bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal combination of arsenic trioxide and copper ions to prevent autoimmunity in a murine HOCl-induced model of systemic sclerosis
Authors: Chêne Charlotte , Rongvaux-Gaïda Dominique , Thomas Marine , Rieger François , Nicco Carole , Batteux Frédéric 
Published: March 2023

IntroductionSystemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by diffuse fibrosis of the skin and internal organs and vascular abnormalities. The etiology and physiopathology are complex due to the heterogeneity of its overall clinical presentation. Arsenic trioxide (ATO) has been proven to be effective against SSc, sclerodermatous Graft-versus-Host Disease, multiple sclerosis, Crohn’s disease or systemic lupus erythematosus animal models and has demonstrated promising effects in human clinical trials. Its efficacy was shown to be related at least in part to the generation of Reactive Oxygen Species (ROS) and the selective deletion of activated immune cells and fibroblasts. However, ATO can induce some adverse effects that must be considered, especially when used for the treatment of a chronic disease.MethodsWe evaluate here, in vitro and in a mouse model of SSc, the improved efficacy of ATO when associated with a Fenton-like divalent cation, namely copper chloride (CuCl2), also known to trigger the production of ROS.ResultsIn preliminary experiments in vitro, ATO 1 µM + CuCl2 0.5 µM increased ROS production and increased apoptosis of NIH 3T3 murine fibroblasts compared to 1 µM ATO alone. In vivo, in the HOCl-induced mouse model of SSc, co-treatment with ATO 2.5 μg/g + CuCl2 0.5 μg/g significantly alleviated clinical signs such as the thickening of the skin (p&lt;0.01) and cutaneous fibrosis, in a manner equivalent to treatment with ATO 5 µg/g. Our results provide evidence that co-treatment with ATO 2.5 μg/g + CuCl2 0.5 μg/g decreases the number of B cells and the activation of CD4+ T lymphocytes. The co-treatment substantially blocks the NRF2 signaling pathway, increases H2O2 production and results in the improvement of the health status of mice with experimental SSc.ConclusionIn conclusion, copper combined with ATO treatment halved the concentration of ATO needed to obtain the same effect as a high dose of ATO alone for the treatment of SSc mice. The strategy of using lower doses of drugs with different mechanisms of action in combination has many potential advantages, the first being to lessen the potential side effects induced by ATO, a drug with side effects quickly increased with dosage.
A maladaptive pleural environment suppresses preexisting anti-tumor activity of pleural infiltrating T cells
Authors: Donnenberg Vera S. , Luketich James D. , Sultan Ibrahim , Lister John , Bartlett David L. , Ghosh Sohini , Donnenberg Albert D. 
Published: March 2023

IntroductionTreatment options for patients with malignant pleural effusions (MPE) are limited due, at least in part, to the unique environment of the pleural space, which drives an aggressive tumor state and governs the behavior of infiltrating immune cells. Modulation of the pleural environment may be a necessary step toward the development of effective treatments. We examine immune checkpoint molecule (ICM) expression on pleural T cells, the secretomes of pleural fluid, pleural infiltrating T cells (PIT), and ability to activate PIT ex vivo.MethodsICM expression was determined on freshly drained and in vitro activated PIT from breast, lung and renal cell cancer. Secretomics (63 analytes) of activated PIT, primary tumor cultures and MPE fluid was determined using Luminex technology. Complementary digital spatial proteomic profiling (42 analytes) of CD45+ MPE cells was done using the Nanostring GeoMx platform. Cytolytic activity was measured against autologous tumor targets.ResultsICM expression was low on freshy isolated PIT; regulatory T cells (T-reg) were not detectable by GeoMx. In vitro activated PIT coexpressed PD-1, LAG-3 and TIGIT but were highly cytotoxic against autologous tumor and uniquely secreted cytokines and chemokines in the &gt; 100 pM range. These included CCL4, CCL3, granzyme B, IL-13, TNFα, IL-2 IFNγ, GM-CSF, and perforin. Activated PIT also secreted high levels of IL-6, IL-8 and sIL-6Rα, which contribute to polarization of the pleural environment toward wound healing and the epithelial to mesenchymal transition. Addition of IL-6Rα antagonist to cultures reversed tumor EMT but did not alter PIT activation, cytokine secretion or cytotoxicity.DiscussionDespite the negative environment, immune effector cells are plentiful, persist in MPE in a quiescent state, and are easily activated and expanded in culture. Low expression of ICM on native PIT may explain reported lack of responsiveness to immune checkpoint blockade. The potent cytotoxic activity of activated PIT and a proof-of-concept clinical scale GMP-expansion experiment support their promise as a cellular therapeutic. We expect that a successful approach will require combining cellular therapy with pleural conditioning using immune checkpoint blockers together with inhibitors of upstream master cytokines such as the IL-6/IL-6R axis.
Maximizing blue carbon stocks through saltmarsh restoration
Authors: McMahon Lucy , Ladd Cai J. T. , Burden Annette , Garrett Ed , Redeker Kelly R. , Lawrence Peter , Gehrels Roland 
Published: March 2023

