bluuebunny/crossref_metadata_2025 huggingface dataset:
Metformin Induces Apoptosis and Inhibits Notch1 in Malignant Pleural Mesothelioma Cells
Authors: Rossini Marika , Martini Fernanda , Torreggiani Elena , Fortini Francesca , Aquila Giorgio , Sega Francesco Vieceli Dalla , Patergnani Simone , Pinton Paolo , Maniscalco Pio , Cavallesco Giorgio , Rizzo Paola , Tognon Mauro
Published: January 2021

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-related cancer arising from the mesothelial cells lining the pleural cavity. MPM is characterized by a silent clinical progression and a highly resistance to conventional chemo/radio-therapies. MPM patients die in a few months/years from diagnosis. Notch signaling is a well-conserved cell communication system, which regulates many biological processes. In humans, the dysregulation of Notch pathway potentially contributes to cancer onset/progression, including MPM. Metformin is the first-line drug used to treat type 2 diabetes mellitus. Metformin is proven to be an effective antitumor drug in preclinical models of different types of cancer. To date, clinical efficacy is being studied in many clinical trials. In this study, the anti-proliferative effect of metformin on MPM cells and the putative involvement of Notch1 as a mediator of metformin activities, were investigated. MPM cells showed high levels of Notch1 activation compared to normal pleural mesothelial cells. Furthermore, metformin treatment hampered MPM cell proliferation and enhanced the apoptotic process, accompanied by decreased Notch1 activation.
The Olfactory Organ Is Populated by Neutrophils and Macrophages During Early Development
Authors: Palominos M. Fernanda , Whitlock Kathleen E.
Published: January 2021

The immune system of vertebrates is characterized by innate and adaptive immunity that function together to form the natural defense system of the organism. During development innate immunity is the first to become functional and is mediated primarily by phagocytic cells, including macrophages, neutrophils, and dendritic cells. In the olfactory sensory system, the same sensory neurons in contact with the external environment have their first synapse within the central nervous system. This unique architecture presents a potential gateway for the entry of damaging or infectious agents to the nervous system. Here we used zebrafish as a model system to examine the development of the olfactory organ and to determine whether it shares immune characteristics of a host defense niche described in other tissues. During early development, both neutrophils and macrophages appear coincident with the generation of the primitive immune cells. The appearance of neutrophils and macrophages in the olfactory organs occurs as the blood and lymphatic vascular system is forming in the same region. Making use of the neurogenic properties of the olfactory organ we show that damage to the olfactory sensory neurons in larval zebrafish triggers a rapid immune response by local and non-local neutrophils. In contrast, macrophages, although present in greater numbers, mount a slower response to damage. We anticipate our findings will open new avenues of research into the role of the olfactory-immune response during normal neurogenesis and damage-induced regeneration and contribute to our understanding of the formation of a potential host defense immune niche in the peripheral nervous system.
Neuronal Mitophagy: Friend or Foe?
Authors: Doxaki Christina , Palikaras Konstantinos
Published: January 2021

Maintenance of neuronal homeostasis is a challenging task, due to unique cellular organization and bioenergetic demands of post-mitotic neurons. It is increasingly appreciated that impairment of mitochondrial homeostasis represents an early sign of neuronal dysfunction that is common in both age-related neurodegenerative as well as in neurodevelopmental disorders. Mitochondrial selective autophagy, known as mitophagy, regulates mitochondrial number ensuring cellular adaptation in response to several intracellular and environmental stimuli. Mounting evidence underlines that deregulation of mitophagy levels has an instructive role in the process of neurodegeneration. Although mitophagy induction mediates the elimination of damaged mitochondria and confers neuroprotection, uncontrolled runaway mitophagy could reduce mitochondrial content overstressing the remaining organelles and eventually triggering neuronal cell death. Unveiling the molecular mechanisms of neuronal mitophagy and its intricate role in neuronal survival and cell death, will assist in the development of novel mitophagy modulators to promote cellular and organismal homeostasis in health and disease.
OTUB1 Promotes Progression and Proliferation of Prostate Cancer via Deubiquitinating and Stabling Cyclin E1
Authors: Liao Yihao , Wu Ning , Wang Keke , Wang Miaomiao , Wang Youzhi , Gao Jie , Zhong Boqiang , Ma Fuling , Wu Yudong , Jiang Ning
Published: January 2021

Background:Prostate cancer (PCa) is currently the most common cancer among males worldwide. It has been reported that OTUB1 plays a critical role in a variety of tumors and is strongly related to tumor proliferation, migration, and clinical prognosis. The aim of this research is to investigate the regulatory effect of OTUB1 on PCa proliferation and the underlying mechanism.

Methods:Using the TCGA database, we identified that OTUB1 was up-regulated in PCa, and observed severe functional changes in PC3 and C4-2 cells through overexpression or knock down OTUB1. Heterotopic tumors were implanted subcutaneously in nude mice and IHC staining was performed on tumor tissues. The relationship between OTUB1 and cyclin E1 was identified via Western blotting and immunoprecipitations assays.

Results:We found that the expression of OTUB1 in PCa was significantly higher than that in Benign Prostatic Hyperplasia (BPH). Overexpression OTUB1 obviously promoted the proliferation and migration of PC3 and C4-2 cells via mediating the deubiquitinated Cyclin E1, while OTUB1 knockout has the opposite effect. The nude mice experiment further explained the above conclusions. We finally determined that OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabling Cyclin E1.

