bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Low-Cost, High-Resolution Camera System for Measuring Peat Subsidence and Water Table Dynamics
Authors: Evans Chris D. , Callaghan Nathan , Jaya Adi , Grinham Alistair , Sjogersten Sofie , Page Susan E. , Harrison Mark E. , Kusin Kitso , Kho Lip Khoon , Ledger Martha , Evers Stephanie , Mitchell Zak , Williamson Jennifer , Radbourne Alan D. , Jovani-Sancho A. Jonay
Published: March 2021

Peatlands are highly dynamic systems, able to accumulate carbon over millennia under natural conditions, but susceptible to rapid subsidence and carbon loss when drained. Short-term, seasonal and long-term peat surface elevation changes are closely linked to key peatland attributes such as water table depth (WTD) and carbon balance, and may be measured remotely using satellite radar and LiDAR methods. However, field measurements of peat elevation change are spatially and temporally sparse, reliant on low-resolution manual subsidence pole measurements, or expensive sensor systems. Here we describe a novel, simple and low-cost image-based method for measuring peat surface motion and WTD using commercially available time-lapse cameras and image processing methods. Based on almost two years’ deployment of peat cameras across contrasting forested, burned, agricultural and oil palm plantation sites in Central Kalimantan, Indonesia, we show that the method can capture extremely high resolution (sub-mm) and high-frequency (sub-daily) changes in peat surface elevation over extended periods and under challenging environmental conditions. WTD measurements were of similar quality to commercially available pressure transducers. Results reveal dynamic peat elevation response to individual rain events, consistent with variations in WTD. Over the course of the relatively severe 2019 dry season, cameras in deep-drained peatlands recorded maximum peat shrinkage of over 8 cm, followed by partial rebound, leading to net annual subsidence of up to 5 cm. Sites with higher water tables, and where borehole irrigation was used to maintain soil moisture, had lower subsidence, suggesting potential to reduce subsidence through altered land-management. Given the established link between subsidence and CO2 emissions, these results have direct implications for the management of peatlands to reduce high current greenhouse gas (GHG) emissions. Camera-based sensors provide a simple, low-cost alternative to commercial elevation, WTD and GHG flux monitoring systems, suitable for deployment at scale, and in areas where existing approaches are impractical or unaffordable. If ground-based observations of peat motion can be linked to measured GHG fluxes and with satellite-based monitoring tools, this approach offers the potential for a large-scale peatland monitoring tool, suitable for identifying areas of active carbon loss, targeting climate change mitigation interventions, and evaluating intervention outcomes.
Study of Four Rainstorm Design Methods in Chongqing
Authors: Liao Daiqiang , Zhang Qiang , Wang Ying , Zhu Haonan , Sun Jia
Published: March 2021

Based on minute-by-minute precipitation data from 1961 to 2016 obtained from the National Basic Weather Station of Shapingba, Chongqing, China, the Chicago rainstorm method, the Pilgrim & Cordery (P&C) method, the Common-frequency method and the natural rainstorm moving regularity (NRMR) method were used to design short-duration (1–3 h) and long-duration (24 h) rainstorm hyetographs. Then, a standardization method for test samples was designed to ensure that each test sample was standardized and underwent an actual precipitation process. The designed rainstorm hyetographs and test samples were compared and analyzed, and the results show that the hyetographs for the 1, 3, and 24-h durations obtained with the NRMR method best represented the actual corresponding precipitation processes. The hyetograph for the 2-h duration obtained with the Chicago rainstorm method was best for the actual 2-h precipitation process. The design results of the Common-frequency method were generally good, but not outstanding. Finally, the P&C method showed a relatively poor performance for each duration.
Changes in Air Pollution Following the COVID-19 Epidemic in Northern China: The Role of Meteorology
Authors: Xian Tian , Li Zhanqing , Wei Jing
Published: March 2021

COVID-19 has a tremendous impact on both human life and the environment due to the unprecedented large-scale shutdown of economic activities at the beginning of 2020. While it was widely expected to see a dramatic reduction in air pollution, reality appears to be much more complex due to the joint influences of emissions and meteorology in dictating air pollution. By analyzing ample meteorological and environmental observational data, this study attempts to evaluate the contribution of an economic lockdown or at a well-below normal level across China to air pollution during the COVID-19 pandemic in the Beijing-Tianjin-Hebei region. Besides the unprecedented emission reductions that helped to improve air quality, multiple other factors came into play, such as high humidity and low wind speed that are favorable for haze formation. After separating long-term trends, seasonal signals, holiday effects, and meteorological contributions concerning climatology, we estimated that the relative contributions of human activities to changes in particulate matter with a diameter of less than 2.5 μm and nitrogen dioxide during the epidemic were −17.13 μg/m3 and −0.03 μg/m3, respectively, with negative quantities denoting reductions to air pollution. Furthermore, comparing the changes in PM2.5 and NO2 concentrations after lockdown revealed that for short-term control measures, meteorological factors mainly affected pollutant particles.
Nonconsumptive Predator Effects on Prey Demography: Recent Advances Using Intertidal Invertebrates
Authors: Scrosati Ricardo A.
Published: March 2021

