bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Progress in 3D Printing of Elastic and High-Strength Hydrogels for the Treatment of Osteochondral and Cartilage Diseases
Authors: Dai Wenli , Sun Muyang , Leng Xi , Hu Xiaoqing , Ao Yingfang
Published: November 2020

Despite considerable progress for the regenerative medicine, repair of full-thickness articular cartilage defects and osteochondral interface remains challenging. This low efficiency is largely due to the difficulties in recapitulating the stratified zonal architecture of articular cartilage and engineering complex gradients for bone-soft tissue interface. This has led to increased interest in three-dimensional (3D) printing technologies in the field of musculoskeletal tissue engineering. Printable and biocompatible hydrogels are attractive materials for 3D printing applications because they not only own high tunability and complexity, but also offer favorable biomimetic environments for live cells, such as porous structure, high water content, and bioactive molecule incorporation. However, conventional hydrogels are usually mechanically weak and brittle, which cannot reach the mechanical requirements for repair of articular cartilage defects and osteochondral interface. Therefore, the development of elastic and high-strength hydrogels for 3D printing in the repairment of cartilage defects and osteochondral interface is crucial. In this review, we summarized the recent progress in elastic and high-strength hydrogels for 3D printing and categorized them into six groups, namely ion bonds interactions, nanocomposites integrated in hydrogels, supramolecular guest–host interactions, hydrogen bonds interactions, dynamic covalent bonds interactions, and hydrophobic interactions. These 3D printed elastic and high-strength hydrogels may provide new insights for the treatment of osteochondral and cartilage diseases.
Blood Vessels and Vascular Niches in Bone Development and Physiological Remodeling
Authors: Hendriks Michelle , Ramasamy Saravana K.
Published: November 2020

Recent advances in our understanding of blood vessels and vascular niches in bone convey their critical importance in regulating bone development and physiology. The contribution of blood vessels in bone functions and remodeling has recently gained enormous interest because of their therapeutic potential. The mammalian skeletal system performs multiple functions in the body to regulate growth, homeostasis and metabolism. Blood vessels provide support to various cell types in bone and maintain functional niches in the bone marrow microenvironment. Heterogeneity within blood vessels and niches indicate the importance of specialized vascular niches in regulating skeletal functions. In this review, we discuss physiology of bone vasculature and their specialized niches for hematopoietic stem cells and mesenchymal progenitor cells. We provide clinical and experimental information available on blood vessels during physiological bone remodeling.
Two-Dimensional Nanomaterials With Enzyme-Like Properties for Biomedical Applications
Authors: Cai Shuangfei , Yang Rong
Published: November 2020

Recently, remarkable progress has been made in nanozyme research due to the rapid development of nanomaterials. Two-dimensional nanomaterials such as metal nanosheets, graphene-based materials, transition metal oxides/dichalcogenides, etc., provide enhanced physical and chemical functionality owing to their ultrathin structures, high surface-to-volume ratios, and surface charges. They have also been found to have high catalytic activities in terms of natural enzymes such as peroxidase, oxidase, catalase, and superoxide dismutase. This review provides an overview of the recent progress of nanozymes based on two-dimensional nanomaterials, with an emphasis on their synthetic strategies, hybridization, catalytic properties, and biomedical applications. Finally, the future challenges and prospects for this research are discussed.
Ultrahigh Adhesion Force Between Silica-Binding Peptide SB7 and Glass Substrate Studied by Single-Molecule Force Spectroscopy and Molecular Dynamic Simulation
Authors: Zhang Xiaoxu , Chen Jialin , Li Enci , Hu Chunguang , Luo Shi-Zhong , He Chengzhi
Published: November 2020

Many proteins and peptides have been identified to effectively and specifically bind on certain surfaces such as silica, polystyrene and titanium dioxide. It is of great interest, in many areas such as enzyme immobilization, surface functionalization and nanotechnology, to understand how these proteins/peptides bind to solid surfaces. Here we use single-molecule force spectroscopy (SMFS) based on atomic force microscopy to directly measure the adhesion force between a silica-binding peptide SB7 and glass surface at single molecule level. SMFS results show that the adhesion force of a single SB7 detaching from the glass surface distributes in two populations at ~220 pN and 610 pN, which is higher than the unfolding forces of most mechanically stable proteins and the unbinding forces of most stable protein-protein interactions. Molecular dynamics simulation reveals that the electrostatic interactions between positively charged arginine residues and the silica surface dominates the binding of SB7 on silica. Our study provides experimental evidence and molecular mechanism at the single-molecule level for the SB7-based immobilization of proteins on silica-based surface, which is able to withstand high mechanical forces, making it an ideal fusion tag for silica surface immobilization or peptide-base adhesive materials.
Does Serum Uric Acid Status Influence the Association Between Left Atrium Diameter and Atrial Fibrillation in Hypertension Patients?
Authors: Hidru Tesfaldet H. , Tang Yuqi , Liu Fei , Hui Simei , Gao Ruiyuan , Li Daobo , Yang Xiaolei , Xia Yunlong
Published: November 2020

Objective: Both serum uric acid (SUA) levels and left atrium diameter (LAD) associate with AF. However, the influence of SUA status for the associated risk of AF related to LAD in hypertension patients is currently unknown.

Methods: We retrospectively analyzed a hospital-based sample of 9,618 hypertension patients. Standard electrocardiograms were performed on all patients and were interpreted by expert electro-physiologists.