Conclusions:Our findings reveal the critical role of OTUB1 in PCa, and OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabilizing Cyclin E1. Blocking OTUB1/Cyclin E1 axis or applying RO-3306 could significantly repress the occurrence and development of PCa. OTUB1/Cyclin E1 axis might provide a new and potential therapeutic target for PCa.
Interplay Between Mitophagy and Apoptosis Defines a Cell Fate Upon Co-treatment of Breast Cancer Cells With a Recombinant Fragment of Human κ-Casein and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
Authors: Wohlfromm Fabian , Richter Max , Otrin Lado , Seyrek Kamil , Vidaković-Koch Tanja , Kuligina Elena , Richter Vladimir , Koval Olga , Lavrik Inna N.
Published: January 2021

A recombinant fragment of human κ-Casein, termed RL2, induces cell death of breast cancer cells; however, molecular mechanisms of RL2-mediated cell death have remained largely unknown. In the current study, we have decoded the molecular mechanism of the RL2-mediated cell death and found that RL2 acts via the induction of mitophagy. This was monitored by the loss of adenosine triphosphate production, LC3B-II generation, and upregulation of BNIP3 and BNIP3L/NIX, as well as phosphatase and tensin homolog-induced kinase 1. Moreover, we have analyzed the cross talk of this pathway with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon combinatorial treatment with RL2 and TRAIL. Strikingly, we found two opposite effects of this co-treatment. RL2 had inhibitory effects on TRAIL-induced cell death upon short-term co-stimulation. In particular, RL2 treatment blocked TRAIL-mediated caspase activation, cell viability loss, and apoptosis, which was mediated via the downregulation of the core proapoptotic regulators. Contrary to short-term co-treatment, upon long-term co-stimulation, RL2 sensitized the cells toward TRAIL-induced cell death; the latter observation provides the basis for the development of therapeutic approaches in breast cancer cells. Collectively, our findings have important implications for cancer therapy and reveal the molecular switches of the cross talk between RL2-induced mitophagy and TRAIL-mediated apoptosis.
Senescence and Apoptosis: Architects of Mammalian Development
Authors: Wanner Emma , Thoppil Harikrishnan , Riabowol Karl
Published: January 2021

Mammalian development involves an exquisite choreography of cell division, differentiation, locomotion, programmed cell death, and senescence that directs the transformation of a single cell zygote to a mature organism containing on the order of 40 trillion cells in humans. How a single totipotent zygote undergoes the rapid stages of embryonic development to form over 200 different cell types is complex in the extreme and remains the focus of active research. Processes such as programmed cell death or apoptosis has long been known to occur during development to help sculpt organs and tissue systems. Other processes such as cellular senescence, long thought to only occur in pathologic states such as aging and tumorigenesis have been recently reported to play a vital role in development. In this review, we focus on apoptosis and senescence; the former as an integral mechanism that plays a critical role not only in mature organisms, but that is also essential in shaping mammalian development. The latter as a well-defined feature of aging for which some reports indicate a function in development. We will dissect the dual roles of major gene families, pathways such as Hox, Rb, p53, and epigenetic regulators such as the ING proteins in both early and the late stages and how they play antagonistic roles by increasing fitness and decreasing mortality early in life but contribute to deleterious effects and pathologies later in life.
The Complexity of TET2 Functions in Pluripotency and Development
Authors: Garcia-Outeiral Vera , de la Parte Cristina , Fidalgo Miguel , Guallar Diana
Published: January 2021

Ten-eleven translocation-2 (TET2) is a crucial driver of cell fate outcomes in a myriad of biological processes, including embryonic development and tissue homeostasis. TET2 catalyzes the demethylation of 5-methylcytosine on DNA, affecting transcriptional regulation. New exciting research has provided evidence for TET2 catalytic activity in post-transcriptional regulation through RNA hydroxymethylation. Here we review the current understanding of TET2 functions on both DNA and RNA, and the influence of these chemical modifications in normal development and pluripotency contexts, highlighting TET2 versatility in influencing genome regulation and cellular phenotypes.
Challenges and Strategies of Chemical Analysis of Drugs of Abuse and Explosives by Mass Spectrometry
Authors: Habib Ahsan , Bi Lei , Hong Huanhuan , Wen Luhong
Published: January 2021

In analytical science, mass spectrometry (MS) is known as a “gold analytical tool” because of its unique character of providing the direct molecular structural information of the relevant analyte molecules. Therefore, MS technique has widely been used in all branches of chemistry along with in proteomics, metabolomics, genomics, lipidomics, environmental monitoring etc. Mass spectrometry-based methods are very much needed for fast and reliable detection and quantification of drugs of abuse and explosives in order to provide fingerprint information for criminal investigation as well as for public security and safety at public places, respectively. Most of the compounds exist as their neutral form in nature except proteins, peptides, nucleic acids that are in ionic forms intrinsically. In MS, ion source is the heart of the MS that is used for ionizing the electrically neutral molecules. Performance of MS in terms of sensitivity and selectivity depends mainly on the efficiency of the ionization source. Accordingly, much attention has been paid to develop efficient ion sources for a wide range of compounds. Unfortunately, none of the commercial ion sources can be used for ionization of different types of compounds. Moreover, in MS, analyte molecules must be released into the gaseous phase and then ionize by using a suitable ion source for detection/quantification. Under these circumstances, fabrication of new ambient ion source and ultrasonic cutter blade-based non-thermal and thermal desorption methods have been taken into account. In this paper, challenges and strategies of mass spectrometry analysis of the drugs of abuse and explosives through fabrication of ambient ionization sources and new desorption methods for non-volatile compounds have been described. We will focus the literature progress mostly in the last decade and present our views for the future study.
Li7La3Zr2O12 Garnet Solid Polymer Electrolyte for Highly Stable All-Solid-State Batteries
Authors: Nguyen Quoc Hung , Luu Van Tung , Nguyen Hoang Long , Lee Young-Woo , Cho Younghyun , Kim Se Young , Jun Yun-Seok , Ahn Wook
Published: January 2021

