bluuebunny/crossref_metadata_2025_split huggingface dataset:
De novo non-synonymous DPYSL2 (CRMP2) variants in two patients with intellectual disabilities and documentation of functional relevance through zebrafish rescue and cellular transfection experiments
Authors: Suzuki Hisato , Li Simo , Tokutomi Tomoharu , Takeuchi Chisen , Takahashi Miyuki , Yamada Mamiko , Okuno Hironobu , Miya Fuyuki , Takenouchi Toshiki , Numabe Hironao , Kosaki Kenjiro , Ohshima Toshio 
Published: July 2022

Abstract
Collapsin response mediator protein 2 (Crmp2) is an evolutionarily well-conserved tubulin-binding cytosolic protein that plays critical roles in the formation of neural circuitry in model organisms including zebrafish and rodents. No clinical evidence that CRMP2 variants are responsible for monogenic neurogenic disorders in humans presently exists. Here, we describe two patients with de novo non-synonymous variants (S14R and R565C) of CRMP2 and intellectual disability associated with hypoplasia of the corpus callosum. We further performed various functional assays of CRMP2 variants using zebrafish and zebrafish Crmp2 (abbreviated as z-CRMP2 hereafter) and an antisense morpholino oligonucleotide [AMO]-based experimental system in which crmp2-morphant zebrafish exhibit the ectopic positioning of caudal primary (CaP) motor neurons. Whereas the co-injection of wild-type z-CRMP2 mRNA suppressed the ectopic positioning of CaP motor neurons in Crmp2-morphant zebrafish, the co-injection of R566C or S15R, z-CRMP2, which corresponds to R565C and S14R of human CRMP2, failed to rescue the ectopic positioning. Transfection experiments of zebrafish or rat Crmp2 using plasmid vectors in HeLa cells, with or without a proteasome inhibitor, demonstrated that the expression levels of mutant Crmp2 protein encoded by R565C and S14R CRMP2 variants were decreased, presumably because of increased degradation by proteasomes. When we compared CRMP2-tubulin interactions using co-immunoprecipitation and cellular localization studies, the R565C and S14R mutations weakened the interactions. These results collectively suggest that the CRMP2 variants detected in the present study consistently led to the loss-of-function of CRMP2 protein and support the notion that pathogenic variants in CRMP2 can cause intellectual disabilities in humans.
Modularity, identity, and the constitutional diagonal
Authors: Langlois Richard N 
Published: July 2022

AbstractThe framework of modular systems articulated in Design Rules can be applied in the larger setting of social institutions. The principles of encapsulation and information hiding operate in society as mechanisms to internalize externalities. This essay focuses on intangible externalities, or “moralisms,” that involve the transmission across module boundaries of pure information rather than materials or energy. Such intangible externalities arise in the practice of identity, the affiliations through which individuals create and define their sense of self. Both formally and informally, individuals tend to modularize themselves into identity groups in order to minimize the costs of the intangible externalities that identities impose on one another. One important way to reduce conflict among identity groups is to create a governance structure in which some interactions are proscribed—the constitutional diagonal. In the end, because of the inherent incompatibilities—the non-modular interactions—between identities that arise inevitably from the very meaning and function of identity, genuine toleration is possible only through the increased standardization of identities. The essay applies these ideas to the problems facing large social networks like Facebook.
Impact of Gestational Haloperidol Exposure on miR-137-3p and Nr3c1 mRNA Expression in Hippocampus of Offspring Mice
Authors: Yoshino Yuta , Kumon Hiroshi , Shimokawa Tetsuya , Yano Hajime , Ochi Shinichiro , Funahashi Yu , Iga Jun-ichi , Matsuda Seiji , Tanaka Junya , Ueno Shu-ichi 
Published: July 2022

Abstract

Background
Schizophrenia is a mental disorder caused by both environmental and genetic factors. Prenatal exposure to antipsychotics, an environmental factor for the fetal brain, induces apoptotic neurodegeneration and cognitive impairment of offspring similar to schizophrenia. The aim was to investigate molecular biological changes in the fetal hippocampus exposed to haloperidol (HAL) by RNA expression as a model of the disorder.

Methods
HAL (1 mg/kg/d) was administered to pregnant mice. Upregulated and downregulated gene expressions in the hippocampus of offspring were studied with RNA-sequencing and validated with the qPCR method, and micro-RNA (miR) regulating mRNA expressional changes was predicted by in silico analysis. An in vitro experiment was used to identify the miRNA using a dual-luciferase assay.

