bluuebunny/crossref_metadata_2025 huggingface dataset:
Processo cuidativo ao paciente cardíaco pós-cirúrgico na Atenção Primária à Saúde: revisão integrativa
Authors: Silveira Jéssica da Silva , Xavier Daiani Modernel , Lima Janice Mendieta , Sena-Castanheira Janaína , Cezar-Vaz Marta Regina
Published: April 2021

Pacientes crônicos e que foram submetidos a um procedimento cirúrgico encontram-se em um período de fragilidade. Frente a isto, o enfermeiro na Atenção Primária à Saúde possui um papel importante no processo cuidativo, pois necessita dispor de habilidades para fortificar o paciente, ajudando-o a enfrentar dificuldades referentes a sua doença, promovendo sua segurança e autoconfiança. Sendo de particularidade deste profissional, o olhar diferenciado ao paciente, analisando-o como um ser biopsicossocial. A partir dessa realidade, objetiva-se com este estudo, evidenciar a produção científica acerca do processo cuidativo de enfermagem ao paciente cardíaco pós-cirúrgico na Atenção Primária à Saúde. Trata-se de uma Revisão Integrativa de Literatura, que busca o aprofundamento acerca da temática de interesse, por meio de análise e síntese de estudos primários. O desenvolvimento deste estudo ocorreu em cinco etapas: formulação do problema, pesquisa de literatura, avaliação dos dados, análise dos dados e apresentação. Referente aos resultados, verificou-se que os pacientes acometidos por doenças cardiovasculares e submetidos à cirurgia cardíaca, estão sujeitos a enfrentar diversas alterações em sua vida, envolvendo aspectos físicos, emocionais e psicossociais. Por fim, percebeu-se que por meio de técnicas assistenciais relevantes, como a escuta terapêutica, e pelo olhar diferenciado do enfermeiro, compreendendo o paciente como um ser amplo e complexo, a assistência de enfermagem na Atenção Primária à Saúde apresenta-se de forma diferenciada, resultando em uma aplicação positiva para o processo cuidativo desse grupo de pacientes.
Evaluasi Penggunaan Prometheus dan Grafana Untuk Monitoring Database Mongodb
Authors: Ramadoni  , Amirudin Mahmud Zunus , Rifki Fahmi  , Ema Utami  , Mustafa Muhammad Syukri
Published: April 2021

Sebuah basis data dituntut untuk selalu dalam keadaan optimal, karena hal tersebut merupakan faktor penting dalam sebuah Sistem Informasi Manajemen. Untuk menjaga sebuah sistem basis data agar selalu optimal tentu saja dibutuhkan mekanisme monitoring yang dapat memberikan informasi kepada pihak yang berkepentingan sehingga setiap kejadian dapat terpantau, sehingga apabila diperlukan sebuah tindakan preventif maupun korektif dapat segera dilakukan. Pemilihan perangkat monitoring perlu mempertimbangkan beberapa faktor seperti fleksibilitas, kemampuan untuk diintegrasikan dengan sistem yang lain. Prometheus dan Grafana adalah kombinasi yang bagus untuk melakukan monitoring pada sistem basis data, tidak hanya terbatas pada sistem sebuah basis data MongoDB, kemampuan Prometheus untuk menyimpan basis data dalam bentuk time series memungkinkan Prometheus untuk menyimpan data dalam jumlah besar. Sedangkan tampilan visualisasi Grafana yang bisa dikustomisasi membuka peluang untuk kita membuat visualisasi dan mendapatkan visibilitas sesuai dengan kebutuhan. Penggunaan Prometheus dan Grafana yang bersifat opensource juga menjadi pilihan untuk mengurangi biaya karena tidak membutuhkan lisensi untuk penggunaannya bahkan di lingkungan komersial sekalipun.
Temperature Based Process Characterization of Pharmaceutical Freeze-Thaw Operations
Authors: Weber Dennis , Hubbuch Jürgen
Published: April 2021

In biopharmaceutical production processes, freeze-thaw operations are used to ensure product integrity during long hold times, but they also introduce additional stresses such as freeze concentration gradients that might lead to a loss of protein activity. Process characterization of freeze-thaw operations at different scales should be conducted with attention to freezing time and boundary effects to ensure the product stability throughout the process and process development. Currently, process characterization often relies on one or very few temperature probes that detect freezing times based on raw temperature, which is largely influenced by freezing-point depression in case of concentrated solutions. A method to detect freezing based on the second derivative of temperature measurements from Fiber-Bragg-Grating sensors is presented to overcome this issue. The applicability of the method is demonstrated by process characterization of a novel small-scale freeze-thaw device with minimized boundary effects using freezing times of purified water and concentrated formulations. Freezing times varied from 35 to 81 min for temperatures between −60 and −20°C and impacted freeze concentration profiles. Furthermore, freezing time estimations based on the Plank equation revealed model limitations due to start-up temperature gradients, that can be corrected by an empirically extended Plank model. As a hypothesis, we conclude that freezing temperature, from a freeze concentration view, is less important in containers with small characteristic freezing distances such as freeze bags. Using a 2D-resolved temperature profile, a shift of the last point to freeze position from top to bottom of a container was observed when freezing above −30°C.
Identification of Gradient Promoters of Gluconobacter oxydans and Their Applications in the Biosynthesis of 2-Keto-L-Gulonic Acid
Authors: Chen Yue , Liu Li , Yu Shiqin , Li Jianghua , Zhou Jingwen , Chen Jian
Published: April 2021