All-solid-state batteries have gained significant attention as promising candidates to replace liquid electrolytes in lithium-ion batteries for high safety, energy storage performance, and stability under elevated temperature conditions. However, the low ionic conductivity and unsuitability of lithium metal in solid polymer electrolytes is a critical problem. To resolve this, we used a cubic garnet oxide electrolyte (Li7La3Zr2O12 – LLZO) and ionic liquid in combination with a polymer electrolyte to produce a composite electrolyte membrane. By applying a solid polymer electrolyte on symmetric stainless steel, the composite electrolyte membrane shows high ionic conductivity at elevated temperatures. The effect of LLZO in suppressing lithium dendrite growth within the composite electrolyte was confirmed through symmetric lithium stripping/plating tests under various current densities showing small polarization voltages. The full cell with lithium iron phosphate as the cathode active material achieved a highest specific capacity of 137.4 mAh g−1 and a high capacity retention of 98.47% after 100 cycles at a current density of 50 mA g−1 and a temperature of 60°C. Moreover, the specific discharge capacities were 137 and 100.8 mAh g−1 at current densities of 100 and 200 mA g−1, respectively. This research highlights the capability of solid polymer electrolytes to suppress the evolution of lithium dendrites and enhance the performance of all-solid-state batteries.
Case Report: Hypertriglyceridemia and Premature Atherosclerosis in a Patient With Apolipoprotein E Gene ε2ε1 Genotype
Authors: Limonova Alena S. , Ershova Alexandra I. , Meshkov Alexey N. , Kiseleva Anna V. , Divashuk Mikhail G. , Kutsenko Vladimir A. , Drapkina Oxana M.
Published: January 2021

We present a case of a 40-year-old male with premature atherosclerosis, with evidence of both eruptive and tendinous xanthomas, which could imply an increase in both low-density lipoprotein (LDL) and triglyceride (TG) levels. However, his LDL was 2.08 mmol/l, TG -11.8 mmol/l on rosuvastatin 20 mg. Genetic evaluation was performed using a custom panel consisting of 25 genes and 280 variants responsible for lipid metabolism. A rare ε2ε1 genotype of apolipoprotein E was detected. The combination of clinical manifestations and genetic factors in this patient leads to the diagnosis of familial dysbetalipoproteinemia. Implementation of genetic testing into routine clinical practice could not only improve disease diagnostics and management, but also help prevent their development.
Biventricular Longitudinal Strain Predict Mortality in COVID-19 Patients
Authors: Xie Yuji , Wang Lufang , Li Meng , Li He , Zhu Shuangshuang , Wang Bin , He Lin , Zhang Danqing , Zhang Yongxing , Yuan Hongliang , Wu Chun , Sun Wei , Zhang Yanting , Cui Li , Cai Yu , Wang Jing , Yang Yali , Lv Qing , Xie Mingxing , Li Yuman , Zhang Li
Published: January 2021

Background: Biventricular longitudinal strain has been recently demonstrated to be predictive of poor outcomes in various cardiovascular settings. Therefore, this study sought to investigate the prognostic implications of biventricular longitudinal strain in patients with coronavirus disease 2019 (COVID-19).

Methods: We enrolled 132 consecutive patients with COVID-19. Left ventricular global longitudinal strain from the apical four-chamber views (LV GLS4CH) and right ventricular free wall longitudinal strain (RV FWLS) were obtained using two-dimensional speckle-tracking echocardiography.

Results: Compared with patients without cardiac injury, those with cardiac injury had higher levels of coagulopathy and inflammatory biomarkers, higher incidence of complications, more mechanical ventilation therapy, and higher mortality. Patients with cardiac injury displayed decreased LV GLS4CH and RV FWLS, elevated pulmonary artery systolic pressure, and higher proportion of pericardial effusion. Higher biomarkers levels of inflammation and cardiac injury, and the presence of pericardial effusion were correlated with decreases in LV GLS4CH and RV FWLS. During hospitalization, 19 patients died. Compared with survivors, LV GLS4CH and RV FWLS were impaired in non-survivors. At a 3-month follow-up after discharge, significant improvements were observed in LV GLS4CH and RV FWLS. Multivariate Cox analysis revealed that LV GLS4CH [hazard ratio: 1.41; 95% confidence interval [CI]: 1.08 to 1.84; P = 0.011] and RV FWLS (HR: 1.29; 95% CI: 1.09–1.52; P = 0.003) were independent predictors of higher mortality in patients with COVID-19.