Results: Overall 1,028 (10.69%) patients had AF out of 9,618 patients. In men >65 years of age, the prevalence of AF in the1st, 2nd, and 3rd tertiles of SUA among those grouped in the third tertile of LAD were 9, 12.3, and 21.7%, respectively. In the hyperuricemia group, the OR (95% CI) of AF for the highest tertile of LAD in men ≤ 65 years of age was 3.150 (1.756, 5.651; P < 0.001). Similarly, the hyperuricemic men in the 3rd LAD tertile had a higher likelihood of AF than those belonging to the 1st tertile. The ORs and (95% CIs) were 3.150 (1.756, 5.651; P < 0.001) and 5.522 (2.932, 10.400; P ≤ 0.001) for patients ≤ 65 and >65 years of age. An increase in SUA values was significantly associated with an increased likelihood of AF among women at the top tertiles of LAD, with the OR (95% CI) = 4.593 (1.857, 11.358; P = 0.001). Also, men> 65 years of age with large LAD, present at the third tertile of SUA, had a higher likelihood of AF, with the OR (95% CI) = 2.427 (1.039, 5.667; P < 0.05).

Conclusion: SUA levels and LAD are associated with AF in patients with hypertension and the risk of AF associated with LAD increases among those with hyperuricemia.
Recent Development in Therapeutic Cardiac Patches
Authors: Mei Xuan , Cheng Ke
Published: November 2020

For the past decades, heart diseases remain the leading cause of death worldwide. In the adult mammalian heart, damaged cardiomyocytes will be replaced by non-contractile fibrotic scar tissues due to the poor regenerative ability of heart, causing heart failure subsequently. The development of tissue engineering has launched a new medical innovation for heart regeneration. As one of the most outstanding technology, cardiac patches hold the potential to restore cardiac function clinically. Consisted of two components: therapeutic ingredients and substrate scaffolds, the fabrication of cardiac patches requires both advanced bioactive molecules and biomaterials. In this review, we will present the most state-of-the-art cardiac patches and analysis their compositional details. The therapeutic ingredients will be discussed from cell sources to bioactive molecules. In the meanwhile, the recent advances to obtain scaffold biomaterials will be highlighted, including synthetic and natural materials. Also, we have focused on the challenges and potential strategies to fabricate clinically applicable cardiac patches.
The Antarctic Crust and Upper Mantle: A Flexible 3D Model and Software Framework for Interdisciplinary Research
Authors: Stål Tobias , Reading Anya M. , Halpin Jacqueline A. , Phipps Steven J. , Whittaker Joanne M.
Published: November 2020

Interdisciplinary research concerning solid Earth–cryosphere interaction and feedbacks requires a working model of the Antarctic crust and upper mantle. Active areas of interest include the effect of the heterogeneous Earth structure on glacial isostatic adjustment, the distribution of geothermal heat, and the history of erosion and deposition. In response to this research need, we construct an adaptable and updatable 3D grid model in a software framework to contain and process solid Earth data. The computational framework, based on an open source software packageagrid, allows different data sources to be combined and jointly analyzed. The grid model is populated with crustal properties from geological observations and geochronology results, where such data exist, and published segmentation from geophysical data in the interior where direct observations are absent. The grid also contains 3D geophysical data such as wave speed and derived temperature from seismic tomographic models, and 2D datasets such as gravity anomalies, surface elevation, subglacial temperature, and ice sheet boundaries. We demonstrate the usage of the framework by computing new estimates of subglacial steady-state heat flow in a continental scale model for east Antarctica and a regional scale model for the Wilkes Basin in Victoria Land. We hope that the 3D model and framework will be used widely across the solid Earth and cryosphere research communities.
Progress in the Pathogenesis, Diagnosis, and Treatment of TSH-Secreting Pituitary Neuroendocrine Tumor
Authors: Luo Peiqiong , Zhang Lin , Yang Lidan , An Zhenmei , Tan Huiwen
Published: November 2020

TSH-secreting pituitary neuroendocrine tumor (PitNET) is one of the causes of central hyperthyroidism. The incidence of TSH PitNET is far lower than that of other PitNETs. The clinical manifestations of TSH PitNETs mainly include thyrotoxicosis or thyroid goiter, secretion disorders of other anterior pituitary hormones, and mass effect on the pituitary gland and its surrounding tissues. The application of high-sensitivity TSH detection methods contributes to the early diagnosis and timely treatment of TSH PitNETs. Improvements in magnetic resonance imaging (MRI) have advanced the noninvasive visualization of smaller PitNETs. Treatments for TSH PitNETs include surgery, drugs, and radiotherapy. This review focuses on the progress in pathogenesis, diagnosis, and treatment of TSH PitNETs to provide more information for the clinician.
Big City Living: A Global Meta-Analysis Reveals Positive Impact of Urbanization on Body Size in Lizards
Authors: Putman Breanna J. , Tippie Zachary A.
Published: November 2020