Results
There were significant gene expressional changes (1370 upregulated and 1260 downregulated genes) in the HAL group compared with the control group on RNA-sequencing analysis (P &lt; .05 and q &lt; 0.05). Of them, the increase of Nr3c1 mRNA expression was successfully validated, and in silico analysis predicted that microRNA-137-3p (miR-137-3p) possibly regulates that gene’s expression. The expression of miR-137-3p in the hippocampus of offspring was significantly decreased in the first generation, but it increased in the second generation. In vitro experiments with Neuro2a cells showed that miR-137-3p inversely regulated Nr3c1 mRNA expression, which was upregulated in the HAL group.

Conclusions
These findings will be key for understanding the impact of the molecular biological effects of antipsychotics on the fetal brain.
Multi-scale modelling of nanoparticle delivery and heat transport in vascularised tumours
Authors: Al Sariri Tahani , Penta Raimondo 
Published: July 2022

AbstractWe focus on modelling of cancer hyperthermia driven by the application of the magnetic field to iron oxide nanoparticles. We assume that the particles are interacting with the tumour environment by extravasating from the vessels into the interstitial space. We start from Darcy’s and Stokes’ problems in the interstitial and fluid vessels compartments. Advection–diffusion of nanoparticles takes place in both compartments (as well as uptake in the tumour interstitium), and a heat source proportional to the concentration of nanoparticles drives heat diffusion and convection in the system. The system under consideration is intrinsically multi-scale. The distance between adjacent vessels (the micro-scale) is much smaller than the average tumour size (the macro-scale). We then apply the asymptotic homogenisation technique to retain the influence of the micro-structure on the tissue scale distribution of heat and particles. We derive a new system of homogenised partial differential equations (PDEs) describing blood transport, delivery of nanoparticles and heat transport. The new model comprises a double Darcy’s law, coupled with two double advection–diffusion–reaction systems of PDEs describing fluid, particles and heat transport and mass, drug and heat exchange. The role of the micro-structure is encoded in the coefficients of the model, which are to be computed solving appropriate periodic problems. We show that the heat distribution is impaired by increasing vessels’ tortuosity and that regularization of the micro-vessels can produce a significant increase (1–2 degrees) in the maximum temperature. We quantify the impact of modifying the properties of the magnetic field depending on the vessels’ tortuosity.
Declining Corticosteroid Use for Inflammatory Bowel Disease Across Alberta: A Population-Based Cohort Study
Authors: Seow Cynthia H , Coward Stephanie , Kroeker Karen I , Stach Jesse , Devitt Katharine Sarah , Targownik Laura E , Nguyen Geoffrey C , Ma Christopher , deBruyn Jennifer C , Carroll Matthew W , Peerani Farhad , Baumgart Daniel C , Ryan David J , Veldhuyzen van Zanten Sander , Benchimol Eric I , Kaplan Gilaad G , Panaccione Remo 
Published: July 2022

Abstract

Background and Aims
Corticosteroid-free remission is a primary treatment goal in IBD which may be achieved with greater use of anti-TNF therapy. We defined temporal trends of corticosteroid use, anti-TNF use, hospitalization and surgery in a prevalent IBD cohort within the province of Alberta, Canada.

Methods
Health administrative data were used to identify medication dispensing, hospitalizations and surgery in individuals with IBD from 2010 to 2015. Temporal trends were calculated using log-binomial regression for medications and log-linear models for hospitalizations and surgery rates. Analyses were stratified based on geographic location.

Results
Of 28890 individuals with IBD, 50.3% had Crohn’s disease. One in six individuals (15.45%) were dispensed a corticosteroid. Corticosteroid use decreased in both metropolitan areas (AAPC −20.08%, 95% CI: −21.78 to −18.04) and non-metropolitan areas (AAPC −18.14%, 95% CI: −20.78 to −18.04) with a similar pattern for corticosteroid dependence. Corticosteroid dependence was more prevalent in UC vs. CD (P &lt; 0.05), and in the pediatric IBD cohort (13.45) compared to the adult (8.89) and elderly (7.54) cohorts (per 100 prevalent population, P &lt; 0.001). The proportion of individuals dispensed an anti-TNF increased over the study period (AAPC 12.58%, 95% CI: 11.56 to 13.61). Significantly more non-metropolitan versus metropolitan residing individuals were hospitalized for any reason, for an IBD-related, or IBD-specific indication (all P &lt; 0.001) though the proportion requiring IBD surgery was similar between groups.