Conclusions: LV GLS4CH and RV FWLS are independent and strong predictors of higher mortality in COVID-19 patients and can track improvement during the convalescent phase of their illness. Therefore, biventricular longitudinal strain may be crucial for risk stratification and serial follow-up in patients with COVID-19.
Monitoring Crop Status in the Continental United States Using the SMAP Level-4 Carbon Product
Authors: Wurster Patrick M. , Maneta Marco , Kimball John S. , Endsley K. Arthur , Beguería Santiago
Published: January 2021

Accurate monitoring of crop condition is critical to detect anomalies that may threaten the economic viability of agriculture and to understand how crops respond to climatic variability. Retrievals of soil moisture and vegetation information from satellite-based remote-sensing products offer an opportunity for continuous and affordable crop condition monitoring. This study compared weekly anomalies in accumulated gross primary production (GPP) from the SMAP Level-4 Carbon (L4C) product to anomalies calculated from a state-scale weekly crop condition index (CCI) and also to crop yield anomalies calculated from county-level yield data reported at the end of the season. We focused on barley, spring wheat, corn, and soybeans cultivated in the continental United States from 2000 to 2018. We found that consistencies between SMAP L4C GPP anomalies and both crop condition and yield anomalies increased as crops developed from the emergence stage (r: 0.4–0.7) and matured (r: 0.6–0.9) and that the agreement was better in drier regions (r: 0.4–0.9) than in wetter regions (r: −0.8–0.4). The L4C provides weekly GPP estimates at a 1-km scale, permitting the evaluation and tracking of anomalies in crop status at higher spatial detail than metrics based on the state-level CCI or county-level crop yields. We demonstrate that the L4C GPP product can be used operationally to monitor crop condition with the potential to become an important tool to inform decision-making and research.
Planned Change: Drivers of High Implementation for a Pedagogical Self-Regulated Learning Intervention
Authors: Faith Laurie Christine , Pyle Angela
Published: January 2021

Resourcefulness and adaptability are essential to success in the modern economy; the motivation, metacognition, and cognitive skills required for self-regulated learning (SRL) have never been more important. Unfortunately, teacher-led SRL interventions rarely survive implementation, and teachers' general practices rarely reflect their intention to promote SRL. After discussing the shortcomings of virtual or modularized SRL education, this study explores the drivers of a human-led, communal, pedagogical approach. Data was collected over 3 months and three timepoints from 81 kindergarten to Grade 8 teachers who were genuinely dissatisfied by their status quo practices, ready for change, and largely eager to implement the novel teaching approach presented to them. Building on established theories of planned change implementation, this research shows a minimal effect of teachers' approval of the intervention on implementation. Rather, specific drivers to the implementation of complex, communal pedagogical interventions included the support of high-status supervisors and peers, while identified constraints to implementation included fears regarding management of student behavior.
Control of Bone Matrix Properties by Osteocytes
Authors: Creecy Amy , Damrath John G. , Wallace Joseph M.
Published: January 2021

Osteocytes make up 90–95% of the cellular content of bone and form a rich dendritic network with a vastly greater surface area than either osteoblasts or osteoclasts. Osteocytes are well positioned to play a role in bone homeostasis by interacting directly with the matrix; however, the ability for these cells to modify bone matrix remains incompletely understood. With techniques for examining the nano- and microstructure of bone matrix components including hydroxyapatite and type I collagen becoming more widespread, there is great potential to uncover novel roles for the osteocyte in maintaining bone quality. In this review, we begin with an overview of osteocyte biology and the lacunar–canalicular system. Next, we describe recent findings from in vitro models of osteocytes, focusing on the transitions in cellular phenotype as they mature. Finally, we describe historical and current research on matrix alteration by osteocytes in vivo, focusing on the exciting potential for osteocytes to directly form, degrade, and modify the mineral and collagen in their surrounding matrix.
The Dynamic Expression of Potential Mediators of Severe Acute Respiratory Syndrome Coronavirus 2 Cellular Entry in Fetal, Neonatal, and Adult Rhesus Monkeys
Authors: Cao Bangrong , Zhang Liping , Liu Huifen , Ma Shiqi , Mi Kun
Published: January 2021

The coronavirus disease 2019 (COVID-19) pandemic, induced by the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly all over the world. There is considerable variability among neonates, children, and adults in the incidence of infection and severe disease following exposure to SARS-CoV-2. In our study, we analyzed the transcriptome data of primate animal model of Rhesus monkeys to evaluate the expression levels of possible SARS-CoV-2 receptors and proteases and immunologic features in the lungs, colons, livers, and brains at different developmental stages. Our results revealed that ACE2 and TMPRSS2 were highly expressed in neonates compared with other populations, which imply the high incidence of infection. Other potential receptors and Type II transmembrane serine proteases (TTSPs) and cathepsin of endosomal proteases also exhibited dynamic and differential expression patterns. The expression of receptors (ACE2, BSG, and DPP4) and proteases (TMPRSS2, TMPRSS9, CTSL, and CTSB) were highly correlated during lung development, suggesting the high susceptibility of the lungs. TMPRSS9 was specifically highly expressed in the lungs and reached the highest level in neonates, similar to TMPRSS2. Moreover, the immune cell infiltration analysis revealed immunity immaturity in neonates, implying the association with the mild or moderate type of COVID-19. The results might help researchers design protective and therapeutic strategies for COVID-19 in populations at different ages.
Integrating Somatic Mutations for Breast Cancer Survival Prediction Using Machine Learning Methods
Authors: He Zongzhen , Zhang Junying , Yuan Xiguo , Zhang Yuanyuan
Published: January 2021

