bluuebunny/crossref_metadata_2025 huggingface dataset:
Metagenomic Next-Generation Sequencing for Pathogenic Diagnosis and Antibiotic Management of Severe Community-Acquired Pneumonia in Immunocompromised Adults
Authors: Sun Ting , Wu Xiaojing , Cai Ying , Zhai Tianshu , Huang Linna , Zhang Yi , Zhan Qingyuan
Published: June 2021

Background

Metagenomic next-generation sequencing (mNGS) is a promising technique for pathogens diagnosis. However, application of mNGS in immunocompromised adults with severe community-acquired pneumonia (SCAP) is relatively limited.

Methods

We retrospectively reviewed 23 immunocompromised and 21 immunocompetent SCAP patients with mNGS detection from April 2019 to December 2019. The performances of pathogenic diagnosis and subsequently antibiotic adjustment in immunocompromised SCAP patients were compared to immunocompetent SCAP patients. The defined by days of therapy (DOT) method was used for estimate daily antibiotic use.

Results

There was a significant difference in the diagnostic positivity rate between mNGS and conventional test in both groups (P<0.001). Compared to immunocompetent patients, more mixed pathogens in immunocompromised patients were found (P=0.023). Before the availability of mNGS, the DOTs in immunocompromise patients were higher than immunocompetent patients (3.0 [3.0, 4.0] vs. 3.0 [2.0, 3.0], P=0.013). Compared to immunocompetent patients, immunocompromised patients had fewer full pathogen covered empirical antibiotic therapy (14.7% vs. 57.1%, P=0.022), more adjustments of antibiotic treatment (87.0%) vs. 57.1%, P=0.027). More than a half (13 of 23) SCAP patients in immunosuppressed group had reduced or downgraded antibiotic adjustments based on the results.

Conclusions

mNGS may be a useful technique for detecting mixed pathogens and personalized antibiotic treatment in immunocompromised SCAP patients.
Geometric and Dynamic Patterns of the Golmud Segment in the Southern Marginal Fault of the Qaidam Basin
Authors: Luo Hao , Wang Ji , Gou Yasen , Yu Hongmei , Shu Peng , Gao Zhanwu
Published: June 2021

The southern marginal fault of the Qaidam Basin (SMQBF) is a block-bounding border fault that has played a key role in the structural evolution of the Kunlun Fault. However, its geometric and dynamic deformation patterns since the Late Pleistocene have not been clearly observed. Field investigations, combined with high-resolution imagery and shallow seismic profiles, show that the SMQBF is a thrust fault with a sinistral strike-slip component composed of several secondary faults. Its Late Quaternary deformation pattern is characterized by piggyback thrust propagation, and the frontal fault may not be exposed to the surface. Due to the flexural slip of the hanging strata of the secondary fault, sub-parallel faults with widths of thousands of meters have formed on high terraces; these are important when assessing the seismic hazard of this area. Based on high-resolution topographic data obtained using an unmanned erial vehicle and optically stimulated luminescence chronology, the slip rates of several secondary faults were obtained. The vertical and strike-slip rates of the SMQBF were determined to be 0.96 ± 0.33 mm/a and 2.66 ± 0.50 mm/a, respectively, which may be the minimum rates for the fault. Considering that the SMQBF is composed of several secondary faults, these rates possibly correspond to minimum deformation only. The evident sinistral strike-slip of the SMQBF indicates that although the sinistral slip of the Kunlun Fault system is concentrated in main fault of this system, the branch faults have a significant influence on the lateral extrusion of the Qinghai-Tibet Plateau.
New Specimen of the Enigmatic Dicynodont Lanthanostegus mohoii (Therapsida, Anomodontia) from the Southwestern Karoo Basin of South Africa, and its Implications for Middle Permian Biostratigraphy
Authors: Rubidge Bruce S. , Day Michael O. , Benoit Julien
Published: June 2021

Lanthanostegus is an unusual dicynodont known from only two partial skulls from a single locality near Jansenville in the Eastern Cape Province of South Africa. Although these specimens can be constrained to near the base of the late middle Permian (Guadalupian) Abrahamskraal Formation, their precise age is uncertain as a result of diachroneity of the base of the Formation and the absence, in the Jansenville area, of index taxa to correlate this horizon with the biostratigraphy established in the Western Cape Province. Here, we describe a third skull that we identify as Lanthanostegus, which we recently discovered from a locality north of Laingsburg, on the western side of the main Karoo Basin. This skull reveals morphological details of the palate, occiput, and lower jaw that are not preserved in the described specimens of Lanthanostegus mohoii and will advance understanding of this poorly known dicynodont. This discovery provides the first direct correlation between the lower Abrahamskraal Formation at Jansenville on the eastern side of the basin and the southwestern part of the basin, and suggests that Lanthanostegus occurs in the lowest Tapinocephalus Assemblage Zone (AZ), or possibly to a new assemblage transitional between the Eodicynodon and Tapinocephalus AZs. This supports earlier work proposing that the Eodicynodon AZ is present only on the western side of the Karoo Basin and that the transition from a marine to continental depositional environment occurred later toward the East.
Antagonistic Interactions Between Fusaria Species and Their Host Plants Are Influenced by Host Taxonomic Distance: A Case Study From Mexico
Authors: Benítez-Malvido Julieta , Rodríguez-Alvarado Gerardo , Álvarez-Añorve Mariana , Ávila-Cabadilla Luis D. , del-Val Ek , Lira-Noriega Andrés , Gregorio-Cipriano Rosario
Published: June 2021

