bluuebunny/crossref_metadata_2025 huggingface dataset:
A Perspective on the Role of Eco-Certification in Eliminating Illegal, Unreported and Unregulated Fishing
Authors: Longo Catherine S. , Buckley Leah , Good Stephanie D. , Gorham Taylor M. , Koerner Lauren , Lees Samantha , Liow Shen Yan , Oloruntuyi Oluyemisi , Schley David , Rice Jake , Currey Rohan J. C.
Published: August 2021

Illegal, unreported and unregulated (IUU) fishing activities threaten marine biodiversity, livelihoods, food security, and human rights across the globe. Often occurring in waters that are difficult to control, and across multi-sector, transboundary, value chains that are hard to regulate, such a complex and heterogeneous problem requires multiple strategies beyond sovereign nations’ legislation alone. Here we explore the mechanisms through which eco-certification, by fostering private-public and cross-jurisdiction cooperation, can incentivize fishers to adopt best practices in harvesting and ecosystem impacts mitigation, increase the transparency of fishery operations and accountability to suppliers. The Marine Stewardship Council (MSC) sets globally recognized standards for fisheries sustainability and supply chain assurance, based on the FAO Code of Conduct for Responsible Fisheries. Building on the MSC experience of over 400 certified fisheries representing 18% of global wild marine catch, we analyze examples and available information on the changes achieved by the seafood industry through engagement with the program, with particular focus on the elimination or reduction of illegal, unreported or unregulated fishing practices. We propose here that different, interlinked mechanisms come into play: the Standards provide best practice guidelines for improved catch documentation, monitoring, control and surveillance (MCS), and strengthening regulations. These lead to change either through (1) direct improvements required for fisheries to achieve the certificate (e.g., in Fishery Improvement Projects) or, (2) once certified, to maintain the certificate, or (3) as an emergent effect of the engagement process itself, requiring stakeholder cooperation and transparent information-sharing leading to a greater culture of compliance, and (4), as an effect of strengthening chain of custody documentation and standardizing it across jurisdictions. We also discuss limitations, such as the capacity for fisheries in low-income regions to embark on the management and social reform required, and evolving challenges in seafood sustainability, such as ethical concerns for forced and child labor and shark finning. While not the single silver bullet against such a complex problem, we argue that certification is an important tool in addressing IUU fishing.
Construction of a circRNA-Related Prognostic Risk Score Model for Predicting the Immune Landscape of Lung Adenocarcinoma
Authors: Li Huawei , Wang Jun , Zhang Linyou
Published: August 2021

The purpose of this study was to construct a circular RNA (circRNA)-related competing endogenous RNA (ceRNA) regulatory network and risk score model for lung adenocarcinoma (LUAD). The relationship of the risk score to immune landscape and sensitivity to chemotherapy and targeted therapy of LUAD was assessed. We downloaded mRNA and miRNA expression data, along with clinical information, from The Cancer Genome Atlas (TCGA) program, and circRNA expression data from the Gene Expression Omnibus (GEO) database and identified differently expressed circRNA (DEcircRNA), miRNA (DEmiRNA), and mRNA (DEmRNA) using R software. We then constructed the circRNA-related network using bioinformatics method. The risk score model was established by LASSO Cox regression analysis based on 10 hub genes. In addition, the risk score model was an independent predictor for overall survival (OS) in both the TCGA and CPTAC datasets. Patients in the high-risk group had shorter OS and disease-free survival (DFS) than those in the low-risk group and were more sensitive to chemotherapy and targeted therapy. The types of tumor-infiltrating immune cells were different in the high- and low-risk groups. Our data revealed that the circRNA-related risk score model is closely associated with the level of immune cell infiltration in the tumor and the effects of adjuvant treatment. This network may be useful in designing personalized treatments for LUAD patients.
Single-Cell RNA Sequencing of Peripheral Blood Reveals Immune Cell Signatures in Alzheimer’s Disease
Authors: Xu Hui , Jia Jianping
Published: August 2021

The peripheral immune system is thought to affect the pathology of the central nervous system in Alzheimer’s disease (AD). However, current knowledge is inadequate for understanding the characteristics of peripheral immune cells in AD. This study aimed to explore the molecular basis of peripheral immune cells and the features of adaptive immune repertoire at a single cell level. We profiled 36,849 peripheral blood mononuclear cells from AD patients with amyloid-positive status and normal controls with amyloid-negative status by 5’ single-cell transcriptome and immune repertoire sequencing using the cell ranger standard analysis procedure. We revealed five immune cell subsets: CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and monocytes–macrophages cells, and disentangled the characteristic alterations of cell subset proportion and gene expression patterns in AD. Thirty-one cell type-specific key genes, comprising abundant human leukocyte antigen genes, and multiple immune-related pathways were identified by protein–protein interaction network and pathway enrichment analysis. We also found high-frequency amplification clonotypes in T and B cells and decreased diversity in T cells in AD. As clone amplification suggested the activation of an adaptive immune response against specific antigens, we speculated that the peripheral adaptive immune response, especially mediated by T cells, may have a role in the pathogenesis of AD. This finding may also contribute to further research regarding disease mechanism and the development of immune-related biomarkers or therapy.
Expanding Horizons in Complement Analysis and Quality Control
Authors: Frazer-Abel Ashley , Kirschfink Michael , Prohászka Zoltán
Published: August 2021

