bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of Silica-Based Solid-Acid Catalyst Material as a Potential Osteochondral Repair Model In Vitro
Authors: Long Rui-Min , Jiang Yan , Guo Jia-Qi , Ren Gang , Guo Xian-Xin , Xie Xue , Wu Yue , Yan Rui-Da , Lin Zi-Zhen , Wang Shi-Bin , Liu Yuan-Gang
Published: December 2021

For osteochondral damage, the pH value change of the damaged site will influence the repair efficacy of the patient. For better understanding the mechanism of the acid-base effect, the construction of in vitro model is undoubtedly a simple and interesting work to evaluate the influence. Here, a novel porous silica-based solid-acid catalyst material was prepared by additive manufacturing technology, exhibiting improved eliminating effects of the residue. SEM, FTIR, and TGA were used to characterize the morphology, structure, and thermal stability of the synthesized 3D material. The reaction between 4-methoxybenzyl alcohol and 3, 4-dihydro-2H-pyran was used as a template reaction to evaluate the eliminating performance of the 3D porous material. Solvents were optimized, and three reaction groups in the presence of 3D SiO2, 3D SiO2-SO3H, and 3D SiO2-NH-SO3H, as well as one without catalyst, were compared. In addition, in consideration of the complicated situation of the physiological environment in vivo, universality of the synthesized 3D SiO2-NH-SO3H catalyst material was studied with different alcohols. The results showed that the sulfonic acid-grafted 3D material had excellent catalytic performance, achieving a yield over 95% in only 20 min. Besides, the catalyst material can be recycled at least 10 times, with yields still higher than 90%. Such a solid catalyst material is expected to have great potential in additive manufacturing because the catalyst material is easy-recyclable, renewable and biocompatible. The 3D material with connective channels may also be utilized as an in vitro model for environment evaluation of osteochondral repair in the future.
Arginase II Promotes Intervertebral Disc Degeneration Through Exacerbating Senescence and Apoptosis Caused by Oxidative Stress and Inflammation via the NF-κB Pathway
Authors: Li Fudong , Sun Xiaofei , Zheng Bing , Sun Kaiqiang , Zhu Jian , Ji Chenglong , Lin Feng , Huan Le , Luo Xi , Yan Chen , Xu Jiashun , Hong Yun , Wang Yuan , Xu Ximing , Sun Jingchuan , Song Zheming , Kong Fanqi , Shi Jiangang
Published: December 2021

Intervertebral disc degeneration (IDD) has been generally accepted as the major cause of low back pain (LBP), which imposes massive clinical and socioeconomic burdens. Previous studies have demonstrated that oxidative stress and inflammation-induced senescence and apoptosis of nucleus pulposus cells (NPCs) are the main cellular processes that cause IDD. Arginase II (ARG2), an enzyme involved in a variety of pathological processes, including cellular senescence, apoptosis, oxidative stress, and inflammation, has been shown to promote degeneration in several degenerative diseases, including osteoarticular diseases. Based on previous studies, we hypothesized that ARG2 deficiency might be conducive to the treatment of IDD by inhibiting the dyshomeostasis of the extracellular matrix (ECM), and the oxidative stress and inflammatory response-induced senescence and apoptosis via NF-κB. In this study, we found that ARG2 deficiency inhibited senescence and apoptosis of NPCs, and degeneration of the ECM induced by oxidative stress and the inflammatory response. Similar results were found with the selective NF-κB pathway inhibitor JSH-23. In contrast, overexpression of ARG2 had the opposite effect. Taken together, our results suggest that ARG2 deficiency prevents IDD via NF-κB, and may therefore, be a potential therapeutic strategy for IDD.
Mechanobiological Strategies to Enhance Stem Cell Functionality for Regenerative Medicine and Tissue Engineering
Authors: Shafiq Muhammad , Ali Onaza , Han Seong-Beom , Kim Dong-Hwee
Published: December 2021

Stem cells have been extensively used in regenerative medicine and tissue engineering; however, they often lose their functionality because of the inflammatory microenvironment. This leads to their poor survival, retention, and engraftment at transplantation sites. Considering the rapid loss of transplanted cells due to poor cell-cell and cell-extracellular matrix (ECM) interactions during transplantation, it has been reasoned that stem cells mainly mediate reparative responses via paracrine mechanisms, including the secretion of extracellular vesicles (EVs). Ameliorating poor cell-cell and cell-ECM interactions may obviate the limitations associated with the poor retention and engraftment of transplanted cells and enable them to mediate tissue repair through the sustained and localized presentation of secreted bioactive cues. Biomaterial-mediated strategies may be leveraged to confer stem cells enhanced immunomodulatory properties, as well as better engraftment and retention at the target site. In these approaches, biomaterials have been exploited to spatiotemporally present bioactive cues to stem cell-laden platforms (e.g., aggregates, microtissues, and tissue-engineered constructs). An array of biomaterials, such as nanoparticles, hydrogels, and scaffolds, has been exploited to facilitate stem cells function at the target site. Additionally, biomaterials can be harnessed to suppress the inflammatory microenvironment to induce enhanced tissue repair. In this review, we summarize biomaterial-based platforms that impact stem cell function for better tissue repair that may have broader implications for the treatment of various diseases as well as tissue regeneration.
Freezing Medium Containing 5% DMSO Enhances the Cell Viability and Recovery Rate After Cryopreservation of Regulatory T Cell Products ex vivo and in vivo
Authors: Kaiser Daniel , Otto Natalie Maureen , McCallion Oliver , Hoffmann Henrike , Zarrinrad Ghazaleh , Stein Maik , Beier Carola , Matz Isabell , Herschel Marleen , Hester Joanna , Moll Guido , Issa Fadi , Reinke Petra , Roemhild Andy
Published: December 2021