Interactions between cultivated and wild plants with their fungal pathogens have strong ecological, evolutionary and economic implications. Antagonistic interactions, however, have been scantily studied in an applied context by using ecological networks, phylogeny and spatial ecology concurrently. In this study, we describe for the first time, the topological structure of plant-fungi networks involving species of the genusFusariumand their native and introduced (exotic) cultivated host plants in Mexico. For this, we based our study on a recent database describing the attack on 75 native and introduced plant species, including 35 species of the genusFusarium. Host plant species varied in their degree of phylogenetical relatedness (Monocots and Dicots) and spatial geographical distribution. Therefore, we also tested whether or not plant-Fusariumnetworks are phylogenetically structured and highlighted the spatial correlation between pathogens and their host plants across the country. In general, the pathogen-plant network is more specialized and compartmentalized in closely related taxa. Closely related hosts are more likely to share the same pathogenicFusariumspecies. Host plants are present in different ecosystems and climates, with regions having more cultivated plant species presenting the highest number of fusaria pathogens. From an economic standpoint, different species of the same taxonomic family may be more susceptible to being attacked by the same species ofFusarium, whereas from an ecological standpoint the movement of pathogens may expose wild and cultivated plants to new diseases. Our study highlights the relevance of interaction intimacy in structuring trophic relationships between plants and fusaria species in native and introduced species. Furthermore, we show that the analytical tools regarding host distribution and phylogeny could permit a rapid assessment of which plant species in a region are most likely to be attacked by a given fusaria.
Colour Discrimination From Perceived Differences by Birds
Authors: Garcia Jair E. , Rohr Detlef H. , Dyer Adrian G.
Published: June 2021

The ability of visual generalists to see and perceive displayed colour signals is essential to understanding decision making in natural environments. Whilst modelling approaches have typically considered relatively simple physiological explanations of how colour may be processed, data on key bee species reveals that colour is a complex multistage perception largely generated by opponent neural representations in a brain. Thus, a biologically meaningful unit of colour information must consider the psychophysics responses of an animal engaged in colour decision making. We extracted previously collected psychophysics data for a Violet-Sensitive (VS) bird, the pigeon (Columba livia), and used a non-linear function that reliably represents the behavioural choices of hymenopteran and dipteran pollinators to produce the first behaviourally validated and biologically meaningful representation of how VS birds use colour information in a probabilistic way. The function describes how similar or dis-similar spectral information can lead to different choice behaviours in birds, even though all such spectral information is above discrimination threshold. This new representation of bird vision will enable enhanced modelling representations of how bird vision can sense and use colour information in complex environments.
Individual and Temporal Variation in Use of Residential Areas by Urban Coyotes
Authors: Thompson Connor A. , Malcolm Jay R. , Patterson Brent R.
Published: June 2021

Coyotes (Canis latrans) have established populations in most major urban centers across North America. While the risk of attacks on humans or their pets is low, the presence of carnivores in areas with high human use has resulted in increased public concern. Having a clearer understanding of which animals are more likely to interact with humans and when interactions are more likely to occur will help mitigate human-carnivore conflicts. Despite clear broad-scale patterns of human avoidance, human-coyote interactions occur most frequently in residential areas. Our purpose was to determine if use of residential areas varied consistently across individuals or time. We used locations from GPS collars deployed on 14 coyotes in the Greater Toronto Area, Ontario, Canada from 2012 to 2017 to fit a step selection function. Average (±SE) home range size estimates were 17.3 ± 4.6 km2 for resident coyotes and 102.8 ± 32.9 km2 for non-residents. We found that coyotes used natural areas more (β = 0.07, SE = 0.02, p < 0.0001), and roads (β = −0.50, SE = 0.13, p < 0.0001) and residential areas (β = −0.79, SE = 0.21, p = 0.0001) less during the day than at night. We also found that coyotes were more likely to use residential areas in the breeding season from January to April (β = 0.69, SE = 0.20, p = 0.0007) and the pup rearing season from May to August (β = 0.54, SE = 0.13, p < 0.0001) than in the dispersal season from September to December. Lastly, we found that resident coyotes were less likely to use residential areas than non-resident coyotes (β = −1.13, SE = 0.26, p < 0.0001). As far as we are aware, our study is the first to identify the seasons when coyotes are more likely to use residential areas. The seasonal patterns in habitat use that we observed reflect patterns that have been previously reported for human-coyote conflicts. Our results demonstrate that reducing the availability of anthropogenic food sources in residential areas, particularly in the winter and spring, should be a priority for managers aiming to reduce human-coyote conflict in urban areas.
Rap1 Is Essential for B-Cell Locomotion, Germinal Center Formation and Normal B-1a Cell Population
Authors: Ishihara Sayaka , Sato Tsuyoshi , Sugioka Risa , Miwa Ryota , Saito Haruka , Sato Ryota , Fukuyama Hidehiro , Nakajima Akihiko , Sawai Satoshi , Kotani Ai , Katagiri Koko
Published: June 2021