The acetic acid bacterium Gluconobacter oxydans is known for its unique incomplete oxidation and therefore widely applied in the industrial production of many compounds, e.g., 2-keto-L-gulonic acid (2-KLG), the direct precursor of vitamin C. However, few molecular tools are available for metabolically engineering G. oxydans, which greatly limit the strain development. Promoters are one of vital components to control and regulate gene expression at the transcriptional level for boosting production. In this study, the low activity of SDH was found to hamper the high yield of 2-KLG, and enhancing the expression of SDH was achieved by screening the suitable promoters based on RNA sequencing data. We obtained 97 promoters from G. oxydans’s genome, including two strong shuttle promoters and six strongest promoters. Among these promoters, P3022 and P0943 revealed strong activities in both Escherichia coli and G. oxydans, and the activity of the strongest promoter (P2703) was about threefold that of the other reported strong promoters of G. oxydans. These promoters were used to overexpress SDH in G. oxydans WSH-003. The titer of 2-KLG reached 3.7 g/L when SDH was under the control of strong promoters P2057 and P2703. This study obtained a series of gradient promoters, including two strong shuttle promoters, and expanded the toolbox of available promoters for the application in metabolic engineering of G. oxydans for high-value products.
Finite Element Modeling of the Dynamic Response of Critical Zones in a Ballasted Railway Track
Authors: Punetha Piyush , Maharjan Krijan , Nimbalkar Sanjay
Published: April 2021

The critical zones are the discontinuities along a railway line that are highly susceptible to differential settlement, due to an abrupt variation in the support conditions over a short span. Consequently, these zones require frequent maintenance to ensure adequate levels of passenger safety and comfort. A proper understanding of the behavior of railway tracks at critical zones is imperative to enhance their performance and reduce the frequency of costly maintenance operations. This paper investigates the dynamic behavior of the critical zone along a bridge-open track transition under moving train loads using two-dimensional finite element approach. The influence of different subgrade types on the track behavior is studied. The effectiveness of using geogrids, wedge-shaped engineered backfill and zone with reduced sleeper spacing in improving the performance of the critical zone is evaluated. The numerical model is successfully validated against the field data reported in the literature. The results indicate that the subgrade soil significantly influences the track response on the softer side of the critical zone. The difference in vertical displacement between the stiffer and the softer side of a track transition decreases significantly with an increase in the strength and stiffness of the subgrade soil. The subgrade layer also influences the contribution of the granular layers (ballast and subballast) to the overall track response. As the subgrade becomes stiffer and stronger, the contribution of the granular layers to the overall track displacement increases. The mitigation techniques that improve the stiffness or strength of granular layers may prove more effective for critical zones with stiff subgrade than critical zones with soft subgrade. Among all the mitigation techniques investigated, the wedge-shaped engineered backfill significantly improved the performance of the critical zone by gradually increasing the track stiffness.
Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a
Authors: Li Shuang , Liu Chengdong , Goldstein Allison , Xin Yi , Ke Caihuan , Duan Cunming
Published: April 2021

The molecular mechanisms regulating cell quiescence-proliferation balance are not well defined. Using a zebrafish model, we report that Stc1a, a secreted glycoprotein, plays a key role in regulating the quiescence-proliferation balance of Ca2+transporting epithelial cells (ionocytes). Zebrafishstc1a, but not the otherstcgenes, is expressed in a Ca2+state-dependent manner. Genetic deletion ofstc1a, but notstc2b, increased ionocyte proliferation, leading to elevated body Ca2+levels, cardiac edema, body swelling, and premature death. The increased ionocyte proliferation was accompanied by an increase in the IGF1 receptor-mediated PI3 kinase-Akt-Tor signaling activity in ionocytes. Inhibition of the IGF1 receptor, PI3 kinase, Akt, and Tor signaling reduced ionocyte proliferation and rescued the edema and premature death instc1a–/–fish, suggesting that Stc1a promotes ionocyte quiescence by suppressing local IGF signaling activity. Mechanistically, Stc1 acts by inhibiting Papp-aa, a zinc metalloproteinase degrading Igfbp5a. Inhibition of Papp-aa proteinase activity restored ionocyte quiescence-proliferation balance. Genetic deletion ofpapp-aaor its substrateigfbp5ain thestc1a–/–background reduced ionocyte proliferation and rescued the edema and premature death. These findings uncover a novel and Ca2+state-dependent pathway regulating cell quiescence. Our findings also provide new insights into the importance of ionocyte quiescent-proliferation balance in organismal Ca2+homeostasis and survival.
A Physics-Aware Neural Network Approach for Flow Data Reconstruction From Satellite Observations
Authors: Schweri Luca , Foucher Sebastien , Tang Jingwei , Azevedo Vinicius C. , Günther Tobias , Solenthaler Barbara
Published: April 2021

