bluuebunny/crossref_metadata_2025 huggingface dataset:
A Blood Bank Standardized Production of Human Platelet Lysate for Mesenchymal Stromal Cell Expansion: Proteomic Characterization and Biological Effects
Authors: Bianchetti Andrea , Chinello Clizia , Guindani Michele , Braga Simona , Neva Arabella , Verardi Rosanna , Piovani Giovanna , Pagani Lisa , Lisignoli Gina , Magni Fulvio , Russo Domenico , Almici Camillo
Published: May 2021

Human platelet lysate (hPL) is considered a valid substitute to fetal bovine serum (FBS) in the expansion of mesenchymal stromal cells (MSC), and it is commonly produced starting from intermediate side products of whole blood donations. Through freeze–thaw cycles, hPL is highly enriched in chemokines, growth factors, and adhesion and immunologic molecules. Cell therapy protocols, using hPL instead of FBS for the expansion of cells, are approved by regulatory authorities without concerns, and its administration in patients is considered safe. However, published data are fairly difficult to compare, since the production of hPL is highly variable. This study proposes to optimize and standardize the hPL productive process by using instruments, technologies, and quality/safety standards required for blood bank activities and products. The quality and improved selection of the starting material (i.e., the whole blood), together with the improvement of the production process, guarantee a product characterized by higher content and quality of growth factors as well as a reduction in batch-to-batch variability. By increasing the number of freeze/thaw cycles from one (hPL1c) to four (hPL4c), we obtained a favorable effect on the release of growth factors from platelet α granules. Those changes have directly translated into biological effects leading to a decreasing doubling time (DT) of MSC expansion at 7 days (49.41 ± 2.62 vs. 40.61 ± 1.11 h, p < 0.001). Furthermore, mass spectrometry (MS)-based evaluation has shown that the proliferative effects of hPL4c are also combined with a lower batch-to-batch variability (10–15 vs. 21–31%) at the proteomic level. In conclusion, we have considered lot-to-lot hPL variability, and by the strict application of blood bank standards, we have obtained a standardized, reproducible, safe, cheap, and ready-to-use product.
GABAergic System Dysfunction and Challenges in Schizophrenia Research
Authors: Jahangir Muhammad , Zhou Jian-Song , Lang Bing , Wang Xiao-Ping
Published: May 2021

Despite strenuous studies since the last century, the precise cause and pathology of schizophrenia are still largely unclear and arguably controversial. Although many hypotheses have been proposed to explain the etiology of schizophrenia, the definitive genes or core pathological mechanism remains absent. Among these hypotheses, however, GABAergic dysfunction stands out as a common feature consistently reported in schizophrenia, albeit a satisfactory mechanism that could be exploited for therapeutic purpose has not been developed yet. This review is focusing on the progress made to date in the field in terms of understanding the mechanisms involving dysfunctional GABAergic system and loops identified in schizophrenia research.
Whole-Body Prolyl Hydroxylase Domain (PHD) 3 Deficiency Increased Plasma Lipids and Hematocrit Without Impacting Plaque Size in Low-Density Lipoprotein Receptor Knockout Mice
Authors: Demandt Jasper A. F. , van Kuijk Kim , Theelen Thomas L. , Marsch Elke , Heffron Sean P. , Fisher Edward A. , Carmeliet Peter , Biessen Erik A. L. , Sluimer Judith C.
Published: May 2021

Background and aims: Atherosclerosis is an important cause of clinical cardiovascular events. Atherosclerotic plaques are hypoxic, and reoxygenation improves plaque phenotype. Central players in hypoxia are hypoxia inducible factors (HIF) and their regulators, HIF-prolyl hydroxylase (PHD) isoforms 1, 2, and 3. PHD inhibitors, targeting all three isoforms, are used to alleviate anemia in chronic kidney disease. Likewise, whole-body PHD1 and PHD2ko ameliorate hypercholesterolemia and atherogenesis. As the effect of whole-body PHD3 is unknown, we investigated the effects of germline whole-body PHD3ko on atherosclerosis.

Approach and Results: To initiate hypercholesterolemia and atherosclerosis low-density lipoprotein receptor knockout (LDLrko) and PHD3/LDLr double knockout (PHD3dko), mice were fed a high-cholesterol diet. Atherosclerosis and hypoxia marker pimonidazole were analyzed in aortic roots and brachiocephalic arteries. In contrast to earlier reports on PHD1- and PHD2-deficient mice, a small elevation in the body weight and an increase in the plasma cholesterol and triglyceride levels were observed after 10 weeks of diet. Dyslipidemia might be explained by an increase in hepatic mRNA expression of Cyp7a1 and fatty acid synthase, while lipid efflux of PHD3dko macrophages was comparable to controls. Despite dyslipidemia, plaque size, hypoxia, and phenotype were not altered in the aortic root or in the brachiocephalic artery of PHD3dko mice. Additionally, PHD3dko mice showed enhanced blood hematocrit levels, but no changes in circulating, splenic or lymphoid immune cell subsets.