Breast cancer is the most common malignancy in women, and because it has a high mortality rate, it is urgent to develop computational methods to increase the accuracy of breast cancer survival predictive models. Although multi-omics data such as gene expression have been extensively used in recent studies, the accurate prognosis of breast cancer remains a challenge. Somatic mutations are another important and promising data source for studying cancer development, and its effect on the prognosis of breast cancer remains to be further explored. Meanwhile, these omics datasets are high-dimensional and redundant. Therefore, we adopted multiple kernel learning (MKL) to efficiently integrate somatic mutation to currently molecular data including gene expression, copy number variation (CNV), methylation, and protein expression data for the prediction of breast cancer survival. Before integration, the maximum relevance minimum redundancy (mRMR) feature selection method was utilized to select features that present high relevance to survival and low redundancy among themselves for each type of data. The experimental results demonstrated that the proposed method achieved the most optimal performance and there was a remarkable improvement in the prediction performance when somatic mutations were included, indicating that somatic mutations are critical for improving breast cancer survival predictions. Moreover, mRMR was superior to other feature selection methods used in previous studies. Furthermore, MKL outperformed the other traditional classifiers in multi-omics data integration. Our analysis indicated that through employing promising omics data such as somatic mutations and harnessing the power of proper feature selection methods and effective integration frameworks, the breast cancer survival predictive accuracy can be further increased, thereby providing a more optimal clinical diagnosis and more effective treatment for breast cancer patients.
IL-15 Upregulates Telomerase Expression and Potently Increases Proliferative Capacity of NK, NKT-Like, and CD8 T Cells
Authors: Watkinson Fiona , Nayar Sandeep Krishan , Rani Aradhana , Sakellariou Christina A. , Elhage Oussama , Papaevangelou Efthymia , Dasgupta Prokar , Galustian Christine
Published: January 2021

Interleukin-15 (IL-15) is a cytokine that has been shown to expand CD8 T cell and natural killer (NK) cell populations, and therefore has potential for potentiating adoptive immune cell therapy for cancer. Previously, IL-15 has been shown to induce proliferation of CD8 memory T cells through activation of telomerase. Here, we investigated whether telomerase is also activated during the IL-15 mediated proliferation of NK and NKT-like (CD56+CD3+) cells. We also examined the extent that each of the three signaling pathways known to be stimulated by IL-2/IL-15 (JAK-STAT, PI3K-AKT Ras-RAF/MAPK) were activated and involved in the telomerase expression in the three cell types NK, NKT, or CD8 T cells. To assess cell proliferation and doubling, peripheral blood mononuclear cells (PBMCs) or isolated NK, NKT-like or CD8 T cells were incubated with varying concentrations of IL-15 or IL-2 for 7 days. CD8 T, NK, and NKT cell expansion was determined by fluorophore-conjugated antibody staining and flow cytometry. Cell doubling was investigated using carboxyfluorescein-succinimidyl-ester (CFSE). Telomerase expression was investigated by staining cells with anti-telomerase reverse transcriptase (anti-TERT). Telomerase activity in CD56+ and CD8 T cells was also measured via Telomerase Repeat Amplification Protocol (TRAP). Analysis of cellular expansion, proliferation and TERT expression concluded that IL-15 increased cellular growth of NK, NKT, and CD8 T cells more effectively than IL-2 using low or high doses. IL-15, increased TERT expression in NK and NKT cells by up to 2.5 fold, the same increase seen in CD8 T cells. IL-2 had effects on TERT expression only at high doses (100–1000 ng/ml). Proteome profiling identified that IL-15 activated selected signaling proteins in the three pathways (JAK-STAT, PI3K-AKT, Ras-MAPK) known to mediate IL-2/IL-15 signaling, more strongly than IL-2. Evaluation by signaling pathway inhibitors revealed that JAK/STAT and PI3K/AKT pathways are important in IL-15’s ability to upregulate TERT expression in NK and NKT cells, whereas all three pathways were involved in CD8 T cell TERT expression. In conclusion, this study shows that IL-15 potently stimulates TERT upregulation in NK and NKT cells in addition to CD8 T cells and is therefore a valuable tool for adoptive cell therapies.
Nanofragmentation of Expanded Polystyrene Under Simulated Environmental Weathering (Thermooxidative Degradation and Hydrodynamic Turbulence)
Authors: Mattsson Karin , Björkroth Frida , Karlsson Therese , Hassellöv Martin
Published: January 2021

