bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differentiation state and culture conditions impact neural stem/progenitor cell-derived extracellular vesicle bioactivity
Authors: Dutta Dipankar , Pirolli Nicholas H , Levy Daniel , Tsao Jeffrey , Seecharan Nicholas , Xu Xiang , Wang Zihui , Jia Xiaofeng , Jay Steven M. 
Published: February 2023

AbstractExtracellular vesicles (EVs) derived from neural progenitor/stem cells (NPSCs) have shown promising efficacy in a variety of preclinical models. However, NPSCs lack critical neuroregenerative functionality such as myelinating capacity. Further, culture conditions used in NPSC EV production lack standardization and identification of optimal conditions for NPSC EV neurogenic bioactivity. Here, we assessed whether further differentiated oligodendrocyte precursor cells (OPCs) and immature oligodendrocytes (iOLs) that give rise to mature myelinating oligodendrocytes could yield EVs with neurotherapeutic properties comparable or superior to those from NPSCs as well as mesenchymal stromal cells (MSCs), as MSC EVs are also commonly reported to have neurotherapeutic activity. We additionally examined the effects of four different extracellular matrix (ECM) coating materials (laminin, fibronectin, Matrigel, and collagen IV) and the presence or absence of growth factors (EGF, bFGF, and NGF) in cell culture on the ultimate properties of EVs. The data show that OPC EVs and iOL EVs performed similarly to NPSC EVs in PC-12 proliferation and RAW264.7 mouse macrophage antiinflammatory assays, but NPSC EVs performed better in a PC-12 neurite outgrowth assay. Additionally, the presence of nerve growth factor (NGF) in culture was found to be maximize NPSC EV bioactivity among the conditions tested. NPSC EVs produced under rationally-selected culture conditions (fibronectin + NGF) enhanced axonal regeneration and muscle reinnervation in a rat nerve crush injury model. These results highlight the impact of culture conditions on NPSC EV neuroregenerative bioactivity, thus providing additional rationale for standardization and optimization of culture conditions for NPSC EV production.Table of ContentsExtracellular vesicles (EVs) purified from neural progenitor/stem cells (NPSCs) have been investigated for neurotherapeutic activity, however significant variability in culture conditions limits reproducibility and efficacy of this approach. Here, we examined the impact of extracellular matrix (ECM) components and growth factors in NPSC culture on the bioactivity on the bioactivity of their EVs. The results show that EVs from NPSCs cultured with a rationally-selected ECM type (fibronectin) and growth factor (nerve growth factor (NGF)) enhanced nerve regeneration and muscle recovery in a rat sciatic nerve crush injury model.
You shall know a species by the company it keeps: leveraging co-occurrence data to improve ecological prediction
Authors: Siefert Andrew , Laughlin Daniel C. , Sabatini Francesco Maria 
Published: February 2023

AbstractMaking predictions about species, including how they respond to environmental change, is a central challenge for ecologists. Due to the huge number of species, ecologists seek generalizations based on species’ traits and phylogenetic relationships, but the predictive power of trait-based and phylogenetic models is often low. Species co-occurrence patterns may contain additional information about species’ ecological attributes not captured by traits or phylogenies.We propose using ordination to encode the information contained in species co-occurrence data in low-dimensional vectors that can be used to represent species in ecological prediction. We present an efficient method to derive species vectors from co-occurrence data using GloVe, an unsupervised learning algorithm originally designed for language modeling. To demonstrate the method, we used GloVe to generate vectors for nearly 40,000 plant species using co-occurrence statistics derived from a global vegetation dataset and tested their ability to predict elevational range shifts in European montane plant species.Co-occurrence-based species vectors were weakly correlated with traits or phylogeny, indicating that they encode unique information about species. Models including co-occurrence-based vectors explained twice as much variation in species range shifts as models including only traits or phylogenetic information.Given the widespread availability of species occurrence data, species vectors learned from co-occurrence patterns are a widely applicable and powerful tool for encoding ecological information about species, with many potential applications for describing and predicting the ecology of species, communities, and ecosystems.
Restructuring of olfactory representations in the fly brain around odor relationships in natural sources
Authors: Yang Jie-Yoon , O’Connell Thomas F. , Hsu Wei-Mien M. , Bauer Matthew S. , Dylla Kristina V. , Sharpee Tatyana O. , Hong Elizabeth J. 
Published: February 2023