Conclusion: Here, we report that whole-body PHD3dko instigated an unfavorable lipid profile and increased hematocrit, in contrast to other PHD isoforms, yet without altering atherosclerotic plaque development.
Loss of Primary Cilia Protein IFT20 Dysregulates Lymphatic Vessel Patterning in Development and Inflammation
Authors: Paulson Delayna , Harms Rebecca , Ward Cody , Latterell Mackenzie , Pazour Gregory J. , Fink Darci M.
Published: May 2021

Microenvironmental signals produced during development or inflammation stimulate lymphatic endothelial cells to undergo lymphangiogenesis, in which they sprout, proliferate, and migrate to expand the vascular network. Many cell types detect changes in extracellular conditions via primary cilia, microtubule-based cellular protrusions that house specialized membrane receptors and signaling complexes. Primary cilia are critical for receipt of extracellular cues from both ligand-receptor pathways and physical forces such as fluid shear stress. Here, we report the presence of primary cilia on immortalized mouse and primary adult human dermal lymphatic endothelial cells in vitro and on both luminal and abluminal domains of mouse corneal, skin, and mesenteric lymphatic vessels in vivo. The purpose of this study was to determine the effects of disrupting primary cilia on lymphatic vessel patterning during development and inflammation. Intraflagellar transport protein 20 (IFT20) is part of the transport machinery required for ciliary assembly and function. To disrupt primary ciliary signaling, we generated global and lymphatic endothelium-specific IFT20 knockout mouse models and used immunofluorescence microscopy to quantify changes in lymphatic vessel patterning at E16.5 and in adult suture-mediated corneal lymphangiogenesis. Loss of IFT20 during development resulted in edema, increased and more variable lymphatic vessel caliber and branching, as well as red blood cell-filled lymphatics. We used a corneal suture model to determine ciliation status of lymphatic vessels during acute, recurrent, and tumor-associated inflammatory reactions and wound healing. Primary cilia were present on corneal lymphatics during all of the mechanistically distinct lymphatic patterning events of the model and assembled on lymphatic endothelial cells residing at the limbus, stalk, and vessel tip. Lymphatic-specific deletion of IFT20 cell-autonomously exacerbated acute corneal lymphangiogenesis resulting in increased lymphatic vessel density and branching. These data are the first functional studies of primary cilia on lymphatic endothelial cells and reveal a new dimension in regulation of lymphatic vascular biology.
The Multifunctional Contribution of FGF Signaling to Cardiac Development, Homeostasis, Disease and Repair
Authors: Khosravi Farhad , Ahmadvand Negah , Bellusci Saverio , Sauer Heinrich
Published: May 2021

The current focus on cardiovascular research reflects society’s concerns regarding the alarming incidence of cardiac-related diseases and mortality in the industrialized world and, notably, an urgent need to combat them by more efficient therapies. To pursue these therapeutic approaches, a comprehensive understanding of the mechanism of action for multifunctional fibroblast growth factor (FGF) signaling in the biology of the heart is a matter of high importance. The roles of FGFs in heart development range from outflow tract formation to the proliferation of cardiomyocytes and the formation of heart chambers. In the context of cardiac regeneration, FGFs 1, 2, 9, 16, 19, and 21 mediate adaptive responses including restoration of cardiac contracting rate after myocardial infarction and reduction of myocardial infarct size. However, cardiac complications in human diseases are correlated with pathogenic effects of FGF ligands and/or FGF signaling impairment. FGFs 2 and 23 are involved in maladaptive responses such as cardiac hypertrophic, fibrotic responses and heart failure. Among FGFs with known causative (FGFs 2, 21, and 23) or protective (FGFs 2, 15/19, 16, and 21) roles in cardiac diseases, FGFs 15/19, 21, and 23 display diagnostic potential. The effective role of FGFs on the induction of progenitor stem cells to cardiac cells during development has been employed to boost the limited capacity of postnatal cardiac repair. To renew or replenish damaged cardiomyocytes, FGFs 1, 2, 10, and 16 were tested in (induced-) pluripotent stem cell-based approaches and for stimulation of cell cycle re-entry in adult cardiomyocytes. This review will shed light on the wide range of beneficiary and detrimental actions mediated by FGF ligands and their receptors in the heart, which may open new therapeutic avenues for ameliorating cardiac complications.
Multistage Extraction of Star Anise and Black Pepper Derivatives for Antibacterial, Antioxidant, and Anticancer Activity
Authors: Li Helin , Wu Xiaoyu , Li Xin , Cao Xiaobing , Li Yanjun , Cao Huaru , Men Yongzhi
Published: May 2021