Urban environments pose different selective pressures than natural ones, leading to changes in animal behavior, physiology, and morphology. Understanding how animals respond to urbanization could inform the management of urban habitats. Non-avian reptiles have important roles in ecosystems worldwide, yet their responses to urbanization have not been as comprehensively studied as those of mammals and birds. However, unlike mammals and birds, most reptiles cannot easily move away from disturbances, making the selective pressure to adapt to urban environments especially strong. In recent years, there has been a surge in research on the responses of lizards to urbanization, yet no formal synthesis has determined what makes an urban lizard, in other words, which phenotypic traits are most likely to change with urbanization and in which direction? Here, we present a qualitative synthesis of the literature and a quantitative phylogenetic meta-analysis comparing phenotypic traits between urban and non-urban lizard populations. The most robust finding from our analysis is that urban lizards are larger than their non-urban counterparts. This result remained consistent between sexes and taxonomic groups. Hence, lizards that pass through the urban filter have access to better resources, more time for foraging, and/or there is selection on attaining a larger body size. Other results included an increase in the diameters of perches used and longer limb and digit lengths, although this may be a result of increased body size. Urban lizards were not bolder, more active or exploratory, and did not differ in immune responses than non-urban populations. Overall, studies are biased to a few geographic regions and taxa. More than 70% of all data came from three species of anoles in the family Dactyloidae, making it difficult to generalize patterns to other clades. Thus, more studies are needed across multiple taxa and habitats to produce meaningful predictions that could help inform conservation and management of urban ecological communities.
Increased NFATC4 Correlates With Poor Prognosis of AML Through Recruiting Regulatory T Cells
Authors: Zhao Chong , Yang Shaoxin , Lu Wei , Liu Jiali , Wei Yanyu , Guo Hezhou , Zhang Yanjie , Shi Jun
Published: November 2020

Despite that immune responses play important roles in acute myeloid leukemia (AML), immunotherapy is still not widely used in AML due to lack of an ideal target. Therefore, we identified key immune genes and cellular components in AML by an integrated bioinformatics analysis, trying to find potential targets for AML. Eighty-six differentially expressed immune genes (DEIGs) were identified from 751 differentially expressed genes (DEGs) between AML patients with fair prognosis and poor prognosis from the TCGA database. Among them, nine prognostic immune genes, including NCR2, NPDC1, KIR2DL4, KLC3, TWIST1, SNORD3B-1, NFATC4, XCR1, and LEFTY1, were identified by univariate Cox regression analysis. A multivariable prediction model was established based on prognostic immune genes. Kaplan–Meier survival curve analysis indicated that patients in the high-risk group had a shorter survival rate and higher mortality than those in the low-risk group (P < 0.001), indicating good effectiveness of the model. Furthermore, nuclear factors of activated T cells-4 (NFATC4) was recognized as the key immune gene identified by co-expression of differentially expressed transcription factors (DETFs) and prognostic immune genes. ATP-binding cassette transporters (ABC transporters) were the downstream KEGG pathway of NFATC4, identified by gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA). To explore the immune responses NFATC4 was involved in, an immune gene set of T cell co-stimulation was identified by single-cell GSEA (ssGSEA) and Pearson correlation analysis, positively associated with NFATC4 in AML (R = 0.323, P < 0.001, positive). In order to find out the immune cell types affected by NFATC4, the CIBERSORT algorithm and Pearson correlation analysis were applied, and it was revealed that regulatory T cells (Tregs) have the highest correlation with NFATC4 (R = 0.526, P < 0.001, positive) in AML from 22 subsets of tumor-infiltrating immune cells. The results of this study were supported by multi-omics database validation. In all, our study indicated that NFATC4 was the key immune gene in AML poor prognosis through recruiting Tregs, suggesting that NFATC4 might serve as a new therapy target for AML.
Alternative Splicing Diversified the Heat Response and Evolutionary Strategy of Conserved Heat Shock Protein 90s in Hexaploid Wheat (Triticum aestivum L.)
Authors: Lu Yunze , Zhao Peng , Zhang Aihua , Ma Lingjian , Xu Shengbao , Wang Xiaoming
Published: November 2020

Crops are challenged by the increasing high temperature. Heat shock protein 90 (HSP90), a molecular chaperone, plays a critical role in the heat response in plants. However, the evolutionary conservation and divergence of HSP90s homeologs in polyploidy crops are largely unknown. Using the newly released hexaploid wheat reference sequence, we identified 18 TaHSP90s that are evenly distributed as homeologous genes among three wheat subgenomes, and were highly conserved in terms of sequence identity and gene structure among homeologs. Intensive time-course transcriptomes showed uniform expression and transcriptional response profiles among the three TaHSP90 homeologs. Based on the comprehensive isoforms generated by combining full-length single-molecule sequencing and Illumina short read sequencing, 126 isoforms, including 90 newly identified isoforms of TaHSP90s, were identified, and each TaHSP90 generated one to three major isoforms. Intriguingly, the numbers and the splicing modes of the major isoforms generated by three TaHSP90 homeologs were obviously different. Furthermore, the quantified expression profiles of the major isoforms generated by three TaHSP90 homeologs are also distinctly varied, exhibiting differential alternative splicing (AS) responses of homeologs. Our results showed that the AS diversified the heat response of the conserved TaHSP90s and provided a new perspective for understanding about functional conservation and divergence of homologous genes.
Temporospatial Flavonoids Metabolism Variation in Ginkgo biloba Leaves
Authors: Guo Ying , Wang Tongli , Fu Fang-Fang , El-Kassaby Yousry A. , Wang Guibin
Published: November 2020

