bluuebunny/crossref_metadata_2025 huggingface dataset:
MODL-29. EXPLORING CELL STATE TRANSITIONS IN GLIOBLASTOMA WITH LIVE REPORTING OF CELL STATES USING CRISPR/CAS9
Authors: Stockgard Rebecka , Yildirim Irem , Kleindienst Sean , Heinold Josephine , Nelander Sven
Published: November 2023

Glioblastoma (GBM) is the most common malignant primary brain tumor, with a median survival time of 12-15 months. The heterogeneity of GBM, ranging from inter-patient to intra-tumoral, poses a significant challenge in identifying effective treatments. At the single-cell level, GBMs comprise a multiplicity of transcriptional cell states that can change over time and in response to therapy. To explore how cell state plasticity shapes tumor progression, new experimental tools to monitor cell state dynamics in real-time will be important, if not essential. Here, we describe a live reporting of GBM cell states that utilize CRISPR/Cas9 and fluorescent proteins for tracking individual glioblastoma patient-derived cells’ (GBM-PDC) physiological gene expression, and cell state transitions over time and during treatment. The method aims to provide real-time reporting of accurate transcriptional phenotypes (e.g. OPC/NPC-like, Mesenchymal, Astrocyte states) over extended periods or in relevant in vitro or in vivo contexts. Our protocols achieved successful endogenous tagging of a common stem cell marker with full-length mCherry in up to 15 % of GBM-PDC (an order of magnitude more effective than previous reports). Real-time imaging (Incucyte S3 and IMX-C) allows us to trace individual cells’ states over time and during treatment, supported by ICC, qPCR, and Western blot, providing a reliable approach. Our next objective is to employ this method to tag several cell-state marker genes with fluorescent proteins. We can directly follow gene expression and cellular state transitions when several state-selective genes are fused with different fluorescent proteins. We anticipate establishing a robust framework to investigate the temporal plasticity and invasion patterns within GBM cells across different patients which may open for new therapeutic opportunities.
MODL-31. USING GENETICALLY-ENGINEERED MOUSE MODELS OF TREATMENT-NAÏVE AND -EXPERIENCED NTRK FUSION-DRIVEN GLIOMAS FOR PRE-CLINICAL TRIALS OF TYROSINE KINASE INHIBITORS
Authors: Schmid Sebastian , Russell Zachary R , West Madeline , Walker Julia , Holland Eric , Szulzewsky Frank
Published: November 2023

Gene fusions that contain the kinase domain of the three neurotrophic tyrosine kinase receptor (NTRK) genes are frequently observed in infantile high and low-grade gliomas. While these tumors initially respond to treatment with NTRK tyrosine kinase inhibitors (TKIs), treatment resistance and recurrence eventually occur. Treatment-resistant tumors frequently harbor either on-target (in the fusion's kinase domain) or off-target mutations (in downstream effectors of mitogen-activated signaling pathways). Therefore, overcoming this resistance requires a three-pronged strategy: 1) identifying new kinase inhibitors capable of targeting NTRK fusions with on-target kinase domain mutations, 2) identifying druggable targets in the downstream pathways activated by these fusions, and 3) targeting persister cells that contribute to disease recurrence. We utilized the RCAS/tv-a system to establish several mouse models of NTRK1/2/3 fusion-driven gliomas. We found that all analyzed fusions were strong oncogenic drivers on their own, while the loss of additional tumor suppressors (Cdkn2a or Pten) further increased the aggressiveness of these tumors. These mouse models exhibit similar treatment responses as human tumors, initially responding to various TKIs but eventually recurring due to the presence of treatment-resistant persister cells. To mimic the emergence of resistance-associated mutations, we directly introduced different kinase domain mutations into the NTRK fusion sequence or co-expressed secondary mutations (BRAF-V600E or KRAS-G12D). These modifications altered the response to TKI treatment both in vitro and in vivo. Overall, these models serve as valuable tools for studying the biology of NTRK fusion tumors, their treatment response in a treatment-naïve or -experienced state, and the mechanisms underlying treatment resistance.
MODL-32. EGFRVIII OVEREXPRESSION AND LOSS OF MOUSE SPECIFIC CDKN2A IN GLIAL CELLS LEADS TO GLIOMAGENESIS IN A NOVEL MOUSE MODEL
Authors: Singh Olivia , Li Mira , Ali Hafsah , Voisin Mathew , Wei Qingxia , Gao Andrew , Agnihotri Sameer , Burrell Kelly , Wilson Mark , Kamiri Shirin , Aldape Kenneth , Zadeh Gelareh
Published: November 2023