An accurate assessment of physical transport requires high-resolution and high-quality velocity information. In satellite-based wind retrievals, the accuracy is impaired due to noise while the maximal observable resolution is bounded by the sensors. The reconstruction of a continuous velocity field is important to assess transport characteristics and it is very challenging. A major difficulty is ambiguity, since the lack of visible clouds results in missing information and multiple velocity fields will explain the same sparse observations. It is, therefore, necessary to regularize the reconstruction, which would typically be done by hand-crafting priors on the smoothness of the signal or on the divergence of the resulting flow. However, the regularizers can smooth the solution excessively and will not guarantee that possible solutions are truly physically realizable. In this paper, we demonstrate that data recovery can be learned by a neural network from numerical simulations of physically realizable fluid flows, which can be seen as a data-driven regularization. We show that the learning-based reconstruction is especially powerful in handling large areas of missing or occluded data, outperforming traditional models for data recovery. We quantitatively evaluate our method on numerically-simulated flows, and additionally apply it to a Guadalupe Island case study—a real-world flow data set retrieved from satellite imagery of stratocumulus clouds.
Antiretroviral Drugs Regulate Epigenetic Modification of Cardiac Cells Through Modulation of H3K9 and H3K27 Acetylation
Authors: Kashyap Shiridhar , Mukker Avni , Gupta Deepti , Datta Prasun K. , Rappaport Jay , Jacobson Jeffrey M. , Ebert Steven N. , Gupta Manish K.
Published: April 2021

Antiretroviral therapy (ART) has significantly reduced the rate of mortality in HIV infected population, but people living with HIV (PLWH) show higher rates of cardiovascular disease (CVD). However, the effect of antiretroviral (ARV) drug treatment on cardiac cells is not clear. In this study, we explored the effect of ARV drugs in cardiomyocyte epigenetic remodeling. Primary cardiomyocytes were treated with a combination of four ARV drugs (ritonavir, abacavir, atazanavir, and lamivudine), and epigenetic changes were examined. Our data suggest that ARV drugs treatment significantly reduces acetylation at H3K9 and H3K27 and promotes methylation at H3K9 and H3K27, which are histone marks for gene expression activation and gene repression, respectively. Besides, ARV drugs treatment causes pathological changes in the cell through increased production of reactive oxygen species (ROS) and cellular hypertrophy. Further, the expression of chromatin remodeling enzymes was monitored in cardiomyocytes treated with ARV drugs using PCR array. The PCR array data indicated that the expression of epigenetic enzymes was differentially regulated in the ARV drugs treated cardiomyocytes. Consistent with the PCR array result, SIRT1, SUV39H1, and EZH2 protein expression was significantly upregulated in ARV drugs treated cardiomyocytes. Furthermore, gene expression analysis of the heart tissue from HIV+ patients showed that the expression of SIRT1, SUV39H1, and EZH2 was up-regulated in patients with a history of ART. Additionally, we found that expression of SIRT1 can protect cardiomyocytes in presence of ARV drugs through reduction of cellular ROS and cellular hypertrophy. Our results reveal that ARV drugs modulate the epigenetic histone markers involved in gene expression, and play a critical role in histone deacetylation at H3K9 and H3K27 during cellular stress. This study may lead to development of novel therapeutic strategies for the treatment of CVD in PLWH.
Insight Into Hartoušov Mofette, Czech Republic: Tales by the Fluids
Authors: Daskalopoulou Kyriaki , Woith Heiko , Zimmer Martin , Niedermann Samuel , Barth Johannes A. C. , Frank Alexander H. , Vieth-Hillebrand Andrea , Vlček Josef , Bağ Cemile Dilara , Bauz Ralf
Published: April 2021

The Cheb Basin (Czech Republic) is characterized by emanations of magma-derived gases and repeated occurrences of mid-crustal earthquake swarms with small to intermediate magnitudes (ML < 4.5). Associated intense mantle degassing occurs at the Hartoušov Mofette, a representative site for the Cheb Basin. Here, we performed 14 sampling campaigns between June 2019 and March 2020. Gas samples of fluids ascending in two boreholes (F1, ∼28 m depth and F2, ∼108 m depth) and from a nearby natural mofette were analyzed for their chemical (CO2, N2, O2, Ar, He, CH4, and H2) and isotope compositions (noble gases and CO2). CO2 concentrations were above 99.1% in most samples, while O2 and N2 were below 0.6%. He ranged from 19 to 34 μmol/mol and CH4 was mostly below 12 μmol/mol. Isotope compositions of helium and carbon in CO2 ranged from 5.39 to 5.86 RA and from −2.4 to −1.3 ‰ versus VPDB, respectively. Solubility differences of the investigated gases resulted in fluctuations of their chemical compositions. These differences were accompanied by observed changes of gas fluxes in the field and at the monitoring station for F1. Variations in solubilities and fluxes also impacted the chemical concentration of the gases and the δ13C values that were also likely influenced by Fischer-Tropsch type reactions. The combination of (a) the Bernard ratio, (b) CH4/3He distributions, (c) P-T conditions, (d) heat flow, and (e) the sedimentary regime led to the hypothesis that CH4 may be of mixed biogenic and volcanic/geothermal origin with a noticeable atmospheric contribution. The drilling of a third borehole (F3) with a depth of ∼238 m in August 2019 has been crucial for providing insights into the complex system of Hartoušov Mofette.
Discrepancies of Upper Troposphere Summer Thermal Contrast Between Tibetan Plateau and Tropical Indian Ocean in Multiple Data
Authors: Luo Xiaoqing , Xu Jianjun , Li Kai
Published: April 2021

