bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-Dose Radiotherapy Leads to a Systemic Anti-Inflammatory Shift in the Pre-Clinical K/BxN Serum Transfer Model and Reduces Osteoarthritic Pain in Patients
Authors: Weissmann Thomas , Rückert Michael , Zhou Jian-Guo , Seeling Michaela , Lettmaier Sebastian , Donaubauer Anna-Jasmina , Nimmerjahn Falk , Ott Oliver J. , Hecht Markus , Putz Florian , Fietkau Rainer , Frey Benjamin , Gaipl Udo S. , Deloch Lisa
Published: January 2022

Osteoarthritis (OA) is the leading degenerative joint disease in the western world and leads, if left untreated, to a progressive deterioration of joint functionality, ultimately reducing quality of life. Recent data has shown, that especially OA of the ankle and foot are among the most frequently affected regions. Current research in OA points towards a complex involvement of various cell and tissue types, often accompanied by inflammation. Low-dose radiotherapy (LDRT) is widely used for the treatment of degenerative and inflammatory diseases. While the reported analgesic effects are well known, the underlying molecular mechanisms are only poorly understood. We therefore correlated a clinical approach, looking at pain reduction in 196 patients treated with LDRT with a pre-clinical approach, utilizing the K/BxN serum transfer mouse model using flow cytometry and multiplex ELISA for analysis. While an improvement of symptoms in the majority of patients was found, patients suffering from symptoms within the tarsi transversa show a significantly lower level of improvement. Further, a significant impact of therapy success was detected depending on whether only one or both feet were affected. Further, patients of younger age showed a significantly better outcome than older ones while needing fewer treatment series. When looking on a cellular level within the mouse model, a systemic alteration of immune cells namely a shift from CD8+ to CD4+ T cells and reduced numbers of DCs was observed. A general reduction of inflammatory cytokines was detected, with significant alterations in IL-4 and IL-17 levels, all of which could potentially be responsible for the highly effective clinical improvement in patients. Taken together our data indicate that LDRT can be regarded as a highly effective treatment option for patients suffering from OA of the foot and ankle, in terms of analgesic effects, especially in younger patients. Furthermore, the observed effects are mediated by an interplay of cellular and soluble immune factors, as observed in the K/BxN serum transfer model. With this interdisciplinary approach we aim to encourage the usage of LDRT as an additive treatment strategy not only as a last resort, but also earlier in the course of disease.
Modulation of IL-6 Expression by KLF4-Mediated Transactivation and PCAF-Mediated Acetylation in Sublytic C5b-9-Induced Rat Glomerular Mesangial Cells
Authors: Xia Lu , Liu Yu , Zhang Zhiwei , Gong Yajuan , Yu Tianyi , Zhao Dan , Qiu Wen , Wang Yingwei , Zhang Jing
Published: January 2022

Interleukin-6 (IL-6) overproduction has been considered to contribute to inflammatory damage of glomerular mesangial cells (GMCs) in human mesangial proliferative glomerulonephritis (MsPGN) and its rat model called Thy-1 nephritis (Thy-1N). However, the regulatory mechanisms of IL-6 expression in GMCs upon sublytic C5b-9 timulation remain poorly understood. We found that Krüppel-like factor 4 (KLF4) bound to the IL-6 promoter (−618 to −126 nt) and activated IL-6 gene transcription. Furthermore, lysine residue 224 of KLF4 was acetylated by p300/CBP-associated factor (PCAF), which was important for KLF4-mediated transactivation. Moreover, lysine residue 5 on histone H2B and lysine residue 9 on histone H3 at the IL-6 promoter were also acetylated by PCAF, which resulted in an increase in IL-6 transcription. Besides, NF-κB activation promoted IL-6 expression by elevating the expression of PCAF. Overall, these findings suggest that sublytic C5b-9-induced the expression of IL-6 involves KLF4-mediated transactivation, PCAF-mediated acetylation of KLF4 and histones, and NF-κB activation in GMCs.
Transcriptome Analysis of Atlantic Salmon (Salmo salar) Skin in Response to Sea Lice and Infectious Salmon Anemia Virus Co-Infection Under Different Experimental Functional Diets
Authors: Cai Wenlong , Kumar Surendra , Navaneethaiyer Umasuthan , Caballero-Solares Albert , Carvalho Laura A. , Whyte Shona K. , Purcell Sara L. , Gagne Nellie , Hori Tiago S. , Allen Melissa , Taylor Richard G. , Balder Rachel , Parrish Christopher C. , Rise Matthew L. , Fast Mark D.
Published: January 2022

