Tracking Openness and Topic Evolution of COVID-19 Publications January 2020-March 2021: Comprehensive Bibliometric and Topic Modeling Analysis.

BACKGROUND: The COVID-19 outbreak highlighted the importance of rapid access to research. OBJECTIVE: The aim of this study was to investigate research communication related to COVID-19, the level of openness of papers, and the main topics of research into this disease. METHODS: Open access (OA) uptake (typologies, license use) and the topic evolution of publications were analyzed from the start of the pandemic (January 1, 2020) until the end of a year of widespread lockdown (March 1, 2021). RESULTS: The sample included 95,605 publications; 94.1% were published in an OA form, 44% of which were published as Bronze OA. Among these OA publications, 42% do not have a license, which can limit the number of citations and thus the impact. Using a topic modeling approach, we found that articles in Hybrid and Green OA publications are more focused on patients and their effects, whereas the strategy to combat the pandemic adopted by different countries was the main topic of articles selecting publication via the Gold OA route. CONCLUSIONS: Although OA scientific production has increased, some weaknesses in OA practice, such as lack of licensing or under-researched topics, still hold back its effective use for further research.

Open Access of COVID-19-related publications in the first quarter of 2020: a preliminary study based in PubMed.

Background: The COVID-19 outbreak has made funders, researchers and publishers agree to have research publications, as well as other research outputs, such as data, become openly available. In this extraordinary research context of the SARS CoV-2 pandemic, publishers are announcing that their coronavirus-related articles will be made immediately accessible in appropriate open repositories, like PubMed Central, agreeing upon funders' and researchers' instigation. Methods: This work uses Unpaywall, OpenRefine and PubMed to analyse the level of openness of articles about COVID-19, published during the first quarter of 2020. It also analyses Open Access (OA) articles published about previous coronavirus (SARS CoV-1 and MERS CoV) as a means of comparison. Results: A total of 5,611 COVID-19-related articles were analysed from PubMed. This is a much higher amount for a period of 4 months compared to those found for SARS CoV-1 and MERS during the first year of their first outbreaks (335 and 116 articles, respectively).  Regarding the levels of openness, 88.8% of the SARS CoV-2 papers are freely available; similar rates were found for the other coronaviruses. Deeper analysis showed that (i) 67.4% of articles belong to an undefined Bronze category; (ii) 76.4% of all OA papers don't carry any license, followed by 10.4% which display restricted licensing. These patterns were found to be repeated in the three most frequent publishers: Elsevier, Springer and Wiley. Conclusions: Our results suggest that, although scientific production is much higher than during previous epidemics and is open, there is a caveat to this opening, characterized by the absence of fundamental elements and values ​​on which Open Science is based, such as licensing.

Elevated p38MAPK activity promotes neural stem cell aging.

Age-progressive neural stem cell (NSC) dysfunction leads to impaired neurogenesis, cognitive decline and the onset of age-related neurodegenerative pathologies. p38MAPK signalling pathway limits stem cell activity during aging in several tissues. Its role in NSCs remains controversial. In this work, we show that p38MAPK activity increases in NSCs with age in the subventricular zone (SVZ) and its pharmacological inhibition is sufficient to rejuvenate their activity in vitro. These data reveal a cell-autonomous role for p38MAPK increase in decreasing NSC homeostasis with age. This information shed light in the role of p38MAPK in NSC aging.

Neuronal p38α mediates age-associated neural stem cell exhaustion and cognitive decline.

Neuronal activity regulates cognition and neural stem cell (NSC) function. The molecular pathways limiting neuronal activity during aging remain largely unknown. In this work, we show that p38MAPK activity increases in neurons with age. By using mice expressing p38α-lox and CamkII-Cre alleles (p38α∆-N), we demonstrate that genetic deletion of p38α in neurons suffices to reduce age-associated elevation of p38MAPK activity, neuronal loss and cognitive decline. Moreover, aged p38α∆-N mice present elevated numbers of NSCs in the hippocampus and the subventricular zone. These results reveal novel roles for neuronal p38MAPK in age-associated NSC exhaustion and cognitive decline.

High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response.

The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas. A major feature possessed by glioma cells that may aid their ability to survive therapy and reconstitute tumors is the capacity for self-renewal. We show here that glioma stem cells (GSCs) express low levels of MKP1, a dual-specificity phosphatase, which acts as a negative inhibitor of JNK, ERK1/2, and p38 MAPK, while induction of high levels of MKP1 expression are associated with differentiation of GSC. Notably, we find that high levels of MKP1 correlate with a subset of glioblastoma patients with better prognosis and overall increased survival. Gain of expression studies demonstrated that elevated MKP1 impairs self-renewal and induces differentiation of GSCs while reducing tumorigenesis in vivo. Moreover, we identified that MKP1 is epigenetically regulated and that it mediates the anti-tumor activity of histone deacetylase inhibitors (HDACIs) alone or in combination with temozolomide. In summary, this study identifies MKP1 as a key modulator of the interplay between GSC self-renewal and differentiation and provides evidence that the activation of MKP1, through epigenetic regulation, might be a novel therapeutic strategy to overcome therapy resistance in glioblastoma.