Under the background of global warming, the summer land-sea thermal contrasts at the upper troposphere exists great discrepancies in radiosonde data (IUK, RICH, and RAOBCORE), reanalysis data (JRA-55, NCEP/DOE, and ERA5) and CMIP6 models results (MPI, FGOALS, and CESM2) for the period of 1979-2014. It can be found that the descriptive statistical indicators (i.e., maximum, minimum, and skewness) of the summer land-sea thermal contrasts index (TTI) between the Tibetan Plateau (TP) and the Tropical Indian Ocean (TIO) vary greatly. The ERA5 and JRA-55 data have the best correlation with radiosonde data. The linear trend and running linear trend (RTL) of the radiosonde data are significantly correlated with the reanalysis data, and both show that the land-sea thermal contrast rapidly increasing are in 1990s and the late 2000s, and the period of rapid weakening was early 2000s. This interannual variation may modulated by the decadal signals such as Pacific Decadal Oscillation (PDO). Except for the NCEP/DOE and IUK, other data show that the most significant warming in the TP-TIO region is at the upper troposphere, and the vertical profiles of the summer temperature trend are quite different in different data, and CMIP6 shows an obvious warm bias in the upper troposphere.
Ontogenetic Changes of the Aquatic Food Uptake Mode in the Danube Crested Newt (Triturus dobrogicus Kiritzescu 1903)
Authors: Natchev Nikolay , Yordanova Kristina , Topliceanu Sebastian , Koynova Teodora , Doichev Dimitar , Cogălniceanu Dan
Published: April 2021

The study of the feeding mechanisms in vertebrates requires an integrative approach since the feeding event consists of a chain of behaviors. In the present study we investigated the food uptake behavior in different ontogenetic stages in the Danube crested newt (Triturus dobrogicus). We focused on the coordination in the kinematics of the elements of the locomotor and the feeding systems at the transition between the approach of the newt to the prey and the food uptake start. In the feeding strategy of the larvae ofT. dobrogicus, the phase of food search is replaced by an initial “food detection phase.” In both larvae and adult specimens, the animals approached the food to a close distance by a precise positioning of the snout besides the food item. The larvae were able to reach food items offered at over 80° relative to the longitudinal midline of the head. When the food was offered at a large distance or laterally, the food uptake was either not successful or the coordination chain at the transition between food approach and food uptake was interrupted. In young larvae we detected an abrupt change in the activity of the locomotor system and the feeding system. The larvae approached the food by tail undulation and after reaching the final position of attack, no further activity of the locomotor apparatus was detectable. The larvae used a pure form of inertial suction to ingest food. In pre-metamorphic larvae and adults we registered an integrated activation of the locomotor apparatus (both limbs and tail) and the feeding apparatus during prey capture in the form of compensatory suction. The drastic change in the feeding mode of the pre-metamorphotic larvae and the adults compared to the younger larvae inT. dobrogicusmay indicate the evolutionary development of a defined relation in the activity of the locomotor system and the control of the feeding apparatus. We propose that in newts, the interaction between the control execution in both systems switched from successive (body movement – feeding) into integrated (body movement – body movement and feeding) during the ontogeny. The main trigger for such a switch (at least inT. dobrogicus) is the formation of functional limbs during the late larval development.
Integrative Analysis of TP53INP2 in Head and Neck Squamous Cell Carcinoma
Authors: Cao Ruoyan , Liu Suyang , Zhang Jiayu , Ren Xianyue , Chen Xijuan , Cheng Bin , Xia Juan
Published: April 2021

TP53INP2 plays an important role in regulating gene transcription and starvation-induced autophagy, however, its function in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, we assessed the expression and prognostic value of TP53INP2. In addition, RNAseq, miRNAseq, copy number variation, and mutation profiles from The Cancer Genome Atlas (TCGA) dataset were applied to evaluate the distinctive genomic patterns related to TP53INP2 expression. We found that TP53INP2 expression was lower in HNSCC compared with normal controls. Patients with higher TP53INP2 expression had longer survival time. Knockdown of TP53INP2 promoted cell viability. Functional analysis exhibited that TP53INP2 was linked to DNA replication, DNA repair, cell cycle, and multiple metabolic pathways. Moreover, TP53INP2 might affect the expression of multiple genes via enhancing the transcriptional activity of nuclear hormone receptors. A competing endogenous RNA (ceRNA) network consisting of 33 lncRNAs, eight miRNAs, and 13 mRNAs was constructed based on the expression of TP53INP2. Taken together, our study highlights the potential value of TP53INP2 in predicting the survival of HNSCC and its important role in the genesis and development of HNSCC.
Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis
Authors: Porritt Rebecca A. , Chase Huizar Carol , Dick Edward J. , Kumar Shyamesh , Escalona Renee , Gomez Angela C. , Marek-Iannucci Stefani , Noval Rivas Magali , Patterson Jean , Forsthuber Thomas G. , Arditi Moshe , Gorelik Mark
Published: April 2021

Objective

Kawasaki disease (KD) is the most common cause of acquired pediatric heart disease in the developed world. 10% of KD patients are resistant to front-line therapy, and no interventions exist to address secondary complications such as myocardial fibrosis. We sought to identify proteins and pathways associated with disease and anti-IL-1 treatment in a mouse model of KD.