Fragmentation of macroplastics into microplastics in the marine environment is probably one of the processes that have generated most drive for developing the microplastics research field. Thus, it is surprising that the level of scientific knowledge on the combinative effect of oxidative degradation and mechanical stressors on fragmentation is relatively limited. Furthermore, it has been hypothesized that plastic fragmentation continues into the nanoplastic size domains, but environmentally realistic studies are lacking. Here the effects of thermooxidative aging and hydrodynamic conditions relevant for the shoreline environment on the fragmentation of expanded polystyrene (EPS) were tested in laboratory simulations. The pre-degraded EPS was cut into pieces and subjected to mechanical, hydrodynamic simulations during four-day stirring experiments. Subsamples were filtered and subsequently analyzed with light microscopy with automated image analysis particle size distribution determinations, polymer identification with Raman spectroscopy, Scanning Electron Microscopy (SEM) with automated image analysis particle size distribution. The nanoplastic size fraction was measured using nanoparticle tracking analysis. In addition, the degree of polymer oxidation was spectroscopically characterized with Fourier transform infrared (FTIR) spectroscopy. The results illustrate that fragmentation of the mesoplastic objects is observed already after 2 days, but that is more distinct after 4 days, with higher abundances for the smaller size fractions, which imply more release of smaller sizes or fragmentation in several steps. For the nanoplastic fraction, day four shows a higher abundance of released or fragmented particles than day two. The conclusions are that nanofragmentation is an important and understudied process and that standardized test protocols for both thermooxidative degradation and mechanical treatments mimicking realistic environmental conditions are needed. Further testing of the most common macro- and mesoplastic materials to assess the rates and fluxes of fragmenting particles to micro- and nanoplastic fractions should be conducted.
An Integrative Model of Carbon and Nitrogen Metabolism in a Common Deep-Sea Sponge (Geodia barretti)
Authors: de Kluijver Anna , Bart Martijn C. , van Oevelen Dick , de Goeij Jasper M. , Leys Sally P. , Maier Sandra R. , Maldonado Manuel , Soetaert Karline , Verbiest Sander , Middelburg Jack J.
Published: January 2021

Deep-sea sponges and their microbial symbionts transform various forms of carbon (C) and nitrogen (N) via several metabolic pathways, which, for a large part, are poorly quantified. Previous flux studies on the common deep-sea sponge Geodia barretti consistently revealed net consumption of dissolved organic carbon (DOC) and oxygen (O2) and net release of nitrate (NO3-). Here we present a biogeochemical metabolic network model that, for the first time, quantifies C and N fluxes within the sponge holobiont in a consistent manner, including many poorly constrained metabolic conversions. Using two datasets covering a range of individual G. barretti sizes (10–3,500 ml), we found that the variability in metabolic rates partially resulted from body size as O2 uptake allometrically scales with sponge volume. Our model analysis confirmed that dissolved organic matter (DOM), with an estimated C:N ratio of 7.7 ± 1.4, is the main energy source of G. barretti. DOM is primarily used for aerobic respiration, then for dissimilatory NO3- reduction to ammonium (NH4+) (DNRA), and, lastly, for denitrification. Dissolved organic carbon (DOC) production efficiencies (production/assimilation) were estimated as 24 ± 8% (larger individuals) and 31 ± 9% (smaller individuals), so most DOC was respired to carbon dioxide (CO2), which was released in a net ratio of 0.77–0.81 to O2 consumption. Internally produced NH4+ from cellular excretion and DNRA fueled nitrification. Nitrification-associated chemoautotrophic production contributed 5.1–6.7 ± 3.0% to total sponge production. While overall metabolic patterns were rather independent of sponge size, (volume-)specific rates were lower in larger sponges compared to smaller individuals. Specific biomass production rates were 0.16% day–1 in smaller compared to 0.067% day–1 in larger G. barretti as expected for slow-growing deep-sea organisms. Collectively, our approach shows that metabolic modeling of hard-to-reach, deep-water sponges can be used to predict community-based biogeochemical fluxes and sponge production that will facilitate further investigations on the functional integration and the ecological significance of sponge aggregations in deep-sea ecosystems.
Vitamin C and COVID-19
Authors: Hemilä Harri , de Man Angelique M. E.
Published: January 2021

In numerous animal studies, vitamin C has prevented and alleviated viral and bacterial infections. In a few dozen placebo-controlled trials with humans, vitamin C has shortened infections caused by respiratory viruses, which indicates that the vitamin can also influence viral infections in humans. In critically ill patients, plasma vitamin C levels are commonly very low. Gram doses of vitamin C are needed to increase the plasma vitamin C levels of critically ill patients to the levels of ordinary healthy people. A meta-analysis of 12 trials with 1,766 patients calculated that vitamin C reduced the length of ICU stay on average by 8%. Another meta-analysis found that vitamin C shortened the duration of mechanical ventilation in ICU patients. Two randomized placebo-controlled trials found statistically significant reduction in the mortality of sepsis patients. The effects of vitamin C on acute respiratory distress syndrome (ARDS) frequently complicating COVID-19 pneumonia should be considered. Vitamin C is a safe and inexpensive essential nutrient.
An Overview of Nucleic Acid Testing for the Novel Coronavirus SARS-CoV-2
Authors: Wang Huiling , Li Gang , Zhao Jing , Li Yanjie , Ai Yushu
Published: January 2021

In this note we analyze the problems in the nucleic acid testing (NAT) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and we also give some suggestions for improving the accuracy of NAT diagnosis. NAT testing is considered to be the diagnostic “gold standard”; at present there are few reviews on NAT for SARS-CoV-2. Moreover, many false-negative results always appear in the procedure of detecting, which has affected early diagnosis of the disease and brought a great challenge to mitigation and containment of the pandemic. In conclusion, comprehensive analyses of serological and imaging findings should be performed to guide the formulation of an accurate clinical diagnosis, treatment plan, and monitoring therapeutic efficacy, in an effort to achieve early diagnosis, containment, and treatment of the disease, thereby effectively reducing progression of the pandemic. This article presents a literature overview of SARS-CoV-2 nucleic acid testing, aiming to provide support for clinicians.
Potential False-Positive and False-Negative Results for COVID-19 IgG/IgM Antibody Testing After Heat-Inactivation
Authors: Lin Jie , Dai Wei , Li Weiwei , Xiao Li , Luo Tao , Guo Yanju , Yang Yang , Han Ying , Zhu Peiran , Wu Qiuyue , He Bangshun , Wu Jian , Xia Xinyi
Published: January 2021

Objectives: With the worldwide spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), various antibody detection kits have been developed to test for SARS-CoV-2– specific IgG, IgM, and total antibody. However, the use of different testing methods under various heat-inactivation conditions might affect the COVID-19 detection results.