Recently, natural resources have attracted considerable interest for their applications in food security and human health problems. Traditional natural spices, such as star anise and black pepper, played important roles in the pharmaceutical and food industries due to their strong pharmacological activity, antioxidant potential and rare complications. In order to achieve biomasses from the natural product with multiple bioactivities, we developed the multistage extraction method to extract and separate various bioactive compounds from these natural plants. Our work demonstrated that various bioactive-rich extractives were achieved using steam distilled- or oxidative-extraction methods with high extraction yields and purity. Furthermore, the extractives in each step can be used not only as bioactive compounds, but also as a resource to further prepare different derivatives during the next extractive step, providing biomass-saving to a great extent. The extractives obtained with high yields and purities (>82%) were identified by 1H NMR, 13C NMR, FTIR, UV-vis, fluorescence spectroscopy, and high-performance liquid chromatography (HPLC). Moreover, these biomasses display potent antibacterial activities against some types of microorganisms such as S.aureus, S.pyogenes, E.coli, and S.typhi with a lowest MIC of 400 μg/ml for the development of antibacterial agents, significant antioxidant activity as the natural antioxidant for enhancing food shelf-life, and excellent anticancer activity that induces significant cancer cell apoptosis. This work showed the different multistage extracts from natural products, which enable them to be applied in the fields of the pharmaceutical industry and the food industry.
A Novel Graphene-Based Nanomaterial Modified Electrochemical Sensor for the Detection of Cardiac Troponin I
Authors: Li Jing , Zhang Shenwei , Zhang Li , Zhang Yu , Zhang Hua , Zhang Chuanxi , Xuan Xuexi , Wang Mingjie , Zhang Jinying , Yuan Yiqiang
Published: May 2021

Acute myocardial infarction has a high clinical mortality rate. The initial exclusion or diagnosis is important for the timely treatment of patients with acute myocardial infarction. As a marker, cardiac troponin I (cTnI) has a high specificity, high sensitivity to myocardial injury and a long diagnostic window. Therefore, its diagnostic value is better than previous markers of myocardial injury. In this work, we propose a novel aptamer electrochemical sensor. This sensor consists of silver nanoparticles/MoS2/reduced graphene oxide. The combination of these three materials can provide a synergistic effect for the stable immobilization of aptamer. Our proposed aptamer electrochemical sensor can detect cTnl with high sensitivity. After optimizing the parameters, the sensor can provide linear detection of cTnl in the range of 0.3 pg/ml to 0.2 ng/ml. In addition, the sensor is resistant to multiple interferents including urea, glucose, myoglobin, dopamine and hemoglobin.
A State-Of-The-Art Perspective on the Characterization of Subterranean Estuaries at the Regional Scale
Authors: Moosdorf Nils , Böttcher Michael Ernst , Adyasari Dini , Erkul Ercan , Gilfedder Benjamin S. , Greskowiak Janek , Jenner Anna-Kathrina , Kotwicki Lech , Massmann Gudrun , Müller-Petke Mike , Oehler Till , Post Vincent , Prien Ralf , Scholten Jan , Siemon Bernhard , Ehlert von Ahn Cátia Milene , Walther Marc , Waska Hannelore , Wunderlich Tina , Mallast Ulf
Published: May 2021

Subterranean estuaries the, subsurface mixing zones of terrestrial groundwater and seawater, substantially influence solute fluxes to the oceans. Solutes brought by groundwater from land and solutes brought from the sea can undergo biogeochemical reactions. These are often mediated by microbes and controlled by reactions with coastal sediments, and determine the composition of fluids discharging from STEs (i.e., submarine groundwater discharge), which may have consequences showing in coastal ecosystems. While at the local scale (meters), processes have been intensively studied, the impact of subterranean estuary processes on solute fluxes to the coastal ocean remains poorly constrained at the regional scale (kilometers). In the present communication, we review the processes that occur in STEs, focusing mainly on fluid flow and biogeochemical transformations of nitrogen, phosphorus, carbon, sulfur and trace metals. We highlight the spatio-temporal dynamics and measurable manifestations of those processes. The objective of this contribution is to provide a perspective on how tracer studies, geophysical methods, remote sensing and hydrogeological modeling could exploit such manifestations to estimate the regional-scale impact of processes in STEs on solute fluxes to the coastal ocean.
Development and Preliminary Analysis of a VLF-Band Electromagnetic-Wave Observation System for Short-Term Earthquake Precursory Monitoring
Authors: Nagao Toshiyasu , Kamogawa Masashi , Izutsu Jun , Suzuki Tomoyuki , Saito Airi , Sugiura Shigeki , Kondo Hitoshi
Published: May 2021

Preseismic VLF electromagnetic pulses occasionally increase a few days before large earthquakes, especially inland earthquakes. More than two decades ago, the Tokai University group developed a digital recording system for collecting the preseismic electromagnetic pulse data and showed remarkable results. However, due to the limitations of personal computers’ data storage and CPU power during that time, they discontinued the observation. We relaunched this research using current technology. This paper shows the development of the new observation system and presents preliminary results. In addition, we introduce an electromagnetic-wave arrival discrimination algorithm that combines the autoregressive model and the Akaike information criterion, which are commonly used for automatic waveform reading in seismology, to obtain accurate data on the time of arrival (TOA) of electromagnetic waves. Then, source positioning was performed using TOA of electromagnetic waves. Seven electromagnetic pulses near the epicenter were observed 2 days before the largest inland earthquake (M = 5.6) that occurred near the observation network during the observation period (2016–2020). These VLF pulses may be a seismic precursory phenomenon because they were not electromagnetic pulses originating from lightning. These results encourage future observations.
GRK Inhibition Potentiates Glucagon-Like Peptide-1 Action
Authors: Lee Seunghun P. , Qi Jenson , Xu Guozhang , Rankin Matthew M. , Littrell James , Xu June Zhi , Bakaj Ivona , Pocai Alessandro
Published: May 2021