ABSTRACTA core challenge of olfactory neuroscience is to understand how neural representations of odor are generated and progressively transformed across different layers of the olfactory circuit into formats that support perception and behavior. The encoding of odor by odorant receptors in the input layer of the olfactory system reflects, at least in part, the chemical relationships between odor compounds. Neural representations of odor in higher order associative olfactory areas, generated by random feedforward networks, are expected to largely preserve these input odor relationships1–3. We evaluated these ideas by examining how odors are represented at different stages of processing in the olfactory circuit of the vinegar flyD. melanogaster. We found that representations of odor in the mushroom body (MB), a third-order associative olfactory area in the fly brain, are indeed structured and invariant across flies. However, the structure of MB representational space diverged significantly from what is expected in a randomly connected network. In addition, odor relationships encoded in the MB were better correlated with a metric of the similarity of their distribution across natural sources compared to their similarity with respect to chemical features, and the converse was true for odor relationships encoded in primary olfactory receptor neurons (ORNs). Comparison of odor coding at primary, secondary, and tertiary layers of the circuit revealed that odors were significantly regrouped with respect to their representational similarity across successive stages of olfactory processing, with the largest changes occurring in the MB. The non-linear reorganization of odor relationships in the MB indicates that unappreciated structure exists in the fly olfactory circuit, and this structure may facilitate the generalization of odors with respect to their co-occurence in natural sources.
Neuronal Transcriptome Disruption, Tau Accumulation and Synapse Loss in Alzheimer’s Knock-in Mice Require Cellular Prion Protein
Authors: Stoner Austin , Fu Li , Nicholson LaShae , Zheng Chao , Toyonaga Takuya , Spurrier Joshua , Laird Will , Cai Zhengxin , Strittmatter Stephen M. 
Published: February 2023

ABSTRACTBackgroundCellular prion protein (PrPC) is a high-affinity cell-surface receptor for Amyloid-β oligomers (Aßo). In certain overexpression models of Alzheimer’s Disease (AD), pharmacology and genetics demonstrate its essential role for synaptic plasticity impairment, memory deficits and synapse loss. However, PrPC’s role in AD-related phenotypes with endogenous expression levels, its role in tau accumulation and its effect on imaging biomarkers are unknown. The necessity of PrPCfor transcriptomic alterations driven by Aß across cell types is unexplored.MethodsThe role of PrPCwas examined as a function of age in homozygousAppNL-G-F/hMaptdouble knock-in mice (DKI). Phenotypes ofAppNL-G-F/hMaptmice with a deletion ofPrnpexpression (DKI;Prnp-/-) were compared with DKI mice with intactPrnp, mice with a targeted deletion ofPrnp (Prnp-/-), and mice with intactPrnp(WT). Phenotypes examined included behavioral deficits, synapse loss by PET imaging, synapse loss by immunohistology, tau pathology, gliosis, inflammatory markers, and snRNA-seq transcriptomic profiling.ResultsBy 9 months age, DKI mice showed learning and memory impairment, but DKI;Prnp-/-andPrnp-/-groups were indistinguishable from WT. Synapse loss in DKI brain, measured by [18F]SynVesT-1 SV2A PET or anti-SV2A immunohistology, was prevented byPrnpdeletion. Accumulation of Tau phosphorylated at aa 217 and 202/205, C1q tagging of synapses, and dystrophic neurites were all increased in DKI mice but each decreased to WT levels withPrnpdeletion. In contrast, astrogliosis, microgliosis and Aß levels were unchanged between DKI and DKI;Prnp-/-groups. Single-nuclei transcriptomics revealed differential expression in neurons and glia of DKI mice relative to WT. For DKI;Prnp-/-mice, the majority of neuronal genes differentially expressed in DKI mice were no longer significantly altered relative to WT, but most glial DKI-dependent gene expression changes persisted. The DKI-dependent neuronal genes corrected byPrnpdeletion associated bioinformatically with synaptic function. Additional genes were uniquely altered only in thePrnp-/-or the DKI;Prnp-/-groups.ConclusionsA functionalPrnpgene is required inAppNL-G-F/hMaptdouble knock-in mice for synapse loss, phospho-tau accumulation and neuronal gene expression. These data support the efficacy of targeting the Aßo-PrPCinteraction to prevent Aßo-neurotoxicity and pathologic tau accumulation in AD.
Mitigation of Antimicrobial Resistance Genes in Greywater Treated at Household Level
Authors: Shuai Weitao , Itzhari Daniella , Ronen Zeev , Hartmann Erica M. 
Published: February 2023

