bluuebunny/crossref_metadata_2025_split huggingface dataset:
MODL-42. BLOOD-BRAIN TUMOR BARRIER ORGANOID MODEL FOR THERAPEUTIC DELIVERY TO GLIOBLASTOMA
Authors: Zhuang Pei , Scott Benjamin , Farquhar Charlotte , Nie Xin , Pentelute Bradley , Lamfers Martine , Chiocca E Antonio , Bei Feng , Cho Fong 
Published: November 2023

Abstract
The integrity of the blood-brain barrier (BBB) is compromised in brain tumors, leading to the formation of the blood-brain tumor barrier (BTB). While the BTB is generally more permeable than the BBB, it is nevertheless heterogeneously restrictive to the entry of therapeutic agents to brain tumors. Modeling the BTB accurately is crucial for understanding its physiological properties and developing effective treatments. Our lab has previously introduced a 3D in vitro human BBB organoid platform that reproduces key BBB markers and predicts compound permeability across the BBB in vivo. Here, we describe incorporating human GBM stem cells (GSC) into the organoid to form BTB organoids, presenting a novel scalable multicellular human brain tumor organoid model that simulates the BTB to facilitate therapeutic development in neuro-oncology. This model involves the self-assembly of essential BTB components, including human brain microvascular endothelial cells, astrocytes, brain pericytes and patient-derived GSCs, co-cultured under ultralow attachment conditions. Immunofluorescence microscopy results show reduced ZO-1 and Mfsd2a expression in the BTB compared to the control BBB organoids, indicating tight junction disruption and BBB breakdown by the GSCs. Correspondingly, we observe increased dextran permeability in the BTB organoids compared to the control BBB organoids, which is dependent on the GSC count per organoid. Electron and confocal microscopy reveal disorganized neovascular structures and invasive GSC behavior in the BTB organoids. Lastly, using a known GBM-targeting peptide (BTP-7), as well as a known BBB-penetrating adeno-associated virus (AAV.CPP.16) as proofs-of-concept, we demonstrate the efficacy of using the BTB organoids for modeling therapeutic delivery to brain tumors. In summary, the BTB organoid platform provides a tractable in vitro system reflecting the brain tumor microenvironment, enabling the study of GBM cell properties, investigation of barrier behavior, and modeling therapeutic delivery to brain tumors.
MODL-43. SOX2 DOWNREGULATION OF PML PROMOTES HCMV GENE EXPRESSION AND GROWTH OF GLIOMA CELLS
Authors: Luo Min-Hua 
Published: November 2023

Abstract
The presence of human cytomegalovirus (HCMV) in glioblastoma (GBM) and improved outcomes of GBM patients receiving therapies targeting the virus have implicated HCMV in GBM progression. However, a unifying mechanism that accounts for the contribution of HCMV to the malignant phenotype of GBM remains incompletely defined. Here we have identified SOX2, a marker of glioma stem cells (GSCs), as a key determinant of HCMV gene expression in gliomas. Our studies demonstrated that SOX2 downregulated promyelocytic leukemia (PML) and Sp100 and consequently facilitated viral gene expression by decreasing the amount of PML nuclear bodies in HCMV-infected glioma cells. Conversely, the expression of PML antagonized the effects of SOX2 on HCMV gene expression. Furthermore, this regulation of SOX2 on HCMV infection was demonstrated in a neurosphere assay of GSCs and in a murine xenograft model utilizing xenografts from patient-derived glioma tissue. In both cases, SOX2 overexpression enhanced HCMV gene expression and facilitated the growth of neurospheres and xenografts implanted in immunodeficient mice. Lastly, the expression of SOX2 and HCMV immediate early 1 (IE1) protein could be correlated in tissues from glioma patients, and interestingly, elevated levels of SOX2 and IE1 were predictive of a worse clinical outcome. These studies argue that HCMV gene expression in gliomas is regulated by SOX2 through its regulation of PML expression and that targeting molecules in this SOX2-PML pathway could identify therapies for glioma treatment.
MODL-48. AUTOMATING ANALYSIS OF ORGANOTYPIC BRAIN SLICE CULTURE USING MACHINE LEARNING-POWERED COMPUTER VISION
Authors: Bell Noah , Buckley Andrew , Mann Breanna , Adefolaju Adebimpe , Dasari Rajaneekar , Hingtgen Shawn , Satterlee Andrew B 
Published: November 2023