Complement not only plays a key role in host microbial defense but also modulates the adaptive immune response through modification of T- and B-cell reactivity. Moreover, a normally functioning complement system participates in hematopoiesis, reproduction, lipid metabolism, and tissue regeneration. Because of its powerful inflammatory potential, multiple regulatory proteins are needed to prevent potential tissue damage. In clinical practice, dysregulation and overactivation of the complement system are major causes of a variety of inflammatory and autoimmune diseases ranging from nephropathies, age-related macular degeneration (AMD), and systemic lupus erythematosus (SLE) to graft rejection, sepsis, and multi-organ failure. The clinical importance is reflected by the recent development of multiple drugs targeting complement with a broad spectrum of indications. The recognition of the role of complement in diverse diseases and the advent of complement therapeutics has increased the number of laboratories and suppliers entering the field. This has highlighted the need for reliable complement testing. The relatively rapid expansion in complement testing has presented challenges for a previously niche field. This is exemplified by the issue of cross-reactivity of complement-directed antibodies and by the challenges of the poor stability of many of the complement analytes. The complex nature of complement testing and increasing clinical demand has been met in the last decade by efforts to improve the standardization among laboratories. Initiated by the IUIS/ICS Committee for the Standardization and Quality Assessment in Complement Measurements 14 rounds of external quality assessment since 2010 resulted in improvements in the consistency of testing across participating institutions, while extending the global reach of the efforts to more than 200 laboratories in 30 countries. Worldwide trends of assay availability, usage, and analytical performance are summarized based on the past years’ experiences. Progress in complement analysis has been facilitated by the quality assessment and standardization efforts that now allow complement testing to provide a comprehensive insight into deficiencies and the activation state of the system. This in turn enables clinicians to better define disease severity, evolution, and response to therapy.
Anti–PD-1 and Anti–PD-L1 in Head and Neck Cancer: A Network Meta-Analysis
Authors: Botticelli Andrea , Cirillo Alessio , Strigari Lidia , Valentini Filippo , Cerbelli Bruna , Scagnoli Simone , Cerbelli Edoardo , Zizzari Ilaria Grazia , Rocca Carlo Della , D’Amati Giulia , Polimeni Antonella , Nuti Marianna , Merlano Marco Carlo , Mezi Silvia , Marchetti Paolo
Published: August 2021

Objective

The monoclonal antibodies anti-programmed death protein-1 (anti–PD-1) nivolumab and pembrolizumab are the first immune checkpoint inhibitors (ICIs) approved for treatment of recurrent/metastatic head and neck carcinoma R/M HNSCC in first line and in platinum refractory disease. This network meta-analysis aims to investigate the efficacy of anti–PD-1- vs anti–PD-L1-based therapy in R/M HNSCC cancer patients through a systematic review of the literature to provide support for evidence-based treatment decisions. In particular, the effectiveness of ICIs for R/M HNSCC is analyzed according to the different mechanisms of action of the check-points inhibitory drugs in different subgroups of patients.

Methods

We did a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) in PubMed, ClinicalTrials.gov, Embase, Medline, the Cochrane Central Register of Controlled Trials, Web of Science. Our search identified a total of five randomized controlled trials: Keynote 040, Keynote 048, Eagle, Condor, Checkmate 141. These trials included 3001 patients. Treatment was sub-categorized into PD-L1–based, PD-1–based, and standard chemotherapy. Treatments were indirectly compared with anti–PD-L1-based therapy.

Results

The network meta-analysis demonstrated no significant differences in OS between different subgroups except for the metastatic patients in which anti–PD-1-based therapy was associated with significantly less risk of death. Furthermore, anti–PD-1-based therapy appeared to be effective in smoker patients and in human papilloma–negative (HPV) patients. Conversely, anti–PD-L1-based therapy seems to be better efficient in female patients, in locally recurrent setting and in HPV positive patients.

Conclusion

This is the first NMA study that aimed to indirectly compare anti–PD-1- and anti–PD-L1-based therapy in HNSCC patients. The results of our NMA could help define a profile of patient responder or resistant to specific classes of immune drugs and can be used to guide/design future studies in the novel scenario of precision immune-oncology.
Insights Into the Structure-Function Relationships of Dimeric C3d Fragments
Authors: Wahid Ayla A. , Dunphy Rhys W. , Macpherson Alex , Gibson Beth G. , Kulik Liudmila , Whale Kevin , Back Catherine , Hallam Thomas M. , Alkhawaja Bayan , Martin Rebecca L. , Meschede Ingrid , Laabei Maisem , Lawson Alastair D. G. , Holers V. Michael , Watts Andrew G. , Crennell Susan J. , Harris Claire L. , Marchbank Kevin J. , van den Elsen Jean M. H.
Published: August 2021