Predators influence prey demography through consumption, but the mere presence of predators may trigger behavioural changes in prey that, if persistent or intense, may also influence prey demography. A tractable system to study such nonconsumptive effects (NCEs) of predators involves intertidal invertebrates. This mini review summarises recent research using barnacles and mussels as prey and dogwhelks as predators. The field manipulation of dogwhelk density revealed that pelagic barnacle larvae avoid benthic settlement near dogwhelks, which limits barnacle recruitment, a relevant outcome because recruitment is the only source of population replenishment for barnacles, as they are sessile. This avoidance behaviour is likely triggered by waterborne dogwhelk cues and may have evolved to limit future predation risk. Increasing densities of barnacle recruits and adults can prevent such NCEs from occurring, seemingly because benthic barnacles attract conspecific larvae through chemical cues. Barnacle recruit density increased with the abundance of coastal phytoplankton (food for barnacle larvae and recruits), so barnacle food supply seems to indirectly limit dogwhelk NCEs. By inhibiting barnacle feeding, dogwhelk cues also limited barnacle growth and reproductive output. Wave action weakens dogwhelk NCEs likely through hydrodynamic influences. Dogwhelk cues also limit mussel recruitment, as mussel larvae also exhibit predator avoidance behaviour. The NCEs on recruitment are weaker for mussels than for barnacles, possibly because mussel larvae can detach themselves after initial settlement, an ability that barnacle larvae lack. Overall, these field experiments provide evidence of predator NCEs on prey demography for coastal marine systems.
Southeast Asia as One of World’s Primary Sources of Biotic Recolonization Following Anthropocene Extinctions
Authors: Procheş Şerban , Ramdhani Syd , Hughes Alice C. , Koh Lian Pin
Published: March 2021

The plight of Southeast Asia’s animals, plants and ecosystems in the face of unsustainable exploitation and habitat destruction has been illustrated in several recent studies, despite often falling outside the global discourse on global conservation priorities. Here, we collate biogeographic and phylogenetic information to argue that this beleaguered region is one of world’s primary macrorefugia, and possibly its best chance of regaining its natural biodiversity distribution patterns after the current Anthropocene upheaval. The region uniquely combines top diversity values in (a) ancient lineage diversity and (b) cosmopolitan lineage diversity, suggesting that it has acted in the past as a biodiversity museum and source of global colonization. This is at least partly due to the interplay between latitudinal diversity gradients and continental connectivity patterns. However, the peak values in South China/North Indochina for cosmopolitan tetrapods and their sister lineages suggest that a key feature is also the availability of diverse climatic conditions. In particular, the north-south orientation of the mountain ranges here has allowed for rapid recolonization within the region following past climatic changes, resulting in high survival values and overall exceptional relict lineage diversity. From this starting point, global colonization occurred on multiple occasions. It is hoped that, with urgent action, the region can once again fulfill this function.
Past, Present, and Future of DNA Typing for Analyzing Human and Non-Human Forensic Samples
Authors: Jordan Deidra , Mills DeEtta
Published: March 2021

Forensic DNA analysis has vastly evolved since the first forensic samples were evaluated by restriction fragment length polymorphism (RFLP). Methodologies advanced from gel electrophoresis techniques to capillary electrophoresis and now to next generation sequencing (NGS). Capillary electrophoresis was and still is the standard method used in forensic analysis. However, dependent upon the information needed, there are several different techniques that can be used to type a DNA fragment. Short tandem repeat (STR) fragment analysis, Sanger sequencing, SNapShot, and capillary electrophoresis-single strand conformation polymorphism (CE-SSCP) are a few of the techniques that have been used for the genetic analysis of DNA samples. NGS is the newest and most revolutionary technology and has the potential to be the next standard for genetic analysis. This review briefly encompasses many of the techniques and applications that have been utilized for the analysis of human and nonhuman DNA samples.
Opportunities and Challenges for Improving the Productivity of Swamp Buffaloes in Southeastern Asia
Authors: Pineda Paulene S. , Flores Ester B. , Herrera Jesus Rommel V. , Low Wai Yee
Published: March 2021

The swamp buffalo is a domesticated animal commonly found in Southeast Asia. It is a highly valued agricultural animal for smallholders, but the production of this species has unfortunately declined in recent decades due to rising farm mechanization. While swamp buffalo still plays a role in farmland cultivation, this species’ purposes has shifted from draft power to meat, milk, and hide production. The current status of swamp buffaloes in Southeast Asia is still understudied compared to its counterparts such as the riverine buffaloes and cattle. This review discusses the background of swamp buffalo, with an emphasis on recent work on this species in Southeast Asia, and associated genetics and genomics work such as cytogenetic studies, phylogeny, domestication and migration, genetic sequences and resources. Recent challenges to realize the potential of this species in the agriculture industry are also discussed. Limited genetic resource for swamp buffalo has called for more genomics work to be done on this species including decoding its genome. As the economy progresses and farm mechanization increases, research and development for swamp buffaloes are focused on enhancing its productivity through understanding the genetics of agriculturally important traits. The use of genomic markers is a powerful tool to efficiently utilize the potential of this animal for food security and animal conservation. Understanding its genetics and retaining and maximizing its adaptability to harsher environments are a strategic move for food security in poorer nations in Southeast Asia in the face of climate change.
Genome-Wide Association Study Identifies New Candidate Markers for Somatic Cells Score in a Local Dairy Sheep
Authors: Sutera Anna Maria , Moscarelli Angelo , Mastrangelo Salvatore , Sardina Maria Teresa , Di Gerlando Rosalia , Portolano Baldassare , Tolone Marco
Published: March 2021

