bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Platelet Lysate Acts Synergistically With Laminin to Improve the Neurotrophic Effect of Human Adipose-Derived Stem Cells on Primary Neurons in vitro
Authors: Guiotto Martino , Raffoul Wassim , Hart Andrew M. , Riehle Mathis O. , di Summa Pietro G.
Published: March 2021

Background

Despite the advancements in microsurgical techniques and noteworthy research in the last decade, peripheral nerve lesions have still weak functional outcomes in current clinical practice. However, cell transplantation of human adipose-derived stem cells (hADSC) in a bioengineered conduit has shown promising results in animal studies. Human platelet lysate (hPL) has been adopted to avoid fetal bovine serum (FBS) in consideration of the biosafety concerns inherent with the use of animal-derived products in tissue processing and cell culture steps for translational purposes. In this work, we investigate how the interplay between hPL-expanded hADSC (hADSChPL) and extracellular matrix (ECM) proteins influences key elements of nerve regeneration.

Methods

hADSC were seeded on different ECM coatings (laminin, LN; fibronectin, FN) in hPL (or FBS)-supplemented medium and co-cultured with primary dorsal root ganglion (DRG) to establish the intrinsic effects of cell–ECM contact on neural outgrowth. Co-cultures were performed “direct,” where neural cells were seeded in contact with hADSC expanded on ECM-coated substrates (contact effect), or “indirect,” where DRG was treated with their conditioned medium (secretome effect). Brain-derived nerve factor (BDNF) levels were quantified. Tissue culture plastic (TCPS) was used as the control substrate in all the experiments.

Results

hPL as supplement alone did not promote higher neurite elongation than FBS when combined with DRG on ECM substrates. However, in the presence of hADSC, hPL could dramatically enhance the stem cell effect with increased DRG neurite outgrowth when compared with FBS conditions, regardless of the ECM coating (in both indirect and direct co-cultures). The role of ECM substrates in influencing neurite outgrowth was less evident in the FBS conditions, while it was significantly amplified in the presence of hPL, showing better neural elongation in LN conditions when compared with FN and TCPS. Concerning hADSC growth factor secretion, ELISA showed significantly higher concentrations of BDNF when cells were expanded in hPL compared with FBS-added medium, without significant differences between cells cultured on the different ECM substrates.

Conclusion

The data suggest how hADSC grown on LN and supplemented with hPL could be active and prone to support neuron–matrix interactions. hPL enhanced hADSC effects by increasing both proliferation and neurotrophic properties, including BDNF release.
ATF3 Suppresses Growth and Metastasis of Clear Cell Renal Cell Carcinoma by Deactivating EGFR/AKT/GSK3β/β-Catenin Signaling Pathway
Authors: Gao Shenglin , Gao Lei , Wang Simin , Shi Xiaokai , Yue Chuang , Wei Shuzhang , Zuo Li , Zhang Lifeng , Qin Xihu
Published: March 2021

Background

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant cancers in East Asia, with high incidence and mortality. Accumulating evidence has shown that ATF3 is associated with tumor progression.

Methods

Using qPCR, the expression of ATF3 was detected in 93 patients with ccRCC, including 24 paired normal and tumor tissues, which were used to further compare ATF3 expression through western blotting and immunohistochemistry. Lentivirus was used for the overexpression or knockdown of ATF3, and the consequent alteration in function was analyzed through CCK8 assay, colony formation assay, wound healing assay, invasion assay, and flow cytometry. The potential mechanism affected by ATF3 was analyzed through gene set enrichment analysis (GSEA) and verified using western blotting, invasion assay, or immunofluorescence staining. Furthermore, a xenograft mouse model was used to assess the function of ATF3 in vivo.

Results

ATF3 expression was significantly decreased in ccRCC compared to that in adjacent normal tissues. Through gain- and loss-of-function experiments performed in an in vitro assay, we found that ATF3 could regulate ccRCC cell proliferation, cycle progression, migration, and invasion. In the in vivo study, the xenograft mouse model revealed that ATF3 overexpression can inhibit the growth of ccRCC. Moreover, the mechanism analysis showed that suppression of ATF3 could lead to an increase the expression of β-catenin and promote β-catenin transfer to the nucleus, and might be affected by EGFR/AKT/GSK3β signaling.

Conclusion

ATF3 could be utilized as an independent protective factor to inhibit the progression of ccRCC. Potential treatment strategies for ccRCC include targeting the ATF3/EGFR/AKT/GSK3β/β−catenin signaling pathway.
Different Effects of Intramedullary Injection of Mesenchymal Stem Cells During the Acute vs. Chronic Inflammatory Phase on Bone Healing in the Murine Continuous Polyethylene Particle Infusion Model
Authors: Utsunomiya Takeshi , Zhang Ning , Lin Tzuhua , Kohno Yusuke , Ueno Masaya , Maruyama Masahiro , Rhee Claire , Huang Ejun , Yao Zhenyu , Goodman Stuart B.
Published: March 2021