Sea lice (Lepeophtheirus salmonis) are ectoparasitic copepods that cause significant economic loss in marine salmoniculture. In commercial salmon farms, infestation with sea lice can enhance susceptibility to other significant pathogens, such as the highly contagious infectious salmon anemia virus (ISAv). In this study, transcriptomic analysis was used to evaluate the impact of four experimental functional feeds (i.e. 0.3% EPA/DHA+high-ω6, 0.3% EPA/DHA+high-ω6+immunostimulant (IS), 1% EPA/DHA+high-ω6, and 1% EPA/DHA+high-ω3) on Atlantic salmon (Salmo salar) during a single infection with sea lice (L. salmonis) and a co-infection with sea lice and ISAv. The overall objectives were to compare the transcriptomic profiles of skin between lice infection alone with co-infection groups and assess differences in gene expression response among animals with different experimental diets. Atlantic salmon smolts were challenged with L. salmonis following a 28-day feeding trial. Fish were then challenged with ISAv at 18 days post-sea lice infection (dpi), and maintained on individual diets, to establish a co-infection model. Skin tissues sampled at 33 dpi were subjected to RNA-seq analysis. The co-infection’s overall survival rates were between 37%-50%, while no mortality was observed in the single infection with lice. With regard to the infection status, 756 and 1303 consensus differentially expressed genes (DEGs) among the four diets were identified in “lice infection vs. pre-infection” and “co-infection vs. pre-infection” groups, respectively, that were shared between the four experimental diets. The co-infection groups (co-infection vs. pre-infection) included up-regulated genes associated with glycolysis, the interferon pathway, complement cascade activity, and heat shock protein family, while the down-regulated genes were related to antigen presentation and processing, T-cell activation, collagen formation, and extracellular matrix. Pathway enrichment analysis conducted between infected groups (lice infection vs. co-infection) resulted in several immune-related significant GO terms and pathways unique to this group, such as “autophagosome”, “cytosolic DNA-sensing pathway” and “response to type I interferons”. Understanding how experimental functional feeds can impact the host response and the trajectory of co-infections will be an essential step in identifying efficacious intervention strategies that account for the complexities of disease in open cage culture.
Spatial and Temporal Heterogeneity of Tumor-Infiltrating Lymphocytes in Advanced Urothelial Cancer
Authors: van Wilpe Sandra , Gorris Mark A. J. , van der Woude Lieke L. , Sultan Shabaz , Koornstra Rutger H. T. , van der Heijden Antoine G. , Gerritsen Winald R. , Simons Michiel , de Vries I. Jolanda M. , Mehra Niven
Published: January 2022

Checkpoint inhibitors targeting PD-(L)1 induce objective responses in 20% of patients with metastatic urothelial cancer (UC). CD8+ T cell infiltration has been proposed as a putative biomarker for response to checkpoint inhibitors. Nevertheless, data on spatial and temporal heterogeneity of tumor-infiltrating lymphocytes in advanced UC are lacking. The major aims of this study were to explore spatial heterogeneity for lymphocyte infiltration and to investigate how the immune landscape changes during the disease course. We performed multiplex immunohistochemistry to assess the density of intratumoral and stromal CD3+, CD8+, FoxP3+ and CD20+ immune cells in longitudinally collected samples of 49 UC patients. Within these samples, spatial heterogeneity for lymphocyte infiltration was observed. Regions the size of a 0.6 tissue microarray core (0.28 mm2) provided a representative sample in 60.6 to 71.6% of cases, depending on the cell type of interest. Regions of 3.30 mm2, the median tumor surface area in our biopsies, were representative in 58.8 to 73.8% of cases. Immune cell densities did not significantly differ between untreated primary tumors and metachronous distant metastases. Interestingly, CD3+, CD8+ and FoxP3+ T cell densities decreased during chemotherapy in two small cohorts of patients treated with neoadjuvant or palliative platinum-based chemotherapy. In conclusion, spatial heterogeneity in advanced UC challenges the use of immune cell infiltration in biopsies as biomarker for response prediction. Our data also suggests a decrease in tumor-infiltrating T cells during platinum-based chemotherapy.
Numerical Flow Modeling of Artificial Ocean Upwelling
Authors: Kemper Jost , Riebesell Ulf , Graf Kai
Published: January 2022

Artificial Upwelling (AU) of nutrient-rich Deep Ocean Water (DOW) to the ocean's sunlit surface layer has recently been put forward as a means of increasing marine CO2 sequestration and fish production. AU and its possible benefits have been studied in the context of climate change mitigation as well as food security for a growing human population. However, extensive research still needs to be done into the feasibility, effectiveness and potential risks, and side effects associated with AU to be able to better predict its potential. Fluid dynamic modeling of the AU process and the corresponding inorganic nutrient transport can provide necessary information for a better quantification of the environmental impacts of specific AU devices and represents a valuable tool for their optimization. Yet, appropriate capture of all flow phenomena relevant to the AU process remains a challenging task that only few models are able to accomplish. In this paper, simulation results obtained with a newly developed numerical solution method are presented. The method is based on the open-source modeling environment OpenFOAM. It solves the unsteady Reynolds-Averaged Navier-Stokes (RANS) equations with additional transport equations for energy, salinity, and inorganic nutrients. The method aims to be widely applicable to oceanic flow problems including temperature- and salinity-induced density stratification and passive scalar transport. The studies presented in this paper concentrate on the direct effects of the AU process on nutrient spread and concentration in the ocean's mixed surface layer. Expected flow phenomena are found to be captured well by the new method. While it is a known problem that cold DOW that is upwelled to the surface tends to sink down again due to its high density, the simulations presented in this paper show that the upwelled DOW settles at the lower boundary of the oceans mixed surface layer, thus keeping a considerable portion of the upwelled nutrients available for primary production. Comparative studies of several design variants, with the aim of maximizing the amount of nutrients that is retained inside the mixed surface layer, are also presented and analyzed.
Mechanical Properties and Deformation Mechanisms of Heterostructured High-Entropy and Medium-Entropy Alloys: A Review
Authors: Jiang Wei , Zhu Yuntian , Zhao Yonghao
Published: January 2022