Integrin regulation by Rap1 is indispensable for lymphocyte recirculation. In mice having B-cell-specific Rap1a/b double knockouts (DKO), the number of B cells in lymph nodes decreased to approximately 4% of that of control mice, and B cells were present in the spleen and blood. Upon the immunization with NP-CGG, DKO mice demonstrated the defective GC formation in the spleen, and the reduced NP-specific antibody production. In vitro, Rap1 deficiency impaired the movement of activated B cells along the gradients of chemoattractants known to be critical for their localization in the follicles. Furthermore, B-1a cells were almost completely absent in the peritoneal cavity, spleen and blood of adult DKO mice, and the number of B-cell progenitor/precursor (B-p) were reduced in neonatal and fetal livers. However, DKO B-ps normally proliferated, and differentiated into IgM+ cells in the presence of IL-7. CXCL12-dependent migration of B-ps on the VCAM-1 was severely impaired by Rap1 deficiency. Immunostaining study of fetal livers revealed defects in the co-localization of DKO B-ps and IL-7-producing stromal cells. This study proposes that the profound effects of Rap1-deficiency on humoral responses and B-1a cell generation may be due to or in part caused by impairments of the chemoattractant-dependent positioning and the contact with stromal cells.
CD22 Blockage Restores Age-Related Impairments of Microglia Surveillance Capacity
Authors: Aires Vanessa , Coulon-Bainier Claire , Pavlovic Anto , Ebeling Martin , Schmucki Roland , Schweitzer Christophe , Kueng Erich , Gutbier Simon , Harde Eva
Published: June 2021

Microglia, the innate immune cells of the brain, are essential for maintaining homeostasis by their ramified, highly motile processes and for orchestrating the immune response to pathological stimuli. They are implicated in several neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. One commonality of these diseases is their strong correlation with aging as the highest risk factor and studying age-related alterations in microglia physiology and associated signaling mechanism is indispensable for a better understanding of age-related pathomechanisms. CD22 has been identified as a modifier of microglia phagocytosis in a recent study, but not much is known about the function of CD22 in microglia. Here we show that CD22 surface levels are upregulated in aged versus adult microglia. Furthermore, in the amyloid mouse model PS2APP, Aβ-containing microglia also exhibit increased CD22 signal. To assess the impact of CD22 blockage on microglia morphology and dynamics, we have established a protocol to image microglia process motility in acutely prepared brain slices from CX3CR1-GFP reporter mice. We observed a significant reduction of microglial ramification and surveillance capacity in brain slices from aged versus adult mice. The age-related decrease in surveillance can be restored by antibody-mediated CD22 blockage in aged mice, whereas surveillance in adult mice is not affected by CD22 inhibition. Moreover to complement the results obtained in mice, we show that human iPSC-derived macrophages exhibit an increased phagocytic capacity upon CD22 blockage. Downstream analysis of antibody-mediated CD22 inhibition revealed an influence on BMP and TGFβ associated gene networks. Our results demonstrate CD22 as a broad age-associated modulator of microglia functionality with potential implications for neurodegenerative disorders.
Cell Therapy With TILs: Training and Taming T Cells to Fight Cancer
Authors: Kumar Amrendra , Watkins Reese , Vilgelm Anna E.
Published: June 2021

The rationale behind cancer immunotherapy is based on the unequivocal demonstration that the immune system plays an important role in limiting cancer initiation and progression. Adoptive cell therapy (ACT) is a form of cancer immunotherapy that utilizes a patient’s own immune cells to find and eliminate tumor cells, however, donor immune cells can also be employed in some cases. Here, we focus on T lymphocyte (T cell)-based cancer immunotherapies that have gained significant attention after initial discoveries that graft-versus-tumor responses were mediated by T cells. Accumulating knowledge of T cell development and function coupled with advancements in genetics and data science has enabled the use of a patient’s own (autologous) T cells for ACT (TIL ACTs). In TIL ACT, tumor-infiltrating lymphocytes (TILs) are collected from resected tumor material, enhanced and expandedex-vivo, and delivered back to the patient as therapeutic agents. ACT with TILs has been shown to cause objective tumor regression in several types of cancers including melanoma, cervical squamous cell carcinoma, and cholangiocarcinoma. In this review, we provide a brief history of TIL ACT and discuss the current state of TIL ACT clinical development in solid tumors. We also discuss the niche of TIL ACT in the current cancer therapy landscape and potential strategies for patient selection.
Pinpointing Drivers of Extirpation in Sea Snakes: A Synthesis of Evidence From Ashmore Reef
Authors: Somaweera Ruchira , Udyawer Vinay , Guinea Michael L. , Ceccarelli Daniela M. , Clarke Rohan H. , Glover Michelle , Hourston Mathew , Keesing John , Rasmussen Arne Redsted , Sanders Kate , Shine Richard , Thomson Damian P. , Webber Bruce L.
Published: June 2021