Abstract
The difficulty of image labeling and analysis poses a problem for many areas of scientific research, including the recently developed Organotypic Brain Slice Culture (OBSC) tumor characterization platform. An OBSC experiment generates dozens of images which, up to this point, had to be manually quantified. In order to increase the efficiency, consistency, and accuracy of the OBSC image analysis process, we have created a computer program which automates the analysis of OBSC images. This platform uses a number of computer vision (CV) techniques to identify objects of interest and measure their corresponding signals. For fluorescent images of single tumor spots, a straightforward thresholding algorithm divides the image into foreground and background. This automated approach substantially reduces analysis time, and the thresholding algorithm measures unusually shaped tumor spots up to 9% more accurately than previously used manual methods. Other images capture an entire plate of up to 12 OBSCs, complicating the image analysis task. A machine-learning algorithm trained on the web-based platform Biodock could identify individual OBSCs, even if they were touching each other or the sides of the wells. The ML-powered methods consistently reproduced killing curves for treatment effects on tumor tissue as well as the brain tissue substrate, and these results were obtained in much less time. By combining various CV approaches to image analysis, we have completely automated the image analysis component of our OBSC platform. This approach could be adapted to other tumor co-culture platforms.
Allocative Efficiency between and within the Formal and Informal Manufacturing Sectors in Zimbabwe
Authors: Kamutando Godfrey , Edwards Lawrence 
Published: November 2023

Abstract
Resource misallocation has the potential to reduce aggregate total factor productivity and undermine industrial development. Aggregate productivity losses are found to be particularly pronounced in emerging economies where large market frictions impede efficient resource allocation. Available estimates, however, almost entirely exclude firms in the informal sector that in some countries, such as Zimbabwe, make up a high share of overall production and employment. The exclusion of informal firms can result in either an over- or under-estimate of the aggregate productivity losses from misallocation. This paper, therefore, uses firm-level survey data to analyze how market distortions contribute to the misallocation of resources within and between the formal and informal manufacturing sectors in Zimbabwe. Applying the approach developed by Hsieh and Klenow (2009) to firm-level microdata, the results reveal extensive resource misallocation in both the formal and informal manufacturing sector. Market shares of informal firms are found to be low relative to their productivity—an outcome associated with relatively large capital market distortions. Misallocation is also more pronounced among relatively productive firms, thus exacerbating aggregate losses in total factor productivity (TFP). Estimates indicate that aggregated gains in TFP of 151.4 percent can be realized through efficient resource allocation.
Pharmacokinetics, Safety, and Tolerability of Once-Daily Darunavir With Cobicistat and Weekly Isoniazid/Rifapentine
Authors: Brooks Kristina M. , Pau Alice K. , Swaim Doris , Bunn Haden T. , Adeojo Lilian , Peloquin Charles A. , Kumar Parag , Kovacs Joseph A. , George Jomy M. 
Published: November 2023

Background:
Once-weekly isoniazid with rifapentine (HP) for 3 months is a recommended treatment for latent tuberculosis infection in persons with HIV. HP reduces exposures of certain antiretroviral medications, resulting in limited options for the concomitant use of these therapies. Here, we examined the pharmacokinetics (PK), safety, and tolerability of darunavir/cobicistat with HP.

Methods:
This was an open-label, fixed sequence, two-period crossover study in persons without HIV. Participants received darunavir 800 mg/cobicistat 150 mg once-daily alone for 4 days, then continued darunavir/cobicistat once-daily for days 5–19 with HP coadministration on days 5, 12, and 19. Intensive PK assessments were performed on days 4, 14, and 19. PK parameters were determined using noncompartmental methods. Geometric mean ratios with 90% confidence intervals (CIs) were calculated and compared between phases using mixed-effects models.