Chronic inflammation is a common feature in many diseases of different organ systems, including bone. However, there are few interventions to mitigate chronic inflammation and preserve host tissue. Previous in vitro studies demonstrated that preconditioning of mesenchymal stem cells (pMSCs) using lipopolysaccharide and tumor necrosis factor-α polarized macrophages from a pro-inflammatory to an anti-inflammatory phenotype and increased osteogenesis compared to unaltered MSCs. In the current study, we investigated the local injection of MSCs or pMSCs during the acute versus chronic inflammatory phase in a murine model of inflammation of bone: the continuous femoral intramedullary polyethylene particle infusion model. Chronic inflammation due to contaminated polyethylene particles decreased bone mineral density and increased osteoclast-like cells positively stained with leukocyte tartrate resistant acid phosphatase (TRAP) staining, and resulted in a sustained M1 pro-inflammatory macrophage phenotype and a decreased M2 anti-inflammatory phenotype. Local injection of MSCs or pMSCs during the chronic inflammatory phase reversed these findings. Conversely, immediate local injection of pMSCs during the acute inflammatory phase impaired bone healing, probably by mitigating the mandatory acute inflammatory reaction. These results suggest that the timing of interventions to facilitate bone healing by modulating inflammation is critical to the outcome. Interventions to facilitate bone healing by modulating acute inflammation should be prudently applied, as this phase of bone healing is temporally sensitive. Alternatively, local injection of MSCs or pMSCs during the chronic inflammatory phase may be a potential intervention to mitigate the adverse effects of contaminated particles on bone.
Non-Coding RNAs Steering the Senescence-Related Progress, Properties, and Application of Mesenchymal Stem Cells
Authors: Cai Jingyi , Qi Hexu , Yao Ke , Yao Yang , Jing Dian , Liao Wen , Zhao Zhihe
Published: March 2021

The thirst to postpone and even reverse aging progress has never been quenched after all these decades. Unequivocally, mesenchymal stem cells (MSCs), with extraordinary abilities such as self-renewal and multi-directional differentiation, deserve the limelight in this topic. Though having several affable clinical traits, MSCs going through senescence would, on one hand, contribute to age-related diseases and, on the other hand, lead to compromised or even counterproductive therapeutical outcomes. Notably, increasing evidence suggests that non-coding RNAs (ncRNAs) could invigorate various regulatory processes. With even a slight dip or an uptick of expression, ncRNAs would make a dent in or even overturn cellular fate. Thereby, a systematic illustration of ncRNAs identified so far to steer MSCs during senescence is axiomatically an urgent need. In this review, we introduce the general properties and mechanisms of senescence and its relationship with MSCs and illustrate the ncRNAs playing a role in the cellular senescence of MSCs. It is then followed by the elucidation of ncRNAs embodied in extracellular vesicles connecting senescent MSCs with other cells and diversified processes in and beyond the skeletal system. Last, we provide a glimpse into the clinical methodologies of ncRNA-based therapies in MSC-related fields. Hopefully, the intricate relationship between senescence and MSCs will be revealed one day and our work could be a crucial stepping-stone toward that future.
SPTBN1 Prevents Primary Osteoporosis by Modulating Osteoblasts Proliferation and Differentiation and Blood Vessels Formation in Bone
Authors: Xu Xuejuan , Yang Jiayi , Ye Yanshi , Chen Guoqiang , Zhang Yinhua , Wu Hangtian , Song Yuqian , Feng Meichen , Feng Xiaoting , Chen Xingying , Wang Xiao , Lin Xu , Bai Xiaochun , Shen Jie
Published: March 2021

Osteoporosis is a common systemic skeletal disorder that leads to increased bone fragility and increased risk of fracture. Although βII-Spectrin (SPTBN1) has been reported to be involved in the development of various human cancers, the function and underlying molecular mechanisms of SPTBN1 in primary osteoporosis remain unclear. In this study, we first established a primary osteoporosis mouse model of senile osteoporosis and postmenopausal osteoporosis. The results showed that the expression of SPTBN1 was significantly downregulated in primary osteoporosis mice model compared with the control group. Furthermore, silencing of SPTBN1 led to a decrease in bone density, a small number of trabecular bones, wider gap, decreased blood volume fraction and number of blood vessels, as well as downregulation of runt-related transcription factor 2 (Runx2), Osterix (Osx), Osteocalcin (Ocn), and vascular endothelial growth factor (VEGF) in primary osteoporosis mice model compared with the control group. Besides, the silencing of SPTBN1 inhibited the growth and induced apoptosis of mouse pre-osteoblast MC3T3-E1 cells compared with the negative control group. Moreover, the silencing of SPTBN1 significantly increased the expression of TGF-β, Cxcl9, and the phosphorylation level STAT1 and Smad3 in MC3T3-E1 cells compared with the control group. As expected, overexpression of SPTBN1 reversed the effect of SPTBN1 silencing in the progression of primary osteoporosis both in vitro and in vivo. Taken together, these results suggested that SPTBN1 suppressed primary osteoporosis by facilitating the proliferation, differentiation, and inhibition of apoptosis in osteoblasts via the TGF-β/Smad3 and STAT1/Cxcl9 pathways. Besides, overexpression of SPTBN1 promoted the formation of blood vessels in bone by regulating the expression of VEGF. This study, therefore, provided SPTBN1 as a novel therapeutic target for osteoporosis.
Krüppel-Like Factor 6 Splice Variant 1: An Oncogenic Transcription Factor Involved in the Progression of Multiple Malignant Tumors
Authors: Hu Kang , Zheng Qing-Kang , Ma Rui-Jie , Ma Chao , Sun Zhi-Gang , Zhang Nan
Published: March 2021