Over the past decade, vertebrate populations globally have experienced significant declines in distribution and abundance. Understanding the reasons behind these population declines is the first step in implementing appropriate management responses to improve conservation outcomes. Uncovering drivers of extirpation events after the fact, however, requires a careful forensic approach to prevent similar declines elsewhere. The once abundant and species-rich sea snake fauna of Ashmore Reef Marine Park, in the Timor Sea, collapsed dramatically in the early 2000s. No such decline has occurred on surrounding reefs. We synthesise the evidence for this collapse and the subsequent slow recovery and evaluate the plausibility of potential drivers for the declines, as well as provide evidence against certain explanations that have been proposed in the past. Our systematic review shows that of seven possible hypotheses considered, at least three are credible and require additional information: (1) stochastic environmental events may have increased the snakes’ susceptibility to pathogens, (2) a resurgence in the abundance of top predators may have induced a localised change in trophic structure, and (3) an acute increase in local boat traffic may have had negative physical impacts. One or more of these factors, possibly acting in combination with as yet other unidentified factors, is the most plausible explanation for the precipitous decline in sea snake populations observed. Based on this position, we identify future research directions with a focus on addressing critical gaps in knowledge to inform and prioritise future management actions.
Micro Gas Turbines in the Future Smart Energy System: Fleet Monitoring, Diagnostics, and System Level Requirements
Authors: Aslanidou Ioanna , Rahman Moksadur , Zaccaria Valentina , Kyprianidis Konstantinos G.
Published: June 2021

The energy generation landscape is changing, pushed by stricter regulations for emissions control and green energy generation. The limitations of renewable energy sources, however, require flexible energy production sources to supplement them. Micro gas turbine based combined heat and power plants, which are used for domestic applications, can fill this gap if they become more reliable. This can be achieved with the use of an engine monitoring and diagnostics system: real-time engine condition monitoring and fault diagnostics results in reduced operating and maintenance costs and increased component and engine life. In order to allow the step change in the connection of small engines to the grid, a fleet monitoring system for micro gas turbines is required. A proposed framework combines a physics-based model and a data-driven model with machine learning capabilities for predicting system behavior, and includes a purpose-developed diagnostic tool for anomaly detection and classification for a multitude of engines. The framework has been implemented on a fleet of micro gas turbines and some of the lessons learned from the demonstration of the concept as well as key takeaways from the general literature are presented in this paper. The extension of fleet monitoring to optimal operation and production planning in relation to the needs of the grid will allow the micro gas turbines to fit in the future green energy system, connect to the grid, and trade in the energy market. The requirements on the system level for the widespread use of micro gas turbines in the energy system are addressed in the paper. A review of the current solutions in fleet monitoring and diagnostics, generally developed for larger engines, is included, with an outlook into a sustainable future.
Determinants of Unresponsiveness to Treatment in Cutaneous Leishmaniasis: A Focus on Anthroponotic Form Due to Leishmania tropica
Authors: Bamorovat Mehdi , Sharifi Iraj , Tavakoli Oliaee Razieh , Jafarzadeh Abdollah , Khosravi Ahmad
Published: June 2021

Cutaneous leishmaniasis (CL) is a curable disease; however, due to various risk factors, unresponsiveness to CL treatments is inevitable. The treatment of CL has been firmly correlated with multiple determinants, such as demographical, clinical, and environmental factors, the host’s immune response, poor treatment adherence, the parasite’s genetic make-up, and Leishmania RNA virus. This study primarily focuses on the risk factors associated with different therapeutic outcomes following meglumine antimoniate (MA; Glucantime®) treatment and policy approaches to prevent unresponsiveness in CL patients with a focus on anthroponotic form (ACL). Findings suggest that effective preventive and therapeutic measures should be more vigorously implemented, particularly in endemic areas. Accordingly, extensive training is essential to monitor drug unresponsiveness regularly, especially in tropical regions where the disease is prevalent. Since humans are the fundamental reservoir host of ACL due to L. tropica, prompt detection, early diagnosis, and timely and effective treatment could help control this disease. Furthermore, major challenges and gaps remain: efficacious vaccine, new tools, and expert staff are crucial before CL can be definitively controlled.
Which Is Stronger? A Continuing Battle Between Cry Toxins and Insects
Authors: Liu Lu , Li Zhou , Luo Xing , Zhang Xia , Chou Shan-Ho , Wang Jieping , He Jin
Published: June 2021

In this article, we review the latest works on the insecticidal mechanisms of Bacillus thuringiensis Cry toxins and the resistance mechanisms of insects against Cry toxins. Currently, there are two models of insecticidal mechanisms for Cry toxins, namely, the sequential binding model and the signaling pathway model. In the sequential binding model, Cry toxins are activated to bind to their cognate receptors in the mid-intestinal epithelial cell membrane, such as the glycophosphatidylinositol (GPI)-anchored aminopeptidases-N (APNs), alkaline phosphatases (ALPs), cadherins, and ABC transporters, to form pores that elicit cell lysis, while in the signaling pathway model, the activated Cry toxins first bind to the cadherin receptor, triggering an extensive cell signaling cascade to induce cell apoptosis. However, these two models cannot seem to fully describe the complexity of the insecticidal process of Cry toxins, and new models are required. Regarding the resistance mechanism against Cry toxins, the main method insects employed is to reduce the effective binding of Cry toxins to their cognate cell membrane receptors by gene mutations, or to reduce the expression levels of the corresponding receptors by trans-regulation. Moreover, the epigenetic mechanisms, host intestinal microbiota, and detoxification enzymes also play significant roles in the insects’ resistance against Cry toxins. Today, high-throughput sequencing technologies like transcriptomics, proteomics, and metagenomics are powerful weapons for studying the insecticidal mechanisms of Cry toxins and the resistance mechanisms of insects. We believe that this review shall shed some light on the interactions between Cry toxins and insects, which can further facilitate the development and utilization of Cry toxins.
Assessing the Response of Ruminal Bacterial and Fungal Microbiota to Whole-Rumen Contents Exchange in Dairy Cows
Authors: Cox Madison S. , Deblois Courtney L. , Suen Garret
Published: June 2021