A new mouse model for the classical subtype of human glioblastoma has been generated using Cre-mediated EGFRvIII overexpression and homozygous p19-ARF deletion (the mouse homolog of human p14-ARF/CDKN2A) in GFAP expressing cells. Transgenic mice develop intraparchenymal and/or leptomeningeal brain lesions with some spinal cord invasion as early as 1 month old and 95% of mice die by 6 months due to hydrocephalus and/or paralysis. Mice with high grade tumors have worse survival and similar features to human classical glioblastoma such as necrosis, high levels of mitosis, and infiltration of tumor cells into normal brain. Immunohistochemical analysis confirms EGFRvIII overexpression and p19-ARF loss in tumor cells, along with patchy positive GFAP and positivity for Olig2, S100β and NeuN, suggesting that tumor cells arise from a progenitor glial cell type. Adherent and neurosphere primary culture of dissociated tumors indicate that tumor cells maintain EGFRvIII expression in culture and are able to generate xenograft tumors by 3 weeks after intracranial injections into NODSCID mice. Xenograft tumors are reminiscent of the primary tumor, with similar histopathological features and immunohistochemical staining. This novel mouse model can be used to study diffuse glioma with a leptomeningeal component.
MODL-33. PATIENT-DERIVED GLIOBLASTOMA MINIATURE AND CANCER STEM CELL SUICIDE-INDUCING NANO-AWAKENER BASED ON IT
Authors: Yoon Seon-Jin , Baek Sewoom , Yu Seung-Eun , Jo Euna , Choi Ran Joo , Moon Ju Hyung , Kim Eui-Hyun , Chang Jong Hee , Sung Hak-Joon , Kang Seok-Gu
Published: November 2023

Patient-specific anti-tumor therapies can evolve by vitalizing the mother tissue-like cancer niche, cellular profile, genetic signature, and drug responsiveness. This evolution elucidated a key mechanism along with the development of the cancer therapy. The present study aimed to meet these clinical demands by approaching the direct culture of GBM patient tissues with a 1 mm post-punching diameter in a 3D microchannel network chip (“GBM miniature”). Hence, we directly cultured of GBM patient tissue (1 mm diameter) in a microchannel network chip (GBM miniature) to preserve mother tissue-like characteristic signatures and microenvironment. When chemoradiation therapy were administered within 1 day, the responsiveness of the tissue in the chip mirroring the clinical outcomes. The characteristics of migrating cells from GBM miniature were analyzed, and peptides that target these migrating CSCs were searched for. And, by attaching this CSC peptide to the nanovesicle, the therapeutic effect was confirmed in GBM miniature. Upon testing within 1 day, the tissue chip reflected patient drug responsiveness as seen in the clinic. As the tissue chip culture was continued, the intact GBM signature was getting lost, and the outward migration of stem cells from the tissue origin increased, indicating a leaving-home effect on the family dismantle. Nanovesicle production using GBM stem cells enabled self-chasing of the cells that escaped the temozolomide effect owing to quiescence. The anti-PTPRZ1 peptide display and temozolomide loading to nanovesicles awaked stem cells from the quiescent stage to death. This research proposes a GBM patient avatar platform and mechanism-learned nanotherapy for translation.
MODL-38. DEFINING THE ROLE OF DAAM2 R414W MUTATION IN GLIOMAGENESIS AND GBM GROWTH
Authors: Choy Tiffany , Ye Qi , Deneen Benjamin , Bondy Melissa , Lee Hyun Kyoung
Published: November 2023