Cell therapies have significant therapeutic potential in diverse fields including regenerative medicine, transplantation tolerance, and autoimmunity. Within these fields, regulatory T cells (Treg) have been deployed to ameliorate aberrant immune responses with great success. However, translation of the cryopreservation strategies employed for other cell therapy products, such as effector T cell therapies, to Treg therapies has been challenging. The lack of an optimized cryopreservation strategy for Treg products presents a substantial obstacle to their broader application, particularly as administration of fresh cells limits the window available for sterility and functional assessment. In this study, we aimed to develop an optimized cryopreservation strategy for our CD4+CD25+Foxp3+ Treg clinical product. We investigate the effect of synthetic or organic cryoprotectants including different concentrations of DMSO on Treg recovery, viability, phenotype, cytokine production, suppressive capacity, and in vivo survival following GMP-compliant manufacture. We additionally assess the effect of adding the extracellular cryoprotectant polyethylene glycol (PEG), or priming cellular expression of heat shock proteins as strategies to improve viability. We find that cryopreservation in serum-free freezing medium supplemented with 10% human serum albumin and 5% DMSO facilitates improved Treg recovery and functionality and supports a reduced DMSO concentration in Treg cryopreservation protocols. This strategy may be easily incorporated into clinical manufacture protocols for future studies.
Multi-Omics Analysis of Novel Signature for Immunotherapy Response and Tumor Microenvironment Regulation Patterns in Urothelial Cancer
Authors: Chu Guangdi , Shan Wenhong , Ji Xiaoyu , Wang Yonghua , Niu Haitao
Published: December 2021

The tumor microenvironment (TME) is mainly composed of tumor cells, tumor-infiltrating immune cells, and stromal components. It plays an essential role in the prognosis and therapeutic response of patients. Nonetheless, the TME landscape of urothelial cancer (UC) has not been fully elucidated. In this study, we systematically analyzed several UC cohorts, and three types of TME patterns (stromal-activation subtype, immune-enriched subtype and immune-suppressive subtype) were defined. The tumor microenvironment signature (TMSig) was constructed by modified Lasso penalized regression. Patients were stratified into high- and low-TMSig score groups. The low-score group had a better prognosis (p < 0.0001), higher M1 macrophage infiltration (p < 0.01), better response to immunotherapy (p < 0.05), and more similar molecular characteristics to the luminal (differentiated) subtype. The accuracy of the TMSig for predicting the immunotherapy response was also verified in three independent cohorts. We highlighted that the TMSig is an effective predictor of patient prognosis and immunotherapy response. Quantitative evaluation of a single sample is valuable for us to combine histopathological and molecular characteristics to comprehensively evaluate the status of the patient. Targeted macrophage treatment has great potential for the individualized precision therapy of UC patients.
Is Gut Microbiota a Key Player in Epilepsy Onset? A Longitudinal Study in Drug-Naive Children
Authors: Ceccarani Camilla , Viganò Ilaria , Ottaviano Emerenziana , Redaelli Maria Gaia , Severgnini Marco , Vignoli Aglaia , Borghi Elisa
Published: December 2021

Microbiota alterations have been recently investigated in individuals with epilepsy and in other neurological diseases as environmental factors that play a role, by acting through the gut-brain axis, in the pathological process. Most studies focus on the contribution of bacterial communities in refractory epilepsy and suggest a beneficial role of ketogenic diet in modulating the gut microbiota and seizure occurrence. However, they do not evaluate whether epilepsy itself alters the gut microbiota in these patients or if the gut microbial communities could contribute as a seizure trigger. In this pilot study, we performed 16S rRNA sequencing and investigated the gut microbial communities of eight children at their seizure onset and after anti-seizure was started (one year follow-up) and we compared microbial data with seven healthy children, age- and sex-matched. In drug-naive subjects, we observed a microbial signature that shared several features with those reported in refractory epilepsy, such as an increased abundance in Akkermansia spp. and Proteobacteria and a decreased relative abundance in Faecalibacterium spp.We suggest that a bacterial-mediated proinflammatory milieu could contribute to seizure occurrence in children with new onset of epilepsy, as already reported for individuals with drug-resistant epilepsy, and that it could vary during treatment in those who are drug-responsive.
Planar Formation Control of a School of Robotic Fish: Theory and Experiments
Authors: Paley Derek A. , Thompson Anthony A. , Wolek Artur , Ghanem Paul
Published: December 2021