In the Mediterranean basin countries, the dairy sheep production is usually based on local breeds, which are very well-adapted to their production systems and environments and can indeed guarantee income, employment, and economic viability in areas where production alternatives are scarce or non-existent. Mastitis is still one of the greatest problems affecting commercial milk production. However, genetic evaluation of mastitis is particularly difficult because of its low heritability and the categorical nature of the trait. The aim of this study was to identify genomic regions putatively associated with somatic cells count (SCC) in the local economically important Valle del Belice sheep breed using of deregressed breeding values (DEBV) as response variables. All the samples were genotyped using the Illumina OvineSNP50K BeadChip. Genome-wide association analysis was carried out based on regression of DEBV. A total of eight markers were found to be significantly associated with log-transformed SCC. Several candidate genes associated with SCC were identified related to immunity system and udder conformation. The results can help improving the competitiveness of the local Valle del Belìce breed. Further studies considering a higher sample size or independent population will be needed to confirm our results.
Autophagy Promotes Cigarette Smoke-Initiated and Elastin-Driven Bronchitis-Like Airway Inflammation in Mice
Authors: Huang Hua-Qiong , Li Na , Li Dan-Yang , Jing Du , Liu Zheng-Yuan , Xu Xu-Chen , Chen Hai-Pin , Dong Ling-Ling , Zhang Min , Ying Song-Min , Li Wen , Shen Hua-Hao , Li Zhou-Yang , Chen Zhi-Hua
Published: March 2021

Cigarette smoke (CS)-induced macrophage activation and airway epithelial injury are both critical for the development of chronic obstructive pulmonary disease (COPD), while the eventual functions of autophagy in these processes remain controversial. We have recently developed a novel COPD mouse model which is based on the autoimmune response sensitized by CS and facilitated by elastin. In the current study, we therefore utilized this model to investigate the roles of autophagy in different stages of the development of bronchitis-like airway inflammation. Autophagic markers were increased in airway epithelium and lung tissues, and Becn+/- or Lc3b-/- mice exhibited reduced neutrophilic airway inflammation and mucus hyperproduction in this COPD mouse model. Moreover, treatment of an autophagic inhibitor 3-methyladenine (3-MA) either during CS-initiated sensitization or during elastin provocation significantly inhibited the bronchitis-like phenotypes in mice. Short CS exposure rapidly induced expression of matrix metallopeptidase 12 (MMP12) in alveolar macrophages, and treatment of doxycycline, a pan metalloproteinase inhibitor, during CS exposure effectively attenuated the ensuing elastin-induced airway inflammation in mice. CS extract triggered MMP12 expression in cultured macrophages, which was attenuated by autophagy impairment (Becn+/- or Lc3b-/-) or inhibition (3-MA or Spautin-1). These data, taken together, demonstrate that autophagy mediates both the CS-initiated MMP12 activation in macrophages and subsequent airway epithelial injury, eventually contributing to development COPD-like airway inflammation. This study reemphasizes that inhibition of autophagy as a novel therapeutic strategy for CS-induced COPD.
Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection
Authors: Lamsfus Calle Carlos , Fendel Rolf , Singh Anurag , Richie Thomas L. , Hoffman Stephen L. , Kremsner Peter G. , Mordmüller Benjamin
Published: March 2021

Malaria can cause life-threatening complications which are often associated with inflammatory reactions. More subtle, but also contributing to the burden of disease are chronic, often subclinical infections, which result in conditions like anemia and immunologic hyporesponsiveness. Although very frequent, such infections are difficult to study in endemic regions because of interaction with concurrent infections and immune responses. In particular, knowledge about mechanisms of malaria-induced immunosuppression is scarce. We measured circulating immune cells by cytometry in healthy, malaria-naïve, adult volunteers undergoing controlled human malaria infection (CHMI) with a focus on potentially immunosuppressive cells. Infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) were inoculated during two independent studies to assess malaria vaccine efficacy. Volunteers were followed daily until parasites were detected in the circulation by RT-qPCR. This allowed us to analyze immune responses during pre-patency and at very low parasite densities in malaria-naïve healthy adults. We observed a consistent increase in circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in volunteers who developed P. falciparum blood stage parasitemia. The increase was independent of preceding vaccination with a pre-erythrocytic malaria vaccine. PMN-MDSC were functional, they suppressed CD4+ and CD8+ T cell proliferation as shown by ex-vivo co-cultivation with stimulated T cells. PMN-MDSC reduced T cell proliferation upon stimulation by about 50%. Interestingly, high circulating PMN-MDSC numbers were associated with lymphocytopenia. The number of circulating regulatory T cells (Treg) and monocytic MDSC (M-MDSC) showed no significant parasitemia-dependent variation. These results highlight PMN-MDSC in the peripheral circulation as an early indicator of infection during malaria. They suppress CD4+ and CD8+ T cell proliferation in vitro. Their contribution to immunosuppression in vivo in subclinical and uncomplicated malaria will be the subject of further research. Pre-emptive antimalarial pre-treatment of vaccinees to reverse malaria-associated PMN-MDSC immunosuppression could improve vaccine response in exposed individuals.
A Requirement of Protein Geranylgeranylation for Chemokine Receptor Signaling and Th17 Cell Function in an Animal Model of Multiple Sclerosis
Authors: Swan Gregory , Geng Jia , Park Eunchong , Ding Quanquan , Zhou John , Walcott Ciana , Zhang Junyi J. , Huang Hsin-I , Hammer Gianna Elena , Wang Donghai
Published: March 2021