Ginkgo (Ginkgo biloba L.) is a high-value medicinal tree species characterized by its flavonoids beneficial effects that are abundant in leaves. We performed a temporospatial comprehensive transcriptome and metabolome dynamics analyses of clonally propagated Ginkgo plants at four developmental stages (time: May to August) across three different environments (space) to unravel leaves flavonoids biosynthesis variation. Principal component analysis revealed clear gene expression separation across samples from different environments and leaf-developmental stages. We found that flavonoid-related metabolism was more active in the early stage of leaf development, and the content of total flavonoid glycosides and the expression of some genes in flavonoid biosynthesis pathway peaked in May. We also constructed a co-expression regulation network and identified eight GbMYBs and combining with other TF genes (3 GbERFs, 1 GbbHLH, and 1 GbTrihelix) positively regulated the expression of multiple structural genes in the flavonoid biosynthesis pathway. We found that part of these GbTFs (Gb_11316, Gb_32143, and Gb_00128) expressions was negatively correlated with mean minimum temperature and mean relative humidity, while positively correlated with sunshine duration. This study increased our understanding of the molecular mechanisms of flavonoids biosynthesis in Ginkgo leaves and provided insight into the proper production and management of Ginkgo commercial plantations.
IL-7 During Antigenic Stimulation Using Allogeneic Dendritic Cells Promotes Expansion of CD45RA-CD62L+CD4+ Invariant NKT Cells With Th-2 Biased Cytokine Production Profile
Authors: Trujillo-Ocampo Abel , Cho Hyun-Woo , Clowers Michael , Pareek Sumedha , Ruiz-Vazquez Wilfredo , Lee Sung-Eun , Im Jin S.
Published: November 2020

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes cells that recognize glycolipid antigens associated with CD1d, non-classical antigen presenting proteins. They can drive either pro-inflammatory (Th-1) or anti-inflammatory (Th-2) immune microenvironment through the production of both Th-1 and Th-2 type cytokines upon activation, thus play a vital role in cancer, infection, and autoimmune diseases. Adoptive cell therapy using ex vivo expanded iNKT cells is a promising approach to enhance anti-tumor immunity or immunosuppression. However, overcoming phenotypic and functional heterogeneity and promoting in vivo persistency of iNKT cells remains to be a challenge. Here, we compared various methods for ex vivo expansion of human iNKT cells and assessed the quality of expansion, phenotype, and cytokine production profile of expanded iNKT cells. While a direct stimulation of iNKT cells in peripheral blood mononuclear cells with agonist glycolipid led to the expansion of iNKT cells in varying degrees, stimulation of enriched iNKT cells by irradiated autologous peripheral blood mononuclear cells or allogeneic dendritic cells resulted in consistent expansion of highly pure iNKT cells. Interestingly, the mode of antigenic stimulation influenced the dominant subtype of expanded iNKT cells. Further, we evaluated whether additional IL-7 or IL-15 during antigenic stimulation with allogeneic dendritic cells can improve the phenotypic heterogeneity and modify cytokine production profile of iNKT cells expanded from 18 consecutive donors. The presence of IL-7 or IL-15 during antigenic stimulation did not affect the fold of expansion or purity of expanded iNKT cells. However, IL-7, but not IL-15, led to a better expansion of CD4+ iNKT cells, enhanced Th-2 type cytokine production of CD4+ iNKT cells, and maintained the expansion of central memory (CD45RA-CD62L+) CD4+ iNKT cells. Our results suggest the addition of IL-7 during antigenic stimulation with allogeneic dendritic cells can promote the expansion of CD62L+Th-2+CD4+ human iNKT cells that can be used as novel immunotherapeutic to control excessive inflammation to treat various autoimmune diseases.
Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways
Authors: Zamyatina Alla , Heine Holger
Published: November 2020

The innate immune response to lipopolysaccharide is essential for host defense against Gram-negative bacteria. In response to bacterial infection, the TLR4/MD-2 complex that is expressed on the surface of macrophages, monocytes, dendritic, and epithelial cells senses picomolar concentrations of endotoxic LPS and triggers the production of various pro-inflammatory mediators. In addition, LPS from extracellular bacteria which is either endocytosed or transfected into the cytosol of host cells or cytosolic LPS produced by intracellular bacteria is recognized by cytosolic proteases caspase-4/11 and hosts guanylate binding proteins that are involved in the assembly and activation of the NLRP3 inflammasome. All these events result in the initiation of pro-inflammatory signaling cascades directed at bacterial eradication. However, TLR4-mediated signaling and caspase-4/11-induced pyroptosis are largely involved in the pathogenesis of chronic and acute inflammation. Both extra- and intracellular LPS receptors—TLR4/MD-2 complex and caspase-4/11, respectively—are able to directly bind the lipid A motif of LPS. Whereas the structural basis of lipid A recognition by the TLR4 complex is profoundly studied and well understood, the atomic mechanism of LPS/lipid A interaction with caspase-4/11 is largely unknown. Here we describe the LPS-induced TLR4 and caspase-4/11 mediated signaling pathways and their cross-talk and scrutinize specific structural features of the lipid A motif of diverse LPS variants that have been reported to activate caspase-4/11 or to induce caspase-4/11 mediated activation of NLRP3 inflammasome (either upon transfection of LPSin vitroor upon infection of cell cultures with intracellular bacteria or by LPS as a component of the outer membrane vesicles). Generally, inflammatory caspases show rather similar structural requirements as the TLR4/MD-2 complex, so that a “basic” hexaacylated bisphosphorylated lipid A architecture is sufficient for activation. However, caspase-4/11 can sense and respond to much broader variety of lipid A variants compared to the very “narrow” specificity of TLR4/MD-2 complex as far as the number and the length of lipid chains attached at the diglucosamine backbone of lipid A is concerned. Besides, modification of the lipid A phosphate groups with positively charged appendages such as phosphoethanolamine or aminoarabinose could be essential for the interaction of lipid A/LPS with inflammatory caspases and related proteins.
Machine Learning to Quantify In Situ Humoral Selection in Human Lupus Tubulointerstitial Inflammation
Authors: Kinloch Andrew J. , Asano Yuta , Mohsin Azam , Henry Carole , Abraham Rebecca , Chang Anthony , Labno Christine , Wilson Patrick C. , Clark Marcus R.
Published: November 2020