This paper presents a nonlinear control design for the stabilization of parallel and circular motion in a school of robotic fish actuated with internal reaction wheels. The closed-loop swimming dynamics of the fish robots are represented by the canonical Chaplygin sleigh. They exchange relative state information according to a connected, undirected communication graph to form a system of coupled, nonlinear, second-order oscillators. Prior work on collective motion of constant-speed, self-propelled particles serves as the foundation of our approach. However, unlike a self-propelled particle, the fish robots follow limit-cycle dynamics to sustain periodic flapping for forward motion with time-varying speed. Parallel and circular motions are achieved in an average sense without feedback linearization of the agents’ dynamics. Implementation of the proposed parallel formation control law on an actual school of soft robotic fish is described, including system identification experiments to identify motor dynamics and the design of a motor torque-tracking controller to follow the formation torque control. Experimental results demonstrate a school of four robotic fish achieving parallel formations starting from random initial conditions.
Neurological Complications in Active Left-Sided Infective Endocarditis Requiring Early Surgery
Authors: Carrascal Yolanda , Segura Bárbara , Velasco Eduardo , Guerrero Ángel L.
Published: December 2021

Introduction: To determine whether preoperative symptomatic neurological complication (SNC) predicts a worse prognosis of patients with active left-sided infective endocarditis who required early surgery.

Methods: We conducted a retrospective chart review and analyzed risk factors for SNCs and immediate, medium-term, and long-term mortality in patients with active left-sided infective endocarditis who required early surgery (median follow-up: 70.5 months).

Results: Of 212 included patients, preoperative SNCs occurred in 22.1%. Independent risk factors for preoperative SNC included early hospital admission (<10 days after symptoms onset), duration of antibiotic therapy <7 days, vegetation diameter > 30 mm, preoperative chronic therapy with steroids, and peripheral embolism. A new postoperative SNC occurred in 12.7% of patients. No significant differences related to preoperative or postoperative SNCs were observed in postoperative mortality (29.8% vs. 31.5%) or during follow-up. No significant differences in postoperative mortality were observed between hemorrhagic or ischemic SNCs. There was a non-significant trend to increased mortality in patients who underwent surgery within 7 days of presenting with SNC (55.5%) compared to those who underwent surgery more than 7 days after SNC (33.3%) (P = 0.171). Concomitant risk of mortality or postoperative hemorrhagic transformation increased when surgery is required during the first week after preoperative SNC (77.5% vs. 25%) (P = 0.017).

Conclusions: Patients with active left-sided infective endocarditis who need early hospital admission are at a higher risk of SNC. Mortality is higher in patients who underwent surgery within 7 days of SNC, but mortality of early surgery is acceptable after the first week of preoperative ischemic or hemorrhagic complication. We have not been able to demonstrate that preoperative nor postoperative SNCs predicted a reduced immediate, medium-term, or long-term survival in the population analyzed in this study.
The Value of Admission Serological Indicators for Predicting 28-Day Mortality in Intensive Care Patients With Acute Heart Failure: Construction and Validation of a Nomogram
Authors: Wei Xiaoyuan , Min Yu , Yu Jiangchuan , Wang Qianli , Wang Han , Li Shuang , Su Li
Published: December 2021

Background: Acute heart failure (AHF) is a severe clinical syndrome characterized as rapid onset or worsening of symptoms of chronic heart failure (CHF). Risk stratification for patients with AHF in the intensive care unit (ICU) may help clinicians to predict the 28-day mortality risk in this subpopulation and further raise the quality of care.

Methods: We retrospectively reviewed and analyzed the demographic characteristics and serological indicators of patients with AHF in the Medical Information Mart for Intensive Care III (MIMIC III) (version 1.4) between June 2001 and October 2012 and our medical center between January 2019 and April 2021. The chi-squared test and the Fisher's exact test were used for comparison of qualitative variables among the AHF death group and non-death group. The clinical variables were selected by using the least absolute shrinkage and selection operator (LASSO) regression. A clinical nomogram for predicting the 28-day mortality was constructed based on the multivariate Cox proportional hazard regression analysis and further validated by the internal and external cohorts.

Results: Age > 65 years [hazard ratio (HR) = 2.47], the high Sequential Organ Failure Assessment (SOFA) score (≥3 and ≤8, HR = 2.21; ≥9 and ≤20, HR = 3.29), lactic acid (Lac) (>2 mmol/l, HR = 1.40), bicarbonate (HCO3-) (>28 mmol/l, HR = 1.59), blood urea nitrogen (BUN) (>21 mg/dl, HR = 1.75), albumin (<3.5 g/dl, HR = 2.02), troponin T (TnT) (>0.04 ng/ml, HR = 4.02), and creatine kinase-MB (CK-MB) (>5 ng/ml, HR = 1.64) were the independent risk factors for predicting 28-day mortality of intensive care patients with AHF (p < 0.05). The novel nomogram was developed and validated with a promising C-index of 0.814 (95% CI: 0.754–0.882), 0.820 (95% CI: 0.721–0.897), and 0.828 (95% CI: 0.743–0.917), respectively.

