bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of an HSV-1 production process involving serum-reduced culturing and bead-to-bead transfer
Authors: Wang Helin , Hu Xiuhua , Zhang Mingfang , Yang Lin , Xu Yueying , Gu Xiaoxu , Jiang Junjun , Hu Weiwei 
Published: June 2024

Abstract
Herpes simplex virus type 1 (HSV-1) plays an important role in the field of gene therapy and viral vaccines, especially as an oncolytic virus. However, the mass production of HSV-1 viral vectors remains a challenge in the industry. In this study, a microcarrier-mediated serum-reduced medium culture was used to improve the bioprocess of HSV-1 production and increase HSV-1 yields. The composition of the culture media, which included a basal medium, serum concentration, and glutamine additive, was optimized. The process was successfully conducted in a 1 L bioreactor, and virus production was threefold greater than that of conventional processes with a 10% serum medium. The bead-to-bead transfer process was also developed to further increase scalability. In spinner flasks, the detachment rate increased from 49.4 to 80.6% when combined agitation was performed during digestion; the overall recovery proportion increased from 37.9 to 71.1% after the operational steps were optimized. Specifically, microcarrier loss was reduced during aspiration and transfer, and microcarriers and detached cells were separated with filters. Comparable cell growth was achieved with the baseline process using 2D culture as the inoculum by exchanging the subculture medium. To increase virus production after bead-to-bead transfer, critical parameters, including shear stress during digestion, TrypLE and EDTA concentrations in the subculture, and the CCI, were identified from 47 parameters via correlation analysis and principal component analysis. The optimized bead-to-bead transfer process achieved an average of 90.4% overall recovery and comparable virus production compared to that of the baseline process. This study is the first to report the optimization of HSV-1 production in Vero cells cultured on microcarriers in serum-reduced medium after bead-to-bead transfer.

Key points
• An HSV-1 production process was developed that involves culturing in serum-reduced medium, and this process achieved threefold greater virus production than that of traditional processes.
• An indirect bead-to-bead transfer process was developed with over 90% recovery yield in bioreactors.
• HSV-1 production after bead-to-bead transfer was optimized and was comparable to that achieved with 2D culture as inoculum.
Comparative transcriptomic and proteomic kinetic analysis of adeno-associated virus production systems
Authors: Lin Yu-Chieh , Lu Min , Cai Wen , Hu Wei-Shou 
Published: June 2024

Abstract
Recombinant adeno-associated virus (rAAV) is a major gene delivery vehicle. We have constructed a stable rAAV producer cell line by integrating essential rAAV genome, viral and helper genes into the genome of HEK293 cell under the control of inducible promoters. Upon induction, the cell line produces transducing rAAV. To gain insight into enhancing rAAV productivity and vector quality, we performed a comparative transcriptomic and proteomic analysis of our synthetic cell line GX2 and two wild-type AAV (wtAAV) production systems, one by virus co-infection and the other by multi-plasmid transfection. The three systems had different kinetics in viral component synthesis but generated comparable copies of AAV genomes; however, the capsid titer of GX2 was an order of magnitude lower compared to those two wtAAV systems, indicating that its capsid production may be insufficient. The genome packaging efficiency was also lower in GX2 despite it produced higher levels of Rep52 proteins than either wtAAV systems, suggesting that Rep52 protein expression may not limit genome packaging. In the two wtAAV systems, VP were the most abundant AAV proteins and their levels continued to increase, while GX2 had high level of wasteful cargo gene expression. Furthermore, upregulated inflammation, innate immune responses, and MAPK signaling, as well as downregulated mitochondrial functions, were commonly observed in either rAAV or wtAAV systems. Overall, this comparative multi-omics study provided rich insights into host cell and viral factors that are potential targets for genetic and process intervention to enhance the productivity of synthetic rAAV producer cell lines.