Each year in the United States, more than 13,000 people are diagnosed with glioblastoma multiforme (GBM), and more than 10,000 are estimated to succumb to the disease, making GBM the most common and lethal primary adult brain tumor. Despite advancing therapies, GBM patient survival has not improved over the decades, so it is critical to better understand glioma etiology. The majority of GBM cases arise from a sporadic accumulation of somatic mutations, but approximately 5-10% of gliomas are classified as “familial”, occurring clustered with hereditary cancer predispositions. These familial gliomas are caused by germline mutations inherited from parent to offspring, and only a few of these mutations have been directly linked to the development of GBM. We recently discovered five germline mutations in Daam2 (Dishevelled associated activator of morphogenesis 2) from GBM patients with a history of familial glioma. To examine the role of these mutations in GBM, we overexpressed these mutations in patient-derived GBM cells, which were then orthotopically xenografted into immunodeficient mice. We identified that one of these mutations, Daam2-R414W, promotes tumor cell proliferation both in vitro and in vivo. To further understand the role of the Daam2-R414W mutation in GBM, we generated a knock-in immunocompetent mouse model that harbors the Daam2-R414W mutation. In these mutant mice, we found increased proliferation of glial progenitor cells in the subventricular zone compared to Daam2 wildtype mice, suggesting the potential of the Daam2-R414W mutation to influence glial progenitor expansion to stimulate glioma initiation. Future experiments aim to answer whether this mutation promotes GBM growth in an immunocompetent model and to decipher the mechanism relating the Daam2-R414W mutation to GBM pathology. These studies will shed light on the repercussions of a human developmental gene variant and its potential to disrupt normal cellular machinery to promote malignancy and GBM development.
MODL-41. LOSS OF DISTAL CHROMOSOME 6Q AND ASSOCIATED PDE10A INDUCES AN AGGRESSIVE GLIOMA PHENOTYPE BY FACILITATING PRONEURAL TO MESENCHYMAL TRANSITION
Authors: Nuechterlein Nicholas , Shelbourn Allison , Alvinez Neriah , Szulzewsky Frank , Arora Sonali , Paddison Patrick , Merino-Galan Leyre , Pattwell Siobhan , Sulman Erik , Jung Mi-Yeon , Brown Desmond , Banasavadi-Siddegowda Yeshavanth Kumar , Tang Kayen , Jackson Sadhana , Stoica Stefan , Chittaboina Prashant , Patel Anoop , Holland Eric , Cimino Patrick , Shapiro Linda
Published: November 2023

Somatic copy number alterations (SCNAs) are common in glioblastoma, with some SCNAs having prognostic implications. Identifying and characterizing SCNA-related genes acting as oncogenes or tumor suppressors may potentially provide new therapeutic avenues for gliomas. In this study, we sought to uncover novel SCNA-related genes by employing an unbiased log rank analysis screen of genomic regions associated with glioblastoma survival. We identified 6q27 loss as an independent poorly-prognostic SCNA across three separate glioblastoma cohorts. An in vitro CRISPR screen using human neural stem cells identified five genes in the 6q27 region that caused increased cellular proliferation. One of these genes, phosphodiesterase 10A (PDE10A), had a gene dosage effect on expression and decreased expression in human and mouse glioma tumor tissue compared to normal brain, which are both common tumor suppressor phenotypes. Knockdown of Pde10a in mouse neural stem cells in vitro validated the human cell CRISPR screen phenotype. Suppression of Pde10a in RCAS/Tva mouse glioma in vivo caused decreased survival with increased tumor grade, mitotic activity, necrosis, Vegfa expression, and AKT/pS6 signaling. Single cell RNA-sequencing of mouse gliomas revealed that Pde10a suppression results in a shift from proneural to mesenchymal-like state. In human glioma tissue, PDE10A loss is also associated with an increased mesenchymal signature. Top activated pathways in Pde10a suppressed gliomas involved cell-cell interaction, including upregulation of cell adhesion molecules and downregulation of focal adhesion complex disassembly genes. Functional analysis in vitro confirmed that Pde10a suppression results in increased extracellular matrix adhesion and decreased migration. Relevant to standard glioblastoma treatment, PDE10A loss was associated with decreased MGMT promoter methylation, decreased DNA methyltransferase gene expression, and it potentiated radiation resistance in vitro. In summary, we leveraged several multiomic and experimental platforms to reveal PDE10A as a tumor suppressor in glioblastoma, predominantly by inducing a proneural to mesenchymal transition phenotype.
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

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

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

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

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.
Effects of Pesticides on Red Rot of Planted Sugarcane
Authors: Cristina da Silva Reis Kézia , Savario Carolyn F. , Hoy Jeffrey W.
Published: November 2023