Methods: Seven different antibody detection kits produced by four manufacturers for detection of SARS-CoV-2 IgG, IgM, and total antibody were tested at Wuhan Huoshenshan Hospital, China. Most of the kits used the indirect immunity, capture, and double-antigen sandwich methods. The effects of various heat-inactivation conditions on SARS-CoV-2-specific IgG, IgM, and total antibody detection were analyzed for the different test methods.

Results: Using the indirect immunity method, values for SARS-CoV-2 IgG antibody significantly increased and those for IgM antibody decreased with increasing temperature of heat-inactivation using indirect immunity method. However, values for SARS-CoV-2 IgM and total antibody showed no change when the capture and double-antigen sandwich methods were used. The changes in IgG and IgM antibody values with the indirect immunity method indicated that heat-inactivation could affect COVID-19 detection results obtained using this method. In particular, 18 (22.2%) SARS-CoV-2 IgM positive samples were detected as negative with heat-inactivation at 65°C for 30 min, and one (25%) IgG negative sample was detected as positive after heat-inactivation at 56°C for 60 min and 60°C for 30 min.

Conclusions: Heat-inactivation could increase SARS-CoV-2 IgG antibody values, and decrease IgM antibody values, causing potential false-positive or false-negative results for COVID-19 antibody detection using the indirect immunity method. Thus, before conducting antibody testing, the testing platforms should be evaluated in accordance with the relevant requirements to ensure accurate COVID-19 detection results.
The Damage-Associated Molecular Patterns (DAMPs) as Potential Targets to Treat Osteoarthritis: Perspectives From a Review of the Literature
Authors: Lambert Cécile , Zappia Jérémie , Sanchez Christelle , Florin Antoine , Dubuc Jean-Emile , Henrotin Yves
Published: January 2021

During the osteoarthritis (OA) process, activation of immune systems, whether innate or adaptive, is strongly associated with low-grade systemic inflammation. This process is initiated and driven in the synovial membrane, especially by synovium cells, themselves previously activated by damage-associated molecular patterns (DAMPs) released during cartilage degradation. These fragments exert their biological activities through pattern recognition receptors (PRRs) that, as a consequence, induce the activation of signaling pathways and beyond the release of inflammatory mediators, the latter contributing to the vicious cycle between cartilage and synovial membrane. The primary endpoint of this review is to provide the reader with an overview of these many molecules categorized as DAMPs and the contribution of the latter to the pathophysiology of OA. We will also discuss the different strategies to control their effects. We are convinced that a better understanding of DAMPs, their receptors, and associated pathological mechanisms represents a decisive issue for degenerative joint diseases such as OA.
Evolutionary Rescue of an Environmental Pseudomonas otitidis in Response to Anthropogenic Perturbation
Authors: García-Ulloa Manuel II , Escalante Ana Elena , Moreno-Letelier Alejandra , Eguiarte Luis E. , Souza Valeria
Published: January 2021

Anthropogenic perturbations introduce novel selective pressures to natural environments, impacting the genomic variability of organisms and thus altering the evolutionary trajectory of populations. Water overexploitation for agricultural purposes and defective policies in Cuatro Cienegas, Coahuila, Mexico, have strongly impacted its water reservoir, pushing entire hydrological systems to the brink of extinction along with their native populations. Here, we studied the effects of continuous water overexploitation on an environmental aquatic lineage ofPseudomonas otitidisover a 13-year period which encompasses three desiccation events. By comparing the genomes of a population sample from 2003 (original state) and 2015 (perturbed state), we analyzed the demographic history and evolutionary response to perturbation of this lineage. Through coalescent simulations, we obtained a demographic model of contraction-expansion-contraction which points to the occurrence of an evolutionary rescue event. Loss of genomic and nucleotide variation alongside an increment in mean and variance of Tajima’sD, characteristic of sudden population expansions, support this observation. In addition, a significant increase in recombination rate (R/θ) was observed, pointing to horizontal gene transfer playing a role in population recovery. Furthermore, the gain of phosphorylation, DNA recombination, small-molecule metabolism and transport and loss of biosynthetic and regulatory genes suggest a functional shift in response to the environmental perturbation. Despite subsequent sampling events in the studied site, no pseudomonad was found until the lagoon completely dried in 2017. We speculate about the causes ofP. otitidisfinal decline or possible extinction. Overall our results are evidence of adaptive responses at the genomic level of bacterial populations in a heavily exploited aquifer.
Search for Antimicrobial Activity Among Fifty-Two Natural and Synthetic Compounds Identifies Anthraquinone and Polyacetylene Classes That Inhibit Mycobacterium tuberculosis
Authors: Pollo Luiz A. E. , Martin Erlon F. , Machado Vanessa R. , Cantillon Daire , Wildner Leticia Muraro , Bazzo Maria Luiza , Waddell Simon J. , Biavatti Maique W. , Sandjo Louis P.
Published: January 2021