The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.
The Potential Roles of Very Low Calorie, Very Low Calorie Ketogenic Diets and Very Low Carbohydrate Diets on the Gut Microbiota Composition
Authors: Rondanelli Mariangela , Gasparri Clara , Peroni Gabriella , Faliva Milena Anna , Naso Maurizio , Perna Simone , Bazire Philip , Sajoux Ignacio , Maugeri Roberto , Rigon Chiara
Published: May 2021

Several studies have described a strong correlation between diet, weight loss, and gut microbiota composition. The aim of this review was to evaluate the potential effects of energy-restricted diets, namely very low calorie diets (VLCDs), very low calorie ketogenic diets (VLCKDs), and very low carbohydrate diets (VLCarbDs), on the composition of the gut microbiota in humans. We performed a literature search using the following terms (with their abbreviations or acronyms): “very low calorie diet”, “very low calorie ketogenic diet”, “very low carbohydrate diet”, and “gut microbiota”. Our search strategy retrieved nine eligible studies. Overall, VLCDs and VLCarbDs affected the Bacteroidetes to Firmicutes ratio in obese patients, leading to a reduction in short-chain fatty acid production by fecal microbiota associated with Clostridial cluster XIVa. This reduction particularly affected Roseburia and Eubacterium rectale, the two most abundant butyrate-producing bacteria in human feces. VLCKDs preserved the core fecal microbiome, but altered the composition of fecal microbial populations in relation to the plasma metabolome and fecal bile acid composition. In particular, VLCKD-induced weight loss resulted in a reduction in E. rectale and Roseburia, an increase in Christensenellaceae and Akkermansia while not all studies show a decrease in Faecalibacterium prausnitzii. Although very few studies have analyzed the effects of VLCarbDs and VLCDs on gut microbiota, significant diet-induced changes in fecal microbiota composition have been observed. Further studies are needed.
CMR-Verified Myocardial Fibrosis Is Associated With Subclinical Diastolic Dysfunction in Primary Aldosteronism Patients
Authors: Zhou Fangli , Wu Tao , Wang Wei , Cheng Wei , Wan Shuang , Tian Haoming , Chen Tao , Sun Jiayu , Ren Yan
Published: May 2021

Objectives

The main cardiac features of primary aldosteronism (PA) are impaired left ventricular (LV) diastolic function, and some articles also reported more cardiac fibrosis in PA patients. However, the correlation between LV dysfunction and diffuse myocardial fibrosis in PA remains unknown.

Methods

We enrolled 84 PA patients and 28 essential hypertension (EH) patients in West China Hospital. Cardiac magnetic resonance imaging (CMR) contrast enhancement was arranged for all subjects. Postcontrast T1 time and left ventricular myocardial strains and strain rates were measured.

Results

76 PA patients and 27 essential hypertension (EH) patients were included in the final analysis. Blood pressure, LV mass indexes, and LV ejection fractions were comparable in both groups, while the global circumferential peak diastolic strain rate (PDSR) was lower (0.9 ± 0.3 vs. 1.1 ± 0.4, p <0.01) and the postcontrast T1 time was shorter (520 ± 38 vs. 538 ± 27, p = 0.01) in PA patients than those in EH patients. Postcontrast T1 time (p = 0.01) was independently related to global circumferential PDSR after adjusting for age and duration of hypertension in PA patients. Furthermore, plasma aldosterone concentration was negatively associated with postcontrast T1 time (R = −0.253, p = 0.028) in PA patients.

Conclusions

The global circumferential PDSR derived by CMR is decreased, and the diffuse myocardial fibrosis is increased in PA patients compared to those in blood pressure matched EH patients. The severity of cardiac diastolic dysfunction independently relates to the degree of diffuse myocardial fibrosis in PA patients, and the diffuse myocardial fibrosis may be caused by high PAC level.

Clinical Trial Registration

http://www.chictr.org.cn/listbycreater.asp, identifier ChiCTR2000031792.
Benefits of Sustained Upregulated Unimolecular GLP-1 and CCK Receptor Signalling in Obesity-Diabetes
Authors: Tanday Neil , English Andrew , Lafferty Ryan A. , Flatt Peter R. , Irwin Nigel
Published: May 2021