Cleavage of C3 to C3a and C3b plays a central role in the generation of complement-mediated defences. Although the thioester-mediated surface deposition of C3b has been well-studied, fluid phase dimers of C3 fragments remain largely unexplored. Here we show C3 cleavage results in the spontaneous formation of C3b dimers and present the first X-ray crystal structure of a disulphide-linked human C3d dimer. Binding studies reveal these dimers are capable of crosslinking complement receptor 2 and preliminary cell-based analyses suggest they could modulate B cell activation to influence tolerogenic pathways. Altogether, insights into the physiologically-relevant functions of C3d(g) dimers gained from our findings will pave the way to enhancing our understanding surrounding the importance of complement in the fluid phase and could inform the design of novel therapies for immune system disorders in the future.
Conjunctival Goblet Cell Responses to TLR5 Engagement Promote Activation of Local Antigen-Presenting Cells
Authors: Logeswaran Abiramy , Contreras-Ruiz Laura , Masli Sharmila
Published: August 2021

Conjunctival epithelium forms a barrier between the ocular surface microbial flora and the ocular mucosa. In addition to secreting gel-forming mucins, goblet cells, located in the conjunctival epithelium, help maintain local immune homeostasis by secreting active TGFβ2 and promoting tolerogenic phenotype of dendritic cells in the vicinity. Although dendritic cell subsets, characteristic of mucosal tissues, are found in the conjunctiva, previous studies provided limited information about their location within the tissue. In this study, we examine immunostained conjunctiva explants to determine the location of CD11c-positive dendritic cells in the context of MUC5AC-positive goblet cells. Considering that conjunctival goblet cells are responsive to signaling induced by pathogen recognition receptors, we also assess if their responses to microbial product, flagellin, can contribute to the disruption of ocular mucosal homeostasis that promotes activation of dendritic cells and results in chronic ocular surface inflammation. We find that dendritic cells in the conjunctiva with an increased microbial colonization are located adjacent to goblet cells. While their cell bodies in the stromal layer are immediately below the epithelial layer, several extensions of dendritic cells are projected across the epithelium towards the ocular surface. Such trans-epithelial dendrites are not detectable in healthy ocular mucosa. In response to topically applied flagellin, increased proportion of CD11c-positive cells in the conjunctiva strongly express MHC class II relative to the untreated conjunctiva. This change is accompanied by reduced immunoreactivity to TGFβ-activating Thrombospondin-1 in the conjunctival epithelium. These findings are supported by in vitro observations in primary cultures of goblet cells that respond to the TLR5 stimulation with an increased expression of IL-6 and reduced level of active TGFβ. The observed changes in the conjunctiva after flagellin application correspond with the development of clinical signs of chronic ocular mucosal inflammation including corneal epitheliopathy. Collectively, these findings demonstrate the ability of ocular mucosal dendritic cells to extend trans-epithelial dendrites in response to increased microbial colonization at the ocular surface. Moreover, this study provides key insight into how goblet cell responses to microbial stimuli may contribute to the disruption of ocular mucosal homeostasis and chronic ocular mucosal inflammation.
Coastal Flooding in the Balearic Islands During the Twenty-First Century Caused by Sea-Level Rise and Extreme Events
Authors: Luque Pau , Gómez-Pujol Lluís , Marcos Marta , Orfila Alejandro
Published: August 2021

Sea-level rise induces a permanent loss of land with widespread ecological and economic impacts, most evident in urban and densely populated areas. Potential coastline retreat combined with waves and storm surges will result in more severe damages for coastal zones, especially over insular systems. In this paper, we quantify the effects of sea-level rise in terms of potential coastal flooding and potential beach erosion, along the coasts of the Balearic Islands (Western Mediterranean Sea), during the twenty-first century. We map projected flooded areas under two climate-change-driven mean sea-level rise scenarios (RCP4.5 and RCP8.5), together with the impact of an extreme event defined by the 100-year return level of joint storm surges and waves. We quantify shoreline retreat of sandy beaches forced by the sea-level rise (scenarios RCP4.5 and RCP8.5) and the continuous action of storm surges and waves (modeled by synthetic time series). We estimate touristic recreational services decrease of sandy beaches caused by the obtained shoreline retreat, in monetary terms. According to our calculations, permanent flooding by the end of our century will extend 7.8–27.7 km2under the RCP4.5 scenario (mean sea-level rise between 32 and 80 cm by 2100), and up to 10.9–36.5 km2under RCP8.5 (mean sea-level rise between 46 and 103 cm by 2100). Some beaches will lose more than 50% of their surface by the end of the century: 20–50% of them under RCP4.5 scenario and 25–60% under RCP8.5 one. Loss of touristic recreational services could represent a gross domestic product (GDP) loss up to 7.2% with respect to the 2019 GDP.
Synthesis of Modified Polycarboxylate and Its Application in Ultra-High Performance Concrete
Authors: Xiang Shuncheng , Tan Yansheng , Gao Yingli
Published: August 2021