Key points
• wtAAV infection was more efficient in producing full viral particles than the synthetic cell GX2.
• Capsid protein synthesis, genome replication, and packaging may limit rAAV production in GX2.
• wtAAV infection and rAAV production in GX2 elicited similar host cell responses.
Exploring operational boundaries for acoustic concentration of cell suspensions
Authors: de Hemptinne Amaury , Gelin Pierre , Bihi Ilyesse , Kinet Romain , Thienpont Benoit , De Malsche Wim 
Published: June 2024

Abstract
The development of a standardized, generic method for concentrating suspensions in continuous flow is challenging. In this study, we developed and tested a device capable of concentrating suspensions with an already high cell concentration to meet diverse industrial requirements. To address typical multitasking needs, we concentrated suspensions with high solid content under a variety of conditions. Cells from Saccharomyces cerevisiae, Escherichia coli, and Chinese hamster ovary cells were effectively focused in the center of the main channel of a microfluidic device using acoustophoresis. The main channel bifurcates into three outlets, allowing cells to exit through the central outlet, while the liquid evenly exits through all outlets. Consequently, the treatment separates cells from two-thirds of the surrounding liquid. We investigated the complex interactions between parameters. Increasing the channel depth results in a decrease in process efficiency, attributed to a decline in acoustic energy density. The study also revealed that different cell strains exhibit distinct acoustic contrast factors, originating from differences in dimensions, compressibility, and density values. Finally, a combination of high solid content and flow rate leads to an increase in diffusion through a phenomenon known as shear-induced diffusion.

Key points
• Acoustic focusing in a microchannel was used to concentrate cell suspensions
• The parameters influencing focusing at high concentrations were studied
• Three different cell strains were successfully concentrated

Graphical abstract
[18F]FDG-PET/CT atypical response patterns to immunotherapy in non-small cell lung cancer patients: long term prognosis assessment and clinical management proposal
Authors: Masse Mathilde , Chardin David , Tricarico Pierre , Ferrari Victoria , Martin Nicolas , Otto Josiane , Darcourt Jacques , Comte Victor , Humbert Olivier 
Published: June 2024

Abstract
Aim
To determine the long-term prognosis of immune-related response profiles (pseudoprogression and dissociated response), not covered by conventional PERCIST criteria, in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs).

Methods
109 patients were prospectively included and underwent [18F]FDG-PET/CT at baseline, after 7 weeks (PETinterim1), and 3 months (PETinterim2) of treatment. On PETinterim1, tumor response was assessed using standard PERCIST criteria. In the event of PERCIST progression at this time-point, the study design provided for continued immunotherapy for 6 more weeks. Additional response patterns were then considered on PETinterim2: pseudo-progression (PsPD, subsequent metabolic response); dissociated response (DR, coexistence of responding and non-responding lesions), and confirmed progressive metabolic disease (cPMD, subsequent homogeneous progression of lesions). Patients were followed up for at least 12 months.

Results
Median follow-up was 21 months. At PETinterim1, PERCIST progression was observed in 60% (66/109) of patients and ICPI was continued in 59/66. At the subsequent PETinterim2, 14% of patients showed PsPD, 11% DR, 35% cPMD, and 28% had a sustained metabolic response. Median overall survival (OS) and progression-free-survival (PFS) did not differ between PsPD and DR (27 vs 29 months, p = 1.0; 17 vs 12 months, p = 0.2, respectively). The OS and PFS of PsPD/DR patients were significantly better than those with cPMD (29 vs 9 months, p < 0.02; 16 vs 2 months, p < 0.001), but worse than those with sustained metabolic response (p < 0.001). This 3-group prognostic stratification enabled better identification of true progressors, outperforming the prognostic value of standard PERCIST criteria (p = 0.03).

Conclusion
[18F]FDG-PET/CT enables early assessment of response to immunotherapy. The new wsPERCIST (“wait and see”) PET criteria proposed, comprising immune-related atypical response patterns, can refine conventional prognostic stratification based on PERCIST criteria.

Trial registration
HDH F20230309081206. Registered 20 April 2023. Retrospectively registered.
Predictive value of C-X-C motif chemokine receptor 4-directed molecular imaging in patients with advanced adrenocortical carcinoma
Authors: Schloetelburg Wiebke , Hartrampf Philipp E. , Kosmala Aleksander , Serfling Sebastian E. , Dreher Niklas , Schirbel Andreas , Fassnacht Martin , Buck Andreas K. , Werner Rudolf A. , Hahner Stefanie 
Published: June 2024

Abstract
Background
In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [68Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters.

Methods
We identified 41 metastasized ACC patients imaged with [68Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUVmean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded.

Results
After [68Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1–96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001–1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03–4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9–4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07).