Combined activation of GLP-1 and CCK1 receptors has potential to synergistically augment the appetite-suppressive and glucose homeostatic actions of the individual parent peptides. In the current study, pancreatic beta-cell benefits of combined GLP-1 and CCK1 receptor upregulation were established, before characterising bioactivity and antidiabetic efficacy of an acylated dual-acting GLP-1/CCK hybrid peptide, namely [Lys12Pal]Ex-4/CCK. Both exendin-4 and CCK exhibited (p<0.001) proliferative and anti-apoptotic effects in BRIN BD11 beta-cells. Proliferative benefits were significantly (p<0.01) augmented by combined peptide treatment when compared to either parent peptide alone. These effects were linked to increases (p<0.001) in GLUT2 and glucokinase beta-cell gene expression, with decreased (p<0.05-p<0.001) expression of NFκB and BAX. [Lys12Pal]Ex-4/CCK exhibited prominent insulinotropic actions in vitro, coupled with beneficial (p<0.001) satiety and glucose homeostatic effects in the mice, with bioactivity evident 24 h after administration. Following twice daily injection of [Lys12Pal]Ex-4/CCK for 28 days in diabetic high fat fed (HFF) mice with streptozotocin (STZ)-induced compromised beta-cells, there were clear reductions (p<0.05-p<0.001) in energy intake and body weight. Circulating glucose was returned to lean control concentrations, with associated increases (p<0.001) in plasma and pancreatic insulin levels. Glucose tolerance and insulin secretory responsiveness were significantly (p<0.05-p<0.001) improved by hybrid peptide therapy. In keeping with this, evaluation of pancreatic histology revealed restoration of normal islet alpha- to beta-cell ratios and reduction (p<0.01) in centralised islet glucagon staining. Improvements in pancreatic islet morphology were associated with increased (p<0.05) proliferation and reduced (p<0.001) apoptosis of beta-cells. Together, these data highlight the effectiveness of sustained dual GLP-1 and CCK1 receptor activation by [Lys12Pal]Ex-4/CCK for the treatment of obesity-related diabetes.
Trends in Childhood Thyroid Cancer incidence in Korea and Its Potential Risk Factors
Authors: Park Jun , Park Hyunju , Kim Tae Hyuk , Kim Sun Wook , Jang Hye Won , Chung Jae Hoon
Published: May 2021

Background

Although the incidence of thyroid cancer had been increasing until a few years ago, a decrease has been observed in the last years, probably due to the reduction of the screening tests in Korea. Childhood thyroid cancer has been increasing in the past with the same trend as in adults, but there have been few reports on recent trends. We analyzed the trends of thyroid cancer in Korean children and related factors.

Methods

From national statistics and cancer register database, the data of age-specific incidence rate in Korean childhood thyroid cancer from 1999 to 2017 was obtained, and levels of seaweed intake, the number of computed tomography (CT) and neck ultrasonography (US), obesity prevalence rate, and smoking and alcohol consumption rates in children were analyzed.

Results

The age-specific incidence of thyroid cancer in Korean children has increased in both genders between 1999 and 2017 (2.0 in 1999 vs. 7.2 in 2017, per population of 100,000), especially in the age group of 14-18 years (1.5 in 1999 vs. 5.5 in 2017, per population of 100,000). During the same period, levels of seaweed intake, number of CT scans and neck US, and prevalence of obesity in children increased significantly, while childhood smoking and alcohol consumption rates decreased.

Conclusion

Unlike the adult thyroid cancer in Korea, childhood thyroid cancer continues to increase, and the cause might be accompanied by actual increases due to the environmental factors such as excessive iodine intake, exposure to medical radiation, and increased obesity prevalence as well as the screening effect.
The Effect of Particle Composition and Concentration on the Partitioning Coefficient for Mercury in Three Ocean Basins
Authors: Cui Xinyun , Lamborg Carl H. , Hammerschmidt Chad R. , Xiang Yang , Lam Phoebe J.
Published: May 2021

The downward flux of sinking particles is a prominent Hg removal and redistribution process in the ocean; however, it is not well-constrained. Using data from three U.S. GEOTRACES cruises including the Pacific, Atlantic, and Arctic Oceans, we examined the mercury partitioning coefficient, Kd, in the water column. The data suggest that the Kd varies widely over three ocean basins. We also investigated the effect of particle concentration and composition on Kd by comparing the concentration of small-sized (1–51 μm) suspended particulate mass (SPM) as well as its compositional fractions in six different phases to the partitioning coefficient. We observed an inverse relationship between Kd and suspended particulate mass, as has been observed for other metals and known as the “particle concentration effect,” that explains much of the variation in Kd. Particulate organic matter (POM) and calcium carbonate (CaCO3) dominated the Hg partitioning in all three ocean basins while Fe and Mn could make a difference in some places where their concentrations are elevated, such as in hydrothermal plumes. Finally, our estimated Hg residence time has a strong negative correlation with average log bulk Kd, indicating that Kd has significant effect on Hg residence time.
Balsam Fir and American Beech Influence Soil Respiration Rates in Opposite Directions in a Sugar Maple Forest Near Its Northern Range Limit
Authors: Bélanger Nicolas , Collin Alexandre , Khlifa Rim , Lebel-Desrosiers Simon
Published: May 2021