Modified polyurethane prepolymer was prepared using the segmental synthesis method. Then, pectiniform polycarboxylate was synthesized at normal temperature in the complex initiation system of H2O2, APS, sodium bisulfite, Vc, and Rongalit according to the free radical polymerization reaction mechanism, using TPEG, AA, and PEG as raw materials and TGA as the chain transfer agent. Compared with commercial Sika polycarboxylate, its flowability, strength, drying shrinkage, and auto-shrinkage were studied. The experimental results show that the synthesized polycarboxylate could be better dispersed. Adding silica fume can enhance the compressive strength of ultra-high performance concrete (UHPC), while slag may decline its strength. By incorporating slag and silica fume, the drying shrinkage of UHPC was reduced, but its auto-shrinkage was increased.
Case Report: Diagnosis of Myelodysplastic Syndrome in a 72-Year-Old Female With Interstitial Lung Disease
Authors: Bizymi Nikoleta , Pitsidianakis Georgios , Ierodiakonou Despo , Stathakis Georgios , Vasarmidi Eirini , Hiraki Stavroti , Bolaki Maria , Karagiannis Konstantinos , Fanaridis Michail , Liopyrakis Konstantinos , Marinos Leonidas , Xilouri Irini , Antoniou Katerina M. , Tzanakis Nikolaos
Published: August 2021

Acute fibrinous and organizing pneumonia (AFOP) is an entity that can be secondary to various conditions leading to lung injury, such as infections, malignancies, and various autoimmune conditions or idiopathic interstitial lung disease, when no obvious underlying cause is identified. Myelodysplastic syndromes (MDS), on the other hand, are a spectrum of clonal myeloid disorders, with a higher risk of acute leukemia, characterized by ineffective bone marrow (BM) hematopoiesis and, thus, peripheral blood (PB) cytopenias. Immune deregulation is thought to take part in the pathophysiology of the disease, including abnormal T and/or B cell responses, innate immunity, and cytokine expression. In the literature, there are a few case reports of patients with MDS that have presented pulmonary infiltrates and were diagnosed as having AFOP or organizing pneumonia (OP). It is rare, though, to have isolated pulmonary infiltrates without Sweet's syndrome or even the pulmonary infiltrates to precede the diagnosis and treatment of MDS, which was our case. We present a 72-year-old female developing new lung infiltrates refractory to antibiotic treatment that responded well to corticosteroids and was histologically described as having OP. The treatment was gradually successfully switched to mycophenolate mofetil (MMF). The patient was later diagnosed with MDS. This interesting case report suggests firstly that a diagnosis of AFOP or OP should alert the clinician to search for an underlying cause including MDS and vice versa, the use of systemic steroids should not be postponed, and, finally, that MMF can successfully be used in these patients.
High-Density Electromyography Provides Improved Understanding of Muscle Function for Those With Amputation
Authors: Kuruganti Usha , Pradhan Ashirbad , Toner Jacqueline
Published: August 2021

Transtibial amputation can significantly impact an individual's quality of life including the completion of activities of daily living. Those with lower limb amputations can harness the electrical activity from their amputated limb muscles for myoelectric control of a powered prosthesis. While these devices use residual muscles from transtibial-amputated limb as an input to the controller, there is little research characterizing the changes in surface electromyography (sEMG) signal generated by the upper leg muscles. Traditional surface EMG is limited in the number of electrode sites while high-density surface EMG (HDsEMG) uses multiple electrode sites to gather more information from the muscle. This technique is promising for not only the development of myoelectric-controlled prostheses but also advancing our knowledge of muscle behavior with clinical populations, including post-amputation. The HDsEMG signal can be used to develop spatial activation maps and features of these maps can be used to gain valuable insight into muscle behavior. Spatial features of HDsEMG can provide information regarding muscle activation, muscle fiber heterogeneity, and changes in muscle distribution and can be used to estimate properties of both the amputated limb and intact limb. While there are a few studies that have examined HDsEMG in amputated lower limbs they have been limited to movements such as gait. The purpose of this study was to examine the quadriceps muscle during a slow, moderate and fast isokinetic knee extensions from a control group as well as a clinical patient with a transtibial amputation. HDsEMG was collected from the quadriceps of the dominant leg of 14 young, healthy males (mean age = 25.5 ± 7 years old). Signals were collected from both the intact and amputated limb muscle of a 23 year old clinical participant to examine differences between the affected and unaffected leg. It was found that there were differences between the intact and amputated limb limb of the clinical participant with respect to muscle activation and muscle heterogeneity. While this study was limited to one clinical participant, it is important to note the differences in muscle behavior between the intact and amputated limb limb. Understanding these differences will help to improve training protocols for those with amputation.
Understanding the Fundamental Basis for Biofilm Formation on Plastic Surfaces: Role of Conditioning Films
Authors: Bhagwat Geetika , O’Connor Wayne , Grainge Ian , Palanisami Thava
Published: August 2021

Graphical Abstract

The formation and composition of conditioning films.
An Ancestral Retrovirus Envelope Protein Regulates Persistent Gammaherpesvirus Lifecycles
Authors: Frey Tiffany R. , Akinyemi Ibukun A. , Burton Eric M. , Bhaduri-McIntosh Sumita , McIntosh Michael T.
Published: August 2021