Results:
Thirteen participants were enrolled. Two withdrew after day 4, and one withdrew after day 14. Of the 3 withdrawals, 2 were attributed to drug-related adverse events. Darunavir area under the concentration–time curve, maximum concentrations (Cmax), and concentrations at 24 hours postdose (C24h) were reduced by 71%, 41%, and 96% ∼48–72 hours after HP administration (day 14), respectively, and 36%, 17%, and 89% with simultaneous HP administration (day 19), respectively. On day 14, 45% of the predose and 73% of C24h concentrations were below the darunavir EC50 (0.055 µg/mL).

Conclusions:
Darunavir exposures were significantly decreased with HP coadministration. Temporal relationships between HP coadministration and the extent of induction or mixed inhibition/induction of darunavir metabolism were apparent. Coadministration of darunavir/cobicistat with 3HP should be avoided.
A Machine Learning Approach to Predict Weight Change in ART-Experienced People Living With HIV
Authors: Motta Federico , Milic Jovana , Gozzi Licia , Belli Michela , Sighinolfi Laura , Cuomo Gianluca , Carli Federica , Dolci Giovanni , Iadisernia Vittorio , Burastero Giulia , Mussini Cristina , Missier Paolo , Mandreoli Federica , Guaraldi Giovanni 
Published: November 2023

Introduction:
The objective of the study was to develop machine learning (ML) models that predict the percentage weight change in each interval of time in antiretroviral therapy–experienced people living with HIV.

Methods:
This was an observational study that comprised consecutive people living with HIV attending Modena HIV Metabolic Clinic with at least 2 visits. Data were partitioned in an 80/20 training/test set to generate 10 progressively parsimonious predictive ML models. Weight gain was defined as any weight change >5%, at the next visit. SHapley Additive exPlanations values were used to quantify the positive or negative impact of any single variable included in each model on the predicted weight changes.

Results:
A total of 3,321 patients generated 18,322 observations. At the last observation, the median age was 50 years and 69% patients were male. Model 1 (the only 1 including body composition assessed with dual-energy x-ray absorptiometry) had an accuracy greater than 90%. This model could predict weight at the next visit with an error of <5%.

Conclusions:
ML models with the inclusion of body composition and metabolic and endocrinological variables had an excellent performance. The parsimonious models available in standard clinical evaluation are insufficient to obtain reliable prediction, but are good enough to predict who will not experience weight gain.
Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics
Authors: Rabadam Gabrielle , Wibrand Camilla , Flynn Emily , Hartoularos George C. , Sun Yang , Ye Chun Jimmie , Kim Susan , Gartner Zev , Sirota Marina , Neely Jessica 
Published: November 2023

AbstractJuvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM. Furthermore, we find that these changes in B cells are paralleled by signatures of Th2-mediated inflammation. Additionally, our work identified SIGLEC-1 expression in monocytes as a composite measure of heterogeneous type I interferon activity in disease. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with dysfunctional protein processing and regulation of cell death programming. This analysis separated the ubiquitously expressed type I interferon response into a central hub and revealed previously masked cell states. Together, these findings reveal the coordinated immune dysregulation underpinning JDM and provide novel insight into strategies for restoring balance in immune function.
Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early-stage neurodegeneration
Authors: Datta Dibyadeep , Perone Isabella , Wijegunawardana Denethi , Liang Feng , Morozov Yury M. , Arellano Jon , Duque Alvaro , Xie Zhongcong , van Dyck Christopher H. , Arnsten Amy F.T. 
Published: November 2023

Structured AbstractINTRODUCTIONpT217-tau is a novel fluid-based biomarker that predicts onset of Alzheimer’s disease (AD) symptoms, but little is known about how pT217-tau arises in brain, as soluble pT217-tau is dephosphorylated postmortem in humans.METHODSWe utilized multi-label immunofluorescence and immunoelectron-microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal and prefrontal cortices of aged macaques with naturally-occurring tau pathology and assayed pT217-tau levels in plasma.RESULTSpT217-tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to CSF/blood. Plasma pT217-tau levels increased across the age-span and thus can serve as a biomarker in macaques.DISCUSSIONThese data help to explain why pT217-tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.
Functional parcellation of the neonatal brain
Authors: Myers Michael J. , Labonte Alyssa K. , Gordon Evan M. , Laumann Timothy O. , Tu Jiaxin Cindy , Wheelock Muriah D. , Nielsen Ashley N. , Schwarzlose Rebecca , Camacho M. Catalina , Warner Barbara B. , Raghuraman Nandini , Luby Joan L. , Barch Deanna M. , Fair Damien A. , Petersen Steven E. , Rogers Cynthia E. , Smyser Christopher D. , Sylvester Chad M. 
Published: November 2023