Conifers and deciduous trees greatly differ in regard to their phylogenetics and physiology as well as their influence on soil microclimate and chemical properties. Soil respiration (Rs) in forests can therefore differ depending on tree species composition, and assessments of the variation in Rsin various forest types will lead to a more thorough understanding of the carbon cycle and more robust long-term simulations of soil carbon. We measured Rsin 2019 and 2020 in stands of various species composition in a sugar maple forest near the northern range limit of temperate deciduous forests in Quebec, Canada. Seasonal variations in soil temperature had the largest influence on Rs, but conditions created by the stands also exerted a significant effect. Relative to the typical sugar maple-yellow birch forest (hardwoods), Rsin stands with >20% of basal area from balsam fir (mixedwoods) was increased by 21%. Whilst, when American beech contributed >20% of litterfall mass (hardwood-beech stands), Rswas decreased by 11 and 36% relative to hardwoods and mixedwoods, respectively. As a whole, Rswas significantly higher in mixedwoods than in other forest types, and Rswas significantly higher in hardwoods than in hardwood-beech stands. Sugar maple and American beech at the study site are near their northern range limit, whereas balsam fir is near its southern limit. Rsin mixedwoods was therefore higher than in hardwoods and hardwood-beech stands due to high root activity in the presence of fir, despite colder and drier soils. We estimated that root respiration in mixedwoods was more than threefold that in hardwoods and hardwood-beech stands. The lower Rsin hardwood-beech stands compared to hardwoods points to the lower soil temperature as well as the poor quality of beech litter (low decomposability) as indicated by a generally lower heterotrophic respiration. Other than soil temperature, regression models identified mixedwoods, soil water potential and Mg2+activity in the soil solution as important predictor variables of Rswith about 90% of its variation explained. Our study shows the benefits of combining forest-specific properties to climatic data for more robust predictions of Rs.
What Are the Contextual Enablers and Impacts of Using Digital Technology to Extend Maternal and Child Health Services to Rural Areas? Findings of a Qualitative Study From Nigeria
Authors: Ebenso Bassey , Okusanya Babasola , Okunade Kehinde , Akeju David , Ajepe Adegbenga , Akaba Godwin O. , Yalma Ramsey M. , Dirisu Osasuyi , Tukur Jamilu , Abdullahi Manir K. , Okuzu Okey , Allsop Matthew J.
Published: May 2021

Background: Strengthening health systems to improve access to maternity services remains challenging for Nigeria due partly to weak and irregular in-service training and deficient data management. This paper reports the implementation of digital health tools for video training (VTR) of health workers and digitization of health data at scale, supported by satellite communications (SatCom) technology and existing 3G mobile networks.

Objective: To understand whether, and under what circumstances using digital interventions to extend maternal, newborn and child health (MNCH) services to remote areas of Nigeria improved standards of healthcare delivery.

Methods: From March 2017 to March 2019, VTR and data digitization interventions were delivered in 126 facilities across three states of Nigeria. Data collection combined documents review with 294 semi-structured interviews of stakeholders across four phases (baseline, midline, endline, and 12-months post-project closedown) to assess acceptability and impacts of digital interventions. Data was analyzed using a framework approach, drawing on a modified Technology Acceptance Model to identify factors that shaped technology adoption and use.

Results: Analysis of documents and interview transcripts revealed that a supportive policy environment, and track record of private-public partnerships facilitated adoption of technology. The determinants of technology acceptance among health workers included ease of use, perceived usefulness, and prior familiarity with technology. Perceptions of impact suggested that at the micro (individual) level, repeated engagement with clinical videos increased staff knowledge, motivation and confidence to perform healthcare roles. At meso (organizational) level, better-trained staff felt supported and empowered to provide respectful healthcare and improved management of obstetric complications, triggering increased use of MNCH services. The macro level saw greater use of reliable and accurate data for policymaking.

Conclusions: Simultaneous and sustained implementation of VTR and data digitization at scale enabled through SatCom and 3G mobile networks are feasible approaches for supporting improvements in staff confidence and motivation and reported MNCH practices. By identifying mechanisms of impact of digital interventions on micro, meso, and macro levels of the health system, the study extends the evidence base for effectiveness of digital health and theoretical underpinnings to guide further technology use for improving MNCH services in low resource settings.

Trial Registration: ISRCTN32105372.
Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation
Authors: Selck Claudia , Dominguez-Villar Margarita
Published: May 2021

Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cellsin vitroorin vivoare currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as thein vivostability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.
GPCRomics of Homeostatic and Disease-Associated Human Microglia
Authors: Hsiao Cheng-Chih , Sankowski Roman , Prinz Marco , Smolders Joost , Huitinga Inge , Hamann Jörg
Published: May 2021