Precisely controlled lymphocyte migration is critically required for immune surveillance and successful immune responses. Lymphocyte migration is strictly regulated by chemokines and chemokine receptors. Here we show that protein geranylgeranylation, a form of post-translational protein lipid modification, is required for chemokine receptor-proximal signaling. Mature thymocytes deficient for protein geranylgeranylation are impaired for thymus egress. Circulating mature T cells lacking protein geranylgeranylation fail to home to secondary lymphoid organs or to transmigrate in response to chemokines in vitro. Mechanistically, protein geranylgeranylation modifies the γ-subunits of the heterotrimeric small GTPases that are essential for chemokine receptor signaling. In addition, protein geranylgeranylation also promotes the differentiation of IL-17-producing T helper cells while inhibiting the differentiation of Foxp3+ regulatory T cells. Finally, mice with T cell lineage-specific deficiency of protein geranylgeranylation are resistant to experimental autoimmune encephalomyelitis induction. This study elucidated a critical role of protein geranylgeranylation in regulating T lymphocyte migration and function.
Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Negatively Regulates Innate Immunity Against RNA Virus by Targeting RIG-I in Macrophages
Authors: Zou Ziqi , Li Mengyao , Zhou Yunlian , Li Jiaying , Pan Ting , Lai Lihua , Wang Qingqing , Zhang Lining , Wang Qun , Song Yinjing , Zhang Yuanyuan
Published: March 2021

A systematic and flexible immunoregulatory network is required to ensure the proper outcome of antiviral immune signaling and maintain homeostasis during viral infection. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been extensively studied in inflammatory response, apoptosis, and cancer. However, the function of TIPE2 in antiviral innate immunity is poorly clarified. In this study, we reported that the expression of TIPE2 declined at the early period and then climbed up in macrophages under RNA virus stimulation. Knockout of TIPE2 in the macrophages enhanced the antiviral capacity and facilitated type I interferon (IFN) signaling after RNA viral infection both in vitro and in vivo. Consistently, overexpression of TIPE2 inhibited the production of type I IFNs and pro-inflammatory cytokines, and thus promoted the viral infection. Moreover, TIPE2 restrained the activation of TBK1 and IRF3 in the retinoic acid inducible gene-I (RIG-I)-like receptors (RLR) signaling pathway by directly interacting with retinoic acid inducible gene-I (RIG-I). Taken together, our results suggested that TIPE2 suppresses the type I IFN response induced by RNA virus by targeting RIG-I and blocking the activation of downstream signaling. These findings will provide new insights to reveal the immunological function of TIPE2 and may help to develop new strategies for the clinical treatment of RNA viral infections.
Meta-Analysis: Randomized Trials of Lactobacillus plantarum on Immune Regulation Over the Last Decades
Authors: Zhao Wei , Peng Chuantao , Sakandar Hafiz Arbab , Kwok Lai-Yu , Zhang Wenyi
Published: March 2021

Lactobacillus (L.) plantarum strains, belong to lactic acid bacteria group, are considered indispensable probiotics. Here, we performed meta-analysis to evaluate the regulatory effects of L. plantarum on the immunity during clinical trials. This meta-analysis was conducted by searching across four most common literature databases, namely, Cochrane Central Register of Controlled Trials, Web of Science, Embase, and PubMed. Clinical trial articles that met the inclusion and exclusion criteria were analyzed by Review Manager (version 5.3). p-value < 0.05 of the total effect was considered statistically significant. Finally, total of 677 references were retrieved, among which six references and 18 randomized controlled trials were included in the meta-analysis. The mean differences observed at 95% confidence interval: interleukin (IL)-4, −0.48 pg/mL (−0.79 to −0.17; p < 0.05); IL-10, 9.88 pg/mL (6.52 to 13.2; p < 0.05); tumor necrosis factor (TNF)-α, −2.34 pg/mL (−3.5 to −1.19; p < 0.05); interferon (IFN)-γ, −0.99 pg/mL (−1.56 to −0.41; p < 0.05). Therefore, meta-analysis results suggested that L. plantarum could promote host immunity by regulating pro-inflammatory and anti-inflammatory cytokines.
A Systems Biology Approach Identifies B Cell Maturation Antigen (BCMA) as a Biomarker Reflecting Oral Vaccine Induced IgA Antibody Responses in Humans
Authors: Mottram Lynda , Lundgren Anna , Svennerholm Ann-Mari , Leach Susannah
Published: March 2021