A major goal for the dairy industry is to improve overall milk production efficiency (MPE). With the advent of next-generation sequencing and advanced methods for characterizing microbial communities, efforts are underway to improve MPE by manipulating the rumen microbiome. Our previous work demonstrated that a near-total exchange of whole rumen contents between pairs of lactating Holstein dairy cows of disparate MPE resulted in a reversal of MPE status for ∼10 days: historically high-efficiency cows decreased in MPE, and historically low-efficiency cows increased in MPE. Importantly, this switch in MPE status was concomitant with a reversal in the ruminal bacterial microbiota, with the newly exchanged bacterial communities reverting to their pre-exchange state. However, this work did not include an in-depth analysis of the microbial community response or an interrogation of specific taxa correlating to production metrics. Here, we sought to better understand the response of rumen communities to this exchange protocol, including consideration of the rumen fungi. Rumen samples were collected from 8 days prior to, and 56 days following the exchange and were subjected to 16S rRNA and ITS amplicon sequencing to assess bacterial and fungal community composition, respectively. Our results show that the ruminal fungal community did not differ significantly between hosts of disparate efficiency prior to the exchange, and no change in community structure was observed over the time course. Correlation of microbial taxa to production metrics identified one fungal operational taxonomic unit (OTU) in the genus Neocallimastix that correlated positively to MPE, and several bacterial OTUs classified to the genus Prevotella. Within the Prevotella, Prevotella_1 was found to be more abundant in high-efficiency cows whereas Prevotella_7 was more abundant in low-efficiency cows. Overall, our results suggest that the rumen bacterial community is a primary microbial driver of host efficiency, that the ruminal fungi may not have as significant a role in MPE as previously thought, and that more work is needed to better understand the functional roles of specific ruminal microbial community members in modulating MPE.
How Machine Learning and Statistical Models Advance Molecular Diagnostics of Rare Disorders Via Analysis of RNA Sequencing Data
Authors: Schlieben Lea D. , Prokisch Holger , Yépez Vicente A.
Published: June 2021

Rare diseases, although individually rare, collectively affect approximately 350 million people worldwide. Currently, nearly 6,000 distinct rare disorders with a known molecular basis have been described, yet establishing a specific diagnosis based on the clinical phenotype is challenging. Increasing integration of whole exome sequencing into routine diagnostics of rare diseases is improving diagnostic rates. Nevertheless, about half of the patients do not receive a genetic diagnosis due to the challenges of variant detection and interpretation. During the last years, RNA sequencing is increasingly used as a complementary diagnostic tool providing functional data. Initially, arbitrary thresholds have been applied to call aberrant expression, aberrant splicing, and mono-allelic expression. With the application of RNA sequencing to search for the molecular diagnosis, the implementation of robust statistical models on normalized read counts allowed for the detection of significant outliers corrected for multiple testing. More recently, machine learning methods have been developed to improve the normalization of RNA sequencing read count data by taking confounders into account. Together the methods have increased the power and sensitivity of detection and interpretation of pathogenic variants, leading to diagnostic rates of 10–35% in rare diseases. In this review, we provide an overview of the methods used for RNA sequencing and illustrate how these can improve the diagnostic yield of rare diseases.
CaMKII in Regulation of Cell Death During Myocardial Reperfusion Injury
Authors: Yang Yingjie , Jiang Kai , Liu Xu , Qin Mu , Xiang Yaozu
Published: June 2021

Cardiovascular disease is the leading cause of death worldwide. In spite of the mature managements of myocardial infarction (MI), post-MI reperfusion (I/R) injury results in high morbidity and mortality. Cardiomyocyte Ca2+ overload is a major factor of I/R injury, initiating a cascade of events contributing to cardiomyocyte death and myocardial dysfunction. Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in cardiomyocyte death response to I/R injury, whose activation is a key feature of myocardial I/R in causing intracellular mitochondrial swelling, endoplasmic reticulum (ER) Ca2+ leakage, abnormal myofilament contraction, and other adverse reactions. CaMKII is a multifunctional serine/threonine protein kinase, and CaMKIIδ, the dominant subtype in heart, has been widely studied in the activation, location, and related pathways of cardiomyocytes death, which has been considered as a potential targets for pharmacological inhibition. In this review, we summarize a brief overview of CaMKII with various posttranslational modifications and its properties in myocardial I/R injury. We focus on the molecular mechanism of CaMKII involved in regulation of cell death induced by myocardial I/R including necroptosis and pyroptosis of cardiomyocyte. Finally, we highlight that targeting CaMKII modifications and cell death involved pathways may provide new insights to understand the conversion of cardiomyocyte fate in the setting of myocardial I/R injury.
Gene Expression Profile in Immortalized Human Periodontal Ligament Fibroblasts Through hTERT Ectopic Expression: Transcriptome and Bioinformatic Analysis
Authors: Nogueira Lygia S. , Vasconcelos Carolina P. , Mitre Geovanni Pereira , Bittencourt Leonardo Oliveira , Plaça Jessica Rodrigues , Kataoka Maria Sueli da Silva , Pinheiro João de Jesus Viana , Garlet Gustavo Pompermaier , De Oliveira Edivaldo H. C. , Lima Rafael R.
Published: June 2021