Human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) persist as life-long infections alternating between latency and lytic replication. Human endogenous retroviruses (HERVs), via integration into the host genome, represent genetic remnants of ancient retroviral infections. Both show similar epigenetic silencing while dormant, but can reactivate in response to cell signaling cues or triggers that, for gammaherpesviruses, result in productive lytic replication. Given their co-existence with humans and shared epigenetic silencing, we asked if HERV expression might be linked to lytic activation of human gammaherpesviruses. We found ERVW-1 mRNA, encoding the functional HERV-W envelope protein Syncytin-1, along with other repeat class elements, to be elevated upon lytic activation of EBV. Knockdown/knockout of ERVW-1 reduced lytic activation of EBV and KSHV in response to various lytic cycle triggers. In this regard, reduced expression of immediate early proteins ZEBRA and RTA for EBV and KSHV, respectively, places Syncytin-1’s influence on lytic activation mechanistically upstream of the latent-to-lytic switch. Conversely, overexpression of Syncytin-1 enhanced lytic activation of EBV and KSHV in response to lytic triggers, though this was not sufficient to induce lytic activation in the absence of such triggers. Syncytin-1 is expressed in replicating B cell blasts and lymphoma-derived B cell lines where it appears to contribute to cell cycle progression. Together, human gammaherpesviruses and B cells appear to have adapted a dependency on Syncytin-1 that facilitates the ability of EBV and KSHV to activate lytic replication from latency, while promoting viral persistence during latency by contributing to B cell proliferation.
Potential Application of Lonicera japonica Extracts in Animal Production: From the Perspective of Intestinal Health
Authors: Tang Xiaopeng , Liu Xuguang , Zhong Jinfeng , Fang Rejun
Published: August 2021

Lonicera japonica (L. japonica) extract is rich in active substances, such as phenolic acids, essential oils, flavones, saponins, and iridoids, which have a broad spectrum of antioxidant, anti-inflammatory, and anti-microbial effect. Previous studies have demonstrated that L. japonica has a good regulatory effect on animal intestinal health, which can be used as a potential antibiotic substitute product. However, previous studies about intestinal health regulation mainly focus on experimental animals or cells, like mice, rats, HMC-1 Cells, and RAW 264.7 cells. In this review, the intestinal health benefits including antioxidant, anti-inflammatory, and antimicrobial activity, and its potential application in animal production were summarized. Through this review, we can see that the effects and mechanism of L. japonica extract on intestinal health regulation of farm and aquatic animals are still rare and unclear. Further studies could focus on the regulatory mechanism of L. japonica extract on intestinal health especially the protective effects of L. japonica extract on oxidative injury, inflammation, and regulation of intestinal flora in farm animals and aquatic animals, thereby providing references for the rational utilization and application of L. japonica and its extracts in animal production.
Free and Immobilised β-Glucosidases in Oenology: Biotechnological Characterisation and Its Effect on Enhancement of Wine Aroma
Authors: Fernández-Pacheco Pilar , García-Béjar Beatriz , Briones Pérez Ana , Arévalo-Villena María
Published: August 2021

In grapes, monoterpenes and norisoprenoids are in the form of non-volatile compounds, flavourless glycosides which could enhance the aroma of wines after its hydrolysis using β- glucosidases enzymes. It is known that the use of immobilised enzymes offers advantages such as reusability and easy recuperation. In this study, a commercial β-glucosidase was immobilised by absorption in sodium alginate. Biotechnological characteristics and terpen hydrolysis (hydrolysis aroma precursors) in muscat wines were studied after treatment with both free and immobilised commercial β- glucosidase with two different concentrations. It was revealed that both forms shared an optimal pH (4.5) and a maximum temperature (64°C), even an increment on the activity between 40and 60°C. A similar Km value has been determined while Vmax from the immobilised enzyme was higher than the free (3.35 and 2.52 μmol min–1 mg–1, respectively). Additionally, the immobilised enzyme showed a better hydrolytic activity during 24 h, and its reusability has been proven. Regarding enzymatic hydrolysis in grape must, the best results were observed for the highest concentration of free β-glucosidase although glucose release was also determined for the immobilised enzyme along the days. In contrast, maximum activity was reached by the immobilised β-glucosidase in less time but in no case equalled the free ones. Finally, volatile compound liberation in wines treated with free or immobilised enzymes was analysed using HRGC-MS. Liberation for both enzymes and the greatest concentrations of some volatiles were detected when a double dose of the free β-glucosidase was used. Nevertheless, the wines treated with the immobilised β-glucosidase showed a high concentration of some volatile compounds such as nerol or geraniol.
miR-330–5p in Small Extracellular Vesicles Derived From Plastrum testudinis-Preconditioned Bone Mesenchymal Stem Cells Attenuates Osteogenesis by Modulating Wnt/β-Catenin Signaling
Authors: Li Xiaoyun , Cui Yan , Lin Qing , Wang Panpan , Chen Rumeng , Zhu Xiaofeng , Yang Li , Zhang Ronghua
Published: August 2021