Krüppel-like factor 6 (KLF6) is one of the most studied members of the specificity protein/Krüppel-like factor (SP/KLF) transcription factor family. It has a typical zinc finger structure and plays a pivotal role in regulating the biological processes of cells. Recently, it has been considered to play a role in combatting cancer. Krüppel-like factor 6 splice variant 1 (KLF6-SV1), being one of the alternative KLF6 splicing isoforms, participates in tumor occurrence and development and has the potential to become a new target for molecular targeted therapy, although its action mechanism remains to be determined. The purpose of this article is to provide a comprehensive and systematic review of the important role of KLF6-SV1 in human malignant tumors to provide novel insights for oncotherapy.
Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase
Authors: Ma Christopher I. , Tirtorahardjo James A. , Jan Sharon , Schweizer Sakura S. , Rosario Shawn A. C. , Du Yanmiao , Zhang Jerry J. , Morrissette Naomi S. , Andrade Rosa M.
Published: March 2021

Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, including Toxoplasma gondii. We generated auranofin resistant T. gondii lines through chemical mutagenesis to identify the molecular target of this drug. Resistant clones were confirmed with a competition assay using wild-type T. gondii expressing yellow fluorescence protein (YFP) as a reference strain. The predicted auranofin target, thioredoxin reductase, was not mutated in any of our resistant lines. Subsequent whole genomic sequencing analysis (WGS) did not reveal a consensus resistance locus, although many have point mutations in genes encoding redox-relevant proteins such as superoxide dismutase (TgSOD2) and ribonucleotide reductase. We investigated the SOD2 L201P mutation and found that it was not sufficient to confer resistance when introduced into wild-type parasites. Resistant clones accumulated less ROS than their wild type counterparts. Our results demonstrate that resistance to auranofin in T. gondii enhances its ability to abate oxidative stress through diverse mechanisms. This evidence supports a hypothesized mechanism of auranofin anti-parasitic activity as disruption of redox homeostasis.
Neonatal Milk Fat Globule Membrane Supplementation During Breastfeeding Ameliorates the Deleterious Effects of Maternal High-Fat Diet on Metabolism and Modulates Gut Microbiota in Adult Mice Offspring in a Sex-Specific Way
Authors: Ye Lin , Zhang Qianren , Xin Fengzhi , Cao Baige , Qian Linxi , Dong Yan
Published: March 2021

Exposure to adverse events in early life increases the risk of chronic metabolic disease in adulthood. The objective of this study was to determine the significance of milk fat globule membrane (MFGM)-mediated alterations in the gut microbiome to the metabolic health of offspring in the long-term. Female C57BL/6 mice were fed either a high-fat diet (HFD) or a control diet for 3 weeks before pregnancy and throughout pregnancy and lactation. During lactation, pups from the HFD group were breast-fed with or without 1,000 mg/kg BW/day MFGM supplementation (HFD and HFD-MS group, respectively). After weaning, the offspring in each group were divided into male and female subgroups. The weaned mice were then shifted to a control diet for 8 weeks. At the eleventh week, stool samples were collected for 16S rRNA gene sequencing. Serum biochemical parameters were analyzed, and intraperitoneal glucose and insulin tolerance tests were performed. Neonatal supplementation with MFGM ameliorated metabolic disorder and improved glucose tolerance in offspring exposed to maternal HFD in a sex-specific manner. Furthermore, maternal HFD induced gut microbiota perturbation in offspring in adulthood. Neonatal MFGM supplementation significantly enriched g-Parabacteroides, g-Bifidobacterium, g-Faecalibaculum, and g-Lactobacillus in male offspring exposed to maternal HFD, while significantly enriched g-Parabacteroides and g-Alistipes in female offspring exposed to maternal HFD. These bacteria may be associated with the favorable changes in metabolism that occur in adulthood. Sex differences in the changes of metagenomic pathways related to oxidative phosphorylation, citrate cycle, electron transfer carries, and ubiquinone biosynthesis were also observed in the offspring. Maternal HFD has an adverse effect on the metabolism of offspring in later life. Neonatal MFGM supplementation could modulate the structure of gut microbiota communities and may have long-term protective effects on lipid and glucose metabolism, but these effects are sex dimorphic.
Taxon-Specific Proteins of the Pathogenic Entamoeba Species E. histolytica and E. nuttalli
Authors: König Constantin , Honecker Barbara , Wilson Ian W. , Weedall Gareth D. , Hall Neil , Roeder Thomas , Metwally Nahla Galal , Bruchhaus Iris
Published: March 2021