Human periodontal ligament fibroblast (hPLF) cells play an important role in maintaining oral cavity homeostasis with special function in tissue regeneration and maintenance of dental alveoli. Although their primary cell cultures are considered a good experimental model with no genetic changes, the finite life span may limit some experimental designs. The immortalization process increases cell life span but may cause genetic changes and chromosomal instability, resulting in direct effects on physiological cell responses. In this way, we aimed to investigate the global gene expression of hPLFs after the immortalization process by the ectopic expression of the catalytic subunit of the enzyme telomerase reverse transcriptase (hTERT) through transcriptome analysis. The embryonic origin of the primary culture of hPLF cells and immortalized hPLF-hTERT was also tested by vimentin staining, hTERT synthesis evaluated by indirect immunocytochemistry, analysis of cell proliferation, and morphology. The results indicated that hPLFs and hPLF-hTERT were positive for vimentin. On the 20th cell passage, hPLFs were in senescence, while hPLF-hTERT maintained their proliferation and morphology characteristics. At the same passage, hPLF-hTERT presented a significant increase in hTERT synthesis, but transcriptome did not reveal overexpression of the hTERT gene. Fifty-eight genes had their expression altered (11 upregulated and 47 downregulated) with the absence of changes in the key genes related to these cell types and in the main cancer-associated genes. In addition, the increase in hTERT protein expression without the overexpression of its gene indicates posttranscriptional level regulation. Successful immortalization of hPLFs through the ectopic expression of hTERT encourages further studies to design experimental protocols to investigate clinical questions from a translational perspective.
Sunday Driver Mediates Multi-Compartment Golgi Outposts Defects Induced by Amyloid Precursor Protein
Authors: Du Qianqian , Chang Jin , Cheng Guo , Zhao Yinyin , Zhou Wei
Published: June 2021

Golgi defects including Golgi fragmentation are pathological features of Alzheimer’s disease (AD). As a pathogenic factor in AD, amyloid precursor protein (APP) induces Golgi fragmentation in the soma. However, how APP regulates Golgi outposts (GOs) in dendrites remains unclear. Given that APP resides in and affects the movements of GOs, and in particular, reverses the distribution of multi-compartment GOs (mcGOs), we investigated the regulatory mechanism of mcGO movements in the Drosophila larvae. Knockdown experiments showed that the bidirectional mcGO movements were cooperatively controlled by the dynein heavy chain (Dhc) and kinesin heavy chain subunits. Notably, only Dhc mediated APP’s regulation of mcGO movements. Furthermore, by loss-of-function screening, the adaptor protein Sunday driver (Syd) was identified to mediate the APP-induced alteration of the direction of mcGO movements and dendritic defects. Collectively, by elucidating a model of bidirectional mcGO movements, we revealed the mechanism by which APP regulates the direction of mcGO movements. Our study therefore provides new insights into AD pathogenesis.
The Use of Heptamethine Cyanine Dyes as Drug-Conjugate Systems in the Treatment of Primary and Metastatic Brain Tumors
Authors: Cooper Elizabeth , Choi Peter J. , Denny William A. , Jose Jiney , Dragunow Mike , Park Thomas I.-H.
Published: June 2021

Effective cancer therapeutics for brain tumors must be able to cross the blood-brain barrier (BBB) to reach the tumor in adequate quantities and overcome the resistance conferred by the local tumor microenvironment. Clinically approved chemotherapeutic agents have been investigated for brain neoplasms, but despite their effectiveness in peripheral cancers, failed to show therapeutic success in brain tumors. This is largely due to their poor bioavailability and specificity towards brain tumors. A targeted delivery system might improve the efficacy of the candidate compounds by increasing the retention time in the tumor tissue, and minimizing the numerous side effects associated with the non-specific distribution of the chemotherapy agent. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence (NIRF) compounds that have recently emerged as promising agents for drug delivery. Initially explored for their use in imaging and monitoring neoplasms, their tumor-targeting properties have recently been investigated for their use as drug carrier systems. This review will explore the recent developments in the tumour-targeting properties of a specific group of NIRF cyanine dyes and the preclinical evidence for their potential as drug-delivery systems in the treatment of primary and metastatic brain tumors.
Tumor Genotyping and Homologous Recombination Repair Gene Variants in Patients With Epithelial Ovarian Cancer: Is Pathogenic Enough?
Authors: Fountzilas Elena , Kotoula Vassiliki , Koliou Georgia-Angeliki , Liontos Michalis , Papadopoulou Kyriaki , Giannoulatou Eleni , Papanikolaou Alexios , Tikas Ioannis , Chrisafi Sofia , Mauri Davide , Chatzopoulos Kyriakos , Fostira Florentia , Pectasides Dimitrios , Oikonomopoulos Georgios , Aivazi Dimitra , Andrikopoulou Angeliki , Visvikis Anastasios , Aravantinos Gerasimos , Zagouri Flora , Fountzilas George
Published: June 2021