The bone microenvironment is crucial for the growth and development of different types of osteocytes. Small extracellular vesicles (sEVs) secreted by bone mesenchymal stem cells are delivered to target cells where their contents regulate biological functions. Here, we evaluated the osteogenic effects and mechanism of sEVs derived from Plastrum testudinis-preconditioned bone mesenchymal stem cells (PT-sEV). The osteogenic effects of PT-sEV were evaluated by the differentiation of osteoblasts and the alternation of bone quality and quantity in ovariectomized rats. The specific mechanism was explored by high-throughput sequencing and verified by transfection with the corresponding miRNA mimic and inhibitor. RNA-sequence identified a unique enrichment of a set of miRNAs in PT-sEV compared with sEVs derived from untreated BMSCs. Overexpression or inhibition in vitro indicated that the osteogenic inducing potential of sEVs was mainly attributable to miR-330-5p, one of the most dramatically downregulated miRNAs in the PT-sEV fraction. Dual luciferase reporter assays showed that miR-330-5p negatively regulated osteogenesis by directly binding to the 3′ untranslated region of Tnc. Additional experiments showed that Tnc regulated Wnt/β-catenin signaling, and rescue experiment showed that miR-330-5p could restore β-catenin expression; additionally, animal experiments indicated that Wnt signaling was inactivated in the ovariectomized rats. These data demonstrated the regenerative potential of PT-sEV, which induced osteogenic differentiation of pre-osteoblasts, leading to bone formation. This process was achieved by delivering miR-330-5p, which regulated Tnc to control Wnt/β-catenin signaling.
RUNX1 Upregulates CENPE to Promote Leukemic Cell Proliferation
Authors: Liu Shan , Yang Jianyu , Sun Guohuan , Zhang Yawen , Cheng Cong , Xu Jin , Yen Kuangyu , Lu Ting
Published: August 2021

RUNX1 is a Runt family transcription factor that plays a critical role in normal hematopoiesis, including the differentiation and proliferation of hematopoietic cells. RUNX1 mutations, including chromosomal translocations, cause abnormal cell differentiation, but the mutation alone is not sufficient to cause leukemia. In MLL-fusion-induced leukemia, dysregulated wild-type RUNX1 can promote leukemia survival. Nevertheless, the underlying mechanisms of dysregulated wild-type RUNX1 in leukemia development have not been fully elucidated. This study overexpressed and knocked down RUNX1 expression in THP-1 human leukemia cells and CD34+ hematopoietic stem/progenitor cells to investigate the biological functions affected by dysregulated RUNX1. Our data indicated RUNX1 facilitated proliferation to promote leukemia cell growth. Furthermore, we demonstrated that RUNX1 knockdown in leukemia cells drastically diminished colony-forming ability. Finally, the RUNX1-knocked down cell depletion phenotype could be rescued by overexpression of CENPE, a cell proliferation gene and a RUNX1 direct target gene. Our results indicate a possible mechanism involving the RUNX1-CENPE axis on promoting leukemic cell growth.
Impact of the Host-Microbiome on Osteomyelitis Pathogenesis
Authors: Chen Jun , Xiong Ailin , Ma Yuhao , Qin Chenghe , Ho Chun Loong
Published: August 2021

The microbiome is a collection of genomes from microbiota, including all microorganisms in a niche, through direct and indirect interactions with the host. Certain microorganisms can exist in areas conventionally considered to be sterile, such as the bone matrix. Osseous microbiota dysbiosis caused by host-microbiome perturbation or external infections may ultimately lead to osteomyelitis, a bone inflammatory disorder. Our review covers the current discoveries on the impact of host-microbiome on osteomyelitis and some common osseous diseases. Some studies suggest that the microbiotas from both osseous and non-osseous tissues (e.g., blood or gut) impact the pathogenicity of osteomyelitis and other osseous diseases (e.g., rheumatoid arthritis). We believe that this review will provide readers with a better understanding on the role of the microbiome to the host’s bone health.
ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies
Authors: Jiang Lejian , Lin Jiachen , Zhao Sen , Wu Jiaqian , Jin Yongming , Yu Li , Wu Nan , Wu Zhihong , Wang Yue , Lin Mao
Published: August 2021

ADAMTS5 is involved in the pathogenesis of OA. As the major aggrecanase-degrading articular cartilage matrix, ADAMTS5, has been regarded as a potential target for OA treatment. We here provide an updated insight on the regulation of ADAMTS5 and newly discovered therapeutic strategies for OA. Pathophysiological and molecular mechanisms underlying articular inflammation and mechanotransduction, as well as chondrocyte hypertrophy were discussed, and the role of ADAMTS5 in each biological process was reviewed, respectively. Senescence, inheritance, inflammation, and mechanical stress are involved in the overactivation of ADAMTS5, contributing to the pathogenesis of OA. Multiple molecular signaling pathways were observed to modulate ADAMTS5 expression, namely, Runx2, Fgf2, Notch, Wnt, NF-κB, YAP/TAZ, and the other inflammatory signaling pathways. Based on the fundamental understanding of ADAMTS5 in OA pathogenesis, monoclonal antibodies and small molecule inhibitors against ADAMTS5 were developed and proved to be beneficial pre-clinically both in vitro and in vivo. Recent novel RNA therapies demonstrated potentials in OA animal models. To sum up, ADAMTS5 inhibition and its signaling pathway–based modulations showed great potential in future therapeutic strategies for OA.
Cochlear Synaptic Degeneration and Regeneration After Noise: Effects of Age and Neuronal Subgroup
Authors: Hickman Tyler T. , Hashimoto Ken , Liberman Leslie D. , Liberman M. Charles
Published: August 2021