Conclusion: This study provides a new insight in early predicting the risk of 28-day mortality in intensive care patients with AHF. The age, the SOFA score, and serum TnT level are the leading three predictors in evaluating the short-term outcome of intensive care patients with AHF. Based on the nomogram, clinicians could better stratify patients with AHF at high risk and make adequate treatment plans.
Preliminary Results of Cryoablation for Surgical Treatment of Arrhythmias in Adults With Congenital Heart Disease
Authors: Poretti Giulia , Hoxha Stiljan , Segreto Antonio , Jacopo Gardellini , Sandrini Camilla , Faggian Giuseppe , Varrica Alessandro , Chessa Massimo , Giamberti Alessandro , Luciani Giovanni Battista
Published: December 2021

Background: Arrhythmias in adult congenital heart disease (ACHD) are responsible for the majority of hospital admissions and 20–25% of late deaths. Since need for further cardiac operations is frequent in ACHD, concomitant arrhythmia surgery represents a strategic treatment modality.

Material and Methods: A two-center retrospective study was undertaken on cryoablation of supraventricular arrhythmias in 25 conescutive ACHD patients (16/9, M/F, median age 38.5 years, IQR 38–60) operated between 01/2017 and 12/2020. Nineteen (76%) had undergone one or more previous cardiac operations and 8 (32%) one or more trans-catheter ablations. Indications included Fontan conversion in seven patients, septal defect repair in 6, pulmonary valve replacement in 10 and tricuspid surgery in 2. Open-heart cryoablation included: 4 cavotricuspid isthmus ablations, 19 right-sided Maze for atrial tachycardia/flutter, and 2 Cox-Maze III for atrial fibrillation.

Results: There were 2 (8%) hospital deaths, unrelated to cryoablation, due to low cardiac output syndrome. There were no intraoperative complications related to cryoablation. Seven (28%) patients required pace-maker implantation due to post-operative atrioventricular block. All patients were discharged on oral antiarrhythmic and anticoagulantion for 6 months. After a median follow-up of 14 months (IQR 7–27) no late mortality was observed. At follow-up, 16/23 (69%) patients are in stable sinus rhythm, 12 without anti-arrhythmic therapy. Two (8.6%) patients had relapse of arrhythmia. Freedom from arrhythmia was 90.9% and cumulative risk of recurrence was 9.6%.

Conclusions: Intraoperative cryoablation is safe and effective procedure. Surgical treatment of arrhythmias should always be considered in ACHD, whenever further open-heart repair is needed.
Variability in Cognitive Performance on Mobile Devices Is Sensitive to Mild Cognitive Impairment: Results From the Einstein Aging Study
Authors: Cerino Eric S. , Katz Mindy J. , Wang Cuiling , Qin Jiyue , Gao Qi , Hyun Jinshil , Hakun Jonathan G. , Roque Nelson A. , Derby Carol A. , Lipton Richard B. , Sliwinski Martin J.
Published: December 2021

Background and Objective: Within-person variability in cognitive performance has emerged as a promising indicator of cognitive health with potential to distinguish normative and pathological cognitive aging. We use a smartphone-based digital health approach with ecological momentary assessments (EMA) to examine differences in variability in performance among older adults with mild cognitive impairment (MCI) and those who were cognitively unimpaired (CU).

Method: A sample of 311 systematically recruited, community-dwelling older adults from the Einstein Aging Study (Mean age = 77.46 years, SD = 4.86, Range = 70–90; 67% Female; 45% Non-Hispanic White, 40% Non-Hispanic Black) completed neuropsychological testing, neurological assessments, and self-reported questionnaires. One hundred individuals met Jak/Bondi criteria for MCI. All participants performed mobile cognitive tests of processing speed, visual short-term memory binding, and spatial working memory on a smartphone device up to six times daily for 16 days, yielding up to 96 assessments per person. We employed heterogeneous variance multilevel models using log-linear prediction of residual variance to simultaneously assess cognitive status differences in mean performance, within-day variability, and day-to-day variability. We further tested whether these differences were robust to the influence of environmental contexts under which assessments were performed.

Results: Individuals with MCI exhibited greater within-day variability than those who were CU on ambulatory assessments that measure processing speed (p < 0.001) and visual short-term memory binding (p < 0.001) performance but not spatial working memory. Cognitive status differences in day-to-day variability were present only for the measure of processing speed. Associations between cognitive status and within-day variability in performance were robust to adjustment for sociodemographic and contextual variables.

Conclusion: Our smartphone-based digital health approach facilitates the ambulatory assessment of cognitive performance in older adults and the capacity to differentiate individuals with MCI from those who were CU. Results suggest variability in mobile cognitive performance is sensitive to MCI and exhibits dissociative patterns by timescale and cognitive domain. Variability in processing speed and visual short-term memory binding performance may provide specific detection of MCI. The 16-day smartphone-based EMA measurement burst offers novel opportunity to leverage digital technology to measure performance variability across frequent assessments for studying cognitive health and identifying early clinical manifestations of cognitive impairment.
Groundwater Interacting at Depth With Hot Plastic Magma Triggers Phreatic Eruptions at Yugama Crater Lake of Kusatsu-Shirane Volcano (Japan)
Authors: Yaguchi Muga , Ohba Takeshi , Terada Akihiko
Published: December 2021