Targeting SOX2 as a Therapeutic Strategy in Glioblastoma.

Glioblastoma is the most common and malignant brain cancer in adults. Current therapy consisting of surgery followed by radiation and temozolomide has a moderate success rate and the tumor reappears. Among the features that a cancer cell must have to survive the therapeutic treatment and reconstitute the tumor is the ability of self-renewal. Therefore, it is vital to identify the molecular mechanisms that regulate this activity. Sex-determining region Y (SRY)-box 2 (SOX2) is a transcription factor whose activity has been associated with the maintenance of the undifferentiated state of cancer stem cells in several tissues, including the brain. Several groups have detected increased SOX2 levels in biopsies of glioblastoma patients, with the highest levels associated with poor outcome. Therefore, SOX2 silencing might be a novel therapeutic approach to combat cancer and particularly brain tumors. In this review, we will summarize the current knowledge about SOX2 in glioblastoma and recapitulate several strategies that have recently been described targeting SOX2 in this malignancy.

mTOR inhibition decreases SOX2-SOX9 mediated glioma stem cell activity and temozolomide resistance.

BACKGROUND: SOX2 and SOX9 are commonly overexpressed in glioblastoma, and regulate the activity of glioma stem cells (GSCs). Their specific and overlapping roles in GSCs and glioma treatment remain unclear. METHODS: SOX2 and SOX9 levels were examined in human biopsies. Gain and loss of function determined the impact of altering SOX2 and SOX9 on cell proliferation, senescence, stem cell activity, tumorigenesis and chemoresistance. RESULTS: SOX2 and SOX9 expression correlates positively in glioma cells and glioblastoma biopsies. High levels of SOX2 bypass cellular senescence and promote resistance to temozolomide. Mechanistic investigations revealed that SOX2 acts upstream of SOX9. mTOR genetic and pharmacologic (rapamycin) inhibition decreased SOX2 and SOX9 expression, and reversed chemoresistance. CONCLUSIONS: Our findings reveal SOX2-SOX9 as an oncogenic axis that regulates stem cell properties and chemoresistance. We identify that rapamycin abrogate SOX protein expression and provide evidence that a combination of rapamycin and temozolomide inhibits tumor growth in cells with high SOX2/SOX9.

Increased gene dosage of Ink4/Arf and p53 delays age-associated central nervous system functional decline.

The impairment of the activity of the brain is a major feature of aging, which coincides with a decrease in the function of neural stem cells. We have previously shown that an extra copy of regulated Ink4/Arf and p53 activity, in s-Ink4/Arf/p53 mice, elongates lifespan and delays aging. In this work, we examined the physiology of the s-Ink4/Arf/p53 brain with aging, focusing on the neural stem cell (NSC) population. We show that cells derived from old s-Ink4/Arf/p53 mice display enhanced neurosphere formation and self-renewal activity compared with wt controls. This correlates with augmented expression of Sox2, Sox9, Glast, Ascl1, and Ars2 NSC markers in the subventricular zone (SVZ) and in the subgranular zone of the dentate gyrus (DG) niches. Furthermore, aged s-Ink4/Arf/p53 mice express higher levels of Doublecortin and PSA-NCAM (neuroblasts) and NeuN (neurons) in the olfactory bulbs (OB) and DG, indicating increased neurogenesis in vivo. Finally, aged s-Ink4/Arf/p53 mice present enhanced behavioral and neuromuscular coordination activity. Together, these findings demonstrate that increased but regulated Ink4/Arf and p53 activity ameliorates age-related deterioration of the central nervous system activity required to maintain the stem cell pool, providing a mechanism not only for the extended lifespan but also for the health span of these mice.

Therapeutic strategies targeting glioblastoma stem cells.

Glioblastoma is the most common, aggressive and lethal brain tumor in adults. However, current therapeutic protocols have low success rates and average overall survival is less than 15 months. The resistance to therapy is largely a result of the remarkable cellular and phenotypical heterogeneity that characterizes this type of tumor. The discovery of a subpopulation of cells exhibiting stem cell properties within the tumor bulk has profound implications for therapy as increasing evidence indicates that these cells, glioblastoma stem cells (GSCs), are responsible for the origin, maintenance and recurrence of the glioblastomas. These findings highlight the need to characterize GSCs in order to find novel treatments directly targeted specifically against them. In this review, we summarize the current knowledge regarding this issue, including some recent and relevant patents.