Political discourse around coastal wetland restoration and blue carbon management strategies has increased in the past decade, yet carbon storage has neither been a reason for restoration, nor a criterion to measure the success of current saltmarsh restoration schemes in the UK. To maximise climate change mitigation through saltmarsh restoration, knowledge on the key drivers of carbon stock variability is required. We use restored saltmarshes of similar age, paired with adjacent natural marshes as references, to identify drivers of carbon stocks following managed realignment within an estuary in southeastern England. From surficial soil cores (top 30 cm), we measured carbon stock alongside environmental characteristics. Carbon stock between natural and restored sites were similar after ~ 30 years when restored sites were above mean high water neap (MHWN) tidal levels. Elevated marsh platforms likely provide suitable conditions for the development of mature plant communities associated with greater capture and production of organic carbon. The restored site at Tollesbury (Essex, UK) had a 2-fold lower carbon stock than other restored sites in the estuary. We attribute this to the site’s low position in the tidal frame, below MHWN tidal levels, coupled with low sediment supply and the dominance of pioneer plant communities. As blue carbon is anticipated to become an important facet of saltmarsh restoration, we recommend that sites above MHWN tidal levels are selected for managed realignment or that preference is given to coastlines with a high sediment supply that may rapidly elevate realignment sites above MHWN. Alternatively, elevation could be artificially raised prior to realignment. Restoration schemes aiming to maximise climate change mitigation should also encourage the establishment of key plant species (e.g., Atriplex portulacoides in our study) to enhance carbon stocks. However, the overall goal of restoration ought to be carefully considered as trade-offs in ecosystem services may ensue if restoration for climate change mitigation alone is pursued.
Impact of porcine circovirus type 2 on porcine epidemic diarrhea virus replication in the IPI-FX cell line depends on the order of infection
Authors: Zhang Hao , Shi Hongyan , Wei Yanwu , Shi Da , Cao Mengxiang , Liu Jianbo , Liu Jianhang , Li Liang , Liu Changming , Feng Li , Huang Liping 
Published: March 2023

IntroductionA study in 2006 showed that the clinical course of PEDV disease was markedly aggravated by transplacental infection of PCV2. Therefore, we investigated whether the small intestine supports PCV2 replication and the effect of PCV2 infection on PEDV replication in epithelial cells in vitro.MethodsTo confirm the intestinal tropism of PCV2, the viral loads in the small-intestinal tissues after PCV2 infection were determined with virus titration, and the viral titers in the infected pig jejunum, ileum, ileocecal valve, and colon were 104.86, 104.09, 102.52, and 102.35 TCID50/g, respectively. We then determined the propagation characteristics of PCV2 in ileal epithelial cells (IPI-FX) and jejunal epithelial cells (IPEC-J2) with an immunoperoxidase monolayer assay, virus titration, and an immunofluorescence assay. Both IPI-FX and IPEC-J2 cells supported the replication of PCV2, with titers of 105.5 and 105.0 TCID50/ml, respectively. We established an infection model of PCV2 and PEDV in IPI-FX cells and found that PEDV and PCV2 infected the cells individually and together. The effects of PCV2 infection on PEDV replication were determined with reverse transcription–quantitative PCR (qPCR), western blotting, and virus titration. When PCV2 infected IPI-FX cells before PEDV, PCV2 significantly inhibited the replication of PEDV in a dose- and time-dependent manner and that the mRNAs of IFN-β, TNF-α, IL1β, and OASL were downregulated (detected with qPCR). Surprisingly, when IPI-FX cells were co-infected with PCV2 and PEDV, PCV2 promoted the replication of PEDV, the expression of the host IFN-β, TNF-α, IL1β, and OASL mRNAs was upregulated.DiscussionThese findings demonstrate that the co-infection of IPI-FX cells with PCV2 and PEDV represents an excellent in vitro model in which to investigate their combined pathogenic mechanisms.
Dystonia-like behaviors and impaired sensory–motor integration following neurotoxic lesion of the pedunculopontine tegmental nucleus in mice
Authors: Su Jun-Hui , Hu Yao-Wen , Song Yun-Ping , Yang Yi , Li Ruo-Yu , Zhou Kai-Ge , Hu Ling , Wan Xin-Hua , Teng Fei , Jin Ling-Jing 
Published: March 2023