Interpreting the triggering mechanisms for phreatic eruptions is a key to improving the hazard assessment of crater lakes. Yugama Crater Lake at Kusatsu-Shirane volcano, Japan, is the site of frequent phreatic eruptions with the recent eruptions in 1982–83, 1989, and 1996, as well as volcanic unrest, including earthquake swarms in 2014 and 2018. To understand the magma–hydrothermal interaction beneath Yugama Crater Lake, we analyzed lake waters from November 2005 to May 2021. From 2005 to 2012, Cl and SO4 concentrations decreased slowly, suggesting the development of a self-sealing zone surrounding the crystallizing magma. We focused on Ca, Al, and Si concentrations as representatives of the breach and dissolution of minerals comprising the self-sealing zone and the Mg/Cl ratio as an indicator for enhanced interaction between groundwater and hot plastic rock within the self-sealing zone. In 2006–2007, the Ca, Al, Si concentrations and the Mg/Cl ratio increased. No Cl and SO4 increase during this period suggests the self-sealing zone was leached by deep circulating groundwater rather than by magmatic fluids injection. After the 2014 earthquakes, Ca, Al, and Si increased again but were associated with a significant Cl increase and a pH decrease. We believe that the HCl-rich magmatic fluids breached the self-sealing zone, leading to fluids injection from the crystallizing magma to the Yugama crater. During this period, the Mg/Cl ratio did not increase, meaning that magmatic fluids ascending from the breached area of the self-sealing zone inhibited deep intrusion of groundwater into the hot plastic rock region. In 2018, magmatic fluids ascended through the self-sealing zone again with less intensity than in 2014. All eruptions since 1982 have been accompanied by a Mg/Cl ratio increase and a Cl decrease, whereas, when a significant HCl input occurs, as in 2014, no eruptions and no Mg/Cl ratio increase occurred. This demonstrates that the groundwater–hot plastic rock interaction, rather than the magmatic fluids input, played an essential role in triggering phreatic eruptions; i.e., phreatic eruptions can potentially occur without clear signs of fresh magma intrusions.
A Novel Method for Extracting Time Series Information of Deformation Area of a Single Landslide Based on Improved U-Net Neural Network
Authors: Dai Bibo , Wang Yunmin , Ye Chunyang , Li Qihang , Yuan Canming , Lu Song , Li Yuyang
Published: December 2021

This paper proposed an improved U-Net fully convolutional neural network to automatically extract a single landslide deformation information under time series based on the physical model experiments. This method extracts time series information for three different landslide deformation ranges. Compared to U-Net and mainstream superpixel method, evaluation indicators of DSC, VOE and RVD verify the high recognition accuracy and strong robustness of our method.
Differential FSH Glycosylation Modulates FSHR Oligomerization and Subsequent cAMP Signaling
Authors: Agwuegbo Uchechukwu T. , Colley Emily , Albert Anthony P. , Butnev Viktor Y. , Bousfield George R. , Jonas Kim C.
Published: December 2021

Follicle-stimulating hormone (FSH) and its target G protein-coupled receptor (FSHR) are essential for reproduction. Recent studies have established that the hypo-glycosylated pituitary FSH glycoform (FSH21/18), is more bioactive in vitro and in vivo than the fully-glycosylated variant (FSH24). FSH21/18 predominates in women of reproductive prime and FSH24 in peri-post-menopausal women, suggesting distinct functional roles of these FSH glycoforms. The aim of this study was to determine if differential FSH glycosylation modulated FSHR oligomerization and resulting impact on cAMP signaling. Using a modified super-resolution imaging technique (PD-PALM) to assess FSHR complexes in HEK293 cells expressing FSHR, we observed time and concentration-dependent modulation of FSHR oligomerization by FSH glycoforms. High eFSH and FSH21/18 concentrations rapidly dissociated FSHR oligomers into monomers, whereas FSH24 displayed slower kinetics. The FSHR β-arrestin biased agonist, truncated eLHβ (Δ121-149) combined with asparagine56-deglycosylated eLHα (dg-eLHt), increased FSHR homomerization. In contrast, low FSH21/18 and FSH24 concentrations promoted FSHR association into oligomers. Dissociation of FSHR oligomers correlated with time points where higher cAMP production was observed. Taken together, these data suggest that FSH glycosylation may modulate the kinetics and amplitude of cAMP production, in part, by forming distinct FSHR complexes, highlighting potential avenues for novel therapeutic targeting of the FSHR to improve IVF outcomes.
Bone Lining Cells Could Be Sources of Bone Marrow Adipocytes
Authors: Lee Ji Yeon , Yang Jae-Yeon , Kim Sang Wan
Published: December 2021

Background

Recently, lineage-tracing studies demonstrated that parathyroid hormone and anti-sclerostin antibody (Scl-Ab) can convert bone lining cells (BLCs) into active osteoblasts. However, BLCs might also be differentiated into other lineages. Here we investigated whether BLCs could differentiate into bone marrow adipocytes (BMAds) and whether Scl-Ab could suppress this process.