The human protozoan parasite Entamoeba histolytica can live in the human intestine for months or years without generating any symptoms in the host. For unknown reasons, amoebae can suddenly destroy the intestinal mucosa and become invasive. This can lead to amoebic colitis or extraintestinal amoebiasis whereby the amoebae spread to other organs via the blood vessels, most commonly the liver where abscesses develop. Entamoeba nuttalli is the closest genetic relative of E. histolytica and is found in wild macaques. Another close relative is E. dispar, which asyptomatically infects the human intestine. Although all three species are closely related, only E. histolytica and E. nuttalli are able to penetrate their host’s intestinal epithelium. Lineage-specific genes and gene families may hold the key to understanding differences in virulence among species. Here we discuss those genes found in E. histolytica that have relatives in only one or neither of its sister species, with particular focus on the peptidase, AIG, Ariel, and BspA families.
Complexity and Relative Complexity in Generative Grammar
Authors: Newmeyer Frederick J.
Published: March 2021

The notions of “complexity” and its antonym “simplicity” have played an important role in the history of generative grammar. However, these terms have been used in different ways. There have been discussions about whether the raw data is complex (or not), about whether a particular theory is complex (or not), and about whether a particular analysis is complex (or not). This article both sorts out the various uses of these terms in the history of generative grammar and demonstrates that motivations have changed over time for whether a complex theory or a simple theory is more desirable. The article concludes with a discussion of the issue of relative complexity in generative grammar, that is, whether the theory embodies the possibility that a grammar of one language can be more or less complex than the grammar of another.
Stepwise Reversion of Multiply Mutated Recombinant Antitrypsin Reveals a Selective Inhibitor of Coagulation Factor XIa as Active as the M358R Variant
Authors: Hamada Mostafa , Bhakta Varsha , Andres Sara N. , Sheffield William P.
Published: March 2021

Alpha-1 antitrypsin (AAT, also known as alpha-1 proteinase inhibitor or SERPINA1) is the most abundant member of the serpin superfamily found in human plasma. The naturally occurring variant AAT M358R, altered at the P1 position of the critical reactive center loop (RCL), is re-directed away from inhibition of AAT's chief natural target, neutrophil elastase, and toward accelerated inhibition of thrombin (FIIa), kallikrein (Kal), and other proteases such as factor XIa (FXIa). FXIa is an emerging target for the development of antithrombotic agents, since patients with FXI deficiency are protected from thromboembolic disease and do not exhibit a strong bleeding tendency. Previously, we used phage display, bacterial lysate screening, and combinatorial mutagenesis to identify AAT-RC, an engineered AAT M358R with additional changes between RCL positions P7-P3', CLEVEPR-STE [with changes bolded and the P1-P1' (R358-S359) reactive center shown as R-S]. AAT-RC was 279- and 16-fold more selective for FXIa/IIa or FXIa/Kal than AAT M358R; the increased selectivity came at a cost of a 2.3-fold decrease in the rate of FXIa inhibition and a 3.3-fold increase in the stoichiometry of inhibition (SI). Here, we asked which alterations in AAT-RC were most important for the observed increases in selectivity for FXIa inhibition. We back-mutated AAT-RC to AAT-RC-1 (P7-P3' FLEVEPRSTE), AAT-RC-2 (P7-P3' FLEAEPRSTE), and AAT RC-3 (P7-P3' FLEAIPR-STE). Proteins were expressed as cleavable, hexahistidine-tagged glutathione sulfotransferase fusion proteins in E. coli and purified by proteolytic elution from glutathione agarose, with polishing on nickel chelate agarose. Selectivity for FXIa over Kal of AAT-RC-1, −2, and −3 was 14, 21, and 2.3, respectively. AAT-RC-2 inhibited FXIa 31% more rapidly than AAT M358R, with the same SI, and enhanced selectivity for FXIa over Kal, FXa, FXIIa, activated protein C, and FIIa of 25-, 130-, 420-, 440-, and 470-fold, respectively. Structural modeling of the AAT-RC-2/FXIa encounter complex suggested that both E (Glu) substitutions at P3 and P3' may promote FXIa binding via hydrogen bonding to K192 in FXIa. AAT-RC-2 is the most selective and active AAT variant reported to date for FXIa inhibition and will be tested in animal models of thrombosis and bleeding.
Different Expressions of Pericardial Fluid MicroRNAs in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy and Ischemic Heart Disease Undergoing Ventricular Tachycardia Ablation
Authors: Khudiakov Aleksandr A. , Panshin Daniil D. , Fomicheva Yulia V. , Knyazeva Anastasia A. , Simonova Ksenia A. , Lebedev Dmitry S. , Mikhaylov Evgeny N. , Kostareva Anna A.
Published: March 2021

Introduction: Pericardial fluid is enriched with biologically active molecules of cardiovascular origin including microRNAs. Investigation of the disease-specific extracellular microRNAs could shed light on the molecular processes underlying disease development. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by life-threatening arrhythmias and progressive heart failure development. The current data about the association between microRNAs and ARVC development are limited.

Methods and Results: We performed small RNA sequence analysis of microRNAs of pericardial fluid samples obtained during transcutaneous epicardial access for ventricular tachycardia (VT) ablation of six patients with definite ARVC and three post-infarction VT patients. Disease-associated microRNAs of pericardial fluid were identified. Five microRNAs (hsa-miR-1-3p, hsa-miR-21-5p, hsa-miR-122-5p, hsa-miR-206, and hsa-miR-3679-5p) were found to be differentially expressed between patients with ARVC and patients with post-infarction VT. Enrichment analysis of differentially expressed microRNAs revealed their close linkage to cardiac diseases.