IntroductionThe pedunculopontine nucleus (PPTg) is a vital interface between the basal ganglia and cerebellum, participating in modulation of the locomotion and muscle tone. Pathological changes of the PPTg have been reported in patients and animal models of dystonia, while its effect and mechanism on the phenotyping of dystonia is still unknown.MethodsIn this study, a series of behavioral tests focusing on the specific deficits of dystonia were conducted for mice with bilateral and unilateral PPTg excitotoxic lesion, including the dystonia-like movements evaluation, different types of sensory-motor integrations, explorative behaviors and gait. In addition, neural dysfunctions including apoptosis, neuroinflammation, neurodegeneration and neural activation of PPTg-related motor areas in the basal ganglia, reticular formations and cerebellum were also explored.ResultsBoth bilateral and unilateral lesion of the PPTg elicited dystonia-like behaviors featured by the hyperactivity of the hindlimb flexors. Moreover, proprioceptive and auditory sensory-motor integrations were impaired in bilaterally lesioned mice, while no overt alterations were found for the tactile sensory-motor integration, explorative behaviors and gait. Similar but milder behavioral deficits were found in the unilaterally lesioned mice, with an effective compensation was observed for the auditory sensory-motor integration. Histologically, no neural loss, apoptosis, neuroinflammation and neurodegeneration were found in the substantia nigra pars compacta and caudate putamen (CPu) following PPTg lesion, while reduced neural activity was found in the dorsolateral part of the CPu and striatal indirect pathway-related structures including subthalamic nucleus, globus pallidus internus and substantia nigra pars reticular. Moreover, the neural activity was decreased for the reticular formations such as pontine reticular nucleus, parvicellular reticular nucleus and gigantocellular reticular nucleus, while deep cerebellar nuclei were spared.ConclusionIn conclusion, lesion of the PPTg could elicit dystonia-like behaviors through its effect on the balance of the striatal pathways and the reticular formations.
Impact of emergency department arrival time on door-to-needle time in patients with acute stroke
Authors: Ganti Latha , Mirajkar Amber , Banerjee Paul , Stead Tej , Hanna Andrew , Tsau Joshua , Khan Mohammed , Garg Ankur 
Published: March 2023