In CBA/CaJ mice, confocal analysis has shown that acoustic overexposure can immediately destroy synapses between auditory-nerve fibers (ANFs) and their peripheral targets, the inner hair cells (IHCs), and that years later, a corresponding number of ANF cell bodies degenerate. In guinea pig, post-exposure disappearance of pre-synaptic ribbons can be equally dramatic, however, post-exposure recovery to near-baseline counts has been reported. Since confocal counts are confounded by thresholding issues, the fall and rise of synaptic ribbon counts could represent “regeneration,” i.e., terminal retraction, re-extension and synaptogenesis, or “recovery,” i.e., down- and subsequent up-regulation of synaptic markers. To clarify, we counted pre-synaptic ribbons, assessed their juxtaposition with post-synaptic receptors, measured the extension of ANF terminals, and quantified the spatial organization and size gradients of these synaptic elements around the hair cell. Present results in guinea pigs exposed as adults (14 months), along with prior results in juveniles (1 month), suggest there is post-exposure neural regeneration in the guinea pig, but not the CBA/CaJ mouse, and that this regenerative capacity extends into adulthood. The results also show, for the first time, that the acute synaptic loss is concentrated on the modiolar side of IHCs, consistent with a selective loss of the high-threshold ANFs with low spontaneous rates. The morphological similarities between the post-exposure neurite extension and synaptogenesis, seen spontaneously in the guinea pig, and in CBA/CaJ only with forced overexpression of neurotrophins, suggest that the key difference may be in the degree of sustained or injury-induced expression of these signaling molecules in the cochlea.
A Review on Wearable Technologies for Tremor Suppression
Authors: Lora-Millan Julio S. , Delgado-Oleas Gabriel , Benito-León Julián , Rocon Eduardo
Published: August 2021

Tremor is defined as a rhythmic, involuntary oscillatory movement of a body part. Although everyone exhibits a certain degree of tremor, some pathologies lead to very disabling tremors. These pathological tremors constitute the most prevalent movement disorder, and they imply severe difficulties in performing activities of daily living. Although tremors are currently managed through pharmacotherapy or surgery, these treatments present significant associated drawbacks: drugs often induce side effects and show decreased effectiveness over years of use, while surgery is a hazardous procedure for a very low percentage of eligible patients. In this context, recent research demonstrated the feasibility of managing upper limb tremors through wearable technologies that suppress tremors by modifying limb biomechanics or applying counteracting forces. Furthermore, recent experiments with transcutaneous afferent stimulation showed significant tremor attenuation. In this regard, this article reviews the devices developed following these tremor management paradigms, such as robotic exoskeletons, soft robotic exoskeletons, and transcutaneous neurostimulators. These works are presented, and their effectiveness is discussed. The article also evaluates the different metrics used for the validation of these devices and the lack of a standard validation procedure that allows the comparison among them.
LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort
Authors: Usnich Tatiana , Vollstedt Eva-Juliane , Schell Nathalie , Skrahina Volha , Bogdanovic Xenia , Gaber Hanaa , Förster Toni M. , Heuer Andreas , Koleva-Alazeh Natalia , Csoti Ilona , Basak Ayse Nazli , Ertan Sibel , Genc Gencer , Bauer Peter , Lohmann Katja , Grünewald Anne , Schymanski Emma L. , Trinh Joanne , Schaake Susen , Berg Daniela , Gruber Doreen , Isaacson Stuart H. , Kühn Andrea A. , Mollenhauer Brit , Pedrosa David J. , Reetz Kathrin , Sammler Esther M. , Valente Enza Maria , Valzania Franco , Volkmann Jens , Zittel Simone , Brüggemann Norbert , Kasten Meike , Rolfs Arndt , Klein Christine ,   The LIPAD Study Group
Published: August 2021

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 (LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2-linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions.

Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data.

Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2-linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants.

Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn &Yahr, and Schwab & England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021).

Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2-linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity

Clinical Trial Registration:ClinicalTrials.gov, NCT04214509.
Personalized Protein Supplementation Improves Total Protein, Leucine, and Energy Intake in (Pre)Sarcopenic Community-Dwelling Older Adults in the ENHANce RCT
Authors: Dedeyne Lenore , Dupont Jolan , Verschueren Sabine , Koppo Katrien , Tournoy Jos , Matthys Christophe , Gielen Evelien
Published: August 2021