Conclusion: Our data extend the knowledge of pericardial fluid microRNA composition and highlight five pericardial fluid microRNAs potentially linked to ARVC pathogenesis. Further studies are required to confirm the use of pericardial fluid RNA sequencing in differential diagnosis of ARVC.
The Cantabrian Fault at Sea. Low Magnitude Seismicity and Its Significance Within a Stable Setting
Authors: Fernández-Viejo Gabriela , Llana-Fúnez Sergio , Acevedo Jorge , López-Fernández Carlos
Published: March 2021

The Cantabrian fault (CF) is a crustal-scale structure that cuts obliquely the western North Iberian Margin (NIM) for 160 km and continues onshore transecting the Cantabrian Mountains (CM) for another 150 km as the Ventaniella fault (VF). For most of its length inland, the fault system is aseismic, except for a 70 km long segment at its southern end. Within this segment, a gently north-dipping linear arrangement of earthquakes was interpreted as related to the intersection of a slightly oblique fault to VF with the basal thrust of the CM. In addition to earthquake nucleation along parts of its length, the CF–VF also stands out regionally as a major seismotectonic boundary, separating a seismically active area to the West from an essentially aseismic region to the East. Contrasting tectonothermal evolution in the crust on either side during the Mesozoic rifting may underlie the observed differences. On the other hand, the seismicity within the subsea segment is low magnitude, persistent, and understudied. The scarcity of the permanent seismic stations distribution in the area did not allow to establish more than a generalized consensus relating the offshore events to the submarine structure. A recent local seismic network monitored the area providing the highest accuracy information on the offshore events to date. Although the location of foci is partially challenged by the lack of recording stations from northern azimuths at sea, the observed pattern shows indeed a broad linear trend in the submarine domain in relation to the crustal-scale structure. Specifically, this study shows that the distribution of foci offshore display two preferential areas along the CF–VF within its southern crustal block. Considering the basement rock types and the deep architectural disposition of the margin crust, two possible explanations for the origin of the clusters are put forward in this contribution.
Learning Curves in COVID-19: Student Strategies in the ‘new normal’?
Authors: Millar Sarah-Kate , Spencer Kirsten , Stewart Tom , Dong Meg
Published: March 2021

In New Zealand, similar to the rest of the world, the COVID-19 pandemic brought unprecedented disruption to higher education, with a rapid transition to mass online teaching. The 1st year (and 1st semester in particular) of any University degree presents unique challenges for students. Literature suggests these students have significant learning concerns as they adjust to University teaching and assessment requirements. These challenges may be exacerbated with the rapid introduction of online learning environments as they are increasingly disconnected from their peers, and, at a greater risk of struggling with web-based learning technologies.
Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium
Authors: Laurent Michaël R. , De Schepper Jean , Trouet Dominique , Godefroid Nathalie , Boros Emese , Heinrichs Claudine , Bravenboer Bert , Velkeniers Brigitte , Lammens Johan , Harvengt Pol , Cavalier Etienne , Kaux Jean-François , Lombet Jacques , De Waele Kathleen , Verroken Charlotte , van Hoeck Koenraad , Mortier Geert R. , Levtchenko Elena , Vande Walle Johan
Published: March 2021

X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the PHEX gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient’s needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium.
Biomass Valorization to Produce Porous Carbons: Applications in CO2 Capture and Biogas Upgrading to Biomethane—A Mini-Review
Authors: Bernardo Maria , Lapa Nuno , Fonseca Isabel , Esteves Isabel A. A. C.
Published: March 2021

Porous carbon materials, derived from biomass wastes and/or as by-products, are considered versatile, economical and environmentally sustainable. Recently, their high adsorption capacity has led to an increased interest in several environmental applications related to separation/purification both in liquid- and gas-phases. Specifically, their use in carbon dioxide (CO2) capture/sequestration has been a hot topic in the framework of gas adsorption applications. Cost effective biomass porous carbons with enhanced textural properties and high CO2 uptakes present themselves as attractive alternative adsorbents with potential to be used in CO2 capture/separation, apart from zeolites, commercial activated carbons and metal-organic frameworks (MOFs). The renewable and sustainable character of the precursor of these bioadsorbents must be highlighted in the context of a circular-economy and emergent renewable energy market to reach the EU climate and energy goals. This mini-review summarizes the current understandings and discussions about the development of porous carbons derived from bio-wastes, focusing their application to capture CO2 and upgrade biogas to biomethane by adsorption-based processes. Biogas is composed by 55–65 v/v% of methane (CH4) mainly in 35–45 v/v% of CO2. The biogas upgraded to bio-CH4 (97%v/v) through an adsorption process yields after proper conditioning to high quality biomethane and replaces natural gas of fossil source. The circular-economy impact of bio-CH4 production is further enhanced by the use of biomass-derived porous carbons employed in the production process.
Resilience of Grain Yield in China Under Climate Change Scenarios
Authors: Chou Jieming , Sun Mingyang , Xu Yuan , Yang Fan , Li Jiangnan , Zhao Weixing
Published: March 2021