Recently, heterostructured (HS) materials, consisting of hard and soft zones with dramatically different strengths, have been developed and received extensive attention because they have been reported to exhibit superior mechanical properties over those predicted by the rule of mixtures. Due to the accumulation of geometrically necessary dislocations during plastic deformation, a back stress is developed in the soft zones to increase the yield strength of HS materials, which also induce forward stress in the hard zones, and a global hetero-deformation induced (HDI) hardening to retain ductility. High-entropy alloys (HEAs) and medium-entropy alloys (MEAs) or multicomponent alloys usually contain three or more principal elements in near-equal atomic ratios and have been widely studied in the world. This review paper first introduces concepts of HS materials and HEAs/MEAs, respectively, and then reviewed emphatically the mechanical properties and deformation mechanisms of HS HEAs/MEAs. Finally, we discuss the prospect for industrial applications of the HS HEAs and MEAs.
Asymmetry Thermal Analyses of Self-Supporting Friction Stir Welding
Authors: Li Zenglou , Li Chong , Li Shuohan , Yin Demeng , Qi Zhenguo , Tian Yalin
Published: January 2022

Due to the inherent issue of requiring rigid back support, friction stir welding (FSW) has serious limitations for the welding of hollow structures. Self-supporting friction stir welding was proposed to join hollow aluminum extrusions, which could reduce the hindrance of the welding tool and the requirement of rigid back support. In this paper, finite element modeling analyses were carried out for the asymmetric temperature field in the process of self-supporting FSW. The peak temperature of the stir zone appeared in the upper shoulder affected zone, followed by the lower shoulder affected zone. In the upper shoulder affected zone, a peak temperature was not shown at the center of the curve due to the positive correlation between heat generation and radius and different heat dissipation rates. Considering the influence of thermal input and rotation speed on joint formation, 200 mm/min travel speed and 800 rpm rotation speed are the most proper parameters for 5-mm-thick 6082-T6 aluminum alloy self-supporting FSW butt welds.
Dysregulated Cell Signaling in Pulmonary Emphysema
Authors: Lin Chih-Ru , Bahmed Karim , Kosmider Beata
Published: January 2022

Pulmonary emphysema is characterized by the destruction of alveolar septa and irreversible airflow limitation. Cigarette smoking is the primary cause of this disease development. It induces oxidative stress and disturbs lung physiology and tissue homeostasis. Alveolar type II (ATII) cells have stem cell potential and can repair the denuded epithelium after injury; however, their dysfunction is evident in emphysema. There is no effective treatment available for this disease. Challenges in this field involve the large complexity of lung pathophysiological processes and gaps in our knowledge on the mechanisms of emphysema progression. It implicates dysregulation of various signaling pathways, including aberrant inflammatory and oxidative responses, defective antioxidant defense system, surfactant dysfunction, altered proteostasis, disrupted circadian rhythms, mitochondrial damage, increased cell senescence, apoptosis, and abnormal proliferation and differentiation. Also, genetic predispositions are involved in this disease development. Here, we comprehensively review studies regarding dysregulated cell signaling, especially in ATII cells, and their contribution to alveolar wall destruction in emphysema. Relevant preclinical and clinical interventions are also described.
Ruptured Emphysematous Prostatic Abscess Caused by K1-ST23 Hypervirulent Klebsiella pneumoniae Presenting as Brain Abscesses: A Case Report and Literature Review
Authors: Konagaya Kensuke , Yamamoto Hiroyuki , Suda Tomoyuki , Tsuda Yusuke , Isogai Jun , Murayama Hiroyuki , Arakawa Yoshichika , Ogino Hidemitsu
Published: January 2022

Emphysematous prostatic abscess (EPA) is an extremely rare but potentially fatal urinary tract infection (UTI). Here, we describe a case (a 69-year-old male with prediabetes) of ruptured EPA caused by a hypervirulent Klebsiella pneumoniae (hvKp) K1-ST23 strain, presenting as motor aphasia. Our patient presented with ruptured EPA concurrent with various severe systemic pyogenic complications (e.g., urethro-prostatic fistula, ascending UTIs, epididymal and scrotal abscesses, and liver, lung, and brain abscesses). Whole-body computed tomography (CT) and next-generation sequencing (NGS) were useful for the detection of ruptured EPA and its systemic complications, and for identification of K1-ST23 hvKp strains, respectively. Subsequently, the infections were successfully treated with aggressive antimicrobial therapy and multiple surgical procedures. This case highlights the significance of awareness of this rare entity, the clinical importance of CT for the early diagnosis of EPA and the detection of its systemic complications in view of hvKp being an important causative organism of severe community-acquired UTI, and the usefulness of NGS to identify hvKp strains.
Favorable Outcomes of Anticoagulation With Unfractioned Heparin in Sepsis-Induced Coagulopathy: A Retrospective Analysis of MIMIC-III Database
Authors: Peng Jiang-Chen , Nie Fang , Li Yu-Jie , Xu Qiao-Yi , Xing Shun-Peng , Li Wen , Gao Yuan
Published: January 2022

Backgrounds: Anticoagulation in sepsis-associated disseminated intravascular coagulation (DIC) remains uncertain. The aim of this study was to investigate whether unfractioned heparin (UFH) could improve clinical outcomes in patients with sepsis-induced coagulopathy (SIC).