Our hypothesis was that the predictive accuracy of pathogenic variants in genes participating in the homologous recombination repair (HRR) system in patients with epithelial ovarian cancer (EOC) could be improved by considering additional next-generation sequencing (NGS) metrics. NGS genotyping was performed in tumor tissue, retrospectively and prospectively collected from patients with EOC, diagnosed from 8/1998 to 10/2016. Variants were considered clonal when variant allele frequencies corresponded to >25%. The primary endpoint was overall survival (OS). This study included 501 patients with EOC, predominantly with high-grade serous (75.2%) and advanced stage tumors (81.7%); median age was 58 years (22-84). Pathogenic and clonal pathogenic variants in HRR and/or TP53 genes were identified in 72.8% and 66.5% tumors, respectively. With a median follow-up of 123.9 months, the presence of either pathogenic or clonal pathogenic HRR-only variants was associated with longer OS compared to HRR/TP53 co-mutation (HR=0.54; 95% CI, 0.34-0.87, Wald’s p=0.012 and HR=0.45; 95% CI, 0.27-0.78, Wald’s p=0.004, respectively). However, only the presence of clonal HRR-only variants was independently associated with improved OS (HR=0.55; 95% CI, 0.32-0.94, p=0.030). Variant clonality and co-occuring TP53 variants affect the predictive value of HRR pathogenic variants for platinum agents in patients with EOC.

Clinical Trial Registration

[ClinicalTrials.gov], identifier [NCT04716374].
Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer
Authors: Principe Daniel R. , Chiec Lauren , Mohindra Nisha A. , Munshi Hidayatullah G.
Published: June 2021

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for lung cancer in recent years. These strategies consist of neutralizing antibodies against negative regulators of immune function, most notably cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1), thereby impeding the ability of tumor cells to escape immune surveillance. Though ICIs have proven a significant advance in lung cancer therapy, overall survival rates remain low, and lung cancer continues to be the leading cause of cancer-related death in the United States. It is therefore imperative to better understand the barriers to the efficacy of ICIs, particularly additional mechanisms of immunosuppression within the lung cancer microenvironment. Recent evidence suggests that regulatory T-lymphocytes (Tregs) serve as a central mediator of immune function in lung cancer, suppressing sterilizing immunity and contributing to the clinical failure of ICIs. Here, we provide a comprehensive summary of the roles of Tregs in lung cancer pathobiology and therapy, as well as the potential means through which these immunosuppressive mechanisms can be overcome.
Antibacterial and Antifungal Activities of Ethiopian Medicinal Plants: A Systematic Review
Authors: Nigussie Dereje , Davey Gail , Tufa Takele Beyene , Brewster Malcolm , Legesse Belete Adefris , Fekadu Abebaw , Makonnen Eyasu
Published: June 2021

Background:Podoconiosis and lymphatic filariasis are the most common causes of lower limb lymphoedema in the tropics. Many sufferers experience frequent painful episodes of acute bacterial infection. Plant based traditional medicines are used to treat infections in many countries and are culturally established in Ethiopia. Ethiopian medicinal plants found to have antibacterial and antifungal activities were reviewed with the aim of increasing information about the treatment of wound infections in patients with lymphoedema.

Methods:This study collates data from published articles on medicinal plants with antibacterial and antifungal activities in Ethiopia. A systematic search of Scopus, EMBASE, PUBMED/MEDLINE and Google Scholar was undertaken. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed. The protocol was registered on PROSPERO with registration number CRD42019127471. All controlled studies ofin vitroantibacterial and antifungal activities were considered. All articles containing the descriptors published until June 28, 2019 were included. The outcome was measured as percent inhibition of microbial growth. For quality assessment of individualin vitrostudies, OECD guidelines and the WHO-Good Laboratory Practice (GLP) handbook were used.

Results:Seventy-nine studies met the inclusion criteria. A total of 150 plant species and three compounds had been tested against 42 species of bacteria, while 43 plant species had been tested against 22 species of fungus.

Conclusion:Materials derived from several Ethiopian medicinal plants have been shown to have promising activity against a variety of bacteria and fungi. Those derived fromAzadiractha indicaA. Juss. andLawsonia inermsL.are the most extensively studied against a wide range of gram-negative and positive bacteria, and fungal species.
Metabolomic and Pharmacologic Insights of Aerial and Underground Parts of Glycyrrhiza uralensis Fisch. ex DC. for Maximum Utilization of Medicinal Resources
Authors: Jiang Liang , Akram Waheed , Luo Biaobiao , Hu Sheng , Faruque Mohammad Omar , Ahmad Shakeel , Yasin Nasim Ahmad , Khan Waheed Ullah , Ahmad Aqeel , Shikov Alexander N. , Chen Jian , Hu Xuebo
Published: June 2021

The roots of Glycyrrhiza spp. have been utilized in Traditional Chinese medicine (TCM) for thousands of years. Non-traditional (aerial) parts constitute a large portion of the biomass of Glycyrrhiza plants and are mostly discarded after harvesting the roots and rhizomes. Through comparative phytochemical and anti-inflammatory activity analyses, this study explored the potential benefits of the aerial parts of Glycyrrhiza uralensis Fisch. ex DC. as medicinal materials. First, a combined approach based on GC/MS and UHPLC-ESI-QTof MS analysis was adopted for the identification and quantitative examination of medicinally important compounds from G. uralensis. Additionally, a bioassay-guided fractioning of ethanolic extracts of G. uralensis leaf material was performed and its anti-inflammatory activity was tested. The aerial portion of G. uralensis was rich in medicinally important compounds. Two compounds (henicosane-1 and decahydroisoquinoline-2) were found to exert a significant anti-inflammatory effect, inhibiting the release of pro-inflammatory mediators (NO and PGE2) and cytokines (IL-1β, IL6, and TNF-α), without exerting cytotoxic effects. Moreover, both compounds down-regulated iNOS and COX-2 mRNA expression. These results suggest that non-traditional parts of G. uralensis are suitable sources of bioactive metabolites that can be explored for medicinal purposes.
Experimental Resonances in Viscoelastic Microfluidics
Authors: Vazquez-Vergara Pamela , Torres-Herrera Ulises , Caballero-Robledo Gabriel A. , Olguin Luis F. , Corvera Poiré Eugenia
Published: June 2021