SUMMARYThe cerebral cortex is organized into distinct but interconnected cortical areas, which can be defined by abrupt differences in patterns of resting state functional connectivity (FC) across the cortical surface. Such parcellations of the cortex have been derived in adults and older infants, but there is no widely used surface parcellation available for the neonatal brain. Here, we first demonstrate that adult- and older infant-derived parcels are a poor fit with neonatal data, emphasizing the need for neonatal-specific parcels. We next derive a set of 283 cortical surface parcels from a sample of n=261 neonates. These parcels have highly homogenous FC patterns and are validated using three external neonatal datasets. The Infomap algorithm is used to assign functional network identities to each parcel, and derived networks are consistent with prior work in neonates. The proposed parcellation may represent neonatal cortical areas and provides a powerful tool for neonatal neuroimaging studies.HIGHLIGHTSNeonatal cortical surface parcels derived based on abrupt changes in functional connectivity (FC) were highly homogenous and were validated in external neonatal datasets.Borders between cortical parcels were smoother (less abrupt) in group-average neonatal data compared to adults, likely due to increased heterogeneity in boundary location across individual neonates.Parcels derived from adults and older infants show poor fit with neonatal resting-state FC data, underscoring the need for a neonatal-specific parcellation.
New model of long-term changes in spatiotemporal patterns of water quality across Shatt-Al-Arab River by applying GIS technique, from 1976 to 2020
Authors: Lazem Laith F. 
Published: November 2023

PurposeUsing a combination of the geographical information system (GIS) and the Canadian water quality index (WQI), the current study sought to provide a long-term general assessment of the water quality of the Shatt Al-Arab River (SAAR), focusing on its suitability for living organisms. Likewise, SPSS statistics was used to develop a nonlinear WQI regression model for the study area.Design/methodology/approachThe study required four decades of data collection on some environmental characteristics of river water. After that, calculate the WQI and conduct the spatial analysis. Eight variables in total, including water temperature, dissolved oxygen, potential hydrogen ions, electrical conductivity (EC), biological oxygen demand, turbidity, nitrate and phosphate, were chosen to calculate the WQI.FindingsThroughout the study periods, the WQI values varied from 55.2 to 79.83, falling into the categories of four (marginal) and three (fair), with the sixth period (2007–2008) showing the most decline. The present research demonstrated that the high concentration of phosphates, the high EC values, and minor changes in the other environmental factors are the major causes of the decline in water quality. The variations in ecological variables' overlap are a senior contributor to changes in water quality in general. Notably, using GIS in conjunction with the WQI has shown to be very effective in reducing the time and effort spent on investigating water quality while obtaining precise findings and information at the lowest possible expense. Calibration and validation of the developed model showed that this model had a perfect estimate of the WQI value. Due to its flexibility and impartiality, this study recommends using the proposed model to estimate and predict the WQI in the study area.Originality/valueEven though the water quality of the SAAR has been the subject of numerous studies, this is the only long-term investigation that has been done to evaluate and predict its water quality.
Capital diversion in Vietnamese state-owned enterprises
Authors: Le-Van Cuong , Nguyen Ngoc-Anh , Nguyen Ngoc-Minh , Nguyen-Van Phu 
Published: November 2023

PurposeThe authors estimated the hidden overhead (capital diversion or wasteful use of capital) of Vietnam state-owned enterprises (SOEs).Design/methodology/approachThe authors used a panel data set of 10,200 Vietnam SOEs observed over the period 2010–2018. The authors modeled and estimated the hidden overhead by using a stochastic production frontier. The hidden overhead parameter is modelled as the technical inefficiency in the production function.FindingsVietnam SOEs are very capital intensive. The hidden overhead (or the wasteful use of capital) is very high with an average rate of 69%.Research limitations/implicationsAlternative estimation methods should be used to account for endogeneity in production inputs. Lack of comparison with the Vietnam private firms.Originality/valueThe paper proposes an original way to quantify hidden overhead (or capital diversion) in the Vietnam SOEs. The finding (a capital diversion rate of 69% on average) is astonishing. It calls for an urgent and profound reform of the Vietnam SOEs.
Online food delivery in the post-pandemic era: moderating role of vaccine confidence
Authors: Shukla Manjula , Pandey Piyush 
Published: November 2023