Conclusions
An increase in anti-TNF use corresponded to a decline in corticosteroid use and dependence in those with IBD. Inequities in IBD care still exist based on location and age.
Accelerated warming in the late 20th century promoted tree radial growth in the Northern Hemisphere
Authors: Liu Jie , Li Zong-Shan , Keyimu Maierdang , Wang Xiaochun , Liang Haibin , Feng Xiaoming , Gao Guangyao , Fu Bojie 
Published: July 2022

AbstractAccelerated global warming in the late 20th century led to frequent forest-decline events in the Northern Hemisphere and increased the complexity of the relationships between tree growth and climate factors. However, few studies have explored the heterogeneity of responses of tree growth to climate factors in different regions of the Northern Hemisphere before and after accelerated warming. In this study, a total of 229 temperature-sensitive tree-ring width chronologies from nine regions on three continents in the Northern Hemisphere were used in the data analysis performed herein. A bootstrapped correlation analysis method was used to investigate whether the tree growth-climate response changed significantly in different regions between the periods before and after rapid warming. Probability density functions and piecewise linear fitting were used to study the fluctuation characteristics of the tree-ring width indices before and after rapid warming. At the end of the 20th century (from 1977 to 2000), rapid warming significantly promoted the radial growth of trees in different regions of the Northern Hemisphere, but tree radial growth was heterogeneous among the different regions from 1950 to 2000. After 1976, except in central North America and northern Europe, the correlation between tree growth and temperature increased significantly in the Northern Hemisphere, especially in Asia. From 1977 to 2000, tree-ring index and temperature divergences were observed in nine regions with a divergence of 2–5 years. From 1950 to 2000, tree growth tracked better average temperature variability in the Northern Hemisphere than regional temperature.
The relation between optical and γ-ray emission in BL Lac sources
Authors: La Mura G , Becerra Gonzalez J , Chiaro G , Ciroi S , Otero-Santos J 
Published: July 2022

ABSTRACT
The relativistic jets produced by some Active Galactic Nuclei (AGNs) are among the most efficient persistent sources of non-thermal radiation and represent an ideal laboratory for studying high-energy interactions. In particular, when the relativistic jet propagates along the observer’s line of sight, the beaming effect produces dominant signatures in the observed spectral energy distribution (SED), from the radio domain up to the highest energies, with the further possibility of resulting in radiation-particle multimessenger associations. In this work, we investigate the relationships between the emission of γ rays and the optical spectra of a sample of AGN, selected from BL Lac sources detected by the Fermi Large Area Telescope (Fermi-LAT). We find that there is a close relationship between the optical and γ-ray spectral indices. Despite all the limitations due to the non-simultaneity of the data, this observation strongly supports a substantial role of Synchrotron-Self Compton (SSC) radiation in a single zone leptonic scenario for most sources. This result simplifies the application of theoretical models to explore the physical parameters of the jets in this type of sources.
New Phylogenetic Models Incorporating Interval-Specific Dispersal Dynamics Improve Inference of Disease Spread
Authors: Gao Jiansi , May Michael R , Rannala Bruce , Moore Brian R 
Published: July 2022

Abstract
Phylodynamic methods reveal the spatial and temporal dynamics of viral geographic spread, and have featured prominently in studies of the COVID-19 pandemic. Virtually all such studies are based on phylodynamic models that assume—despite direct and compelling evidence to the contrary—that rates of viral geographic dispersal are constant through time. Here, we: (1) extend phylodynamic models to allow both the average and relative rates of viral dispersal to vary independently between pre-specified time intervals; (2) implement methods to infer the number and timing of viral dispersal events between areas; and (3) develop statistics to assess the absolute fit of discrete-geographic phylodynamic models to empirical datasets. We first validate our new methods using simulations, and then apply them to a SARS-CoV-2 dataset from the early phase of the COVID-19 pandemic. We show that: (1) under simulation, failure to accommodate interval-specific variation in the study data will severely bias parameter estimates; (2) in practice, our interval-specific discrete-geographic phylodynamic models can significantly improve the relative and absolute fit to empirical data; and (3) the increased realism of our interval-specific models provides qualitatively different inferences regarding key aspects of the COVID-19 pandemic—revealing significant temporal variation in global viral dispersal rates, viral dispersal routes, and the number of viral dispersal events between areas—and alters interpretations regarding the efficacy of intervention measures to mitigate the pandemic.
Sex Differences in the Association of E-cigarette and Cigarette Use and Dual Use With Self-Reported Hypertension Incidence in US Adults
Authors: Shi Hangchuan , Leventhal Adam M , Wen Qiang , Ossip Deborah J , Li Dongmei 
Published: July 2022

Abstract

Background
While there is some evidence and conceptual plausibility that tobacco product use is associated with hypertension incidence and that this association varies by sex, extant longitudinal research had been conducted prior to the emergence of e-cigarette and dual e-cigarette and cigarette use.