Methods: Septic patients with SIC were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Cox-proportional hazards model, logistic regression model and linear regression were used to assess the associations between UFH administration and 28-day mortality, hospital mortality, occurrence of bleeding complications and length of stay, respectively. Propensity score matching (PSM) analysis was used to match the imbalance between patients in the UFH group and the control group. Patients were further stratified according to SIC score and Simplified Acute Physiology Score II (SAPS II).

Results: A total of 1,820 septic patients with SIC were included in the data analysis. After PSM, 652 pairs of patients were matched between the patients in the UFH group and the control group. UFH was significantly associated with reduced 28-day mortality (HR, 0.323, 95% CI, 0.258–0.406; p < 0.001) and hospital mortality (HR, 0.380, 95% CI, 0.307–0.472; p < 0.001) without increasing the risks of intracranial hemorrhage (OR, 1.480, 95% CI, 0.955–2.294; p = 0.080) or gastrointestinal bleeding (OR, 1.094, 95% CI, 0.503–2.382; p = 0.820). For subgroup analysis, it didn't change the favorable results of UFH on mortality and UFH didn't increase the risk of hemorrhage in patients with severe disease.

Conclusions: The analysis of MIMIC-III database indicated that anticoagulant therapy with UFH may be associated with a survival benefit in patients with SIC.
The Model for End-Stage Liver Disease Score and the Follow-Up Period Can Cause the Shift of Circulating Lymphocyte Subsets in Liver Transplant Recipients
Authors: Pan Fei , Cao Shuang , Li Xian-Liang , Jia Ya-nan , Wang Ruo-lin , He Qiang , Zhu Ji-Qiao
Published: January 2022

Little is known about the shift of lymphocytes under the condition of the model for end-stage liver disease score and the follow-up period. Then, we detected the peripheral blood from liver transplant recipients by flow cytometry and compared the results. The model for end-stage liver disease score affected the percentages of T-cell subsets and B cells during the short-term follow-up period, but failed to influence the lymphocyte subsets during the long-term follow-up period. In contrast, the follow-up period not only affected the absolute counts of T-cell subsets and natural killer (NK) cells in patients with the low model for end-stage liver disease scores, but also influenced the percentages and absolute counts of T-cell subsets in patients with the high model for end-stage liver disease scores. In the two-way ANOVA, we further revealed that the model for end-stage liver disease score was associated with the percentages of T cells and CD4+ T cells and the absolute numbers of T-cell subsets and B cells, while the follow-up period was associated with the percentages of T-cell subsets and the absolute numbers of lymphocyte subsets. Therefore, patients with either the low model for end-stage liver disease scores or the long-term follow-up period are in a relatively activated immune condition.
Trajectories of Vital Signs and Risk of In-Hospital Cardiac Arrest
Authors: Tsai Chu-Lin , Lu Tsung-Chien , Wang Chih-Hung , Fang Cheng-Chung , Chen Wen-Jone , Huang Chien-Hua
Published: January 2022

Background: Little is known about the trajectories of vital signs prior to in-hospital cardiac arrest (IHCA), which could explain the heterogeneous processes preceding this event. We aimed to identify clinically relevant subphenotypes at high risk of IHCA in the emergency department (ED).

Methods: This retrospective cohort study used electronic clinical warehouse data from a tertiary medical center. We retrieved data from 733,398 ED visits over a 7-year period. We selected one ED visit per person and retrieved patient demographics, triage data, vital signs (systolic blood pressure [SBP], heart rate [HR], body temperature, respiratory rate, oxygen saturation), selected laboratory markers, and IHCA status. Group-based trajectory modeling was performed.

Results: There were 37,697 adult ED patients with a total of 1,507,121 data points across all vital-sign categories. Three to four trajectory groups per vital-sign category were identified, and the following five trajectory groups were associated with a higher rate of IHCA: low and fluctuating SBP, high and fluctuating HR, persistent hypothermia, recurring tachypnea, and low and fluctuating oxygen saturation. The IHCA-prone trajectory group was associated with a higher triage level and a higher mortality rate, compared to other trajectory groups. Except for the persistent hypothermia group, the other four trajectory groups were more likely to have higher levels of C-reactive protein, lactic acid, cardiac troponin I, and D-dimer. Multivariable analysis revealed that hypothermia (adjusted odds ratio [aOR], 2.20; 95% confidence interval [95%CI], 1.35–3.57) and recurring tachypnea (aOR 2.44; 95%CI, 1.24–4.79) were independently associated with IHCA.