PurposeIn the post-pandemic period and following widespread inoculation against the infection, this research aims to pinpoint the variables that affect consumers' behavioural intentions (BIs) towards online food delivery (OFD) services. The study goes further to investigate the potential impact of vaccine confidence (VC) in modifying the association between consumers' BI to utilise OFD services and their actual usage behaviour (UB).Design/methodology/approachUsing information gathered through a structured questionnaire from 372 Indian customers, a proposed model based on the technology acceptance model (TAM) and theory of planned behaviour (TPB) models was put to the test using structural equation modelling (SEM).FindingsResults demonstrate that perceptions of ease of use, attitude (ATT) and perceived behavioural control (PBC) have a favourable and significant impact on behaviour intention amongst Indian OFD users. Contrary to what the TAM and TPB models had predicted, perceived usefulness (PU) and subjective norms (SN) did not significantly affect the BI of the sample of Indian OFD users. Furthermore, the association between BI and actual UB of OFD users is not moderated by the consumers' VC.Practical implicationsThe study contributes by shedding light on the variables that affect Indian OFD users' BIs after the coronavirus disease 2019 (COVID-19) pandemic era and mass immunisation and whether VC has a role to play in affecting consumer behaviour, which will aid OFD service providers, eateries and marketers in redesigning their marketing plans.Originality/valueThe present study is the first in making a literary contribution through analysis of the moderating effect of VC on the relationship between BI and actual UB. Additionally, this study presents evidence from India, one of the first nations to implement widespread COVID-19 inoculation.
Unlocking the Pensions Debate: The Origins and Future of the ‘Triple Lock’
Authors: Portes Jonathan 
Published: November 2023

AbstractThe ‘triple lock’ mechanism governing the uprating of state pensions is often framed as a transfer from workers to mostly well‐off pensioners, driven by the latter's outsize political influence. Others note that pensioner poverty remains widespread and that the UK state pension remains relatively low compared to other advanced economies. Both perspectives—but especially the first—often omit the historical context and, particularly, the post‐1979 steady fall in the value of the state pension as a proportion of earnings and the resulting increasing dependence on means‐tested benefits. The key insight of the Turner report was that failure to reverse this trend would further erode any incentive to save for lower‐ and middle‐income earners. Reforms that solely focus on the short‐term impacts on current pensioners, rich and poor, risk long‐term damage.
Culicoides dokdoensis, sp. nov. (Diptera: Ceratopogonidae): A new biting midge species from Dokdo Island, Republic of Korea
Authors: Lee Wongyu , Kim Sun Yi , Hur Junmi , Park Taeseo , Do Min Seock , Choi Hyun Ki , Kim Jisoo , Lim Changseob , Lee Taekjun , Bae Yeon Jae 
Published: November 2023

AbstractRecent molecular approaches toward insect taxonomy are revealing cryptic diversity within biting midge genus Culicoides Latreille, 1809. A new biting midge species was collected from highly restricted area of Dokdo Island, East Sea of the Republic of Korea, and was identified as Culicoides dokdoensis, sp. nov., based on morphological characters and DNA barcoding. The specimens collected from the island were previously known as Culicoides circumscriptus Kieffer, 1918, a cosmopolitan blood‐feeder, due to its morphological similarity. However, the specimens from Dokdo Island can be distinguished from other congeners by the following characters: more curved arms in male aedeagus, wing spot pattern, sensory pit depth, and absence of a spermatheca neck in female. In addition, mitochondrial cytochrome c oxidase I sequence exhibited substantial genetic difference compared to C. circumscriptus populations from the Korean Peninsula, sufficiently supporting the genetic differentiation between the two species. The discovery of this cryptic species highlights the necessity of integrated taxonomy for Culicoides.