Vaccines against enteric diseases could improve global health. Despite this, only a few oral vaccines are currently available for human use. One way to facilitate such vaccine development could be to identify a practical and relatively low cost biomarker assay to assess oral vaccine induced primary and memory IgA immune responses in humans. Such an IgA biomarker assay could complement antigen-specific immune response measurements, enabling more oral vaccine candidates to be tested, whilst also reducing the work and costs associated with early oral vaccine development. With this in mind, we take a holistic systems biology approach to compare the transcriptional signatures of peripheral blood mononuclear cells isolated from volunteers, who following two oral priming doses with the oral cholera vaccine Dukoral®, had either strong or no vaccine specific IgA responses. Using this bioinformatical method, we identify TNFRSF17, a gene encoding the B cell maturation antigen (BCMA), as a candidate biomarker of oral vaccine induced IgA immune responses. We then assess the ability of BCMA to reflect oral vaccine induced primary and memory IgA responses using an ELISA BCMA assay on a larger number of samples collected in clinical trials with Dukoral® and the oral enterotoxigenic Escherichia coli vaccine candidate ETVAX. We find significant correlations between levels of BCMA and vaccine antigen-specific IgA in antibodies in lymphocyte secretion (ALS) specimens, as well as with proportions of circulating plasmablasts detected by flow cytometry. Importantly, our results suggest that levels of BCMA detected early after primary mucosal vaccination may be a biomarker for induction of long-lived vaccine specific memory B cell responses, which are otherwise difficult to measure in clinical vaccine trials. In addition, we find that ALS-BCMA responses in individuals vaccinated with ETVAX plus the adjuvant double mutant heat-labile toxin (dmLT) are significantly higher than in subjects given ETVAX only. We therefore propose that as ALS-BCMA responses may reflect the total vaccine induced IgA responses to oral vaccination, this BCMA ELISA assay could also be used to estimate the total adjuvant effect on vaccine induced-antibody responses, independently of antigen specificity, further supporting the usefulness of the assay.
Insights Into Human Intrahepatic NK Cell Function From Single Cell RNA Sequencing Datasets
Authors: Jameson Gráinne , Robinson Mark W.
Published: March 2021

Diverse populations of natural killer (NK) cells have been identified in circulating peripheral blood and a wide variety of different tissues and organs. These tissue-resident NK cell populations are phenotypically distinct from circulating NK cells, however, functional descriptions of their roles within tissues are lacking. Recent advances in single cell RNA sequencing (scRNA-seq) have enabled detailed transcriptional profiling of tissues at the level of single cells and provide the opportunity to explore NK cell diversity within tissues. This review explores potential novel functions of human liver-resident (lr)NK cells identified in human liver scRNA-seq studies. By comparing these datasets we identified up-regulated and down-regulated genes associated with lrNK cells clusters. These genes encode a number of activating and inhibiting receptors, as well as signal transduction molecules, which highlight potential unique pathways that lrNK cells utilize to respond to stimuli within the human liver. This unique receptor repertoire of lrNK cells may confer the ability to regulate a number of immune cell populations, such as circulating monocytes and T cells, while avoiding activation by liver hepatocytes and Kupffer cells. Validating the expression of these receptors on lrNK cells and the proposed cellular interactions within the human liver will expand our understanding of the liver-specific homeostatic roles of this tissue-resident immune cell population.
Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation
Authors: Borges Paula Alvarenga , Waclawiak Ingrid , Georgii Janaína Lima , Fraga-Junior Vanderlei da Silva , Barros Janaína Figueiredo , Lemos Felipe Simões , Russo-Abrahão Thaís , Saraiva Elvira Maria , Takiya Christina M. , Coutinho-Silva Robson , Penido Carmen , Mermelstein Claudia , Meyer-Fernandes José Roberto , Canto Fábio B. , Neves Josiane Sabbadini , Melo Paulo A. , Canetti Claudio , Benjamim Claudia Farias
Published: March 2021

Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our aim was to better understand the pathophysiology of tissue repair in diabetes in order to find alternative strategies to accelerate wound healing. Nucleotides have been described as extracellular signaling molecules in different inflammatory processes, including tissue repair. Adenosine-5’-diphosphate (ADP) plays important roles in vascular and cellular response and is immediately released after tissue injury, mainly from platelets. However, despite the well described effect on platelet aggregation during inflammation and injury, little is known about the role of ADP on the multiple steps of tissue repair, particularly in skin wounds. Therefore, we used the full-thickness excisional wound model to evaluate the effect of local ADP application in wounds of diabetic mice. ADP accelerated cutaneous wound healing, improved new tissue formation, and increased both collagen deposition and transforming growth factor-β (TGF-β) production in the wound. These effects were mediated by P2Y12 receptor activation since they were inhibited by Clopidogrel (Clop) treatment, a P2Y12 receptor antagonist. Furthermore, P2Y1 receptor antagonist also blocked ADP-induced wound closure until day 7, suggesting its involvement early in repair process. Interestingly, ADP treatment increased the expression of P2Y12 and P2Y1 receptors in the wound. In parallel, ADP reduced reactive oxygen species (ROS) formation and tumor necrosis factor-α (TNF-α) levels, while increased IL-13 levels in the skin. Also, ADP increased the counts of neutrophils, eosinophils, mast cells, and gamma delta (γδ) T cells (Vγ4+ and Vγ5+ cells subtypes of γδ+ T cells), although reduced regulatory T (Tregs) cells in the lesion. In accordance, ADP increased fibroblast proliferation and migration, myofibroblast differentiation, and keratinocyte proliferation. In conclusion, we provide strong evidence that ADP acts as a pro-resolution mediator in diabetes-associated skin wounds and is a promising intervention target for this worldwide problem.
Thymidine Phosphorylase Is Increased in COVID-19 Patients in an Acuity-Dependent Manner
Authors: Li Wei , Yue Hong
Published: March 2021