Methods

Vasculitis was induced via Lactobacillus casei cell wall extract (LCWE) injection in 5-week-old male mice. Groups of mice were injected with LCWE alone, LCWE and IL-1 receptor antagonist anakinra, or saline for controls. Upper heart tissue was assessed by quantitative mass spectrometry analysis. Expression and activation of STAT3 was assessed by immunohistochemistry, immunofluorescence and Western blot, and IL-6 expression by RNA-seq and ELISA. A STAT3 small molecular inhibitor and anti-IL-6R antibody were used to evaluate the role of STAT3 and IL-6 in disease development.

Results

STAT3 was highly expressed and phosphorylated in cardiac tissue of LCWE-injected mice, and reduced following anakinra treatment. Il6 and Stat3 gene expression was enhanced in abdominal aorta of LCWE-injected mice and reduced with Anakinra treatment. IL-6 serum levels were enhanced in LCWE-injected mice and normalized by anakinra. However, neither inhibition of STAT3 nor blockade of IL-6 altered disease development.

Conclusion

Proteomic analysis of cardiac tissues demonstrates differential protein expression between KD-like, control and anakinra treated cardiac tissue. STAT3 and IL-6 were highly upregulated with LCWE and normalized by anakinra treatment. However, both STAT3 and IL-6 were dispensable for disease development indicating they may be bystanders of inflammation.
The First Contact of Human Dendritic Cells With Trypanosoma cruzi Reveals Response to Virus as an Unexplored Central Pathway
Authors: Gil-Jaramillo Natalia , Rocha Amanda Pereira , Raiol Tainá , Motta Flávia Nader , Favali Cecília , Brigido Marcelo M. , Bastos Izabela M. D. , Santana Jaime M.
Published: April 2021

Chagas disease is a debilitating and neglected disease caused by the protozoanTrypanosoma cruzi. Soon after infection, interactions amongT. cruziand host innate immunity cells can drive/contribute to disease outcome. Dendritic cells (DCs), present in all tissues, are one of the first immune cells to interact withTrypanosoma cruzimetacyclic trypomastigotes. Elucidating the immunological events triggered immediately after parasite-human DCs encounter may aid in understanding the role of DCs in the establishment of infection and in the course of the disease. Therefore, we performed a transcriptomic analysis of a 12 h interaction betweenT. cruziand MoDCs (monocyte-derived DCs) from three human donors. Enrichment analyses of the 468 differentially expressed genes (DEGs) revealed viral infection response as the most regulated pathway. Additionally, exogenous antigen processing and presentation through MHC-I, chemokine signaling, lymphocyte co-stimulation, metallothioneins, and inflammasome activation were found up-regulated. Notable, we were able to identify the increased gene expression of alternative inflammasome sensors such as AIM2, IFI16, and RIG-I for the first time in aT. cruziinfection. Both transcript and protein expression levels suggest proinflammatory cytokine production during earlyT. cruzi-DCs contact. Our transcriptome data unveil antiviral pathways as an unexplored process duringT. cruzi-DC initial interaction, disclosing a new panorama for the study of Chagas disease outcomes.
To Ki or Not to Ki: Re-Evaluating the Use and Potentials of Ki-67 for T Cell Analysis
Authors: Di Rosa Francesca , Cossarizza Andrea , Hayday Adrian C.
Published: April 2021

This study discusses substantive advances in T cell proliferation analysis, with the aim to provoke a re-evaluation of the generally-held view that Ki-67 is a reliable proliferation markerper se, and to offer a more sensitive and effective method for T cell cycle analysis, with informative examples in mouse and human settings. We summarize recent experimental work from our labs showing that, by Ki-67/DNA dual staining and refined flow cytometric methods, we were able to identify T cells in the S-G2/M phases of the cell-cycle in the peripheral blood (collectively termed “T Double S” forTcells inS-phaseinSanguine: in short “TDS” cells). Without our refinement, such cells may be excluded from conventional lymphocyte analyses. Specifically, we analyzed clonal expansion of antigen-specific CD8 T cells in vaccinated mice, and demonstrated the potential of TDScells to reflect immune dynamics in human blood samples from healthy donors, and patients with type 1 diabetes, infectious mononucleosis, and COVID-19. The Ki-67/DNA dual staining, or TDSassay, provides a reliable approach by which human peripheral blood can be used to reflect the dynamics of human lymphocytes, rather than providing mere steady-state phenotypic snapshots. The method does not require highly sophisticated “-omics” capabilities, so it should be widely-applicable to health care in diverse settings. Furthermore, our results argue that the TDSassay can provide a window on immune dynamics in extra-lymphoid tissues, a long-sought potential of peripheral blood monitoring, for example in relation to organ-specific autoimmune diseases and infections, and cancer immunotherapy.
Ex-TFRs: A Missing Piece of the SLE Puzzle?
Authors: Wei Xundong , Zhang Jianhua , Zhou Xuyu
Published: April 2021

Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease involving the production of a wide range of autoantibodies and complement activation. The production of these high-affinity autoantibodies requires T cell/B cell collaboration as well as germinal center (GC) formation. T follicular regulatory cells (TFRs) are functional specialized T regulatory cells (Tregs) that safeguard against both self-reactive T and B cells. However, recent evidence suggests that TFRs are not always stable and can lose Foxp3 expression to become pathogenic “ex-TFRs” that gain potent effector functions. In this review, we summarize the literature on intrinsic and extrinsic mechanisms of regulation of TFR stability and discuss the potential role of TFR reprogramming in autoantibody production and SLE pathogenesis.
MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rheumatoid Arthritis Patients
Authors: Heinicke Fatima , Zhong Xiangfu , Flåm Siri T. , Breidenbach Johannes , Leithaug Magnus , Mæhlen Marthe T. , Lillegraven Siri , Aga Anna-Birgitte , Norli Ellen S. , Mjaavatten Maria D. , Haavardsholm Espen A. , Zucknick Manuela , Rayner Simon , Lie Benedicte A.
Published: April 2021

Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.
Traditional Dimensions of Seabed Resource Management in the Context of Deep Sea Mining in the Pacific: Learning From the Socio-Ecological Interconnectivity Between Island Communities and the Ocean Realm
Authors: Tilot Virginie , Willaert Klaas , Guilloux Bleuenn , Chen Wenting , Mulalap Clement Y. , Gaulme François , Bambridge Tamatoa , Peters Kimberley , Dahl Arthur
Published: April 2021

In many of the Pacific Islands, local communities have long-held cultural and spiritual attachments to the sea, in particular to species and specific marine areas, processes, habitats, islands, and natural seabed formations. Traditional knowledge, customary marine management approaches and integrated relationships between biodiversity, ecosystems and local communities promote conservation and ensure that marine benefits are reaped in a holistic, sustainable and equitable manner. However, the interaction between local traditional knowledge, contemporary scientific approaches to marine resource management and specific regulatory frameworks has often been challenging. To some extent, the value of community practices and customary law, which have provided an incentive for regional cooperation and coordination around ocean governance, is acknowledged in several legal systems in the Pacific and a number of regional and international instruments, but this important connection can be further enhanced. In this article we present a science-based overview of the marine habitats that would be affected by deep seabed mining (DSM) along with an analysis of some traditional dimensions and cultural/societal aspects of marine resource management. We then assess whether the applicable legal frameworks at different levels attach sufficient importance to these traditional dimensions and to the human and societal aspects of seabed (mineral) resource management in the region. On the basis of this analysis, we identify best practices and formulate recommendations with regard to the current regulatory frameworks and seabed resource management approaches. Indeed, the policies and practices developed in the Pacific could well serve as a suitable model elsewhere to reconcile commercial, ecological, cultural and social values within the context of deep sea mineral exploitation in addition to sustaining the Human Well-being and Sustainable Livelihoods (HWSL) of the Pacific communities and the health of the Global Ocean.
RNAs as Regulators of Cellular Matchmaking
Authors: Fernandes Nikita , Buchan J. Ross
Published: April 2021

RNA molecules are increasingly being identified as facilitating or impeding the interaction of proteins and nucleic acids, serving as so-called scaffolds or decoys. Long non-coding RNAs have been commonly implicated in such roles, particularly in the regulation of nuclear processes including chromosome topology, regulation of chromatin state and gene transcription, and assembly of nuclear biomolecular condensates such as paraspeckles. Recently, an increased awareness of cytoplasmic RNA scaffolds and decoys has begun to emerge, including the identification of non-coding regions of mRNAs that can also function in a scaffold-like manner to regulate interactions of nascently translated proteins. Collectively, cytoplasmic RNA scaffolds and decoys are now implicated in processes such as mRNA translation, decay, protein localization, protein degradation and assembly of cytoplasmic biomolecular condensates such as P-bodies. Here, we review examples of RNA scaffolds and decoys in both the nucleus and cytoplasm, illustrating common themes, the suitability of RNA to such roles, and future challenges in identifying and better understanding RNA scaffolding and decoy functions.
Validation of Induced Microglia-Like Cells (iMG Cells) for Future Studies of Brain Diseases
Authors: Banerjee Atoshi , Lu Yimei , Do Kenny , Mize Travis , Wu Xiaogang , Chen Xiangning , Chen Jingchun
Published: April 2021