Recommendations concerning protein quantity, source, and leucine intake for older adults are difficult to reach by regular dietary intake. This randomized clinical trial assesses in sarcopenic community-dwelling older adults (i) the regular (non-supplemented) daily protein and leucine intake; and (ii) the effect of personalized protein supplementation (aiming for an evenly distributed total protein intake of 1.5 g·kg−1·d−1 of body mass, accounting for energy intake) on regular and total (dietary and supplemental) intake. A preliminary feasibility study in participants of the ongoing Exercise and Nutrition for Healthy AgeiNg (ENHANce) study was performed with the objective to assess the intake and distribution of regular dietary protein and leucine, protein source and energy intake in (pre)sarcopenic community-dwelling older adults. Moreover, this study aimed to assess if personalized protein supplementation was feasible without negatively affecting regular dietary intake. ENHANce (NCT03649698) is a 5-armed RCT that assesses the effect of anabolic interventions on physical performance in (pre)sarcopenic older adults. In August 2019, n = 51 participants were included in ENHANce with complete available data on dietary intake at screening and thus eligible for inclusion in present analysis. Of these, n = 35 participants completed the intervention period of ENHANce at the moment of analysis, allowing an exploration of the effect of supplementation on regular dietary intake. The regular dietary protein intake of 51 (pre)sarcopenic adults (73.6 ± 6.5 years) was 1.06 ± 0.3 g·kg−1·d−1 of body mass. Protein supplementation (n = 20) improved total protein intake to 1.55 ± 0.3 g·kg−1·d−1 of body mass (P < 0.001) without affecting regular dietary protein (P = 0.176) or energy intake (P = 0.167). Placebo supplementation (n = 15) did not affect regular dietary protein intake (P = 0.910) but decreased regular dietary energy intake (P = 0.047). Regular leucine intake was unevenly distributed over the day, but increased by supplementation at breakfast (P < 0.001) and dinner (P = 0.010) to at least 2.46 g leucine·meal−1, without reducing regular dietary leucine intake (P = 0.103). Animal-based protein intake—the main protein source—was not affected by supplementation (P = 0.358). Personalized protein supplementation ensured an adequate quantity and even distribution of protein and leucine over the day, without affecting regular dietary protein or energy intake.
Associations of Dietary Fat Intake With Mortality From All Causes, Cardiovascular Disease, and Cancer: A Prospective Study
Authors: Yao Xiaolin , Xu Xin , Wang Shuo , Xia Dan
Published: August 2021

The impact of fat intake on health has become a growing public concern. The existing evidence linking specific dietary fat intake with mortality is controversial. We aimed to investigate the association between fat intake and total and cause-specific mortality in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Intakes of saturated fatty acids (SFAs), trans-fatty acids (TFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were assessed via food frequency questionnaires. The primary outcomes were total, cardiovascular disease (CVD), and cancer mortality. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression model adjusting for confounders. Overall, 24,141 deaths were recorded over a total 1,672,715 person-years of follow-up. There was a significant positive association between SFA consumption and total mortality (HRQ5 vs. Q1 = 1.13, 95% CI 1.05–1.22; Pfor trend < 0.001). PUFA intake was strongly inversely associated with total mortality (HRQ5 vs. Q1 = 0.79, 95% CI 0.73–0.85; Pfor trend < 0.001) and CVD mortality (HRQ5 vs. Q1 = 0.66, 95% CI 0.58–0.75; Pfor trend < 0.001). There was a similar, but to a lesser extent, association between MUFA intake and total and CVD mortality [HRQ5 vs. Q1 0.91 (95% CI: 0.84–0.99), Pfor trend = 0.044 and 0.85 (0.73–0.98), Pfor trend = 0.020, respectively]. None of these types of dietary fat were associated with cancer mortality (all Pfor trend > 0.05). In conclusion, this study observed a detrimental effect of SFA intake on total mortality; in contrast, greater consumption of PUFAs and MUFAs were associated with lower risks of all-cause death and CVD mortality.
Could Camrelizumab Plus Chemotherapy Improve Clinical Outcomes in Advanced Malignancy? A Systematic Review and Network Meta-Analysis
Authors: Yang Chao , Xu Chang , Li Xiang , Zhang Yaowen , Zhang Simeng , Zhang Tongyu , Zhang Yingshi
Published: August 2021

Purpose

Camrelizumab is a novel programmed cell death 1 (PD-1) inhibitor. To determine the efficacy and safety of the combination treatment of camrelizumab+chemotherapy and camrelizumab monotherapy, and determine which is the most suitable malignancy type to be treated with camrelizumab, we performed a systematic review and network meta-analysis.

Methods

We searched PubMed, Embase, and the Cochrane Library for published clinical trials from database inception until April 2021. Studies that compared camrelizumab+chemotherapy and camrelizumab monotherapy in patients with advanced malignancy were included. We estimated odds ratios (ORs) with credible intervals (CIs) using network meta-analysis with random effects.

Results

We included four clinical trials with 946 advanced malignancy patients. In terms of the efficacy evaluation of the objective response rate and progression-free survival, camrelizumab treatment for Hodgkin lymphoma (HL), camrelizumab treatment for esophageal squamous cell carcinoma (OSCC), and camrelizumab+chemo treatment for HL always ranked first. In terms of safety evaluation from leukocytopenia, hypothyroidism, and asthenia, camrelizumab treatment for OSCC and chemo always ranked first. This study was registered with PROSPERO, number CRD42021249193.

Conclusions

Patients with advanced OSCC should be treated with camrelizumab. Patients with severely relapsed/refractory HL could use camrelizuma+chemo for combination treatment when they can tolerate adverse reactions.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=249193, PROSPERO (identifier, CRD42021249193).