In human lupus nephritis, tubulointerstitial inflammation (TII) is associated with in situ expansion of B cells expressing anti-vimentin antibodies (AVAs). The mechanism by which AVAs are selected is unclear. Herein, we demonstrate that AVA somatic hypermutation (SHM) and selection increase affinity for vimentin. Indeed, germline reversion of several antibodies demonstrated that higher affinity AVAs can be selected from both low affinity B cell germline clones and even those that are strongly reactive with other autoantigens. While we demonstrated affinity maturation, enzyme-linked immunosorbent assays (ELISAs) suggested that affinity maturation might be a consequence of increasing polyreactivity or even non-specific binding. Therefore, it was unclear if there was also selection for increased specificity. Subsequent multi-color confocal microscopy studies indicated that while TII AVAs often appeared polyreactive by ELISA, they bound selectively to vimentin fibrils in whole cells or inflamed renal tissue. Using a novel machine learning pipeline (CytoSkaler) to quantify the cellular distribution of antibody staining, we demonstrated that TII AVAs were selected for both enhanced binding and specificity in situ. Furthermore, reversion of single predicted amino acids in antibody variable regions indicated that we could use CytoSkaler to capture both negative and positive selection events. More broadly, our data suggest a new approach to assess and define antibody polyreactivity based on quantifying the distribution of binding to native and contextually relevant antigens.
Glioblastoma Immunotherapy Targeting the Innate Immune Checkpoint CD47-SIRPα Axis
Authors: Hu Jinyang , Xiao Qungen , Dong Minhai , Guo Dongsheng , Wu Xudong , Wang Baofeng
Published: November 2020

Glioblastoma Multiforme (GBM) is the most common and aggressive form of intracranial tumors with poor prognosis. In recent years, tumor immunotherapy has been an attractive strategy for a variety of tumors. Currently, most immunotherapies take advantage of the adaptive anti-tumor immunity, such as cytotoxic T cells. However, the predominant accumulation of tumor-associated microglia/macrophages (TAMs) results in limited success of these strategies in the glioblastoma. To improve the immunotherapeutic efficacy for GBM, it is detrimental to understand the role of TAM in glioblastoma immunosuppressive microenvironment. In this review, we will discuss the roles of CD47-SIRPα axis in TAMs infiltration and activities and the promising effects of targeting this axis on the activation of both innate and adaptive antitumor immunity in glioblastoma.
Differential Immune Response to Infection and Acute Inflammation Along the Epididymis
Authors: Pleuger Christiane , Silva Erick José Ramo , Pilatz Adrian , Bhushan Sudhanshu , Meinhardt Andreas
Published: November 2020

The epididymis is a tubular structure connecting the vas deferens to the testis. This organ consists of three main regions—caput, corpus, and cauda—that face opposing immunological tasks. A means of combating invading pathogens is required in the distally located cauda, where there is a risk of ascending bacterial infections originating from the urethra. Meanwhile, immune tolerance is necessary at the caput, where spermatozoa with immunogenic neo-antigens originate from the testis. Consistently, when challenged with live bacteria or inflammatory stimuli, the cauda elicits a much stronger immune response and inflammatory-inflicted damage than the caput. At the cellular level, a role for diverse and strategically positioned mononuclear phagocytes is emerging. At the mechanistic level, differential expression of immunoprotective and immunomodulatory mediators has been detected between the three main regions of the epididymis. In this review, we summarize the current state of knowledge about region-specific immunological characteristics and unveil possible underlying mechanisms on cellular and molecular levels. Improved understanding of the different immunological microenvironments is the basis for an improved therapy and counseling of patients with epididymal infections.
Antioxidant Activity and Phenolic Content of Marine Dissolved Organic Matter and Their Relation to Molecular Composition
Authors: Catalá Teresa S. , Rossel Pamela E. , Álvarez-Gómez Félix , Tebben Jan , Figueroa Félix L. , Dittmar Thorsten
Published: November 2020

The potential of marine dissolved organic matter (DOM) for free radical scavenging has been extensively evaluated, however, the quantitative assessment of the antioxidant potential has been recently measured for the first time. The linkage of the DOM antioxidant potential to its molecular composition has not yet been examined. Following this line, this article takes a step forward by assessing, throughout a polarity-mediated fractionation, (1) the antioxidant capacity and phenolic content and (2) the molecular characterization of DOM in a more exhaustive manner. (3) The DOM antioxidant potential and phenolic content was linked to the molecular composition of DOM, which was molecularly characterized using ultrahigh resolution Fourier transform Ion Cyclotron Resonance mass spectrometry (FT-ICR MS). Antioxidant activity and phenolic content were quantified by the free radical 2,2’-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS⋅) and the Folin-Ciocalteu methods, respectively. We considered three types of different natural DOM samples: the deep North Pacific Ocean, the oligotrophic surface of the North Pacific Ocean and porewater from the sulfidic tidal flats of the Wadden Sea. Bulk porewater and its individual polarity fractions presented the highest antioxidant activity and phenolic content. DOM from the water column samples had lower antioxidant activity and phenolic content than porewater, but exceeded what it is commonly found in macroalgae, microalgae, fruits and vegetables with cosmeceutical purposes. Our values were similar to published values for terrestrial DOM. The variations in bioactivity were dependent on polarity and molecular composition. The high resolution and high mass accuracy used to determine the molecular composition of marine DOM and the chemometric and multistatistical analyses employed have allowed to distinguish molecular categories that are related to the bioactive potential. As a future perspective, we performed cytotoxicity tests with human cells and propose marine DOM as a natural ingredient for the development of cosmeceutical products.
The Influence of Si3N4w Volume Fraction on the Microstructure and Properties of Si3N4w/Si3N4 Composites via CVI Technique
Authors: Chen Chao , Liu Yongsheng , Yue Wei , Ye Fang , Wang Jing , Zeng Qingfeng
Published: November 2020