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), is a human respiratory disease. Hitherto, there is no effective treatment has been established. Patients with cardiovascular or diabetes comorbidities are a high-risk cohort. COVID-19 is accompanied by excessive systemic thrombotic events, but the mechanism is not yet known. Recent studies have indicated that thymidine phosphorylase (TYMP) plays an important role in platelet activation, thrombosis, and TYMP expression is increased in diabetic patients. By using data provided by the MGH (Massachusetts General Hospital) Emergency Department COVID-19 Cohort with Olink Proteomics, here we show that plasma TYMP level is correlated with the COVID-19 associated thrombotic event, inflammation, and organ damage, as evidenced by the positive correlations with plasma D-dimer, CRP (C reactive protein), and LDH (lactate dehydrogenase), as well as Interferons (IFN). Plasma TYMP is also positively correlated with COVID-19 patients who had respiratory symptoms. TYMP thus could be an acuity marker for COVID-19 diagnosis. Targeting TYMP with tipiracil, a selective TYMP inhibitor, which has been approved by the Food and Drug Administration for clinical use, could be a novel effective medicine for COVID-19.
Characterization of CRN-Like Genes From Plasmopara viticola: Searching for the Most Virulent Ones
Authors: Xiang Gaoqing , Yin Xiao , Niu Weili , Chen Tingting , Liu Ruiqi , Shang Boxing , Fu Qingqing , Liu Guotian , Ma Hui , Xu Yan
Published: March 2021

Grapevine downy mildew is an insurmountable disease that endangers grapevine production and the wine industry worldwide. The causal agent of the disease is the obligate biotrophic oomycete Plasmopara viticola, for which the pathogenic mechanism remains largely unknown. Crinkling and necrosis proteins (CRN) are an ancient class of effectors utilized by pathogens, including oomycetes, that interfere with host plant defense reactions. In this study, 27 CRN-like genes were cloned from the P. viticola isolate YL genome, hereafter referred to as PvCRN genes, and characterized in silico and in planta. PvCRN genes in ‘YL’ share high sequence identities with their ortholog genes in the other three previously sequenced P. viticola isolates. Sequence divergence among the genes in the PvCRN family indicates that different PvCRN genes have different roles. Phylogenetic analysis of the PvCRN and the CRN proteins encoded by genes in the P. halstedii genome suggests that various functions might have been acquired by the CRN superfamily through independent evolution of Plasmopara species. When transiently expressed in plant cells, the PvCRN protein family shows multiple subcellular localizations. None of the cloned PvCRN proteins induced hypersensitive response (HR)-like cell death on the downy mildew-resistant grapevine Vitis riparia. This was in accordance with the result that most PvCRN proteins, except PvCRN11, failed to induce necrosis in Nicotiana benthamiana. Pattern-triggered immunity (PTI) induced by INF1 was hampered by several PvCRN proteins. In addition, 15 PvCRN proteins prevented Bax-induced plant programmed cell death. Among the cell death-suppressing members, PvCRN17, PvCRN20, and PvCRN23 were found to promote the susceptibility of N. benthamiana to Phytophthora capsici, which is a semi-biotrophic oomycete. Moreover, the nucleus-targeting member, PvCRN19, promoted the susceptibility of N. benthamiana to P. capsici. Therefore, these PvCRN proteins were estimated to be virulent effectors involved in the pathogenicity of P. viticola YL. Collectively, this study provides comprehensive insight into the CRN effector repertoire of P. viticola YL, which will help further elucidate the molecular mechanisms of the pathogenesis of grapevine downy mildew.
Switching Between Methanol Accumulation and Cell Growth by Expression Control of Methanol Dehydrogenase in Methylosinus trichosporium OB3b Mutant
Authors: Ito Hidehiro , Yoshimori Kosei , Ishikawa Masahito , Hori Katsutoshi , Kamachi Toshiaki
Published: March 2021

Methanotrophs have been used to convert methane to methanol at ambient temperature and pressure. In order to accumulate methanol using methanotrophs, methanol dehydrogenase (MDH) must be downregulated as it consumes methanol. Here, we describe a methanol production system wherein MDH expression is controlled by using methanotroph mutants. We used the MxaF knockout mutant of Methylosinus trichosporium OB3b. It could only grow with MDH (XoxF) which has a cerium ion in its active site and is only expressed by bacteria in media containing cerium ions. In the presence of 0 μM copper ion and 25 μM cerium ion, the mutant grew normally. Under conditions conducive to methanol production (10 μM copper ion and 0 μM cerium ion), cell growth was inhibited and methanol accumulated (2.6 μmol·mg−1 dry cell weight·h−1). The conversion efficiency of the accumulated methanol to the total amount of methane added to the reaction system was ~0.3%. The aforementioned conditions were repeatedly alternated by modulating the metal ion composition of the bacterial growth medium.
Molecular Evolution of Human Norovirus GII.2 Clusters
Authors: Li Xingguang , Liu Haizhou , Rife Magalis Brittany , Kosakovsky Pond Sergei L. , Volz Erik M.
Published: March 2021

Background

The human norovirus GII.2 outbreak during the 2016–2017 winter season was of unprecedented scale and geographic distribution.