As global warming issues become increasingly serious, grain yield and socioeconomic development have been seriously threatened. The key to ensuring grain yield is to recognize the risks caused by climate change. In this paper, the trends of temperature and precipitation over the next thirty years in China are analysed using CMIP6 under the SSP1–2.6, SSP2–4.5 and SSP 5–8.5 climate scenarios. The resilience indicators of grain yield are proposed for the first time. We find that the higher the emission concentration is, the greater the temperature increase will be and further northward the precipitation belt will move. Meanwhile, the resilience varies across different climate zones. The temperate monsoon climate zone has a stronger resilience to adapt to climate change compared to that of other areas. The resilience of the temperate continental and plateau alpine climate zones are moderate. However, the resilience of the subtropical and tropical monsoon climates zones are poor.
Tracing Colonial Maternalism Within the Gendered Morals of Humanitarianism: Experiences of Migrant Women at the Moroccan-Spanish Border
Authors: Sahraoui Nina , Tyszler Elsa
Published: March 2021

By bringing together two sets of qualitative fieldwork conducted in 2016 and 2017 with humanitarian organizations and migrant women on the two sides of the Eastern Moroccan-Spanish border, this article examines the ways in which women humanitarians exercise power over women’s lives, bodies and mobility. Though humanitarianism in the border context has been researched at European and United States-Mexico borders, the specifically gendered implications of humanitarian governance at borders needs further investigation. Drawing on interviews and participant observation with a religious humanitarian organization on the Moroccan side of the border and with medical humanitarians and social workers on the Spanish side, we researched women humanitarians’ interventions toward migrant women from West African, North African and Middle Eastern countries. Beyond the differences that characterize these religious and socio-medical humanitarian settings and the different migration regimes in which they are inscribed, we argue that the power exerted by women humanitarians reproduces a form of maternalism underpinned by gendered moral beliefs regarding women’s bodies, mobility and family life. We foreground that such maternalism represents a cornerstone of women’s humanitarian engagement across time and we identify continuities between colonial maternalism, contemporary forms of humanitarian care carried out by women and maternalist integration politics in Western postcolonial societies. Rooted in colonial maternalism, racialized beliefs justified women’s (religious, medical, social) prominent role in intervening in the intimate spaces of women casted as radically Other. Our contemporary case studies demonstrate how the practices of women humanitarians impact on racialized migrant women’s daily lives, intruding on their intimacy, imposing controls over their bodies and impacting on their possibilities for mobility. The article explores how the racialization of migrant women, articulated with moral ideas around women’s reproductive health and mothering responsibilities, produce varied forms of disciplining and control on both sides of the border Moroccan-Spanish border.
Discipline in Stages: Regulating CD8+ Resident Memory T Cells
Authors: Mora-Buch Rut , Bromley Shannon K.
Published: March 2021

Resident memory CD8+ T (TRM) cells are a lymphocyte lineage distinct from circulating memory CD8+ T cells. TRM lodge within peripheral tissues and secondary lymphoid organs where they provide rapid, local protection from pathogens and control tumor growth. However, dysregulation of CD8+ TRM formation and/or activation may contribute to the pathogenesis of autoimmune diseases. Intrinsic mechanisms, including transcriptional networks and inhibitory checkpoint receptors control TRM differentiation and response. Additionally, extrinsic stimuli such as cytokines, cognate antigen, fatty acids, and damage signals regulate TRM formation, maintenance, and expansion. In this review, we will summarize knowledge of CD8+ TRM generation and highlight mechanisms that regulate the persistence and responses of heterogeneous TRM populations in different tissues and distinct microenvironments.
Mice Heterozygous for the Sodium Channel Scn8a (Nav1.6) Have Reduced Inflammatory Responses During EAE and Following LPS Challenge
Authors: Alrashdi Barakat , Dawod Bassel , Tacke Sabine , Kuerten Stefanie , Côté Patrice D. , Marshall Jean S.
Published: March 2021

Voltage gated sodium (Nav) channels contribute to axonal damage following demyelination in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). The Nav1.6 isoform has been implicated as a primary contributor in this process. However, the role of Nav1.6 in immune processes, critical to the pathology of both MS and EAE, has not been extensively studied. EAE was induced with myelin oligodendrocyte (MOG35-55) peptide inScn8admu/+mice, which have reduced Nav1.6 levels.Scn8admu/+mice demonstrated improved motor capacity during the recovery and early chronic phases of EAE relative to wild-type animals. In the optic nerve, myeloid cell infiltration and the effects of EAE on the axonal ultrastructure were also significantly reduced inScn8admu/+mice. Analysis of innate immune parameters revealed reduced plasma IL-6 levels and decreased percentages of Gr-1high/CD11b+and Gr-1int/CD11b+myeloid cells in the blood during the chronic phase of EAE inScn8admu/+mice. Elevated levels of the anti-inflammatory cytokines IL-10, IL-13, and TGF-β1 were also observed in the brains of untreatedScn8admu/+mice. A lipopolysaccharide (LPS) model was used to further evaluate inflammatory responses.Scn8admu/+mice displayed reduced inflammation in response to LPS challenge. To further evaluate if this was an immune cell-intrinsic difference or the result of changes in the immune or hormonal environment, mast cells were derived from the bone marrow ofScn8admu/+mice. These mast cells also produced lower levels of IL-6, in response to LPS, compared with those from wild type mice. Our results demonstrate that in addition to its recognized impact on axonal damage, Nav1.6 impacts multiple aspects of the innate inflammatory response.
Is Ferroptosis a Future Direction in Exploring Cryptococcal Meningitis?
Authors: Xu Xianbin , Lin Danfeng , Tu Sheng , Gao Shiqi , Shao Anwen , Sheng Jifang
Published: March 2021