Conclusions: We identified five novel vital-sign sub-phenotypes associated with a higher likelihood of IHCA, with distinct patterns in clinical course and laboratory markers. A better understanding of the pre-IHCA vital-sign trajectories may help with the early identification of deteriorating patients.
Exercise-Induced Bronchoconstriction in Children
Authors: Klain Angela , Indolfi Cristiana , Dinardo Giulio , Contieri Marcella , Decimo Fabio , Miraglia Del Giudice Michele
Published: January 2022

Exercise-induced bronchoconstriction (EIB) is a transient airflow obstruction, typically 5–15 min after physical activity. The pathophysiology of EIB is related to the thermal and osmotic changes of the bronchial mucosa, which cause the release of mediators and the development of bronchoconstriction in the airways. EIB in children often causes an important limitation to physical activities and sports. However, by taking appropriate precautions and through adequate pharmacological control of the condition, routine exercise is extremely safe in children. This review aims to raise awareness of EIB by proposing an update, based on the latest studies, on pathological mechanisms, diagnosis, and therapeutic approaches in children.
Crossing Treeline: Bacterioplankton Communities of Alpine and Subalpine Rocky Mountain Lakes
Authors: Vincent Kim , Holland-Moritz Hannah , Solon Adam J. , Gendron Eli M. S. , Schmidt Steven K.
Published: January 2022

From the aboveground vegetation to the belowground microbes, terrestrial communities differ between the highly divergent alpine (above treeline) and subalpine (below treeline) ecosystems. Yet, much less is known about the partitioning of microbial communities between alpine and subalpine lakes. Our goal was to determine whether the composition of bacterioplankton communities of high-elevation mountain lakes differed across treeline, identify key players in driving the community composition, and identify potential environmental factors that may be driving differences. To do so, we compared bacterial community composition (using 16S rDNA sequencing) of alpine and subalpine lakes in the Southern Rocky Mountain ecoregion at two time points: once in the early summer and once in the late summer. In the early summer (July), shortly after peak runoff, bacterial communities of alpine lakes were distinct from subalpine lakes. Interestingly, by the end of the summer (approximately 5 weeks after the first visit in August), bacterial communities of alpine and subalpine lakes were no longer distinct. Several bacterial amplicon sequence variants (ASVs) were also identified as key players by significantly contributing to the community dissimilarity. The community divergence across treeline found in the early summer was correlated with several environmental factors, including dissolved organic carbon (DOC), pH, chlorophyll-a (chl-a), and total dissolved nitrogen (TDN). In this paper, we offer several potential scenarios driven by both biotic and abiotic factors that could lead to the observed patterns. While the mechanisms for these patterns are yet to be determined, the community dissimilarity in the early summer correlates with the timing of increased hydrologic connections with the terrestrial environment. Springtime snowmelt brings the flushing of mountain watersheds that connects terrestrial and aquatic ecosystems. This connectivity declines precipitously throughout the summer after snowmelt is complete. Regional climate change is predicted to bring alterations to precipitation and snowpack, which can modify the flushing of solutes, nutrients, and terrestrial microbes into lakes. Future preservation of the unique alpine lake ecosystem is dependent on a better understanding of ecosystem partitioning across treeline and careful consideration of terrestrial-aquatic connections in mountain watersheds.
Bacterial Communities and Prediction of Microbial Metabolic Pathway in Rice Wine Koji From Different Regions in China
Authors: Zhao Xinxin , Xiang Fanshu , Tang Fengxian , Cai Wenchao , Guo Zhuang , Hou Qiangchuan , Yang Xinquan , Song Wen , Shan Chunhui
Published: January 2022

Rice wine koji, a traditional homemade starter culture in China, is nutritious and delicious. The final quality of rice wine koji is closely related to the structure of its microbial community. However, the diversity of natural microorganisms in rice wine koji from different regions has not been evaluated. In this study, the microbial population of 92 naturally fermented rice koji samples collected from Hubei, Guangxi, and Sichuan was systematically analyzed by high-throughput sequencing. From all the rice wine koji samples, 22 phyla and 479 bacterial genera were identified. Weissella, Pediococcus, Lactobacillus, Enterobacter, Lactococcus, Pantoea, Bacillus, Staphylococcus, and Leuconostoc were the dominant genera in rice wine koji. The bacterial community structure of rice wine koji samples from different regions was significantly different (p < 0.05). The bacterial community composition of the samples from Hubei and Guangxi was similar, but significantly different from that of SC samples (p < 0.05). These differences may be caused by variations in geography, environment, or manufacturing. In addition, the results of microbial phenotype prediction by BugBase and bacterial functional potential prediction by PICRUSt showed that eight of the nine predicted phenotypic functions of rice wine koji samples from different regions were significantly different (p < 0.05) and that vigorous bacterial metabolism occurred in rice wine koji samples.
Cover Crop Species Composition Alters the Soil Bacterial Community in a Continuous Pepper Cropping System
Authors: Gao Huan , Tian Gangming , Khashi u Rahman Muhammad , Wu Fengzhi
Published: January 2022