Methods

We analyzed 519 complete VP1 gene sequences of the human norovirus GII.2 genotype sampled during the 2016–2017 winter season, as well as prior (dating back to 1976) from 7 countries. Phylodynamic analyses of these sequences were performed using maximum likelihood and Bayesian statistical frameworks in order to estimate viral evolutionary and population dynamics associated with the outbreak.

Results

Our results revealed an increase in the genetic diversity of human norovirus GII.2 during the recent Asian outbreak and diversification was characterized by at least eight distinct clusters. Bayesian estimation of viral population dynamics revealed a highly fluctuating effective population size, increasing in frequency during the past 15 years.

Conclusion

Despite an increasing viral diversity, we found no evidence of an elevated evolutionary rate or significant selection pressure in human norovirus GII.2, indicating viral evolutionary adaptation was not responsible for the volatility of or spread of the virus during this time.
Pathophysiological Changes in the Enteric Nervous System of Rotenone-Exposed Mice as Early Radiological Markers for Parkinson's Disease
Authors: Schaffernicht Gabriela , Shang Qi , Stievenard Alicia , Bötzel Kai , Dening Yanina , Kempe Romy , Toussaint Magali , Gündel Daniel , Kranz Mathias , Reichmann Heinz , Vanbesien-Mailliot Christel , Brust Peter , Dieterich Marianne , Funk Richard H. W. , Ravens Ursula , Pan-Montojo Francisco
Published: March 2021

Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.
Dysregulation of Ambient Glutamate and Glutamate Receptors in Epilepsy: An Astrocytic Perspective
Authors: Alcoreza Oscar B. , Patel Dipan C. , Tewari Bhanu P. , Sontheimer Harald
Published: March 2021

Given the important functions that glutamate serves in excitatory neurotransmission, understanding the regulation of glutamate in physiological and pathological states is critical to devising novel therapies to treat epilepsy. Exclusive expression of pyruvate carboxylase and glutamine synthetase in astrocytes positions astrocytes as essential regulators of glutamate in the central nervous system (CNS). Additionally, astrocytes can significantly alter the volume of the extracellular space (ECS) in the CNS due to their expression of the bi-directional water channel, aquaporin-4, which are enriched at perivascular endfeet. Rapid ECS shrinkage has been observed following epileptiform activity and can inherently concentrate ions and neurotransmitters including glutamate. This review highlights our emerging knowledge on the various potential contributions of astrocytes to epilepsy, particularly supporting the notion that astrocytes may be involved in seizure initiation via failure of homeostatic responses that lead to increased ambient glutamate. We also review the mechanisms whereby ambient glutamate can influence neuronal excitability, including via generation of the glutamate receptor subunit GluN2B-mediated slow inward currents, as well as indirectly affect neuronal excitability via actions on metabotropic glutamate receptors that can potentiate GluN2B currents and influence neuronal glutamate release probabilities. Additionally, we discuss evidence for upregulation of System xc-, a cystine/glutamate antiporter expressed on astrocytes, in epileptic tissue and changes in expression patterns of glutamate receptors.
Vitamin A, D, and E Levels and Reference Ranges for Pregnant Women: A Cross-Sectional Study 2017–2019
Authors: Gao Fan , Guo Fanfan , Zhang Yidan , Yuan Yufei , Chen Dunjin , Bai Guiqin
Published: March 2021

Background: Pregnancy-specific vitamin reference ranges are currently not available for maternal vitamin management during pregnancy. This study aimed to propose pregnancy-specific vitamin reference ranges and to investigate the factors influencing vitamin levels during pregnancy.

Methods: A cross-sectional study that included pregnant women from 17 cities in 4 provinces in western China was conducted from 2017 to 2019. A total of 119,286 subjects were enrolled in the study. Serum vitamin A, vitamin D, and vitamin E levels were measured. A multivariable linear regression model and restricted cubic spline function were used to analyze the factors related to vitamin levels.

Results: The reference ranges for vitamin A, D, and E levels were 0.22–0.62 mg/L, 5–43 ng/mL, and 7.4–23.5 mg/L, respectively. A linear relationship was found between vitamin E level and age (β = 0.004; 95% confidence interval [CI], 0.0037–0.0042; p < 0.001), and a nonlinear relationship was found between vitamin D (p nonlinear = 0.033) and vitamin A levels and age (p nonlinear < 0.001). Season, gestational trimester, and regions were related to the levels of the three vitamins in the multivariable models (p < 0.05).