Red rot, caused by Colletotrichum falcatum, is an important constraint to sugarcane production. In Louisiana, red rot primarily affects planted seed-cane and is more severe when billets (stalk sections) are planted rather than whole stalks. At planting, application of seed-treatment pesticides, particularly a combination of a fungicide and the insecticide thiamethoxam, has improved stand establishment and increased yields in billet plantings in Louisiana. However, information on the effect of chemicals on disease development is lacking. Greenhouse experiments were conducted to evaluate stalk rot symptom severity and initial plant growth for billets dip-treated with a combination of the fungicides azoxystrobin and propiconazole, thiamethoxam, a combination of both fungicides and the insecticide, and, as a control, untreated billets. Reductions in disease severity recorded for different treatments were similar for billets inoculated with the fungus or exposed to natural inoculum. Disease severity was consistently reduced by the combination treatment, while reductions resulting from treatment with fungicides and insecticide alone were variable. Reductions occurred for both internode and node rot severity. The effects of pesticide treatments on plant growth after 6 weeks were minor; however, there was evidence of disease adversely affecting germination, particularly for nontreated billets exposed to natural inoculum, where germination was reduced by one third. The treatments that reduced disease severity prevented this reduction. The results provide evidence that reduction in disease severity is an important contributor to the stand establishment and yield improvements observed for treated billets in field experiments.
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

Juvenile 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 Abstract

INTRODUCTION

pT217-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.

METHODS

We 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.

RESULTS

pT217-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.

DISCUSSION

These 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

The 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.

HIGHLIGHTS

Neonatal 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

Purpose

Using 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/approach

The 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.

Findings

Throughout 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/value

Even 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

Purpose

The authors estimated the hidden overhead (capital diversion or wasteful use of capital) of Vietnam state-owned enterprises (SOEs).

Design/methodology/approach

The 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.

Findings

Vietnam 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/implications

Alternative estimation methods should be used to account for endogeneity in production inputs. Lack of comparison with the Vietnam private firms.

Originality/value

The 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

Purpose

In 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/approach

Using 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).

Findings

Results 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 implications

The 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/value

The 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

The ‘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

Recent 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.
Predicting the risk of variceal rehemorrhage in cirrhotic patients with portal vein thrombosis: A two‐center retrospective study
Authors: Zhang Shuo , Zhong Xuan , Zhong Hui , Zhong Lan , Li Jing , Zhu Feng Shang , Xia Lu , Yang Chang Qing
Published: November 2023

Objectives

Although portal vein thrombosis (PVT) was thought to deteriorate portal hypertension and contribute to poor prognosis, risk stratification remains unclear. This study aimed to evaluate its effect on the risk of variceal rehemorrhage and to develop a competitive risk model in cirrhotic patients with PVT.

Methods

Cirrhotic patients with and without PVT admitted for acute variceal hemorrhage were retrospectively included after matching (1:1) for age, gender and etiology of cirrhosis from two tertiary centers with 1‐year follow‐up. Those with PVT were subsequently divided into the training and validation cohorts. Cox regression analysis was performed to identify risk factors and develop a competitive risk model, of which the predictive performance and optimal decision threshold were evaluated by C‐index, competitive risk curves, calibration curves and decision curve analysis.

Results

Among 398 patients, PVT significantly increased the variceal rehemorrhage risk. Multivariate Cox regression analysis identified that the Child–Turcotte–Pugh score (P = 0.013), chronic PVT (P = 0.025), C‐reactive protein (P < 0.001), and aspartate aminotransferase (P = 0.039) were independently associated with variceal rehemorrhage, which were incorporated into the competitive risk model, with high C‐index (0.804 and 0.742 of the training and validation cohorts, respectively), risk stratification ability, and consistency. The optimal decision range of the threshold probability was 0.2–1.0.

Conclusion

We confirmed the adverse effect of PVT on variceal rehemorrhage and developed a competitive risk model for variceal rehemorrhage in cirrhotic patients with PVT, which might be conveniently used for clinical decision‐making.
DARS2 promotes the occurrence of lung adenocarcinoma via the ERK/c‐Myc signaling pathway
Authors: Fang Tao , Jiang Jin , Yu Wenhao , Li Rongyang , Tian Hui
Published: November 2023

Background

DARS2 expression is upregulated in lung adenocarcinoma (LUAD) which correlates with tumor patient stage and prognosis. The mechanism of DARS2 involvement in LUAD still needs to be further explored.

Methods

In this study, we found that DARS2 expression in LUAD tissue was significantly higher than that in normal tissue. At the same time, the Kaplan–Meier curve showed that the survival prognosis of LUAD patients with high expression of DARS2 was significantly worse than low expression of DARS2. The expression of DARS2 was detected in LUAD and adjacent normal tissues by IHC staining, histochemical scoring and a survival curve was generated. In addition, we demonstrated that the knockdown and overexpression of DARS2 significantly affected the proliferation, invasion, and migration of LUAD cells in vitro and in vivo. Finally, western blot and rescue assay were performed on LUAD cells to further explore and verify the signaling pathway.