BackgroundThis study aimed to identify which emergency department (ED) factors impact door-to-needle (DTN) time in acute stroke patients eligible for intravenous thrombolysis. The purpose of analyzing emergency department factors is to determine whether any modifiable factors could shorten the time to thrombolytics, thereby increasing the odds of improved clinical outcomes.MethodsThis was a prospective observational quality registry study that included all patients that received alteplase for stroke. These data are our hospital data from the national Get With The Guidelines Registry. The Get With The Guidelines® Stroke Registry is a hospital-based program focused on improving care for patients diagnosed with a stroke. The program has over five million patients, and hospitals can access their own program data. The registry promotes the use of and adherence to scientific treatment guidelines to improve patient outcomes. The time of patient arrival to the ED was captured via the timestamp in the electronic health record. Arriving between Friday 6 p.m. and Monday 6 a.m. was classified as “weekend,” regardless of the time of arrival. Time to CT, time-to-lab, and presence of a dedicated stroke team were also recorded. Emergency medical services (EMS) run sheets were used to verify arrival via ambulance.ResultsForty-nine percent of the cohort presented during the day shift, 24% during the night shift, and 27% on the weekend. A total of 85% were brought by EMS, and 15% of patients were walk-ins. The median DTN time during the day shift was 37 min (IQR 26–51, range 10–117). The median DTN time during the night shift was 59 min (IQR 39–89, range 34–195). When a dedicated stroke team was present, the median DTN time was 36 min, compared to 51 min when they were not present. The median door-to-CT time was 24 min (IQR 18–31 min). On univariate analyses, arriving during the night shift (P &lt; 0.0001), arriving as a walk-in (P = 0.0080), and longer time-to-CT (P &lt; 0.0001) were all associated with longer DTN time. Conversely, the presence of a dedicated stroke team was associated with a significantly shorter DTN time (P &lt; 0.0001).ConclusionFactors that contribute most to a delay in DTN time include arrival during the night shift, lack of a dedicated stroke team, longer time-to-CT read, and arrival as a walk-in. All of these are addressable factors from an operational standpoint and should be considered when performing quality improvement of hospital protocols.
Functional and anatomical alterations in bilateral vestibulopathy: A multimodal neuroimaging study and clinical correlation
Authors: Lee Eek-Sung , Weon Young Cheol , Kim Ji-Soo , Lee Tae-Kyeong , Park Ji-Yun 
Published: March 2023

ObjectTo study multimodal neuroimaging study including resting state functional MRI (rs-fMRI), anatomical connectivity and brain morphology in patients with bilateral vestibulopathy (BVP) and relationship with clinical correlation.MethodsThirteen patients with BVP (7 women; mean age ± SD = 63.5 ± 14.7 years, 22–80 years) and eighteen age and gender-matched controls were compared rs-fMRI and anatomical MRI. Also, we analyzed the relationship between multimodal neuroimaging and Dizziness Handicap Inventory score (DHI), Vestibular Disorders Activities of Daily Living Scale (VDRL), Geriatric Depression Scale (GDS) and Hospital Anxiety and Depression Scale (HADS).ResultsCompared with controls, BVP patients showed decreased functional connectivity among the key nodes of the salience network, auditory (including vestibular) network, bilateral posterior parahippocampal gyri, bilateral paracingulate gyri, and right frontoparietal network, and the anatomical connectivity in the right cerebellum, corpus callosum tapetum, and left fornix. BVP patients showed decreased gray matter volume in the bilateral parahippocampal gyri, right precentral gyrus, anterior cingulate gyrus, and right middle temporal gyrus and increased gray matter volume in the right superior frontal gyrus compared with controls. Correlation analyses showed rs-fMRI and clinical variables showed no significant result. DHI correlated negatively with anatomical connectivity in the bilateral frontal parahippocampal cingulum, corpus callosum, right inferior fronto-occipital fasciculus, bilateral fornix, and gray matter volumes in the bilateral middle occipital gyri, right superior occipital gyrus, left angular gyrus, and right cuneus in BVP. VADL correlated negatively with Anatomical connectivity in the corpus callosum, bilateral fornix, bilateral cerebellum, bilateral superior and anterior thalamic radiation, right inferior fronto-occipital fasciculus, bilateral fronto-parietal cingulum, right dentatoruburothalamic tract and gray matter volumes in the right angular gyri, bilateral parahippocampal gyri, right middle temporal gyrus, right cuneus, bilateral inferior occipital gyri, left middle occipital gyrus, right superior frontal gyrus, left fusiform gyrus, bilateral caudate, left cerebellar crus, and bilateral calcarine gyri in BVP.ConclusionsThis study identified reductions in the volume of the hippocampus and alterations in functional and anatomical connectivity that concurs with previously established characteristics of BVP. The degree of disability can be inferred from the change in the connectivity and volume between vestibular cortical areas and their network.
A dual-task-embedded virtual reality system for intelligent quantitative assessment of cognitive processing speed
Authors: Zhou Yuzhao , Zhao Yixuan , Xiang Zirui , Yan Zhixin , Shu Lin , Xu Xiangmin , Zhang Lulu , Tian Xiang 
Published: March 2023