Microglia are the primary resident immune cells of the central nervous system that maintain physiological homeostasis in the brain and contribute to the pathogenesis of many psychiatric disorders and neurodegenerative diseases. Due to the lack of appropriate human cellular models, it is difficult to study the basic pathophysiological processes linking microglia to brain diseases. In this study, we adopted a microglia-like cellular model derived from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). We characterized and validated this in vitro cellular model by morphology, immunocytochemistry, gene expression profiles, and functional study. Our results indicated that the iMG cells developed typical microglial ramified morphology, expressed microglial specific surface markers (P2RY12 and TMEM119), and possessed phagocytic activity. Principal component analyses and multidimensional scaling analyses of RNA-seq data showed that iMG cells were distinct from monocytes and induced macrophages (iMacs) but clustered closer to human microglia and hiPSC-induced microglia. Heatmap analyses also found that iMG cells, but not monocytes, were closely clustered with human primary microglia. Further pathway and relative expression analysis indicated that unique genes from iMG cells were involved in the regulation of the complement system, especially in the synapse and ion transport. Overall, our data demonstrated that the iMG model mimicked many features of the brain resident microglia, highlighting its utility in the study of microglial function in many brain diseases, such as schizophrenia and Alzheimer's disease (AD).
Tonic Control of Secretory Acid Sphingomyelinase Over Ventral Hippocampal Synaptic Transmission and Neuron Excitability
Authors: Lin Chih-Hung , Kornhuber Johannes , Zheng Fang , Alzheimer Christian
Published: April 2021

The acid sphingomyelinase (ASM) converts sphingomyelin into ceramide. Recent work has advanced the ASM/ceramide system as a major player in the pathogenesis of major depressive disorder (MDD). Indeed, ASM activity is enhanced in MDD patients and antidepressant drugs like fluoxetine act as functional inhibitors of ASM. Here, we employed the specific ASM inhibitor ARC39 to explore the acute effects of the enzyme on hippocampal synaptic transmission and cell excitability in adult mouse brain slice preparations. In both field potential and whole-cell recordings, ARC39 (1–3 μM) enhanced excitatory synaptic input onto ventral hippocampal CA1 pyramidal cells. The specificity of drug action was demonstrated by its lacking effect in slices from ASM knockout mice. In control condition, ARC39 strongly reduced firing in most CA1 pyramidal cells, together with membrane hyperpolarization. Such pronounced inhibitory action of ARC39 on soma excitability was largely reversed when GABAA receptors were blocked. The idea that ARC39 recruits GABAergic inhibition to dampen cell excitability was further reinforced by the drug’s ability to enhance the inhibitory synaptic drive onto pyramidal cells. In pyramidal cells that were pharmacologically isolated from synaptic input, the overall effect of ARC39 on cell firing was inhibitory, but some neurons displayed a biphasic response with a transient increase in firing, suggesting that ARC39 might alter intrinsic firing properties in a cell-specific fashion. Because ARC39 is charged at physiological pH and exerted all its effects within minutes of application, we propose that the neurophysiological actions reported here are due to the inhibition of secretory rather than lysosomal ASM. In summary, the ASM inhibitor ARC39 reveals a tonic control of the enzyme over ventral hippocampal excitability, which involves the intrinsic excitability of CA1 pyramidal cells as well as their excitatory and inhibitory synaptic inputs.
Neurotropic Viruses, Astrocytes, and COVID-19
Authors: Tavčar Petra , Potokar Maja , Kolenc Marko , Korva Miša , Avšič-Županc Tatjana , Zorec Robert , Jorgačevski Jernej
Published: April 2021

At the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered in China, causing a new coronavirus disease, termed COVID-19 by the WHO on February 11, 2020. At the time of this paper (January 31, 2021), more than 100 million cases have been recorded, which have claimed over 2 million lives worldwide. The most important clinical presentation of COVID-19 is severe pneumonia; however, many patients present various neurological symptoms, ranging from loss of olfaction, nausea, dizziness, and headache to encephalopathy and stroke, with a high prevalence of inflammatory central nervous system (CNS) syndromes. SARS-CoV-2 may also target the respiratory center in the brainstem and cause silent hypoxemia. However, the neurotropic mechanism(s) by which SARS-CoV-2 affects the CNS remain(s) unclear. In this paper, we first address the involvement of astrocytes in COVID-19 and then elucidate the present knowledge on SARS-CoV-2 as a neurotropic virus as well as several other neurotropic flaviviruses (with a particular emphasis on the West Nile virus, tick-borne encephalitis virus, and Zika virus) to highlight the neurotropic mechanisms that target astroglial cells in the CNS. These key homeostasis-providing cells in the CNS exhibit many functions that act as a favorable milieu for virus replication and possibly a favorable environment for SARS-CoV-2 as well. The role of astrocytes in COVID-19 pathology, related to aging and neurodegenerative disorders, and environmental factors, is discussed. Understanding these mechanisms is key to better understanding the pathophysiology of COVID-19 and for developing new strategies to mitigate the neurotropic manifestations of COVID-19.
Freely Behaving Mice Can Brake and Turn During Optogenetic Stimulation of the Mesencephalic Locomotor Region
Authors: van der Zouwen Cornelis Immanuel , Boutin Joël , Fougère Maxime , Flaive Aurélie , Vivancos Mélanie , Santuz Alessandro , Akay Turgay , Sarret Philippe , Ryczko Dimitri
Published: April 2021