Cover crops can improve soil biological health and alter the composition of soil microbial communities in agricultural systems. However, the effects of diversified cover crops on soil microbial communities in continuous cropping systems are unclear. Here, using different soil biochemical analysis, quantitative PCR and 16S rRNA amplicon sequencing, we investigated the effects of cover crops, alone or in mixture, on soil physicochemical properties in 2019 and 2020, and soil bacterial communities in 2020 in a continuous pepper cropping system. A field trial was established before pepper planting and eight treatments were included: fallow (no cover crop; CK); three sole cover crop treatments: wheat (Triticum aestivum L.; W), faba bean (Vicia faba L.; B), and wild rocket (Diplotaxis tenuifolia; R); and four mixed treatments: wheat + wild rocket (WR), wheat + faba bean (WB), wild rocket + faba bean (RB), and wheat + wild rocket + faba bean (WRB). The pepper yield was increased in the WR and WB in 2019 and 2020, and in the WRB in 2020. Cover crops increased the soil pH, but decreased the concentrations of NH4+ and available phosphorus. Bacterial abundance was increased by cover crop treatments, and community structure was altered in the W, WB, and WRB treatments. Moreover, we found that pH was the key factor associated with the changes in the abundance and structure of the bacterial community. Cover crop treatments altered the bacterial community structure with shifts in the dominant genera, which have plant-growth-promoting and/or pathogen-antagonistic potentials, e.g., increased the abundances of Streptomyces, Arthrobacter, and Bacillus spp. in the W and WRB, and Gaiella spp. in the WB. Overall, we found that cover crops altered the soil physicochemical properties and bacterial community, and these changes varied with species composition of the cover crops, with wheat and its combination with legumes as most effective treatments. These results suggest that the diversification within cover crops could provide better crop yield stimulatory affects by altering soil biochemical environment.
Mesenchymal Stem Cell-Derived Exosome Therapy of Microbial Diseases: From Bench to Bed
Authors: Wu Xiaolan , Jin Shanshan , Ding Chengye , Wang Yu , He Danqing , Liu Yan
Published: January 2022

Microbial diseases are a global health threat, leading to tremendous casualties and economic losses. The strategy to treat microbial diseases falls into two broad categories: pathogen-directed therapy (PDT) and host-directed therapy (HDT). As the typical PDT, antibiotics or antiviral drugs directly attack bacteria or viruses through discerning specific molecules. However, drug abuse could result in antimicrobial resistance and increase infectious disease morbidity. Recently, the exosome therapy, as a HDT, has attracted extensive attentions for its potential in limiting infectious complications and targeted drug delivery. Mesenchymal stem cell-derived exosomes (MSC-Exos) are the most broadly investigated. In this review, we mainly focus on the development and recent advances of the application of MSC-Exos on microbial diseases. The review starts with the difficulties and current strategies in antimicrobial treatments, followed by a comprehensive overview of exosomes in aspect of isolation, identification, contents, and applications. Then, the underlying mechanisms of the MSC-Exo therapy in microbial diseases are discussed in depth, mainly including immunomodulation, repression of excessive inflammation, and promotion of tissue regeneration. In addition, we highlight the latest progress in the clinical translation of the MSC-Exo therapy, by summarizing related clinical trials, routes of administration, and exosome modifications. This review will provide fundamental insights and future perspectives on MSC-Exo therapy in microbial diseases from bench to bedside.
Conservation of Differential Animal MicroRNA Processing by Drosha and Dicer
Authors: Zhang Xiaoxiao , Yang Fanming , Liu Fanzou , Tian Qiuhuan , Hu Min , Li Peng , Zeng Yan
Published: January 2022

In complex biochemical systems, an enzyme, protein, or RNA, symbolized as E, has hundreds or thousands of substrates or interacting partners. The relative specificity hypothesis proposes that such an E would differentially interact with and influence its many distinct, downstream substrates, thereby regulating the underlying biological process (es). The importance of relative specificity has been underappreciated, and evidence of its physiological consequences particularly lacking. Previously we showed that human Drosha and Dicer ribonucleases (RNases) both discriminate their respective microRNA (miRNA) substrates, and that differential cleavage by Drosha contributes to global differential miRNA expression. If relative specificity is an important biological mechanism, it should be evolutionarily conserved. To test this hypothesis, we hereby examined the cleavage of hundreds of zebrafish and fruitfly miRNA intermediates by Drosha and Dicer and the impact on miRNA biogenesis in these organisms. We showed that Drosha action regulates differential miRNA expression in zebrafish and fruitflies and identified the conserved secondary structure features and sequences in miRNA transcripts that control Drosha activity and miRNA expression. Our results established the conservation of miRNA processing mechanisms and regulatory functions by Drosha and Dicer, greatly strengthened the evidence for the physiological consequences of relative specificity as well as demonstrated its evolutionary significance.
A Review on the Role of miR-1246 in the Pathoetiology of Different Cancers
Authors: Ghafouri-Fard Soudeh , Khoshbakht Tayyebeh , Hussen Bashdar Mahmud , Taheri Mohammad , Samadian Mohammad
Published: January 2022

miR-1246 is a microRNA firstly recognized through application of a high throughput sequencing technique in human embryonic stem cells. Subsequent studies have shown the role of this microRNA in the carcinogenesis. miR-1246 has been found to exert oncogenic roles in colorectal, breast, renal, oral, laryngeal, pancreatic and ovarian cancers as well as melanoma and glioma. In lung, cervical and liver cancers, studies have reported contradictory results regarding the role of miR-1246. miR-1246 has been reported to regulate activity of RAF/MEK/ERK, GSK3β, Wnt/β-catenin, JAK/STAT, PI3K/AKT, THBS2/MMP and NOTCH2 pathways. In addition to affecting cell cycle progression and proliferation, miR-1246 can influence stemness and resistance of cancer cells to therapeutics. In the current review, we describe the summary of in vitro and in vivo studies about the influence of miR-1246 in carcinogenesis in addition to studies that measured expression levels of miR-1246 in clinical samples.
miR-3587 Inhibitor Attenuates Ferroptosis Following Renal Ischemia-Reperfusion Through HO-1
Authors: Tao Wenqiang , Liu Fen , Zhang Jianguo , Fu Shangmiao , Zhan Hui , Qian Kejian
Published: January 2022