Methods

Dmp1-CreERt2:mTmG mice were injected with 0.5 mg of 4-hydroxytamoxifen once weekly from postnatal week 4 to week 8. The mice were treated with either vehicle or rosiglitazone for 8 weeks (weeks 12–20). Moreover, they were administered either vehicle or Scl-Ab (50 mg/kg) twice weekly for 4 weeks (weeks 16–20, N = 4–6/group). We chased the GFP+ cells from the endosteal surface to the bone marrow (BM) of the femur. Using immunohistochemical staining, the numbers of perilipin+ or GFP+/perilipin double+ cells in the BM were quantified. In addition, serum N-terminal propeptide of type I procollagen (P1NP) levels were measured at each time point, and bone mass was analyzed at 20 weeks using micro-computed tomography.

Results

Scl-Ab administration significantly reversed the decreases in bone parameters induced by rosiglitazone. Plump GFP+ cells, presumably active osteoblasts, and extremely flat GFP+ cells, presumably BLCs, were present on the endosteal surface of the femur at 8 and 12 weeks, respectively, in line with prior findings. When we chased the GFP+ cells, rosiglitazone significantly increased the number of GFP/perilipin double+ BMAds compared to the effects of the vehicle (P < 0.001), and overlapping Scl-Ab administration decreased the number of GFP/perilipin double + BMAd compared to rosiglitazone alone (P < 0.001). In addition, we found that osteoblast lineage cells such as BLCs might express PPARγ on immunohistochemical staining. When rosiglitazone was administered to Rip-Cre:mTmG mice, GFP+ cells were not present on the endosteal surface or in the BM of the femur; however, they were present in the pancreas.

Conclusion

BLCs could be sources of BMAds, and rosiglitazone could stimulate the differentiation of osteoblast lineage cells into BMAds. Suppression of the differentiation of osteoblast lineage cells into BMAds might contribute to anabolic effects resulting from the pharmacologic inhibition of sclerostin.
Current and Potential Therapies Targeting Inflammation in NASH
Authors: Albhaisi Somaya , Noureddin Mazen
Published: December 2021

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD). It is characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. Inflammation plays a key role in the progression of NASH and can be provoked by intrahepatic (e.g., lipotoxicity, immune responses, oxidative stress and cell death) and extrahepatic sources (adipose tissue or gut). The identification of triggers of inflammation is central to understanding the mechanisms in NASH development and progression and in designing targeted therapies that can halt or reverse the disease. In this review, we summarize the current and potential therapies targeting inflammation in NASH.
Attenuation Value in Adrenal Incidentalomas: A Longitudinal Study
Authors: Ceccato Filippo , Tizianel Irene , Voltan Giacomo , Maggetto Gianmarco , Merante Boschin Isabella , Quaia Emilio , Crimì Filippo , Scaroni Carla
Published: December 2021

Context

A tendency to grow has been reported in adrenal incidentalomas. However, long-term data regarding attenuation value, a measure of lipid content, are not available.

Aim

This study aims to collect radiological data (diameter in mm and attenuation value in Hounsfield units, HU) with computed tomography (CT) in adrenal incidentalomas, in order to compare baseline characteristics with the last follow-up imaging.

Design

This is a longitudinal study which included patients with a new diagnosis of adrenal incidentaloma, evaluated from January 2002 to June 2020.

Setting

Referral University-Hospital center.

Patients

Two hundred seventy-seven patients with 355 different cortical adenomas (baseline group) were evaluated at the first outpatient visit; the follow-up cohort consists of 181 patients with 234 adenomas (12–175 months after baseline). Inclusion criteria were conservative management and radiological features able to minimize malignancy or risk of progression.

Main Outcome Measure

CT modification according to endocrine function: autonomous cortisol secretion (ACS) if cortisol >50 nmol/L after 1-mg dexamethasone test (DST).

Results

At baseline CT, mean diameter was 18.7 mm and attenuation value was 0.8 HU (higher in ACS, 66 cases >10 HU), without modification in early imaging (12–36 months). The size increased over time (r = 0.289), achieving the largest differences after at least 60 months of follow-up (mean diameter, +2 mm; attenuation value, −4 HU), combined with a reduction in the attenuation value (r = −0.195, especially in patients with ACS). Lipid-poor adenomas (>10 HU) presented a reduced cortisol suppression after 1-mg DST, an increase in size and the largest decrease in attenuation value during follow-up. Univariate analysis confirmed that larger adenomas presented reduced suppression after DST and increase in size during follow-up.

Conclusions

Growth is clinically modest in adrenal incidentaloma: the first follow-up CT 5 years after baseline is a reasonable choice, especially in ACS. Mean density is increased in patients with ACS and overt hypercortisolism. Mean density reduces during follow-up in all adrenal adenomas, suggesting an increase in lipid content, especially in those with ACS.
Assessment of CHF and Post-CHF Heat Transfer Models for High-Pressure Condition
Authors: Song Meiqi , Liu Xiaojing
Published: December 2021