A key function of the mesencephalic locomotor region (MLR) is to control the speed of forward symmetrical locomotor movements. However, the ability of freely moving mammals to integrate environmental cues to brake and turn during MLR stimulation is poorly documented. Here, we investigated whether freely behaving mice could brake or turn, based on environmental cues during MLR stimulation. We photostimulated the cuneiform nucleus (part of the MLR) in mice expressing channelrhodopsin in Vglut2-positive neurons in a Cre-dependent manner (Vglut2-ChR2-EYFP) using optogenetics. We detected locomotor movements using deep learning. We used patch-clamp recordings to validate the functional expression of channelrhodopsin and neuroanatomy to visualize the stimulation sites. In the linear corridor, gait diagram and limb kinematics were similar during spontaneous and optogenetic-evoked locomotion. In the open-field arena, optogenetic stimulation of the MLR evoked locomotion, and increasing laser power increased locomotor speed. Mice could brake and make sharp turns (~90°) when approaching a corner during MLR stimulation in the open-field arena. The speed during the turn was scaled with the speed before the turn, and with the turn angle. Patch-clamp recordings in Vglut2-ChR2-EYFP mice show that blue light evoked short-latency spiking in MLR neurons. Our results strengthen the idea that different brainstem neurons convey braking/turning and MLR speed commands in mammals. Our study also shows that Vglut2-positive neurons of the cuneiform nucleus are a relevant target to increase locomotor activity without impeding the ability to brake and turn when approaching obstacles, thus ensuring smooth and adaptable navigation. Our observations may have clinical relevance since cuneiform nucleus stimulation is increasingly considered to improve locomotion function in pathological states such as Parkinson’s disease, spinal cord injury, or stroke.
Maintenance Therapy With Everolimus for Subependymal Giant Cell Astrocytoma in Patients With Tuberous Sclerosis – Final Results From the EMINENTS Study
Authors: Bobeff Katarzyna , Krajewska Karolina , Baranska Dobromila , Kotulska Katarzyna , Jozwiak Sergiusz , Mlynarski Wojciech , Trelinska Joanna
Published: April 2021

The aim of this EMINENTS prospective, single-center, open-label, single-arm study was to evaluate the cumulative efficacy and safety of reduced doses of everolimus (maintenance therapy) in patients with tuberous sclerosis and subependymal giant cell astrocytoma (SEGA).

Methods: The trial included 15 patients who had undergone at least 12 months of treatment with a standard everolimus dose. The dose of everolimus was reduced to three times a week, with a daily dose as in standard regimen. Data of 14 patients were analyzed. SEGA volume (SV) was evaluated at study entry and subsequent time points by an experienced radiologist. Adverse events (AEs) noted during maintenance therapy were compared to the AEs of standard dose period.

Results: Patients were followed over a mean duration 58.37 months (95%CI: 45.95–70.78). The differences in SEGA volume between subsequent time points (0, 3, 6,12, 18, 24, 36, 48, and 60 months) were not statistically significant (p = 0.16). At the end of the study, 7 out of 10 patients had stable SEGA volume. No clinical symptoms of progression were observed in any patients. No patient or tumor-related risk factors of progression were identified. Regarding AEs, infections (stomatitis, bronchitis, diarrhea) and laboratory abnormalities (neutropenia, anemia, hyperglycemia) occurred less frequently during maintenance therapy compared to the standard dose regimen.

Conclusions: Final results from EMINENTS study confirm that maintenance therapy with everolimus might represent a rational therapeutic option for patients TSC and SEGA after effective full dose treatment. It could be an option for patients who experienced everolimus-related AEs, instead of discontinuation of therapy. Careful evaluation of possible progression, especially concerning first six months of maintenance therapy should be advised.

Clinical Trial Registration:www.drks.de, identifier DRKS00005584.
Neural Representation of the English Vowel Feature [High]: Evidence From /ε/ vs. /ɪ/
Authors: Yu Yan H. , Shafer Valerie L.
Published: April 2021

Many studies have observed modulation of the amplitude of the neural index mismatch negativity (MMN) related to which member of a phoneme contrast [phoneme A, phoneme B] serves as the frequent (standard) and which serves as the infrequent (deviant) stimulus (i.e., AAAB vs. BBBA) in an oddball paradigm. Explanations for this amplitude modulation range from acoustic to linguistic factors. We tested whether exchanging the role of the mid vowel /ε/ vs. high vowel /ɪ/ of English modulated MMN amplitude and whether the pattern of modulation was compatible with an underspecification account, in which the underspecified height values are [−high] and [−low]. MMN was larger for /ε/ as the deviant, but only when compared across conditions to itself as the standard. For the within-condition comparison, MMN was larger to /ɪ/ deviant minus /ε/ standard than to the reverse. A condition order effect was also observed. MMN amplitude was smaller to the deviant stimulus if it had previously served as the standard. In addition, the amplitudes of late discriminative negativity (LDN) showed similar asymmetry. LDN was larger for deviant /ε/ than deviant /ɪ/ when compared to themselves as the standard. These findings were compatible with an underspecification account, but also with other accounts, such as the Natural Referent Vowel model and a prototype model; we also suggest that non-linguistic factors need to be carefully considered as additional sources of speech processing asymmetries.