Results

DARS2 expression was significantly upregulated in LUAD tissues and cell lines. What is more, the increased expression of DARS2 was closely related to proliferation, invasion and metastasis. The tumorigenic assay in nude mice further showed that the tumorigenic ability of nude mice was significantly improved with the increase in DARS2 expression. Finally, we determined that DARS2 plays its role in LUAD by targeting the ERK/c‐Myc signaling pathway.

Conclusion

Our data revealed the oncogenic role of DARS2 in LUAD, indicating that DARS2 may be a predictive biomarker and novel therapeutic target for LUAD.
Programme for prevention of foot dermatoses in patients with work‐related skin diseases: Follow‐up data of a prospective cohort study (OCCUPES)
Authors: Hübner Anja , John Swen Malte , Wilke Annika , Brans Richard
Published: November 2023

Background

A programme based on health education has been developed to prevent foot dermatoses (FD) in patients with work‐related skin diseases (WRSD).

Objective

To evaluate the effectiveness of the programme in a prospective cohort study (OCCUPES).

Methods

Six and 12 months after completing the programme, follow‐up questionnaires were sent to 231 patients with WRSD and FD. Assessments included occupational footwear and foot care, self‐reported disease course, and health‐related quality of life.

Results

Response to follow‐ups was >70%. Wearing functional socks and changing footwear and socks during one work shift increased (all p < 0.001). Complaints about occupational footwear decreased, including sweating and exposure to moisture/wetness. More than 60% reported improved FD while quality of life significantly increased. After 12 months, all foot symptoms were less frequent, including itch (p = 0.009), pain when walking (p = 0.005), pain in rest (p = 0.015) and smell (p = 0.001). The programme received very good ratings by the participants.

Conclusions

The intervention was effective in improving occupational footwear, foot care and preventive behaviour. It resulted in a reduced burden of FD and should be implemented in the general care of patients with WRSD.
Design Thinking and AI: A New Frontier for Designing Human‐Centered AI Solutions
Authors: Böckle Martin , Kouris Iana
Published: November 2023

In recent years, design thinking (DT) has become a pervasive innovation approach in the managerial community as a structured way of solving challenging problems through a human‐centered perspective. The approach fosters lateral thinking and has a huge impact on the organizational culture and the core elements of the innovation process. At the same time, the number of organizations trying to solve problems through the application of artificial intelligence (AI) is constantly growing, although more than 80% of AI projects never reach deployment due to the wrong strategic approach, poor data quality, or a lack of AI awareness among employees—and those that do remain below profitability expectations. The aim of this paper is therefore to connect the AI and DT communities by proposing a first framework supporting the development of AI solutions in a human‐centered way. The contribution of this paper is thus twofold: First, we investigate ways in which design thinking adds real value along the design process of intelligent solutions, thereby enriching the present body of design management literature. Second, we propose a first framework by linking core elements of both worlds to support strategic designers and data engineers in designing such applications. Finally, we propose a research agenda that can serve as a basis for future research directions in order to advance contributions at the intersection of the two fields.
Implementing Evidence‐Based Design to Improve Adherence in Self‐Administered Treatment Technology
Authors: Elmansy Rafiq , English Stuart
Published: November 2023

A low level of treatment adherence is one of the challenges facing the UK's healthcare system. An estimated 30% to 50% of patients with chronic diseases fail to adhere to prescribed medical interventions. While medical technology provides an opportunity to overcome existing challenges, poor adherence blurs this opportunity by reducing the intervention's positive impact. The spread of the Covid pandemic dramatically increased the pressure on healthcare systems and highlighted the urgency to address the low adherence problem. Various studies have investigated the underlying factors behind low adherence. However, two main gaps were identified: 1) lack of adherence frameworks that consider self‐administered treatment technology, and 2) lack of a practical mechanism to help companies consider adherence factors during the design and development of the technology.

This paper introduces the development of an Adherence Framework for self‐administered treatment technology and a design‐focused adherence canvas used as a practical resource for companies to consider during the design process. Adherence factor data from literature and case studies were triangulated to an eDelphi study used to develop the adherence framework. The presented adherence canvas and Adherence Framework allow companies to consider adherence during the design of self‐administered treatment technology.