Pulsatile flows of viscoelastic fluids are very important for lab-on-a-chip devices, because most biofluids have viscoelastic character and respond distinctively to different periodic forcing. They are also very important for organ-on-a-chip devices, where the natural mechanical conditions of cells are emulated. The resonance frequency of a fluid refers to a particular pulsatile periodicity of the pressure gradient that maximizes the amplitude of flow velocity. For viscoelastic fluids, this one has been measured experimentally only at macroscales, since fine tuning of rheological properties and system size is needed to observe it at microscales. We study the dynamics of a pulsatile (zero-mean flow) fluid slug formed by a viscoelastic fluid bounded by two air-fluid interfaces, in a microchannel of polymethyl methacrylate. We drive the fluid slug by a single-mode periodic pressure drop, imposed by a piezoactuator. We use three biocompatible polymer solutions of polyethylene oxide as model viscoelastic fluids, and find resonances. We propose a model accounting for surface tension and fluid viscoelasticity that has an excellent agreement with our experimental findings. It also provides an alternative way of measuring relaxation times. We validate the method with parameters reported in the literature for two of the solutions, and estimate the relaxation time for the third one.
Trolls Without Borders: A Cross-Cultural Examination of Victim Reactions to Verbal and Silent Aggression Online
Authors: Cook Christine Linda , Schaafsma Juliette , Antheunis Marjolijn L. , Shahid Suleman , Lin Jih-Hsuan Tammy , Nijtmans Hanne W.
Published: June 2021

Trolling—the online exploitation of website, chat, or game mechanics at another user's expense—can and does take place all over cyberspace. It can take myriad forms, as well—some verbal, like trash-talking an opponent in a game, and some silent, like refusing to include a new player in a team effort during an in-game quest. However, despite this variety, there are few to no studies comparing the effects of these differing trolling types on victims. In addition, no study has yet taken into account users' offline cultural context and norms into the trolling victim experience. To fill this gap in the literature, the present study put participants from three culturally-distinct countries—Pakistan, Taiwan, and the Netherlands—in a simulated trolling interaction using the Cyberball game. Participants were either flamed (read: harshly insulted) or ostracized by a member of their own cultural group (ingroup) or a minority member (outgroup), and the participants' emotional responses, behavioral intentions toward the other players, and messages sent during the game were taken as indicators of their response to the trolling. Results showed that our Taiwanese sample used the most reactive aggression when trolled and our Dutch sample was the most passive. In addition, ostracism generally produced the desire to repair relationships, irrespective of cultural context, and perpetrator culture (ingroup or outgroup) only produced an effect in the behavioral intentions of our Pakistani sample. Overall, it would appear that online and offline culture interact to produce the variety of responses to trolling seen in extant literature. Additional implications for future research into computer-mediated communication and online aggression are also discussed.
Fear in the Chinese Population: Influential Patterns in the Early Stage of the COVID-19 Pandemic
Authors: Chen Beijing , Sun Xiaoxiao , Xie Fei , Zhang Mengjia , Shen Sitong , Chen Zhaohua , Yuan Yuan , Shi Peixia , Qin Xuemei , Liu Yingzhe , Wang Yuan , Dai Qin
Published: June 2021

Major global public health emergencies challenge public mental health. Negative emotions, and especially fear, may endanger social stability. To better cope with epidemics and pandemics, early emotional guidance should be provided based on an understanding of the status of public emotions in the given circumstances. From January 27 to February 11, 2020 (during which the cases of COVID-19 were increasing), a national online survey of the Chinese public was conducted. A total of 132,482 respondents completed a bespoke questionnaire, the Emotion Regulation Questionnaire, and the Berkeley Expressivity Questionnaire (BEQ). Results showed that at the early stage of the COVID-19 epidemic, 53.0% of the Chinese population reported varying degrees of fear, mostly mild. As seen from regression analysis, for individuals who were unmarried and with a relatively higher educational level, living in city or area with fewer confirmed cases, cognitive reappraisal, positive expressivity and negative inhibition were the protective factors of fear. For participants being of older age, female, a patient or medical staff member, risk perception, negative expressivity, positive impulse strength and negative impulse strength were the risk factors for fear. The levels of fear and avoidant behavior tendencies were risk factors for disturbed physical function. Structural equation modeling suggested that fear emotion had a mediation between risk perception and escape behavior and physical function disturbance. The findings help to reveal the public emotional status at the early stage of the pandemic based on a large Chinese sample, allowing targeting of the groups that most need emotional guidance under crisis. Findings also provide evidence of the need for psychological assistance in future major public health emergencies.