Wave-transparent ceramic composites with excellent comprehensive performances are of particular significance for the development of space vehicles. In this study, Si3N4w was prepared by the gel-casting process and then combined with chemical vapor infiltration (CVI)-obtained Si3N4 to yield Si3N4w/Si3N4 composites with five Si3N4w volume fractions. The influence of the Si3N4w volume fraction on the microstructures, mechanical properties, and dielectric characteristics of the Si3N4w/Si3N4 composites were all studied. The results showed that Si3N4w/Si3N4 composites possess A sandwich structures. Higher Si3N4w volume fractions led to less incorporated amounts of the Si3N4 matrix at the same depth. The 25 vol% Si3N4w/Si3N4 composites integrated relatively higher Si3N4w volume fraction and load transfer ability of the matrix, leading to better flexural strengths reaching up to 41.37 MPa. The dielectric constants of the five prepared Si3N4w/Si3N4 composites ranged from 2.25 to 4.0. The dielectric losses were all lower than 0.005, demonstrating the good dielectric properties of the Si3N4w/Si3N4 composites.
Numerical Assessment of the Performance of Elastic Cloaks for Transient Flexural Waves
Authors: Rossi Marco , Veber Daniele , Gei Massimiliano
Published: November 2020

A relevant application of transformation elastodynamics has shown that flexural waves in a Kirchhoff-Love plate can be diverted and channeled to cloak a region of the ambient space. To achieve the goal, an orthotropic meta-structural plate should be employed. However, the corresponding mathematical transformation leads to the presence of an unwanted strong compressive prestress, likely beyond the buckling threshold of the structure, with a set of in-plane body forces to warrant equilibrium. In addition, the plate must possess, at the same time, high bending stiffnesses, but a null twisting rigidity. With the aim of estimating the performance of cloaks modelled with approximate parameters, an in-house finite element code, based on a subparametric technique, is implemented to deal with the cloaking of transient waves in orthotropic thin plates. The tool allows us to explore the sensitivity of specific stiffness parameters that may be difficult to match in a real cloak design. In addition, the finite element code is extended to investigate a meta-plate interacting with a Winkler foundation, to confirm how the subgrade modulus should transform in the cloak region.
Thromboprofilaxys With Fondaparinux vs. Enoxaparin in Hospitalized COVID-19 Patients: A Multicenter Italian Observational Study
Authors: Russo Vincenzo , Cardillo Giuseppe , Viggiano Giuseppe Vito , Mangiacapra Sara , Cavalli Antonella , Fontanella Andrea , Agrusta Federica , Bellizzi Annamaria , Amitrano Maria , Iannuzzo Mariateresa , Sacco Clara , Lodigiani Corrado , Castaldo Giampiero , Di Micco Pierpaolo
Published: November 2020

Importance: The use of anticoagulant therapy with heparins decreased mortality in hospitalized patients with severe coronavirus disease 2019 (COVID-19). Even if enoxaparin and fondaparinux have the same clinical indication for venous thromboembolism (VTE) prevention; to date, there are no data about the use of fondaparinux in terms of safety, effectiveness, and impact on clinical prognosis among COVID-19 patients.

Objective: To evaluate the safety, effectiveness, and clinical impact of VTE prophylaxis with fondaparinux and enoxaparin among COVID-19 patients hospitalized in internal medicine units.

Design, Setting, and Participants: This was a retrospective multicenter observation study, including consecutive symptomatic patients with laboratory-proven COVID-19 admitted to internal medicine units of five Italian hospitals from 15th February to 15th March 2020.

Main Outcomes and Measures: The primary safety outcome was the composite of major bleeding and clinically relevant non-major bleeding; the primary effectiveness outcome was the composite of all events classified as pulmonary embolism and deep venous thrombosis. The secondary effectiveness outcome included acute respiratory distress syndrome and all-cause death.

Results: Among 120 COVID-19 patients enrolled in the study, 74 were taking enoxaparin (4,000 or 6,000 units/day) and 46 fondaparinux (2.5 units/day). No statistically significant difference in demographic and laboratory and clinical characteristics between the two groups has been shown. During a median follow-up of 32 (interquartile range: 14–51) days, the cumulative incidence rates of VTE and bleeding events on pharmacological thromboprophylaxis with heparins were 19% and 8%, respectively. The incidence of both VTE (6.5 vs. 13.5%; P = 0.36) and bleeding events (6.5 vs. 4.1%; P = 0.68) did not show a significant difference between COVID-19 patients on fondaparinux compared with those on enoxaparin therapy. The regression model for the risk of outcome events according to different VTE prophylaxis drugs did not show significant differences.