Supercritical heat transfer systems may undergo trans-critical procedures and work at subcritical conditions during startup, shutdown, or some accidents. However, well-validated heat transfer models for the high-pressure condition (P/Pc>0.7) are still missing. In the present work, with exhaustive literature review, extensive experimental databanks of CHF and post-dryout heat transfer under high-pressure condition are established, respectively. Existing prediction models for the high-pressure condition are also summarized from all over the world. Thereby, with the aid of the high-pressure experimental databank, prediction models get evaluated. It has been demonstrated that CHF correlation developed by Song et al. shows good predictive capability. Post-dryout heat transfer could get well predicted by the Song correlation. These recommended prediction models could be implemented to upgrade safety analysis codes for simulation of trans-critical transients.
CrowdQC+—A Quality-Control for Crowdsourced Air-Temperature Observations Enabling World-Wide Urban Climate Applications
Authors: Fenner Daniel , Bechtel Benjamin , Demuzere Matthias , Kittner Jonas , Meier Fred
Published: December 2021

In recent years, the collection and utilisation of crowdsourced data has gained attention in atmospheric sciences and citizen weather stations (CWS), i.e., privately-owned weather stations whose owners share their data publicly via the internet, have become increasingly popular. This is particularly the case for cities, where traditional measurement networks are sparse. Rigorous quality control (QC) of CWS data is essential prior to any application. In this study, we present the QC package “CrowdQC+,” which identifies and removes faulty air-temperature (ta) data from crowdsourced CWS data sets, i.e., data from several tens to thousands of CWS. The package is a further development of the existing package “CrowdQC.” While QC levels and functionalities of the predecessor are kept, CrowdQC+ extends it to increase QC performance, enhance applicability, and increase user-friendliness. Firstly, two new QC levels are introduced. The first implements a spatial QC that mainly addresses radiation errors, the second a temporal correction of the data regarding sensor-response time. Secondly, new functionalities aim at making the package more flexible to apply to data sets of different lengths and sizes, enabling also near-real time application. Thirdly, additional helper functions increase user-friendliness of the package. As its predecessor, CrowdQC+ does not require reference meteorological data. The performance of the new package is tested with two 1-year data sets of CWS data from hundreds of “Netatmo” CWS in the cities of Amsterdam, Netherlands, and Toulouse, France. Quality-controlled data are compared with data from networks of professionally-operated weather stations (PRWS). Results show that the new package effectively removes faulty data from both data sets, leading to lower deviations between CWS and PRWS compared to its predecessor. It is further shown that CrowdQC+ leads to robust results for CWS networks of different sizes/densities. Further development of the package could include testing the suitability of CrowdQC+ for other variables than ta, such as air pressure or specific humidity, testing it on data sets from other background climates such as tropical or desert cities, and to incorporate added filter functionalities for further improvement. Overall, CrowdQC+ could lead the way to utilise CWS data in world-wide urban climate applications.
Meta-Analysis Enables Prediction of the Maximum Permissible Arsenic Concentration in Asian Paddy Soil
Authors: Mandal Jajati , Sengupta Sudip , Sarkar Soumyajit , Mukherjee Abhijit , Wood Michael D. , Hutchinson Simon M. , Mondal Debapriya
Published: December 2021

It is now well-established that not just drinking water, but irrigation water contaminated with arsenic (As) is an important source of human As exposure through water-soil-rice transfer. While drinking water As has a permissible, or guideline value, quantification of guideline values for soil and irrigation water is limited. Using published data from 26 field studies (not pot-based experiments) from Asia, each of which reported irrigation water, soil and rice grain As concentrations from the same site, this meta-analysis quantitatively evaluated the relationship between soil and irrigation water As concentrations and the As concentration in the rice grain. A generalized linear regression model revealed As in soil to be a stronger predictor of As in rice than As in irrigation water (beta of 16.72 and 0.6, respectively, p < 0.01). Based on the better performing decision tree model, using soil and irrigation water As as independent variables we determined that Asian paddy soil As concentrations greater than 14 mg kg−1 may result in rice grains exceeding the Codex recommended maximum allowable inorganic As (i-As) concentrations of 0.2 mg kg−1 for polished rice and 0.35 mg kg−1 for husked rice. Both logistic regression and decision tree models, identified soil As as the main determining factor and irrigation water to be a non-significant factor, preventing determination of any guideline value for irrigation water. The seemingly non-significant contribution of irrigation water in predicting grain i-As concentrations below or above the Codex recommendation may be due to the complexity in the relationship between irrigation water As and rice grains. Despite modeling limitations and heterogeneity in meta-data, our findings can inform the maximum permissible As concentrations in Asian paddy soil.
Combined Wavelet Transform With Long Short-Term Memory Neural Network for Water Table Depth Prediction in Baoding City, North China Plain
Authors: Liang Zehua , Liu Yaping , Hu Hongchang , Li Haoqian , Ma Yuqing , Khan Mohd Yawar Ali
Published: December 2021