Conclusions: The lower limit of vitamin A during pregnancy was the same as the reference value currently used for the general population. The reference ranges of vitamins D and E during pregnancy were lower and higher, respectively, than the currently used criteria for the general population. Vitamin A, D, and E levels differed according to age, season, gestational trimester, and region.
Can a Higher Protein/Low Glycemic Index vs. a Conventional Diet Attenuate Changes in Appetite and Gut Hormones Following Weight Loss? A 3-Year PREVIEW Sub-study
Authors: Buso Marion E.C. , Seimon Radhika V. , McClintock Sally , Muirhead Roslyn , Atkinson Fiona S. , Brodie Shannon , Dodds Jarron , Zibellini Jessica , Das Arpita , Wild-Taylor Anthony L. , Burk Jessica , Fogelholm Mikael , Raben Anne , Brand-Miller Jennie C. , Sainsbury Amanda
Published: March 2021

Background: Previous research showed that weight-reducing diets increase appetite sensations and/or circulating ghrelin concentrations for up to 36 months, with transient or enduring perturbations in circulating concentrations of the satiety hormone peptide YY.

Objective: This study assessed whether a diet that is higher in protein and low in glycemic index (GI) may attenuate these changes.

Methods: 136 adults with pre-diabetes and a body mass index of ≥25 kg/m2 underwent a 2-month weight-reducing total meal replacement diet. Participants who lost ≥8% body weight were randomized to one of two 34-month weight-maintenance diets: a higher-protein and moderate-carbohydrate (CHO) diet with low GI, or a moderate-protein and higher-CHO diet with moderate GI. Both arms involved recommendations to increase physical activity. Fasting plasma concentrations of total ghrelin and total peptide YY, and appetite sensations, were measured at 0 months (pre-weight loss), at 2 months (immediately post-weight loss), and at 6, 12, 24, and 36 months.

Results: There was a decrease in plasma peptide YY concentrations and an increase in ghrelin after the 2-month weight-reducing diet, and these values approached pre-weight-loss values by 6 and 24 months, respectively (P = 0.32 and P = 0.08, respectively, vs. 0 months). However, there were no differences between the two weight-maintenance diets. Subjective appetite sensations were not affected by the weight-reducing diet nor the weight-maintenance diets. While participants regained an average of ~50% of the weight they had lost by 36 months, the changes in ghrelin and peptide YY during the weight-reducing phase did not correlate with weight regain.

Conclusion: A higher-protein, low-GI diet for weight maintenance does not attenuate changes in ghrelin or peptide YY compared with a moderate-protein, moderate-GI diet.

Clinical Trial Registry:ClinicalTrials.gov registry ID NCT01777893 (PREVIEW) and ID NCT02030249 (Sub-study).
Clinical Utility of a Cell-Free DNA Assay in Patients With Colorectal Cancer
Authors: Chan Ren-Hao , Lin Peng-Chan , Chen Shang-Hung , Lin Shao-Chieh , Chen Po-Chuan , Lin Bo-Wen , Shen Meng-Ru , Yeh Yu-Min
Published: March 2021

The analysis of cell-free DNA (cfDNA) is rapidly emerging as a powerful approach to guide the clinical care of cancer patients. Several comprehensive cfDNA assays designed to detect mutations across several genes are now available. Here, we analyzed the use of a cfDNA panel in colorectal cancer (CRC) patients. Twenty-eight CRC patients with relapse or metastatic disease and 31 patients with no evidence of disease (NED) were enrolled. Genomic alterations in cfDNA were analyzed by the Oncomine™ Pan-Cancer Cell-Free Assay that detects hotspot mutations, small indels, copy number changes, and gene fusions across 52 genes. In the NED group, genomic alterations in cfDNA were detected in 12/31 patients (38.7%). The detection of alterations was more common in patients who were ≥60 years old, and the most common genomic alteration was a TP53 mutation. Fifty percent of the TP53 mutations were frequently or very frequently found in human cancers. Among 28 patients with relapse or metastatic disease, 22 (78.6%) had genomic alterations in cfDNA. The alterations were detected most frequently in TP53 (n = 10), followed by KRAS (n = 9). Actionable targets for CRC, including ERBB2 amplification and BRAF mutations, could be identified by this cfDNA assay. Compared with mutational profiling routinely analyzed using tumor samples, several additional targets with currently available therapies, including IDH1, IDH2, and PDGFRA mutations, were discovered. The cfDNA assay could identify potentially actionable targets for CRC. Identifying how to filter out cancer-like genomic alterations not derived from tumors remains a challenge.
MR-Guided Radiotherapy for Head and Neck Cancer: Current Developments, Perspectives, and Challenges
Authors: Boeke Simon , Mönnich David , van Timmeren Janita E. , Balermpas Panagiotis
Published: March 2021

Based on the development of new hybrid machines consisting of an MRI and a linear accelerator, magnetic resonance image guided radiotherapy (MRgRT) has revolutionized the field of adaptive treatment in recent years. Although an increasing number of studies have been published, investigating technical and clinical aspects of this technique for various indications, utilizations of MRgRT for adaptive treatment of head and neck cancer (HNC) remains in its infancy. Yet, the possible benefits of this novel technology for HNC patients, allowing for better soft-tissue delineation, intra- and interfractional treatment monitoring and more frequent plan adaptations appear more than obvious. At the same time, new technical, clinical, and logistic challenges emerge. The purpose of this article is to summarize and discuss the rationale, recent developments, and future perspectives of this promising radiotherapy modality for treating HNC.