Renal ischemia-reperfusion (IR) is frequently observed in patients who are critically ill, yet there are no reliable or effective approaches for the treatment of this condition. Ferroptosis, a form of programmed cell death, is regulated by key genes such as glutathione peroxidase 4 (GPX4) and heme oxygenase-1 (HMOX1) and participates in the injury of renal tubular epithelial cells during IR. This study aimed to investigate the miRNA-mRNA regulatory networks involved in ferroptosis following renal IR. Using bioinformatics analysis, HMOX1 was found to be significantly upregulated during the early stages of renal IR injury, and microRNA-3587 (miR-3587) was identified as a putative regulator of HMOX1. When a miR-3587 inhibitor was applied in a hypoxia-reoxygenation (HR) model system using renal tubular epithelial cells, HO-1 protein (encoded by HMOX1) expression was significantly increased relative to that observed in the HR group, with concomitant increases in GPX4 protein levels, enhanced cell viability, a reduction in malondialdehyde content, decreased Fe2+ level, and the restoration of normal mitochondrial membrane potential. Transmission electron microscopy showed a reduced or absent mitochondrial crest and a damaged mitochondrial outer membrane. Targeting of HMOX1 by miR-3587 was confirmed by luciferase reporter gene assay. In conclusion, these preliminary results indicate that inhibition of miR-3587 promotes HO-1 upregulation, thereby protecting renal tissues from IR-induced ferroptosis.
The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I
Authors: Padavannil Abhilash , Ayala-Hernandez Maria G. , Castellanos-Silva Eimy A. , Letts James A.
Published: January 2022

Complex I (CI) is the largest protein complex in the mitochondrial oxidative phosphorylation electron transport chain of the inner mitochondrial membrane and plays a key role in the transport of electrons from reduced substrates to molecular oxygen. CI is composed of 14 core subunits that are conserved across species and an increasing number of accessory subunits from bacteria to mammals. The fact that adding accessory subunits incurs costs of protein production and import suggests that these subunits play important physiological roles. Accordingly, knockout studies have demonstrated that accessory subunits are essential for CI assembly and function. Furthermore, clinical studies have shown that amino acid substitutions in accessory subunits lead to several debilitating and fatal CI deficiencies. Nevertheless, the specific roles of CI’s accessory subunits have remained mysterious. In this review, we explore the possible roles of each of mammalian CI’s 31 accessory subunits by integrating recent high-resolution CI structures with knockout, assembly, and clinical studies. Thus, we develop a framework of experimentally testable hypotheses for the function of the accessory subunits. We believe that this framework will provide inroads towards the complete understanding of mitochondrial CI physiology and help to develop strategies for the treatment of CI deficiencies.
2-Sulfonylpyrimidines as Privileged Warheads for the Development of S. aureus Sortase A Inhibitors
Authors: Barthels Fabian , Meyr Jessica , Hammerschmidt Stefan J. , Marciniak Tessa , Räder Hans-Joachim , Ziebuhr Wilma , Engels Bernd , Schirmeister Tanja
Published: January 2022

Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar KI values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the SNAr reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog.
Brain Imaging Biomarkers for Chronic Pain
Authors: Zhang Zhengwu , Gewandter Jennifer S. , Geha Paul
Published: January 2022

The prevalence of chronic pain has reached epidemic levels. In addition to personal suffering chronic pain is associated with psychiatric and medical co-morbidities, notably substance misuse, and a huge a societal cost amounting to hundreds of billions of dollars annually in medical cost, lost wages, and productivity. Chronic pain does not have a cure or quantitative diagnostic or prognostic tools. In this manuscript we provide evidence that this situation is about to change. We first start by summarizing our current understanding of the role of the brain in the pathogenesis of chronic pain. We particularly focus on the concept of learning in the emergence of chronic pain, and the implication of the limbic brain circuitry and dopaminergic signaling, which underly emotional learning and decision making, in this process. Next, we summarize data from our labs and from other groups on the latest brain imaging findings in different chronic pain conditions focusing on results with significant potential for translation into clinical applications. The gaps in the study of chronic pain and brain imaging are highlighted in throughout the overview. Finally, we conclude by discussing the costs and benefits of using brain biomarkers of chronic pain and compare to other potential markers.
Percentile Curves for Multiple Physical Fitness Components Among Chinese Han Children and Adolescents Aged 7–18 Years From a National Survey Based on the Total and the Normal Weight Population
Authors: Ma Ning , Dang Jiajia , Liu Yunfei , Zhong Panliang , Yan Xiaojin , Zhang Jingshu , Dong Yanhui , Song Yi , Ma Jun , Lau Patrick W. C.
Published: January 2022

Introduction:To develop sex- and age-specific percentile curves for seven physical fitness components for Chinese Han children and adolescents aged 7–18 years based on the total and the normal weight population using a nationally representative sample.