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.
The Role of Proteasomes in the Thymus
Authors: Frantzeskakis Melina , Takahama Yousuke , Ohigashi Izumi
Published: March 2021

The thymus provides a microenvironment that supports the generation and selection of T cells. Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) are essential components of the thymic microenvironment and present MHC-associated self-antigens to developing thymocytes for the generation of immunocompetent and self-tolerant T cells. Proteasomes are multicomponent protease complexes that degrade ubiquitinated proteins and produce peptides that are destined to be associated with MHC class I molecules. cTECs specifically express thymoproteasomes that are essential for optimal positive selection of CD8+ T cells, whereas mTECs, which contribute to the establishment of self-tolerance in T cells, express immunoproteasomes. Immunoproteasomes are also detectable in dendritic cells and developing thymocytes, additionally contributing to T cell development in the thymus. In this review, we summarize the functions of proteasomes expressed in the thymus, focusing on recent findings pertaining to the functions of the thymoproteasomes and the immunoproteasomes.
HLA Alleles B*53:01 and C*06:02 Are Associated With Higher Risk of P. falciparum Parasitemia in a Cohort in Uganda
Authors: Digitale Jean C. , Callaway Perri C. , Martin Maureen , Nelson George , Viard Mathias , Rek John , Arinaitwe Emmanuel , Dorsey Grant , Kamya Moses , Carrington Mary , Rodriguez-Barraquer Isabel , Feeney Margaret E.
Published: March 2021

Variation within the HLA locus been shown to play an important role in the susceptibility to and outcomes of numerous infections, but its influence on immunity to P. falciparum malaria is unclear. Increasing evidence indicates that acquired immunity to P. falciparum is mediated in part by the cellular immune response, including NK cells, CD4 and CD8 T cells, and semi-invariant γδ T cells. HLA molecules expressed by these lymphocytes influence the epitopes recognized by P. falciparum-specific T cells, and class I HLA molecules also serve as ligands for inhibitory receptors including KIR. Here we assessed the relationship of HLA class I and II alleles to the risk of P. falciparum infection and symptomatic malaria in a cohort of 892 Ugandan children and adults followed prospectively via both active and passive surveillance. We identified two HLA class I alleles, HLA-B*53:01 and HLA-C*06:02, that were associated with a higher prevalence of P. falciparum infection. Notably, no class I or II HLA alleles were found to be associated with protection from P. falciparum parasitemia or symptomatic malaria. These findings suggest that class I HLA plays a role in the ability to restrict parasitemia, supporting an essential role for the cellular immune response in P. falciparum immunity. Our findings underscore the need for better tools to enable mechanistic studies of the T cell response to P. falciparum at the epitope level and suggest that further study of the role of HLA in regulating pre-erythrocytic stages of the P. falciparum life cycle is warranted.
Gut Microbiome Homeostasis and the CD4 T- Follicular Helper Cell IgA Axis in Human Immunodeficiency Virus Infection
Authors: Onabajo Olusegun O. , Mattapallil Joseph J.
Published: March 2021

Human Immunodeficiency Virus (HIV) and Simian Immunodeficiency Virus (SIV) are associated with severe perturbations in the gut mucosal environment characterized by massive viral replication and depletion of CD4 T cells leading to dysbiosis, breakdown of the epithelial barrier, microbial translocation, immune activation and disease progression. Multiple mechanisms play a role in maintaining homeostasis in the gut mucosa and protecting the integrity of the epithelial barrier. Among these are the secretory IgA (sIgA) that are produced daily in vast quantities throughout the mucosa and play a pivotal role in preventing commensal microbes from breaching the epithelial barrier. These microbe specific, high affinity IgA are produced by IgA+ plasma cells that are present within the Peyer’s Patches, mesenteric lymph nodes and the isolated lymphoid follicles that are prevalent in the lamina propria of the gastrointestinal tract (GIT). Differentiation, maturation and class switching to IgA producing plasma cells requires help from T follicular helper (Tfh) cells that are present within these lymphoid tissues. HIV replication and CD4 T cell depletion is accompanied by severe dysregulation of Tfh cell responses that compromises the generation of mucosal IgA that in turn alters barrier integrity leading to commensal bacteria readily breaching the epithelial barrier and causing mucosal pathology. Here we review the effect of HIV infection on Tfh cells and mucosal IgA responses in the GIT and the consequences these have for gut dysbiosis and mucosal immunopathogenesis.
The Association Between Pleural Empyema and Peripheral Arterial Disease in Younger Patients: A Retrospective National Population-Based Cohort Study
Authors: Wang Tzu-Yuan , Chen Hsin-Hung , Su Chun-Hung , Hsu Sheng-Pang , Ho Chun-Wei , Hsieh Ming-Chia , Lin Cheng-Li , Kao Chia-Hung
Published: March 2021

Background: To investigate the relationship between pleural empyema (PE) and peripheral arterial disease (PAD).