Conclusions and Relevance: Although these results need confirmation by prospective studies including a larger population, our study provides preliminary evidence of a safe and efficacy use of fondaparinux for VTE prophylaxis in hospitalized COVID-19 patients.
Transnasal Humidified Rapid Insufflation Ventilatory Exchange With Nasopharyngeal Airway Facilitates Apneic Oxygenation: A Randomized Clinical Noninferiority Trial
Authors: Chen Lingke , Yang Liu , Tian Weitian , Zhang Xiao , Zhao Yanhua , Huang Lili , Tian Jie , Zhang Jiaqiang , Wu Jiangxia , Yu Weifeng , Su Diansan
Published: November 2020

Background: Transnasal humidified rapid insufflation ventilatory exchange (THRIVE) was used to extend the safe apnea time. However, THRIVE is only effective in patients with airway opening. Nasopharyngeal airway (NPA) is a simple device that can help to keep airway opening. This study aimed to investigate the noninferiority of NPA to jaw thrust for airway opening during anesthesia-induced apnea.

Methods: This was a prospective randomized single-blinded noninferiority clinical trial on the use of THRIVE in patients with anesthesia-induced apnea. The participants were randomly allocated to receive NPA or jaw thrust. The primary outcomes were PaO2 and PaCO2 at 20 min after apnea, with noninferiority margin criteria of −6.67 and 0.67 kPa, respectively.

Results: A total of 123 patients completed the trial: 61 in the NPA group and 62 in the jaw thrust group. PaO2 at 20 min after apnea was 42.9 ± 14.0 kPa in the NPA group and 42.7 ± 13.6 kPa in the jaw thrust group. The difference between these two means was 0.25 kPa (95% CI, −3.87 to 4.37 kPa). Since the lower boundary of the 95% CI was > −6.67 kPa, noninferiority was established because higher PO2 is better. PaCO2 at 20 min after apnea was 10.74 ± 1.09 kPa in the NPA group and 10.54 ± 1.18 kPa in the jaw thrust group. The difference between the two means was 0.19 kPa (95% CI, −0.14 to 0.53 kPa). Since the upper boundary of the 95% CI was <0.67 kPa, noninferiority was established because lower PCO2 is better. No patient had a SpO2 < 90% during apnea.

Conclusion: When THRIVE was applied during anesthesia-induced apnea, NPA placement kept airway opening and was noninferior to jaw thrust in terms of its effects on PaO2 and PaCO2 at 20 min after apnea.

Clinical Trial Registration:ClinicalTrials.gov (NCT03741998).
Case Report: Unmasked Inherited Dysfibrinogenemia After Everolimus Therapy
Authors: Merkulova Alona A. , Mitchell Steven C. , Merkulov Sergei , Wolberg Alisa S. , Neerman-Arbez Marguerite , Schmaier Alvin H.
Published: November 2020

A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months, the patient developed a severe bleeding disorder. The bleeding was due to fibrin polymerization defect that upon sequencing was shown to be dysfibrinogenemia Krakow III. Elimination of the mTor inhibitor ameliorated the clinical bleeding state.
A Checklist for Implementing Rural Pathways to Train, Develop and Support Health Workers in Low and Middle-Income Countries
Authors: O'Sullivan Belinda , Chater Bruce , Bingham Amie , Wynn-Jones John , Couper Ian , Hegazy Nagwa Nashat , Kumar Raman , Lawson Henry , Martinez-Bianchi Viviana , Randenikumara Sankha , Rourke James , Strasser Sarah , Worley Paul
Published: November 2020

Background:There is an urgent need to scale up global action on rural workforce development. This World Health Organization-sponsored research aimed to develop a Rural Pathways Checklist. Its purpose was to guide the practical implementation of rural workforce training, development, and support strategies in low and middle-income countries (LMICs). It was intended for any LMICs, stakeholder, health worker, context, or health problem.

Method:Multi-methods involved: (1) focus group concept testing; (2) a policy analysis; (3) a scoping review of LMIC literature; (4) consultation with a global Expert Reference Group and; (5) field-testing over an 18-month period.

Results:The Checklist included eight actions for implementing rural pathways in LMICs: establishing community needs; policies and partners; exploring existing workers and scope; selecting health workers; education and training; working conditions for recruitment and retention; accreditation and recognition of workers; professional support/up-skilling and; monitoring and evaluation. For each action, a summary of LMICs-specific evidence and prompts was developed to stimulate reflection and learning. To support implementation, rural pathways exemplars from different WHO regions were also compiled. Field-testing showed the Checklist is fit for purpose to guide holistic planning and benchmarking of rural pathways, irrespective of LMICs, stakeholder, or health worker type.

Conclusion:The Rural Pathways Checklist provides an agreed global conceptual framework for the practical implementation of “grow your own” strategies in LMICs. It can be applied to scale-up activity for rural workforce training and development in LMICs, where health workers are most limited and health needs are greatest.
Case Report: Treatment of Anti-MDA5-Positive Amyopathic Dermatomyositis Accompanied by a Rapidly Progressive Interstitial Lung Diseases With Methylprednisolone Pulse Therapy Combined With Cyclosporine A and Hydroxychloroquine
Authors: Zhang Qia-Chun , Liu Min-Ying , Chen Zhi-Xin , Chen Yimin Talia , Lin Chang-Song , Xu Qiang
Published: November 2020

Introduction: Patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive amyopathic dermatomyositis (ADM) often develop rapidly progressive interstitial lung diseases (RP-ILD), with poor treatment success. Many studies have shown that this is the main cause of death in patients with anti-MDA5 antibody-positive ADM.