G-protein-coupled receptors (GPCRs) are critical sensors affecting the state of eukaryotic cells. To get systematic insight into the GPCRome of microglia, we analyzed publicly available RNA-sequencing data of bulk and single cells obtained from human and mouse brains. We identified 17 rhodopsin and adhesion family GPCRs robustly expressed in microglia from human brains, including the homeostasis-associated genes CX3CR1, GPR34, GPR183, P2RY12, P2RY13, and ADGRG1. Expression of these microglial core genes was lost upon culture of isolated cells ex vivo but could be acquired by human induced pluripotent stem cell (iPSC)-derived microglial precursors transplanted into mouse brains. CXCR4 and PTGER4 were higher expressed in subcortical white matter compared to cortical grey matter microglia, and ADGRG1 was downregulated in microglia obtained from normal-appearing white and grey matter tissue of multiple sclerosis (MS) brains. Single-cell RNA sequencing of microglia from active lesions, obtained early during MS, revealed downregulation of homeostasis-associated GPCR genes and upregulation of CXCR4 expression in a small subset of MS-associated lesional microglia. Functional presence of low levels of CXCR4 on human microglia was confirmed using flow cytometry and transwell migration towards SDF-1. Microglia abundantly expressed the GPCR down-stream signaling mediator genes GNAI2 (αi2), GNAS (αs), and GNA13 (α13), the latter particularly in white matter. Drugs against several microglia GPCRs are available to target microglia in brain diseases. In conclusion, transcriptome profiling allowed us to identify expression of GPCRs that may contribute to brain (patho)physiology and have diagnostic and therapeutic potential in human microglia.
Autoantibodies in Rheumatoid Arthritis – Laboratory and Clinical Perspectives
Authors: Rönnelid Johan , Turesson Carl , Kastbom Alf
Published: May 2021

Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment.
Spatio-Temporal Determination of Small-Scale Vessels’ Fishing Grounds Using a Vessel Monitoring System in the Southeastern Gulf of Mexico
Authors: Torres-Irineo Edgar , Salas Silvia , Euán-Ávila Jorge Iván , Palomo Leopoldo E. , Quijano Quiñones Daniel R. , Coronado Eva , Joo Rocío
Published: May 2021

In most small-scale fisheries (SSF), there is limited or null information about the distribution and spatial extent of the fishing grounds where the fleets operate, due to the lack of explicit spatial and temporal data. This information is key when addressing marine spatial planning and fisheries management programs for SSF. In addition to technical or biogeographic restrictions, environmental conditions in the area influence the way fishers operate. Making use of data from a pilot Vessel Monitoring System (VMS) project tested in a small-scale fleet in the Southeastern Gulf of Mexico (SGoM), for the first time in the region, we were able to learn what role environmental factors play in the distribution of potential fishing grounds for this fleet. We got tracking information of 1,608 daily fishing trips from vessels operating in four states using the VMS for 7 months. We used a correlative modeling approach to identify potential fishing grounds where this fleet operates along the SGoM, accounting for environmental variables. We assumed that environmental conditions can shape the spatial distribution of species targeted by this fleet and hence influence fishers’ operations. The results indicated that net primary production and sea surface temperature were the main drivers that shape the spatio-temporal potential distribution of fishing grounds in the study site. The approach employed here seems appropriated and opens an opportunity to learn more about the factors that define the spatial distribution of small-scale fleets and their potential fishing grounds.
Fatigue Reliability Assessment for Orthotropic Steel Bridge Decks Considering Load Sequence Effects
Authors: Xu Jun-Hong , Zhou Guang-Dong , Zhu Tai-Yong
Published: May 2021

Fatigue damage accumulations would dramatically reduce the reliability and service life of the orthotropic steel decks. Incorrect fatigue assessment results may be obtained when load sequence effects are omitted. In the present study, fatigue reliability assessments of rib-to-deck weld joints in orthotropic steel bridge decks are conducted with the consideration of load sequence effects. The method, which judiciously considers the fatigue loading history and is derived from the sequential law and the whole-range S-N curve, is first proposed for fatigue reliability calculation. And then, the whole-range S-N curve describing the fatigue propagating process of the rib-to-deck weld joint is introduced. Finally, the developed method is applied to evaluate the fatigue reliability of two rib-to-deck weld joints in an orthotropic steel deck based on long-term measured strain histories. The influence of traffic growth and initial damage on the fatigue reliability is discussed. The results indicate that it is advisable to consider load sequence effects when assessing the fatigue reliability of orthotropic steel decks equipped with long-term strain monitoring systems and the initial damage significantly reduces the fatigue reliability of orthotropic steel decks.
Arthroscopic “Debridement and Implant Retention” With Local Administration of Exebacase (Lysin CF-301) Followed by Suppressive Tedizolid as Salvage Therapy in Elderly Patients for Relapsing Multidrug-Resistant S. epidermidis Prosthetic Knee Infection
Authors: Ferry Tristan , Batailler Cécile , Souche Aubin , Cassino Cara , Chidiac Christian , Perpoint Thomas , le Corvaisier Claire , Josse Jérôme , Gaillard Romain , Roger Julien , Kolenda Camille , Lustig Sébastien , Laurent Frédéric ,   The Lyon BJI Study Group
Published: May 2021