Drug-resistant tuberculosis threatens to undermine global control programs by limiting treatment options. New antimicrobial drugs are required, derived from new chemical classes. Natural products offer extensive chemical diversity and inspiration for synthetic chemistry. Here, we isolate, synthesize and test a library of 52 natural and synthetic compounds for activity against Mycobacterium tuberculosis. We identify seven compounds as antimycobacterial, including the natural products isobavachalcone and isoneorautenol, and a synthetic chromene. The plant-derived secondary metabolite damnacanthal was the most active compound with the lowest minimum inhibitory concentration of 13.07 μg/mL and a favorable selectivity index value. Three synthetic polyacetylene compounds demonstrated antimycobacterial activity, with the lowest MIC of 17.88 μg/mL. These results suggest new avenues for drug discovery, expanding antimicrobial compound chemistries to novel anthraquinone and polyacetylene scaffolds in the search for new drugs to treat drug-resistant bacterial diseases.
PfAP2-G2 Is Associated to Production and Maturation of Gametocytes in Plasmodium falciparum via Regulating the Expression of PfMDV-1
Authors: Xu Yaozheng , Qiao Dan , Wen Yuhao , Bi Yifei , Chen Yuxi , Huang Zhenghui , Cui Liwang , Guo Jian , Cao Yaming
Published: January 2021

Gametocyte is the sole form of the Plasmodium falciparum which is transmissible to the mosquito vector. Here, we report that an Apicomplexan Apetala2 (ApiAP2) family transcription factor, PfAP2-G2 (Pf3D7_1408200), plays a role in the development of gametocytes in P. falciparum by regulating the expression of PfMDV-1 (Pf3D7_1216500). Reverse transcriptase-quantitative PCR (RT-qPCR) analysis showed that PfAP2-G2 was highly expressed in the ring stage. Indirect immunofluorescence assay showed nuclear localization of PfAP2-G2 in asexual stages. The knockout of PfAP2-G2 led to a ~95% decrease in the number of mature gametocytes with a more substantial influence on the production and maturation of the male gametocytes, resulting in a higher female/male gametocyte ratio. To test the mechanism of this phenotype, RNA-seq and RT-qPCR showed that disruption of PfAP2-G2 led to the down-regulation of male development gene-1 (PfMDV-1) in asexual stages. We further found that PfAP2-G2 was enriched at the transcriptional start site (TSS) of PfMDV-1 by chromatin immunoprecipitation and qPCR assay in both ring stage and schizont stage, which demonstrated that PfMDV-1 is one of the targets of PfAP2-G2. In addition, RT-qPCR also showed that PfAP2-G (Pf3D7_1222600), the master regulator for sexual commitment, was also down-regulated in the PfAP2-G2 knockout parasites in the schizont stage, but no change in the ring stage. This phenomenon suggested that PfAP2-G2 played a role at the asexual stage for the development of parasite gametocytes and warrants further investigations in regulatory pathways of PfAP2-G2.
Mechanisms of Pulmonary Hypertension in Acute Respiratory Distress Syndrome (ARDS)
Authors: Revercomb Lucy , Hanmandlu Ankit , Wareing Nancy , Akkanti Bindu , Karmouty-Quintana Harry
Published: January 2021

Background: Acute respiratory distress syndrome (ARDS) is a severe and often fatal disease. The causes that lead to ARDS are multiple and include inhalation of salt water, smoke particles, or as a result of damage caused by respiratory viruses. ARDS can also arise due to systemic complications such as blood transfusions, sepsis, or pancreatitis. Unfortunately, despite a high mortality rate of 40%, there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies.

Aim of review: A complication of ARDS is the development of pulmonary hypertension (PH); however, the mechanisms that lead to PH in ARDS are not fully understood. In this review, we summarize the known mechanisms that promote PH in ARDS.

Key scientific concepts of review: (1) Provide an overview of acute respiratory distress syndrome; (2) delineate the mechanisms that contribute to the development of PH in ARDS; (3) address the implications of PH in the setting of coronavirus disease 2019 (COVID-19).
A Customizable Low-Cost System for Massively Parallel Zebrafish Behavioral Phenotyping
Authors: Joo William , Vivian Michael D. , Graham Brett J. , Soucy Edward R. , Thyme Summer B.
Published: January 2021

High-throughput behavioral phenotyping is critical to genetic or chemical screening approaches. Zebrafish larvae are amenable to high-throughput behavioral screening because of their rapid development, small size, and conserved vertebrate brain architecture. Existing commercial behavioral phenotyping systems are expensive and not easily modified for new assays. Here, we describe a modular, highly adaptable, and low-cost system. Along with detailed assembly and operation instructions, we provide data acquisition software and a robust, parallel analysis pipeline. We validate our approach by analyzing stimulus response profiles in larval zebrafish, confirming prepulse inhibition phenotypes of two previously isolated mutants, and highlighting best practices for growing larvae prior to behavioral testing. Our new design thus allows rapid construction and streamlined operation of many large-scale behavioral setups with minimal resources and fabrication expertise, with broad applications to other aquatic organisms.