Conclusions
In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [68Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information.
Interstate Air Pollution Governance in the United States: Exploring Clean Air Act Section 126
Authors: Underwood Alixandra , Marcantonio Richard , Wood Danielle , Crippa Paola 
Published: June 2024

AbstractAir pollution is arguably the most pressing human health concern today, accounting for approximately 7–9 million premature deaths worldwide. In the United States, more than 40% of early deaths caused by air pollution are assessed to be caused by emissions produced by neighboring states. This article examines one of the governance mechanisms used by the U.S. to address this issue: section 126 of the Clean Air Act. Critical factors including case length, evidence used, and case outcome are compiled for the population of section 126 petitions submitted from 2000–2022. This evidence is assessed using comparative case analysis. The findings reinforce two issues with the petition process already identified in the literature–the use of cost as a proxy for significance and the excessive and unclear burden of proof placed on downwind states–adding texture to the latter issue by examining the modeling techniques used by downwind states. This analysis identifies lengthy response timelines as an additional issue and calls to attention the infrequency with which the EPA has formally accepted petitions. Collectively, these issues increase the cost, complexity, and unpredictability of filing a section 126 petition.
Machine Learning to Predict Prostate Artery Embolization Outcomes
Authors: Vigneswaran G. , Doshi N. , Maclean D. , Bryant T. , Harris M. , Hacking N. , Farrahi K. , Niranjan M. , Modi S. 
Published: June 2024

Abstract
Purpose
This study leverages pre-procedural data and machine learning (ML) techniques to predict outcomes at one year following prostate artery embolization (PAE).

Materials and Methods
This retrospective analysis combines data from the UK-ROPE registry and patients that underwent PAE at our institution between 2012 and 2023. Traditional ML approaches, including linear regression, lasso regression, ridge regression, decision trees and random forests, were used with leave-one-out cross-validation to predict international prostate symptom score (IPSS) at baseline and change at 1 year. Predictors included age, prostate volume, Qmax (maximum urinary flow rate), post-void residual volume, Abrams-Griffiths number (urodynamics score) and baseline IPSS (for change at 1 year). We also independently confirmed our findings using a separate dataset. An interactive digital user interface was developed to facilitate real-time outcome prediction.

Results
Complete data were available in 128 patients (66.7 ± 6.9 years). All models predicting IPSS demonstrated reasonable performance, with mean absolute error ranging between 4.9–7.3 for baseline IPSS and 5.2–8.2 for change in IPSS. These numbers represent the differences between the patient-reported and model-predicted IPSS scores. Interestingly, the model error in predicting baseline IPSS (based on objective measures alone) significantly correlated with the change in IPSS at 1-year post-PAE (R2 = 0.2, p < 0.001), forming the basis for our digital user interface.

Conclusion
This study uses ML methods to predict IPSS improvement at 1 year, integrated into a user-friendly interface for real-time prediction. This tool could be used to counsel patients prior to treatment.
The prognostic importance of traumatic axonal injury on early MRI: the Trondheim TAI-MRI grading and quantitative models
Authors: Moen Kent Gøran , Flusund Anne-Mari Holte , Moe Hans Kristian , Andelic Nada , Skandsen Toril , Håberg Asta , Kvistad Kjell Arne , Olsen Øystein , Saksvoll Elin Hildrum , Abel-Grüner Sebastian , Anke Audny , Follestad Turid , Vik Anne 
Published: June 2024

Abstract
Objectives
We analysed magnetic resonance imaging (MRI) findings after traumatic brain injury (TBI) aiming to improve the grading of traumatic axonal injury (TAI) to better reflect the outcome.

Methods
Four-hundred sixty-three patients (8–70 years) with mild (n = 158), moderate (n = 129), or severe (n = 176) TBI and early MRI were prospectively included. TAI presence, numbers, and volumes at predefined locations were registered on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging, and presence and numbers on T2*GRE/SWI. Presence and volumes of contusions were registered on FLAIR. We assessed the outcome with the Glasgow Outcome Scale Extended. Multivariable logistic and elastic-net regression analyses were performed.

Results
The presence of TAI differed between mild (6%), moderate (70%), and severe TBI (95%). In severe TBI, bilateral TAI in mesencephalon or thalami and bilateral TAI in pons predicted worse outcomes and were defined as the worst grades (4 and 5, respectively) in the Trondheim TAI-MRI grading. The Trondheim TAI-MRI grading performed better than the standard TAI grading in severe TBI (pseudo-R2 0.19 vs. 0.16). In moderate-severe TBI, quantitative models including both FLAIR volume of TAI and contusions performed best (pseudo-R2 0.19–0.21). In patients with mild TBI or Glasgow Coma Scale (GCS) score 13, models with the volume of contusions performed best (pseudo-R2 0.25–0.26).