Accurate estimation of water table depth dynamics is essential for water resource management, especially in areas where groundwater is overexploited. In recent years, as a data-driven model, artificial neural networks (NNs) have been widely used in hydrological modeling. However, due to the non-stationarity of water table depth data, the performance of NNs in areas of over-exploitation is challenging. Therefore, reducing data noise is an essential step before simulating the water table depth. This research proposed a novel method to model the non-stationary time series data of water table depth through combing the advantages of wavelet analysis and Long Short-Term Memory (LSTM) neural network (NN). A typical groundwater over-exploitation area, Baoding, North China Plain (NCP), was selected as a study area. To reflect the impact of anthropogenic activities, the variables harnessed to develop the model includes temperature, precipitation, evaporation, and some socio-economic data. The results show that decomposing the time series of the water table depth into three sub-temporal components by Meyer wavelets can significantly improve the simulation effect of LSTM on the water table depth. The average NSE (Nash-Sutcliffe efficiency coefficient) value of all the sites increased from 0.432 to 0.819. Additionally, a feedforward neural network (FNN) is used to compare forecasts over 12-months. As expected, wavelet-LSTM outperforms wavelet-FNN. As the prediction time increases, the advantages of wavelet-LSTM become more evident. The wavelet-LSTM is satisfactory for forecasting the water table depth at most in 6 months. Furthermore, the importance of input variables of wavelet-LSTM is analysed by the weights of the model. The results indicate that anthropogenic activities influence the water table depth significantly, especially in the sites close to the Baiyangdian Lake, the largest lake in the North China Plain. This study demonstrates that the wavelet-LSTM model provides an option for water table depth simulation and predicting areas of over-exploitation of groundwater.
Immune Infiltration, Cancer Stemness, and Targeted Therapy in Gastrointestinal Stromal Tumor
Authors: Wang Jingjing , Ren Hui , Wu Wenhui , Zeng Qianlin , Chen Jingyao , Han Juanjuan , Lin Minquan , Zhang Changhua , He Yulong , Li Mingzhe
Published: December 2021

Objective

To investigate the characteristics of the tumor immune microenvironment in patients with gastrointestinal stromal tumor (GIST) and identify cancer stem-like properties of GIST to screen potential druggable molecular targets.

Methods

The gene expression data of 60 patients with GIST was retrieved from the Array Express database. CIBERSORT was applied to calculate the level of immune infiltration. ssGSEA and ESTIMATE were used to calculate the cancer stemness index and tissue purity. The Connectivity Map (CMAP) database was implemented to screen targeted drugs based on cancer stem-like properties of GIST.

Result

There was a difference in the level of immune infiltration between the metastasis and non-metastasis GIST groups. The low level of T-cell infiltration was correlated with high tumor purity and tumor stemness index, and the correlation coefficients were -0.87 and -0.61 (p < 0.001), respectively. Furthermore, there was a positive correlation between cancer stemness index and cell purity (p < 0.001). The cancer stemness index in the metastasis group was higher than that in the non-metastasis group (p = 0.0017). After adjusting for tumor purity, there was no significant correlation between T-cell infiltration and cancer stemness index (p = 0.086). Through the pharmacological mechanism of topoisomerase inhibitors, six molecular complexes may be the targets of GIST treatment.

Conclusion

Immune infiltration in GIST patients is related to cancer stem-like properties, and the correlation relies on tumor purity. Cancer stemness index can be used as a new predictive biomarker of tumor metastasis and targets of drug therapy for GIST patients.
The Humoral Immune Response to BNT162b2 Vaccine Is Associated With Circulating CD19+ B Lymphocytes and the Naïve CD45RA to Memory CD45RO CD4+ T Helper Cells Ratio in Hemodialysis Patients and Kidney Transplant Recipients
Authors: Duni Anila , Markopoulos Georgios S. , Mallioras Ioannis , Pappas Haralampos , Pappas Efthymios , Koutlas Vasileios , Tzalavra Eirini , Baxevanos Gerasimos , Priska Silvia , Gartzonika Konstantina , Mitsis Michael , Dounousi Evangelia
Published: December 2021

Background

The humoral and cellular immune responses to SARS-COV-2 vaccination remain to be elucidated in hemodialysis (HD) patients and kidney transplant recipients (KTRs), considering their baseline immunosuppressed status. The aim of our study was to assess the associations of vaccine-induced antibody responses with circulating lymphocytes sub-populations and their respective patterns of alterations in maintenance HD patients and KTRs.

Materials and Methods

We included 34 HD patients and 54 KTRs who received two doses of the mRNA-vaccine BNT162b2. Lymphocyte subpopulations were analyzed by flow cytometry before vaccination (T0), before the second vaccine dose (T1) and 2 weeks after the second dose (T2). The anti-SARS-CoV2 antibody response was assessed at T1 and at T2.

Results

31 HD patients (91.8%) and 16 KTRs (29.6%) became seropositive at T2. HD patients who became seropositive following the first dose displayed higher CD19+ B lymphocytes compared to their seronegative HD counterparts. A positive correlation was established between CD19+ B cells counts and antibody titers at all time-points in both groups (p < 0.001). KTRs showed higher naïve CD4+CD45RA+ T helper cells compared to HD patients at baseline and T2 whereas HD patients displayed higher memory CD45RO+ T cells compared to KTRs at T2. The naïve CD4+CD45RA to memory CD4+CD45RO+ T helper cells fraction was negatively associated with antibody production in both groups.

Conclusions

Our study provides a potential conceptual framework for monitoring vaccination efficacy in HD patients and KTRs considering the correlation established between CD19+ B cells, generation of memory CD4+ T helper cells and anti SARS-CoV2 antibody response to vaccination.
Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review
Authors: Roulleaux Dugage Matthieu , Nassif Elise F. , Italiano Antoine , Bahleda Rastislav
Published: December 2021

Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.