Case Presentation: A 37-years-old woman developed a cough, shortness of breath, and a rash on both hands, which resembled Gottron's signs. Upon laboratory examination, the results were as follows: antinuclear antibody (ANA) positive; anti-Ro52 antibody positive; and anti-MDA5 antibody positive. Pulmonary high-resolution CT (HRCT) scan showed pulmonary interstitial inflammatory changes, and mediastinal and subcutaneous emphysema. She was finally diagnosed with anti-MDA5 antibody-positive ADM accompanied by RP-ILD. She was first given high-dose-steroid pulse therapy with methylprednisolone (500 mg per day for 3 days) followed by methylprednisolone (40 mg, daily), cyclosporine A (100 mg, twice per day), and hydroxychloroquine (200 mg, twice per day). Since her discharge from our hospital in March of 2018, she has maintained the methylprednisolone therapy (tapered to 10 mg daily), cyclosporine A (100 mg, twice per day), and hydroxychloroquine (200 mg, twice per day).

Outcomes: Pulmonary HRCT scans taken on 4, 9, and 26 months after her discharge from our hospital showed that the interstitial pneumonitis had significantly improved and that mediastinal and subcutaneous emphysema had been gradually absorbed. The patient can now participate in regular work and activities of daily living.

Conclusion: The treatment of methylprednisolone pulse therapy combined with cyclosporine A and hydroxychloroquine may be an option for the RP-ILD accompanied by anti-MDA-positive ADM. After the acute phase, this combination therapy strategy is helpful to the disease control of patients.
Pharmacodynamic Functions of Synthetic Derivatives for Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis
Authors: Dinarvand Mojdeh , Spain Malcolm P. , Vafaee Fatemeh
Published: November 2020

Drug resistant bacteria have emerged, so robust methods are needed to evaluate combined activities of known antibiotics as well as new synthetic compounds as novel antimicrobial agents to treatment efficacy in severe bacterial infections. Marine natural products (MNPs) have become new strong leads in the drug discovery endeavor and an effective alternative to control infections. Herein, we report the bioassay guided fractionation of marine extracts from the sponges Lendenfeldia, Ircinia, and Dysidea that led us to identify novel compounds with antimicrobial properties. Chemical synthesis of predicted compounds and their analogs has confirmed that the proposed structures may encode novel chemical structures with promising antimicrobial activity against the medically important pathogens. Several of the synthetic analogs exhibited potent and broad spectrum in vitro antibacterial activity, especially against the Methicillin-resistant Staphylococcus aureus (MRSA) (MICs to 12.5 μM), Mycobacterium tuberculosis (MICs to 0.02 μM), uropathogenic Escherichia coli (MIC o 6.2 μM), and Pseudomonas aeruginosa (MIC to 3.1 μM). Checkerboard assay (CA) and time-kill studies (TKS) experiments analyzed with the a pharmacodynamic model, have potentials for in vitro evaluation of new and existing antimicrobials. In this study, CA and TKS were used to identify the potential benefits of an antibiotic combination (i.e., synthetic compounds, vancomycin, and rifampicin) for the treatment of MRSA and M. tuberculosis infections. CA experiments indicated that the association of compounds 1a and 2a with vancomycin and compound 3 with rifampicin combination have a synergistic effect against a MRSA and M. tuberculosis infections, respectively. Furthermore, the analysis of TKS uncovered bactericidal and time-dependent properties of the synthetic compounds that may be due to variations in hydrophobicity and mechanisms of action of the molecules tested. The results of cross-referencing antimicrobial activity, and toxicity, CA, and Time-Kill experiments establish that these synthetic compounds are promising potential leads, with a favorable therapeutic index for antimicrobial drug development.
Comparative Analysis of Physicochemical Properties and Microbial Composition in High-Temperature Daqu With Different Colors
Authors: Deng Ling , Mao Xiang , Liu Dan , Ning Xin-Qiang , Shen Yi , Chen Bo , Nie Hong-Fang , Huang Dan , Luo Hui-Bo
Published: November 2020

High-temperature Daqu, also called Jiang-flavor Daqu, is the saccharifying and fermenting agent for brewing Jiang-flavor Baijiu. During the spontaneous solid-state fermentation of high-temperature Daqu, variations in temperature and moisture lead to microbial diversity and various metabolites, contributing to the different colors of high-temperature Daqu (customarily referred to as white Daqu, black Daqu, yellow Daqu, and red Daqu in production). We aimed to investigate the differences in microbial communities, physicochemical indices, and potential functions among different high-temperature Daqu with different colors (labeled as QW, QB, QY, and QR) by amplicon sequencing. We found that Kroppenstedtia, Bacillus, and Thermoascus were predominant in all samples; Saccharopolyspora and Thermomyces were predominant in QB and QR; and Unclassfied_O_Eurotiales were predominant in QY. The results on the physicochemical characteristics indicated that compared with other Daqu samples, QW exhibited higher protease activity and lower acidity, whereas QB showed the opposite results. QR had the highest esterification yield, and QY exhibited the highest saccharification but lowest esterification yield. Functional prediction demonstrated that the higher abundances of genes encoding bacterial enzymes of QW and QY were related to the considerably higher abundances of Kroppenstedtia in QW (59%) and QY (87%), respectively. The highest abundance of Thermomyces in QB (80%) contributed to the highest abundance of genes encoding fungal enzymes in QB. This study revealed the microbial and functional dissimilarities of color-based high-temperature starters and helped facilitate the liquor fermentation process.