2 × 2 factorial in the nursery portion of the study to evaluate the effects of previous sow feed flavoring treatment (control vs. flavor) and nursery diets formulated with or without a feed flavor on growth performance in a 38-d trial. Nursery treatments were either a control diet or a diet containing a feed flavor (Delistart #NA 21, Adisseo). Offspring from sows fed with the flavor diet were heavier at weaning (P < 0.001) which was maintained throughout the study. Overall, progeny from sows fed with a diet containing a feed flavor had greater (P < 0.05) ADG, ADFI, and final BW during the trial. The presence of a feed flavor in the nursery did not improve overall nursery performance. In conclusion, when sow lactation feed intake was increased in the old farrowing house, pigs weaned from sows fed with the flavor diet were heavier (P = 0.039) at weaning compared to pigs weaned from sows fed with the control diet. Adding the feed flavor increased sow feed intake and piglet ADG in a warm environment, but not in a cool environment.
Refining risk estimates for lead in drinking water based on the impact of genetics and diet on blood lead levels using the Collaborative Cross mouse population
Authors: Cuomo Danila , Nitcher Megan , Barba Estefania , Feinberg Andrew P , Rusyn Ivan , Chiu Weihsueh A , Threadgill David W
Published: May 2023

Blood lead (Pb) level (BLL) is a commonly used biomarker to evaluate associations with health effects. However, interventions to reduce the adverse effects of Pb require relating BLL to external exposure. Moreover, risk mitigation actions need to ensure protection of more susceptible individuals with a greater tendency to accumulate Pb. Because little data is available to quantify inter-individual variability in biokinetics of Pb, we investigated the influence of genetics and diet on BLL in the genetically diverse Collaborative Cross (CC) mouse population. Adult female mice from 49 CC strains received either a standard mouse chow or a chow mimicking the American diet while being provided water ad libitum with 1000 ppm Pb for 4 weeks. In both arms of the study, inter-strain variability was observed; however, in American diet-fed animals, the BLL was greater and more variable. Importantly, the degree of variation in BLL among strains on the American diet was greater (2.3) than the default variability estimate (1.6) used in setting the regulatory standards. Genetic analysis identified suggestive diet-associated haplotypes that were associated with variation in BLL, largely contributed by the PWK/PhJ strain. This study quantified the variation in BLL that is due to genetic background, diet, and their interactions, and observed that it may be greater than that assumed for current regulatory standards for Pb in drinking water. Moreover, this work highlights the need of characterizing inter-individual variation in BLL to ensure adequate public health interventions aimed at reducing human health risks from Pb.
Endoscopic-assisted Surgical Removal of Infected Interosseous Wires 40 Years After Mandibular Surgery
Authors: Sukegawa Shintaro , Miyazaki Ryo , Matsuki Yusuke , Iwata Masashi , Nakai Fumi , Nakai Yasuhiro , Miyake Minoru
Published: May 2023

We demonstrate a highly reliable minimally invasive treatment for removal of residual wire from the mandible. The patient was a 55-year-old Japanese man who was referred to our department for a fistula in his submental area. The patient had undergone open reduction and fixation with wires for mandibular fractures (left parasymphysis, right angle fracture) more than 40 years prior and mandibular tooth extraction and drainage 6 months prior. Minimally invasive endoscopy-assisted wire removal surgery was performed under general anesthesia with good visualization in a narrow surgical field. Bone resection was minimized using an ultrasonic cutting instrument with a wide choice of tip shapes.

The use of endoscopy with ultrasonic cutting tools makes it possible to effectively utilize narrow surgical fields with a small skin incision and minimal bone cutting. The advantages and disadvantages of the newer endoscopic systems in oral and maxillofacial surgical units are discussed.
Assortative mating and parental genetic relatedness drive the pathogenicity of variably expressive variants
Authors: Smolen Corrine , Jensen Matthew , Dyer Lisa , Pizzo Lucilla , Tyryshkina Anastasia , Banerjee Deepro , Rohan Laura , Huber Emily , Khattabi Laila El , Prontera Paolo , Caberg Jean-Hubert , Van Dijck Anke , Schwartz Charles , Faivre Laurence , Callier Patrick , Mosca-Boidron Anne-Laure , Lefebvre Mathilde , Pope Kate , Snell Penny , Lockhart Paul J. , Castiglia Lucia , Galesi Ornella , Avola Emanuela , Mattina Teresa , Fichera Marco , Mandarà Giuseppa Maria Luana , Bruccheri Maria Grazia , Pichon Olivier , Le Caignec Cedric , Stoeva Radka , Cuinat Silvestre , Mercier Sandra , Bénéteau Claire , Blesson Sophie , Nordsletten Ashley , Martin-Coignard Dominique , Sistermans Erik , Kooy R. Frank , Amor David J. , Romano Corrado , Isidor Bertrand , Juusola Jane , Girirajan Santhosh
Published: May 2023