IntroductionProcessing speed is defined as the ability to quickly process information, which is generally considered as one of the affected cognitive functions of multiple sclerosis and schizophrenia. Paper–pencil type tests are traditionally used in the assessment of processing speed. However, these tests generally need to be conducted under the guidance of clinicians in a specific environment, which limits their application in cognitive assessment or training in daily life. Therefore, this paper proposed an intelligent evaluation method of processing speed to assist clinicians in diagnosis.MethodsWe created an immersive virtual street embedded with Stroop task (VR-Street). The behavior and performance information was obtained by performing the dual-task of street-crossing and Stroop, and a 50-participant dataset was established with the label of standard scale. Utilizing Pearson correlation coefficient to find the relationship between the dual-task features and the cognitive test results, and an intelligent evaluation model was developed using machine learning.ResultsStatistical analysis showed that all Stroop task features were correlated with cognitive test results, and some behavior features also showed correlation. The estimated results showed that the proposed method can estimate the processing speed score with an adequate accuracy (mean absolute error of 0.800, relative accuracy of 0.916 and correlation coefficient of 0.804). The combination of Stroop features and behavior features showed better performance than single task features.DiscussionThe results of this work indicates that the dual-task design in this study better mobilizes participants’ attention and cognitive resources, and more fully reflects participants’ cognitive processing speed. The proposed method provides a new opportunity for accurate quantitative evaluation of cognitive function through virtual reality.
Pattern of prefrontal cortical activation and network revealed by task-based and resting-state fNIRS in Parkinson’s disease’s patients with overactive bladder symptoms
Authors: Hou Miaomiao , Mao Xiaowei , Wei Yarong , Wang Jiali , Zhang Yu , Qi Chen , Song Lu , Wan Ying , Liu Zhihua , Gan Jing , Liu Zhenguo 
Published: March 2023

BackgroundOveractive bladder (OAB) symptoms are common in Parkinson’s disease (PD), and negatively contribute to the quality of life (QoL) of patients. To explore the underlying pathophysiological mechanism, we investigated the correlation between the prefrontal cortex (PFC) function and OAB symptoms in PD patients.MethodsOne hundred fifty-five idiopathic PD patients were recruited and classified either as PD-OAB or PD-NOAB candidates based on their corresponding OAB symptom scores (OABSS). A linear regression analysis identified a correlative connection of cognitive domains. Then cortical activation during the performance of the verbal fluency test (VFT) and brain connectivity during resting state were conducted by functional near-infrared spectroscopy (fNIRS) for 10 patients in each group to investigate their frontal cortical activation and network pattern.ResultsIn cognitive function analysis, a higher OABS score was significantly correlated with a lower FAB score, MoCA total score, and sub-scores of visuospatial/executive, attention, and orientation as well. In the fNIRS study, the PD-OAB group exhibited significant activations in 5 channels over the left hemisphere, 4 over the right hemisphere, and 1 in the median during the VFT process. In contrast, only 1 channel over the right hemisphere showed significant activation in the PD-NOAB group. The PD-OAB group revealed hyperactivation, particularly in certain channel in the left dorsolateral prefrontal cortex (DLPFC), compared with PD-NOAB (FDR P &lt; 0.05). In the resting state, there was a significant increase of the resting state functional connectivity (RSFC) strength between the bilateral Broca area, left frontopolar area (FPA-L) and right Broca’s area (Broca-R), between the FPA and Broca’s area if merging the bilateral regions of interest (ROI), and also between the two hemispheres in the PD-OAB group. The Spearman’s correlation confirmed that the OABS scores were positively correlated with RSFC strength between the bilateral Broca area, FPA-L and Broca-R, between the FPA and Broca area if merging the bilateral ROI.ConclusionIn this PD cohort, OAB was related to decreased PFC functions, with particularly hyperactivated left DLPFC during VTF and an enhanced neural connectivity between the two hemispheres in the resting state as observed by fNIRS imaging.