Methods:A total of 214,228 Chinese Han children and adolescents aged 7–18 years old with all nutritional status and 161,999 with normal weight were examined. Seven physical fitness components [forced vital capacity (FVC), standing long jump (SLJ), 50-m dash, sit-and-reach (SR), grip strength (GS), body muscle strength (BMS), and endurance running (ER)] were measured, and percentile curves for each physical fitness component at the 20th, 40th, 60th, and 80th percentiles were calculated using the general additive model for location, scale, and shape (GAMLSS).

Results:Physical fitness presents different characteristics in each subgroup of sex, age, and nutritional status among children and adolescents. Sex- and age-specific percentiles for the seven physical fitness components among the Chinese Han children and adolescents aged 7–18 years based on the total and the normal weight population were provided as curves. Boys performed better than girls in FVC, SLJ, 50-m dash, GS, and ER but worse in SR. The performances of FVC, SLJ, 50-m dash, GS, BMS, and ER increased with age, but the estimates of SR were at the bottom among boys aged 12 years and girls aged 11 years. The annual increments of all components were larger in boys than girls at the peak time, which was earlier in girls than boys. The gap of physical fitness components between sexes increased with age, especially during puberty (since after 11 years old).

Conclusion:The present study described the percentile curves of seven physical fitness components among the Chinese Han children and adolescents based on the total and the normal weight population at the national level, which could help to chart the level of physical fitness across age span and identify the extreme populations with either health concerns or potential talents.
MRI-Based Radiomic Signature Identifying Secondary Loss of Response to Infliximab in Crohn's Disease
Authors: Feng Jing , Feng Qi , Chen Yueying , Yang Tian , Cheng Saiming , Qiao Yuqi , Shen Jun
Published: January 2022

Up to 50% of patients with Crohn's disease (CD) experience secondary loss of response (SLR) to infliximab. Patients with SLR may show clinical signs of iron deficiency as a result of inflammation despite being iron-replete. The magnetic resonance imaging (MRI)-based radiomic index, R2*, can detect changes in iron metabolism. Therefore, the R2* parameter has considerable potential for detection of SLR to infliximab. The aims of this study were to explore the correlation between R2* and inflammation and to develop a non-invasive nomogram based on R2* to identify SLR to infliximab in patients with CD. Three hundred and twenty-two infliximab-treated patients with CD who underwent magnetic resonance enterography within 2 weeks before or after 54 weeks of infliximab therapy were divided into training and validation datasets at a ratio of 8:2. Point-biserial analysis was conducted to confirm the relationship between R2* and inflammation. A multivariate logistic regression model was created using R2*, CRP and hemoglobin (OR, 1.10, 1.04 and 0.98; P < 0.05). Receiver-operating characteristic curves and the Hosmer-Lemeshow test were used to assess the performance of the model. A correlation between R2* and inflammation was identified. Different trends in R2* and iron status indices were observed between patients with responsive and non-responsive CD, which is worthy of further study. The model was converted to a visualized nomogram that had a good ability to discriminate the outcomes of infliximab therapy with an area under the curve of 0.723 (95% CI, 0.661–0.785) in the training dataset and 0.715 (95% CI, 0.587–0.843) in the validation dataset. We confirmed a correlation between R2* and inflammation in patients with CD. Based on the MRI-based radiomic signature, a novel nomogram was established and validated to facilitate individualized identification of SLR to infliximab in patients with CD.
Development of Carrot Nutraceutical Products as an Alternative Supplement for the Prevention of Nutritional Diseases
Authors: Riaz Nadia , Yousaf Zubaida , Yasmin Zarina , Munawar Muneeb , Younas Afifa , Rashid Madiha , Aftab Arusa , Shamsheer Bushra , Yasin Hamna , Najeebullah Muhammad , Simon Philipp W.
Published: January 2022

Nutraceuticals can serve as an alternative supplement to overcome nutritional deficiency for a healthy lifestyle. They can also play a key role in disease management. To develop carrot nutraceutical products, 64 genotypes from four different continents were evaluated for a range of morpho-nutrition variables. Genetic variability, heritability, strength and direction of association among variables, and direct and indirect relationships among physiochemical and nutritional traits with β-carotene content were evaluated. Core diameter, foliage weight, root weight and shoulder weight showed significant association with β-carotene accumulation. Principal component analysis for physiochemical and nutritional assessment divided these genotypes into two distinctive groups, Eastern carrots and Western carrots. Caloric and moisture content had high positive associations with β-carotene content while carbohydrate content was negatively associated. Five genotypes (T-29, PI 634658, PI 288765, PI 164798, and Ames 25043) with the highest β-carotene contents were selected for making three nutraceutical supplements (carrot-orange juice, carrot jam and carrot candies). These nutraceutical supplements retained high β-carotene content coupled with antioxidant properties. Carrot jam (6.5 mg/100 g) and carrot candies (4.8 mg/100 g) had greater concentrations of β-carotene than carrot-orange juice (1.017 mg/100 g). Carrot jam presented high antioxidant activity with the highest values in T-29 (39% inhibition of oxidation) followed by PI 634658 (37%), PI 164798 (36.5%), Ames 25043 (36%) and PI 288765 (35.5%). These nutraceutical products, with 4–6.5 mg/100 g β-carotene content, had higher values than the USDA recommended dietary intake of 3–6 mg β-carotene/day can be recommended for daily use to lower the risk of chronic disease.