We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as obsessive-compulsive disorder (R=0.31-0.49, p<0.001), and two measures of sub-clinical autism features in parents affecting several autism severity measures in children, such as bi-parental mean Social Responsiveness Scale (SRS) scores affecting proband SRS scores (regression coefficient=0.11, p=0.003). We further describe patterns of phenotypic and genetic similarity between spouses, where spouses show both within- and cross-disorder correlations for seven neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R=0.25-0.72, p<0.001) and a cross-disorder correlation between schizophrenia and personality disorder (R=0.20-0.57, p<0.001). Further, these spouses with similar phenotypes were significantly correlated for rare variant burden (R=0.07-0.57, p<0.0001). We propose that assortative mating on these features may drive the increases in genetic risk over generations and the appearance of “genetic anticipation” associated with many variably expressive variants. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse correlations with burden and pathogenicity of rare variants and propose that parental relatedness drives disease risk by increasing genome-wide homozygosity in children (R=0.09-0.30, p<0.001). Our results highlight the utility of assessing parent phenotypes and genotypes in predicting features in children carrying variably expressive variants and counseling families carrying these variants.
The implementation and effectiveness of multi-tasked, paid community health workers on maternal and child health: A cluster-randomized pragmatic trial and qualitative process evaluation in Tanzania
Authors: Baynes Colin , Kanté Almamy Malick , Exavery Amon , Kassimu Tani , Sikustahili Gloria , Mushi Hildegalda , Baraka Jitihada , Ramsey Kate , Sherr Kenneth , Weiner Bryan , Phillips James F.
Published: May 2023

Community health worker programs have proliferated worldwide based on evidence that they help prevent mortality, particularly among children. However, there is limited evidence from randomized studies on the processes and effectiveness of implementing community health worker programs through public health systems. This paper describes the results of a cluster-randomized pragmatic implementation trial (registration numberISRCTN96819844) and qualitative process evaluation of a community health worker program in Tanzania that was implemented from 2011-2015. Program effects on maternal, newborn and child health service utilization, childhood morbidity and sick childcare seeking were evaluated using difference-in-difference regression analysis with outcomes measured through pre and post-intervention household surveys in intervention and comparison trial arms. A qualitative process evaluation was conducted between 2012 and 2014 and comprised of in-depth interviews and focus group discussions with community health workers, community members, facility-based health workers and staff of district health management teams. The community health worker program reduced incidence of childhood illness and improved access to timely and appropriate sick childcare; however, there was no effect on maternal, newborn and child health service utilization. The positive outcomes occurred because of high levels of acceptability of community health workers within communities, as well as the durability of community health workers’ motivation and confidence. Implementation factors that generated these effects were the engagement of communities in program startup; the training, remuneration and supervision of the community health workers from the local health system and community. The lack of program effects on maternal, newborn and child health service utilization were attributed to lapses in the availability of needed care at facilities and of working materials among community health workers. Strategies that strengthen and align communities’ and health systems core capacities, and their ability to learn, adapt and integrate evidence-based interventions, are needed to maximize the health impact of community health workers.
Mining multi-omics data for molecular subtyping in gliomas facilitates precise clinical treatment
Authors: Feng Peng , Pan Yawen
Published: May 2023

Glioma is the most common malignancy in the skull, accounting for approximately 2% of adult systemic tumors. It is characterized by a high recurrence rate, high disability rate, and poor sensitivity to chemotherapy. Different subtypes of glioma exhibit varying prognosis and chemotherapy sensitivities. Currently, researchers extensively study the molecular classification of glioma based on transcriptomic features, facilitating the evaluation of prognosis. However, identification of tumor subtypes based on the single-layer-omics data have several limitations. In this regard, the present study aimed to identify new subtypes of glioma using three omics datasets for prognosis prediction. As a result, cluster A subtype was identified to be associated with lower activation of cell proliferation and better prognosis, while cluster B subtype exhibited higher infiltration of M2-type macrophages and higher activation of the epithelial-mesenchymal transition (EMT) pathway, potentially leading to a poorer prognosis. Furthermore, we employed the Weighted Gene Co-expression Network Analysis (WGCNA) algorithm and limma R package to identify driver genes for clusters A and B. Consequently, nine genes were identified as gene signatures for cluster A. Based on this finding, we quantified the two subtypes using the single-sample gene set enrichment analysis (ssGSEA) algorithm, where a higher score were linked to elevated tumor mutation burden (TMD) and signaling pathways related to cell proliferation. Low scores indicated enrichment of tumorigenesis-related pathways and poor prognosis. In silico drug screening suggested that AGI-6780 could be an effective compound for high cluster subtypes, based on brain tumor cell lines. Consequently, our study determined that the score can serve as an effective index to predict the prognosis of glioma.