Aims and Methods
Data were analyzed from the US Population Assessment of Tobacco and Health study for adults with no lifetime history of hypertension at wave 1 (2013–2014) who completed waves 2–4 follow-up surveys (2014–2018; n = 16 434). Sex-stratified weighted covariate-adjusted multivariable Cox regression models were used to examine the association between established current e-cigarette or cigarette exclusive or dual-use (as a time-varying and time-lagged regressor) and subsequent self-reported hypertension onset.

Results
Weighted cumulative hypertension incidence by wave 4 varied by waves 1–3 e-cigarette, cigarette, and dual use status in females (nonuse [incidence: 9.9%], exclusive e-cigarette use [11.8%], exclusive cigarette use [14.8%], dual-use [12.4%]; p = .003 for omnibus differences among all groups) but not males (nonuse [12.6%], exclusive e-cigarette use [9.7%], exclusive cigarette use [13.7%], dual-use [9.3%]; p = .231). Among females, exclusive cigarette (vs. no) use (hazard ratio: 1.69, 95%CI 1.21 to 2.34; p = .002), but not exclusive e-cigarette or dual-use, was significantly associated with subsequent hypertension. Dose–response models were suggestive that consistent exclusive e-cigarette or dual-use versus nonuse across multiple may be associated with hypertension among females, but results were nonsignificant.

Conclusions
The association of e-cigarette, cigarette, and dual use with hypertension may differ by sex, whereby exclusive cigarette use could be a prospective risk factor for subsequent self-reported hypertension in US adult females.

Implications
This nationally representative cohort study provides the very first evidence of whether there are prospective associations of established e-cigarette and cigarette use and dual use with future hypertension onset among US adult females and males. We found that exclusive cigarette smoking was associated with an increased risk of incident hypertension among females, but not males. We observed a trend of a dose–response relationship between e-cigarette use and risk of incident hypertension among female exclusive e-cigarette users or dual e-cigarette and cigarette users. Our study will contribute to understanding the chronic health risks of vaping to prevent the potential long-term e-cigarette use-related health burden.
Association Between Geriatric Assessment and Post-Chemotherapy Functional Status in Older Patients with Cancer
Authors: Rier Hánah N , Meinardi Marieke C , van Rosmalen Joost , Westerweel Peter E , de Jongh Eva , Kitzen Jos J E M , van den Bosch Joan , Trajkovic Marija , Levin Mark-David 
Published: July 2022

Abstract

Background
Maintaining functional status is among the most important patient-centered outcomes for older adults with cancer. This study investigated the association between comprehensive geriatric assessment (CGA) and progressive disease or decline of IADL-independence 1 year after chemotherapy, overall survival (OS), and premature termination of chemotherapy. CGA-based functional status and quality of life (QOL) 1 year after chemotherapy are also described.

Methods
This prospective cohort study involved patients aged ≥65 years treated with chemotherapy for any cancer type. CGA and the G8-screening tool were performed before and after the completion of chemotherapy. Analyses were adjusted for tumor type and treatment intent: (a) indolent hematological malignancies, (b) aggressive hematological malignancies, c) solid malignancies treated with curative intent, and (d) solid malignancies treated with palliative intent.

Results
All 291 included patients lived in The Netherlands; 193 (67.4%) lived fully independent prior to chemotherapy. The median age was 72 years; 164 (56.4%) were male. IADL independence, CGA-based functional status, and QOL were maintained in half of the patients 1 year after chemotherapy. An abnormal G8-score before chemotherapy was a higher risk for progressive disease or a decline of IADL-independence (OR 3.60, 95% CI, 1.98-6.54, P &lt; .0001), prematurely terminated chemotherapy (OR 2.12, 95% CI, 1.24-3.65, P = .006), and shorter median OS (HR 1.71, 95% CI, 1.16-2.52, P = .007). The impact of an abnormal G8-score differed across tumor type (oncological or hematological) and treatment indication (adjuvant or palliative).