AbstractGreywater often contains microorganisms carrying antimicrobial resistance genes (ARGs). Reuse of greywater thus potentially facilitates the enrichment and spread of multidrug resistance, posing a possible hazard for communities that use it. As water reuse becomes increasingly necessary, it is imperative to determine how greywater treatment impacts ARGs. In this study, we characterize ARG patterns in greywater microbial communities before and after treatment by a recirculating vertical flow constructed wetland (RVFCW). This greywater recycling method has been adopted by some small communities and households for greywater treatment; however, its ability to remove ARGs is unknown. We examined the taxonomic and ARG compositions of microbial communities in raw and treated greywater from five households using shotgun metagenomic sequencing. Total ARGs decreased in abundance and diversity in greywater treated by the RVFCW. In parallel, the microbial communities decreased in similarity in treated greywater. Potentially pathogenic bacteria associated with antimicrobial resistance and mobile genetic elements were detected in both raw and treated water, with a decreasing trend after treatment. This study indicates that RVFCW systems have the potential to mitigate antimicrobial resistance-related hazards when reusing treated greywater, but further measures need to be taken regarding persistent mobile ARGs and potential pathogens.
Oncogenic KrasG12Dspecific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8+T cells dependent manner
Authors: Mahadevan Krishnan K. , McAndrews Kathleen M. , LeBleu Valerie S. , Yang Sujuan , Lyu Hengyu , Li Bingrui , Sockwell Amari M. , Kirtley Michelle L. , Morse Sami J. , Moreno Diaz Barbara A. , Kim Michael P. , Feng Ningping , Lopez Anastasia M. , Guerrero Paola A. , Sugimoto Hikaru , Arian Kent A. , Ying Haoqiang , Barekatain Yasaman , Kelly Patience J. , Maitra Anirban , Heffernan Timothy P. , Kalluri Raghu 
Published: February 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and theKRASG12Dmutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the KrasG12Dmutant protein. Here we explore the impact of KrasG12Dinhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8+T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8+T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.
DNA 5-methylcytosine regulates genome-wide formation of G-quadruplex structures
Authors: Niu Kangkang , Xiang Lijun , Li Xiaoyu , Li Jin , Li Yuanli , Zhang Chu , Liu Junpeng , Zhang Xiaojuan , Peng Yuling , Xu Guanfeng , Xiang Hui , Wang Hao , Song Qisheng , Feng Qili 
Published: February 2023

ABSTRACTG-quadruplex structures (G4s) have been identified in genomes of multiple organisms and proven to play important epigenetic regulatory roles in various cellular functions. However, the G4 formation mechanism remains largely unknown. Here, we found a negative correlation between DNA 5mC methylation and G4 abundance. The abundance of genomic G4s significantly increased when the whole-genome methylation level was reduced in DNMT1-knockout cells. This increase was then suppressed by DNMT1 over-expression. And more G4s were detected in the hypomethylated cancer cell line HepG2 and rectal cancer tissues. Besides, 5mC modification significantly inhibited G4 formation of the potential G-quadruplex sequences (PQSs). The transcription of genes with 5mC modification sites in their promoter PQSs was affected after treatment with G4 stabilizer pyridostatin or methylation inhibitor 5-aza-dC. The global reduction of genomic methylation elevates gene transcription levels through increased G4s. Taken together, DNA 5mC methylation prevents PQSs from folding into G4s in genomes.
C9orf72poly(PR) mediated neurodegeneration is associated with nucleolar stress
Authors: Cicardi ME , Hallgren JH , Mawrie D , Krishnamurthy K , Markandaiah SS , Nelson AT , Kankate V , Anderson EN , Pasinelli P , Pandey UB , Eischen CM , Trotti D 
Published: February 2023

ABSTRACTThe ALS/FTD-linked intronic hexanucleotide repeat expansion in theC9orf72gene is translated into dipeptide repeat proteins, among which poly-proline-arginine (PR) displays the most aggressive neurotoxicityin-vitroandin-vivo. PR partitions to the nucleus when expressed in neurons and other cell types. Usingdrosophilaand primary rat cortical neurons as model systems, we show that by lessening the nuclear accumulation of PR, we can drastically reduce its neurotoxicity. PR accumulates in the nucleolus, a site of ribosome biogenesis that regulates the cell stress response. We examined the effect of nucleolar PR accumulation and its impact on nucleolar function and determined that PR caused nucleolar stress and increased levels of the transcription factor p53. Downregulating p53 levels, either genetically or by increasing its degradation, also prevented PR-mediated neurotoxic phenotypes both inin-vitroandin-vivomodels. We also investigated whether PR could cause the senescence phenotype in neurons but observed none. Instead, we found induction of apoptosisviacaspase-3 activation. In summary, we uncovered the central role of nucleolar dysfunction upon PR expression in the context of C9-ALS/FTD.
Numerical investigation of aerodynamically efficient wing tip-mounted propeller configuration using coupled RANS–BEM approach
Authors: Chandukrishna Y. , Venkatesh T.N. 
Published: February 2023

Purpose
Recent interest in electric aircraft has opened avenues for exploring innovative concepts and designs. Because of its potential to increase wing aerodynamic efficiency, the idea of wing tip-mounted propellers is becoming more popular in the context of electric aircraft. This paper aims to address the question of which configuration, tractor or pusher at wing tip is more beneficial.