Exebacase, a recombinantly produced lysin has recently (i) reported proof-of-concept data from a phase II study in S. aureus bacteremia and (ii) demonstrated antibiofilm activity in vitro against S. epidermidis. In patients with relapsing multidrug-resistant (MDR) S. epidermidis prosthetic knee infection (PKI), the only surgical option is prosthesis exchange. In elderly patients who have undergone several revisions, prosthesis explantation could be associated with definitive loss of function and mortality. In our BJI reference regional center, arthroscopic debridement and implant retention with local administration of exebacase (LysinDAIR) followed by suppressive tedizolid as salvage therapy is proposed for elderly patients with recurrent MDR S. epidermidis PKI with no therapeutic option or therapeutic dead end (for whom revision or transfemoral amputation is not feasible and no other oral option is available). Each use was decided in agreement with the French health authority and in accordance with the local ethics committee. A written consent was obtained for each patient. Exebacase (75 mg/mL; 30 mL) was administered directly into the joint during arthroscopy. Four patients (79–89 years old) were treated with the LysinDAIR procedure. All had several previous prosthetic knee revisions without prosthesis loosening. Three had relapsing PKI despite suppressive antibiotics following open DAIR. Two had clinical signs of septic arthritis; the two others had sinus tract. After the LysinDAIR procedure, no adverse events occurred during arthroscopy; all patients received daptomycin 8 mg/kg and linezolid 600 mg bid (4–6 weeks) as primary therapy, followed by tedizolid 200 mg/day as suppressive therapy. At 6 months, recurrence of the sinus tract occurred in the two patients with sinus tract at baseline. After >1 year follow up, the clinical outcome was favorable in the last two patients with total disappearance of clinical signs of septic arthritis even if microbiological persistence was detected in one of them. Exebacase has the potential to be used in patients with staphylococci PKI during arthroscopic DAIR as salvage therapy to improve the efficacy of suppressive antibiotics and to prevent major loss of function.
Comparing COVID-19 and Influenza Presentation and Trajectory
Authors: Reiner Benaim Anat , Sobel Jonathan A. , Almog Ronit , Lugassy Snir , Ben Shabbat Tsviel , Johnson Alistair , Eytan Danny , Behar Joachim A.
Published: May 2021

Background: COVID-19 is a newly recognized illness with a predominantly respiratory presentation. It is important to characterize the differences in disease presentation and trajectory between COVID-19 patients and other patients with common respiratory illnesses. These differences can enhance knowledge of pathogenesis and help in guiding treatment.

Methods: Data from electronic medical records were obtained from individuals admitted with respiratory illnesses to Rambam Health Care Campus, Haifa, Israel, between October 1st, 2014 and October 1st, 2020. Four groups of patients were defined: COVID-19 (693), influenza (1,612), severe acute respiratory infection (SARI) (2,292), and Others (4,054). The variable analyzed include demographics (7), vital signs (8), lab tests (38), and comorbidities (15) from a total of 8,651 hospitalized adult patients. Statistical analysis was performed on biomarkers measured at admission and for their disease trajectory in the first 48 h of hospitalization, and on comorobidity prevalence.

Results: COVID-19 patients were overall younger in age and had higher body mass index, compared to influenza and SARI. Comorbidity burden was lower in the COVID-19 group compared to influenza and SARI. Severely- and moderately-ill COVID-19 patients older than 65 years of age suffered higher rate of in-hospital mortality compared to hospitalized influenza patients. At admission, white blood cells and neutrophils were lower among COVID-19 patients compared to influenza and SARI patients, while pulse rate and lymphoctye percentage were higher. Trajectories of variables during the first 2 days of hospitalization revealed that white blood count, neutrophils percentage and glucose in blood increased among COVID-19 patients, while decreasing among other patients.

Conclusions: The intrinsic virulence of COVID-19 appeared higher than influenza. In addition, several critical functions, such as immune response, coagulation, heart and respiratory function, and metabolism were uniquely affected by COVID-19.
Case Report: A Case of Intestinal Behçet's Disease Exhibiting Enhanced Expression of IL-6 and Forkhead Box P3 mRNA After Treatment With Infliximab
Authors: Yoshikawa Keisuke , Watanabe Tomohiro , Sekai Ikue , Takada Ryutaro , Hara Akane , Kurimoto Masayuki , Masuta Yasuhiro , Otsuka Yasuo , Yoshikawa Tomoe , Masaki Sho , Kamata Ken , Minaga Kosuke , Komeda Yoriaki , Chikugo Takaaki , Kudo Masatoshi
Published: May 2021

Behçet's disease (BD) is a rare inflammatory condition characterized by oral and genital ulcers, skin lesions, as well as ophthalmological, neurological, and gastrointestinal manifestations. BD involving the gastrointestinal tract is known as intestinal BD. The mucosa of the gastrointestinal tract of patients with intestinal BD exhibits enhanced levels of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These proinflammatory cytokines play pathogenic roles in the development of BD, as evidenced by the fact that biologics targeting these cytokines effectively induce BD remission. It should be noted, however, that the molecular mechanisms by which the blockade of these cytokines suppresses chronic inflammatory responses in BD are poorly understood. Herein, we report a case of intestinal BD resistant to prednisolone that was successfully treated with infliximab (IFX). The induction of remission by IFX was accompanied by a marked elevation of IL-6 and forkhead box P3 (FOXP3) at mRNA level. This case suggests that induction of remission by IFX is mediated not only by the suppression of TNF-α-mediated signaling pathways, but also by the promotion of IL-6 expression and accumulation of regulatory T cells expressing FOXP3.