Methods: We conducted a retrospective cohort study using data from the National Health Institute Research Database. Univariable and multivariable Cox's proportional hazard regressions were performed to investigate the association between PE and the risk of PAD. Kaplan–Meier method and the differences were assessed using a log-rank test.

Results: The overall incidence of PAD was higher in the PE cohort than in the non-PE cohort (2.76 vs. 1.72 per 1,000 person-years) with a crude hazard ratio (HR) of 1.61 [95% confidence interval (CI) = 1.41–1.83]. After adjustment for age, gender, and comorbidities, patients with PE were noted to be associated with an increased risk of PAD compared with those without PE [adjusted HR (aHR) = 1.18, 95% CI = 1.03–1.35]. Regarding the age-specific comparison between the PE and non-PE cohorts, PAD was noted to be significantly high in the ≤ 49 years age group (aHR = 5.34, 95% CI = 2.34–10.1). The incidence of PAD was higher in the first 2 years, with an aHR of 1.35 (95% CI = 1.09–1.68) for patients with PE compared with those without PE.

Conclusion: The risk of PAD was higher if patients with PE were younger than 49 years and within the 2-year diagnosis of PE.
Indole Inhibits IncP-1 Conjugation System Mainly Through Promoting korA and korB Expression
Authors: Xiong Rui , Liu Yuyang , Pu Jieying , Liu Jianping , Zheng Dexiang , Zeng Jianming , Chen Cha , Lu Yang , Huang Bin
Published: March 2021

Indole works as an interspecies signal molecule to regulate multiple physiological activities, like antibiotic resistance, acid resistance, and virulence. However, the effect of indole on conjugation is unknown. Here, with Escherichia coli SM10λπ as a donor strain that carries a chromosomally integrated conjugative RP4 plasmid, we explored the effect of indole on conjugation of a mobilizable pUCP24T plasmid imparting gentamycin resistance. The results showed that exogenous indole treatment inhibited conjugative transfer of pUCP24T from SM10λπ to recipient strains, Pseudomonas aeruginosa PAO1 and E. coli EC600. Furthermore, raising endogenous indole production through overexpression of TnaA, a tryptophanase, in SM10λπ significantly inhibited both SM10λπ-PAO1 and SM10λπ-EC600 conjugation, whereas deficiency of tnaA reversed the phenotype. Subsequent mechanistic studies revealed that exogenous indole significantly inhibited the expression of mating pair formation gene (trbB) and the DNA transfer and replication gene (trfA), mainly due to the promotion of regulatory genes (korA and korB), and the result was confirmed in tnaA knockout and overexpression strains. Additionally, we found that both extracellular indole production and tnaA expression of SM10λπ were downregulated by ciprofloxacin (CIP). Intriguingly, one-eighth minimum inhibitory concentration of CIP treatment clearly facilitated both SM10λπ-PAO1 and SM10λπ-EC600 conjugation, and indole inhibited CIP-induced conjugation frequency. These data suggest that indole may play a negative role in the process of CIP-induced conjugation. This is the first study to reveal the biological function of indole-inhibiting conjugation and its role in CIP-induced conjugation, which may be developed into a new way of controlling the spread of antibiotic resistance.
Adaptation of Microbial Communities to Environmental Arsenic and Selection of Arsenite-Oxidizing Bacteria From Contaminated Groundwaters
Authors: Zecchin Sarah , Crognale Simona , Zaccheo Patrizia , Fazi Stefano , Amalfitano Stefano , Casentini Barbara , Callegari Matteo , Zanchi Raffaella , Sacchi Gian Attilio , Rossetti Simona , Cavalca Lucia
Published: March 2021

Arsenic mobilization in groundwater systems is driven by a variety of functionally diverse microorganisms and complex interconnections between different physicochemical factors. In order to unravel this great ecosystem complexity, groundwaters with varying background concentrations and speciation of arsenic were considered in the Po Plain (Northern Italy), one of the most populated areas in Europe affected by metalloid contamination. High-throughput Illumina 16S rRNA gene sequencing, CARD-FISH and enrichment of arsenic-transforming consortia showed that among the analyzed groundwaters, diverse microbial communities were present, both in terms of diversity and functionality. Oxidized inorganic arsenic [arsenite, As(III)] was the main driver that shaped each community. Several uncharacterized members of the genusPseudomonas, putatively involved in metalloid transformation, were revealedin situin the most contaminated samples. With a cultivation approach, arsenic metabolisms potentially active at the site were evidenced. In chemolithoautotrophic conditions, As(III) oxidation rate linearly correlated to As(III) concentration measured at the parental sites, suggesting that local As(III) concentration was a relevant factor that selected for As(III)-oxidizing bacterial populations. In view of the exploitation of these As(III)-oxidizing consortia in biotechnology-based arsenic bioremediation actions, these results suggest that contaminated aquifers in Northern Italy host unexplored microbial populations that provide essential ecosystem services.