Design/methodology/approach
The interactions between the wing and tip-mounted propellers in tractor and pusher configurations have been studied computationally. In this study, the propeller is modeled as a disk, and the blade element method (BEM) coupled with the computational fluid dynamics (CFD)–Reynolds-averaged Navier–Stokes (RANS) solver is used to calculate propeller blade loading recursively. A direct comparison between the wing with tip-mounted propellers in tractor and pusher configurations is made by varying the direction of rotation and thrust.

Findings
Wing with tip-mounted propellers having inboard-up rotation is found to offer less drag in tractor and pusher configurations than those without propeller cases. Wing tip-mounted propeller in tractor configuration with inboard-up rotation offers higher wing aerodynamic efficiency than the other configurations. In tractor and pusher configurations with inboard-up rotating propellers, wing tip vortex attenuation is seen, whereas with outboard-up rotating propellers, the wing tip vortex amplification is observed.

Originality/value
SU2, an open-source CFD tool, is used in this study and BEM is coupled to perform RANS–BEM simulations. Both qualitative and quantitative comparisons were made between the tractor and pusher configurations, which may find its value when a question arises about the aerodynamically best propeller configuration at wing tips.
A multi-objective optimization model for outpatient care delivery with service fairness
Authors: Datta Soumyajyoti , Kapoor Rohit , Mehta Peeyush 
Published: February 2023

PurposeOutpatient care delivery is one of the key revenue sources of a hospital which plays a salient role in timely care delivery. The key purpose of the study is to propose a multi-objective simulation-based decision support model that considers the cost of care delivery and patient dissatisfaction as its two key conflicting objectives. Patient dissatisfaction considers service fairness. Patient idiosyncrasies such as no-show, unpunctuality and balking have been considered in the model involving multiple classes of patients.Design/methodology/approachA model has been designed using data collected from field investigations. In the first stage, queuing theory based discrete event simulation model has been developed. Genetic algorithm has been used to solve the scalarized problem and obtain actionable insights. In the second stage, non-dominated sorting genetic algorithm II (NSGA-II) has been involved to achieve the Pareto optimal fronts considering equal priority of the two objectives.FindingsThe computational results considering various parameter settings can help in efficient resource planning while ensuring better care delivery. The model proposed in the study provides structural insights on the business strategy of healthcare service providers on optimizing the dual goals of care delivery cost and service fairness.Originality/valueThe study is one of the early works that helps to improve the care delivery process by taking into consideration the environmental factors as well as service fairness. The study demonstrates the usage of simulation-based multi-objective optimization to provide a more sustainable patient centric care delivery.
Using Slutsky equation to find the hotel growth model in the destination life cycle: an empirical study in Myrtle Beach
Authors: Tran Xuan V. 
Published: February 2023

PurposeThe purpose of this paper is to examine the hotel growth model including hotel brand, culture and life cycle phases of the Myrtle Beach, South Carolina, the fastest growing tourism destination in the United States.Design/methodology/approachCulture reflecting consuming behaviour of low-context innovators and high-context imitators is measured by the price elasticity of demand (PED). Hotel brand reflecting guests’ hotel class is measured by the income elasticity of demand. Autoregressive distributed lag has been conducted on the Smith Travel Research data in 33 years (1989–2022) to determine the relationship among hotel brand, culture and life cycles.FindingsSkilled labour is the key to make hotels grow. Therefore, increase room rates when hotels possess skilled professionals and decrease room rates when hotels have no skilled professionals. During the rejuvenation in Myrtle Beach (1999–2003), hoteliers increased room rates for innovators due to skilled professionals to increase revenue. Otherwise, a decrease in room rates due to lack of skilled professionals would lead to increase revenue.Research limitations/implications(1) Although Myrtle Beach is one of the fastest growing tourism destinations in the US, it has a relatively small geographic area relative to the country. (2) Data cover over one tourist life cycle, so the time span is relatively short. Hoteliers can forecast the number of guests in different culture by changing room rates.Practical implicationsTo optimize revenue, hoteliers can select skilled labour in professional design hotel brands which could make an increase in demand for leisure transient guests no matter what room rates increase after COVID-19 pandemic.Social implicationsThe study has considered the applied ethical processes regarding revenue management that would maximize both revenue and customer satisfaction when it set up an increase in room rates to compensate for professional hotel room design or it decreases room rates for low-income imitators in exploration and development.Originality/valueThis research highlights that (1) skilled design in the luxury hotel brand is the key for the hotel growth and (2) there is a steady state of the growth model in the destination life cycle.