Conclusions
We propose the Trondheim TAI-MRI grading (grades 1–5) with bilateral TAI in mesencephalon or thalami, and bilateral TAI in pons as the worst grades. The predictive value was highest for the quantitative models including FLAIR volume of TAI and contusions (GCS score <13) or FLAIR volume of contusions (GCS score ≥ 13), which emphasise artificial intelligence as a potentially important future tool.

Clinical relevance statement
The Trondheim TAI-MRI grading reflects patient outcomes better in severe TBI than today’s standard TAI grading and can be implemented after external validation. The prognostic importance of volumetric models is promising for future use of artificial intelligence technologies.

Key Points

Traumatic axonal injury (TAI) is an important injury type in all TBI severities. Studies demonstrating which MRI findings that can serve as future biomarkers are highly warranted.

This study proposes the most optimal MRI models for predicting patient outcome at 6 months after TBI; one updated pragmatic model and a volumetric model.

The Trondheim TAI-MRI grading, in severe TBI, reflects patient outcome better than today’s standard grading of TAI and the prognostic importance of volumetric models in all severities of TBI is promising for future use of AI.
The Hanging Chain Problem in the Sphere and in the Hyperbolic Plane
Authors: López Rafael 
Published: June 2024

AbstractIn this paper, the notion of the catenary curve in the sphere and in the hyperbolic plane is introduced. In both spaces, a catenary is defined as the shape of a hanging chain when its potential energy is determined by the distance to a given geodesic of the space. Several characterizations of the catenary are established in terms of the curvature of the curve and of the angle that its unit normal makes with a vector field of the ambient space. Furthermore, in the hyperbolic plane, we extend the concept of catenary substituting the reference geodesic by a horocycle or the hyperbolic distance by the horocycle distance.
A clock for all seasons
Authors: Helfrich-Förster Charlotte , Rieger Dirk 
Published: June 2024

AbstractCircadian clocks play an essential role in adapting locomotor activity as well as physiological, and metabolic rhythms of organisms to the day-night cycles on Earth during the four seasons. In addition, they can serve as a time reference for measuring day length and adapt organisms in advance to annual changes in the environment, which can be particularly pronounced at higher latitudes. The physiological responses of organisms to day length are also known as photoperiodism. This special issue of the Journal of Comparative Physiology A aims to account for diurnal and photoperiodic adaptations by presenting a collection of ten review articles, five original research articles, and three perspective pieces. The contributions include historical accounts, circadian and photoperiodic clock models, epigenetic, molecular, and neuronal mechanisms of seasonal adaptations, latitudinal differences in photoperiodic responses and studies in the wild that address the challenges of global change.
Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection
Authors: Bertero Edoardo , Popoiu Tudor-Alexandru , Maack Christoph 
Published: June 2024

AbstractMitochondrial calcium (Ca2+) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca2+ levels modulate the rate of oxidative metabolism to match the rate of adenosine triphosphate consumption in the cytosol. During ischemia/reperfusion (I/R) injury, pathologically high levels of Ca2+ in the mitochondrial matrix trigger the opening of the mitochondrial permeability transition pore, which releases solutes and small proteins from the matrix, causing mitochondrial swelling and ultimately leading to cell death. Pharmacological and genetic approaches to tune mitochondrial Ca2+ handling by regulating the activity of the main Ca2+ influx and efflux pathways, i.e., the mitochondrial Ca2+ uniporter and sodium/Ca2+ exchanger, represent promising therapeutic strategies to protect the heart from I/R injury.
Annexin A11 aggregation in FTLD–TDP type C and related neurodegenerative disease proteinopathies
Authors: Robinson John L. , Suh EunRan , Xu Yan , Hurtig Howard I. , Elman Lauren , McMillan Corey T. , Irwin David J. , Porta Sílvia , Van Deerlin Vivianna M. , Lee Edward B. 
Published: June 2024

AbstractTAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD–TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD–TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD–TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3–6%) of sporadic and genetic forms of FTLD–TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD–TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.