Conclusion
An abnormal G8 score before chemotherapy is associated with progressive disease and functional decline after chemotherapy and shorter median OS, especially in patients with solid malignancies.
Parasitic plant small RNA analyses unveil parasite-specific signatures of microRNA retention, loss, and gain
Authors: Zangishei Zahra , Annacondia Maria Luz , Gundlach Heidrun , Didriksen Alena , Bruckmüller Julien , Salari Hooman , Krause Kirsten , Martinez German 
Published: July 2022

Abstract
Parasitism is a successful life strategy that has evolved independently in several families of vascular plants. The genera Cuscuta and Orobanche represent examples of the two profoundly different groups of parasites: one parasitizing host shoots and the other infecting host roots. In this study, we sequenced and described the overall repertoire of small RNAs from Cuscuta campestris and Orobanche aegyptiaca. We showed that C. campestris contains a number of novel microRNAs (miRNAs) in addition to a conspicuous retention of miRNAs that are typically lacking in other Solanales, while several typically conserved miRNAs seem to have become obsolete in the parasite. One new miRNA appears to be derived from a horizontal gene transfer event. The exploratory analysis of the miRNA population (exploratory due to the absence of a full genomic sequence for reference) from the root parasitic O. aegyptiaca also revealed a loss of a number of miRNAs compared to photosynthetic species from the same order. In summary, our study shows partly similar evolutionary signatures in the RNA silencing machinery in both parasites. Our data bear proof for the dynamism of this regulatory mechanism in parasitic plants.
Assessment of Neutron HP(10) Using Workplace Correction Factors Obtained Through Monte Carlo Simulation for Alnor Albedo Dosemeter
Authors: Ferreira Max S , Silva Everton R , Mauricio Claudia L P 
Published: July 2022

Abstract
Albedo dosemeters for neutron individual monitoring are used worldwide and their response to the same dose can vary by more than one order of magnitude, depending on the neutron workplace spectrum. Two-component albedo dosemeters use two pairs of TLDs, one pair to measure incident neutrons (i) and another to measure albedo neutrons (a), used to corrections to the neutron HP(10). A Workplace Correction Factor (WCF) as a function of the i/a ratio can be plotted from experimental or simulated measurements. This paper uses a Monte Carlo MCNPX simulation of the Alnor albedo dosemeter response to plot WCF × i/a curves for several neutron fields. Experimental results were used to validate the simulation. The use of the proposed curves to calculate WCF can reduce the inaccuracies of the neutron dose assessment for different neutron fields of several facilities. However, it is necessary to be careful with the uncertainties of the i/a values.
Direct TLR2 Signaling Through mTOR and TBK1 Induces C/EBPβ and IRF7-Dependent Macrophage Differentiation in Hematopoietic Stem and Progenitor Cells
Authors: Bono Cristina , Guerrero Paula , Erades Ana , Jordán-Pla Antonio , Yáñez Alberto , Gil María Luisa 
Published: July 2022

Abstract
During an infection, hematopoiesis is altered to increase the output of mature myeloid cells to fight off the pathogen. Despite convincing evidence that hematopoietic stem and progenitor cells (HSPCs) can sense pathogens directly, more mechanistic studies are needed to reveal whether pattern recognition receptor (PRR) signaling initiates myeloid development directly, or indirectly through the production of cytokines by HSPCs that can act in an autocrine/paracrine manner, or by a combination of both direct and indirect mechanisms. In this study, we have used an in vitro model of murine HSPCs to study myeloid differentiation in response to the TLR2 ligand Pam3CSK4 and showed that, besides indirect mechanisms, TLR2 stimulation of HSPCs promotes myelopoiesis directly by initiating a MyD88-dependent signaling. This direct differentiation program involves a combined activation of the transcription factors PU.1, C/EBPβ, and IRF7 driven by TBK1 and PI3K/mTOR. Notably, downstream of MyD88, the activated TBK1 kinase can activate mTOR directly and IRF7 induction is mediated by both TBK1 and mTOR. TLR2 signaling also induces NF-κB dependent IL-6 production that may further induce indirect myeloid differentiation. Our results have identified the direct signaling pathways and the transcription factors involved in macrophage development from HSPCs in response to TLR2 engagement, a critical process to trigger a rapid immune response during infection.