bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cannabinoid receptor 1 signalling modulates stress susceptibility and microglial responses to chronic social defeat stress
Authors: Beins Eva C. , Beiert Thomas , Jenniches Imke , Hansen Jan N. , Leidmaa Este , Schrickel Jan W. , Zimmer Andreas 
Published: March 2021

AbstractPsychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (Cnr1−/−) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed Cnr1+/+ and Cnr1−/− mice to chronic social defeat stress (CSDS). Cnr1−/− mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible Cnr1−/− mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in Cnr1−/− mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of Cnr1−/− mice showed increased expression of Fkbp5, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.
Physiological parameters of mental health predict the emergence of post-traumatic stress symptoms in physicians treating COVID-19 patients
Authors: Dolev T. , Zubedat S. , Brand Z. , Bloch B. , Mader E. , Blondheim O. , Avital A. 
Published: March 2021

AbstractLack of established knowledge and treatment strategies, and change in work environment, may altogether critically affect the mental health and functioning of physicians treating COVID-19 patients. Thus, we examined whether treating COVID-19 patients affect the physicians’ mental health differently compared with physicians treating non-COVID-19 patients. In this cohort study, an association was blindly computed between physiologically measured anxiety and attention vigilance (collected from 1 May 2014 to 31 May 31 2016) and self-reports of anxiety, mental health aspects, and sleep quality (collected from 20 April to 30 June 2020, and analyzed from 1 July to 1 September 2020), of 91 physicians treating COVID-19 or non-COVID-19 patients. As a priori hypothesized, physicians treating COVID-19 patients showed a relative elevation in both physiological measures of anxiety (95% CI: 2317.69–2453.44 versus 1982.32–2068.46; P < 0.001) and attention vigilance (95% CI: 29.85–34.97 versus 22.84–26.61; P < 0.001), compared with their colleagues treating non-COVID-19 patients. At least 3 months into the pandemic, physicians treating COVID-19 patients reported high anxiety and low quality of sleep. Machine learning showed clustering to the COVID-19 and non-COVID-19 subgroups with a high correlation mainly between physiological and self-reported anxiety, and between physiologically measured anxiety and sleep duration. To conclude, the pattern of attention vigilance, heightened anxiety, and reduced sleep quality findings point the need for mental intervention aimed at those physicians susceptible to develop post-traumatic stress symptoms, owing to the consequences of fighting at the forefront of the COVID-19 pandemic.
Quantification of biomarker functionality predicts patient outcomes
Authors: Larijani Banafshé , Miles James , Ward Stephen G. , Parker Peter J. 
Published: March 2021

SummaryImplementation of a quantitative molecular imaging method (iFRET), which determines receptor–ligand interactions, has led to the finding that patients with a low extent of PD-1/PD-L1 interaction in metastatic NSCLC, and malignant melanoma, display significantly worsened overall survival compared to those with a high level of interaction.
MiR-127-3p targeting CISD1 regulates autophagy in hypoxic–ischemic cortex
Authors: Zhang Zi-Bin , Xiong Liu-Lin , Xue Lu-Lu , Deng Yan-Ping , Du Ruo-Lan , Hu Qiao , Xu Yang , Yang Si-Jin , Wang Ting-Hua 
Published: March 2021

AbstractNeonatal hypoxic–ischemic (HI) injury derived from asphyxia during perinatal period, is a serious complication of neonatal asphyxia and the main cause of neonatal acute death and chronic neurological injury. Aberrant autophagy occurs in many nervous system diseases, but its role and underlying mechanism in HI injury is largely unknown. Here, we successfully constructed a newborn rat model of HI brain injury, and the knockout-miR-127-3p (KO-miR-127-3p) rats were structured by using CRISPR/Cas9. Subsequently, the in vitro functional experiments, in vivo zea-longa scores, as well as bioinformatics analyses and biological experiments were applied. The expression of autophagy-related proteins, including ATG12, P62, Beclin-1, LC3II in HI cortex with miR-127-3p knockout was significantly decreased, and autophagic vacuoles were disappeared. Moreover, miR-127-3p has a specific regulatory effect on CISD1 expression, another crucial molecule in autophagy process. Accordingly, the overexpression of CISD1 effectively inhibited the autophagic cell death and physiological dysfunction in the brain of HI injury, whereas si-CISD1 reversed the neuroprotective effects of KO-miR-127-3p. Our findings explained the underlying mechanism for HI injury, and miR-127-3p targeting CISD1 signal could be supposed as a new treatment strategy to prevent and treat HI injury.
Shc3 promotes hepatocellular carcinoma stemness and drug resistance by interacting with β-catenin to inhibit its ubiquitin degradation pathway
Authors: Liu Yun , Zhuang Hao , Cao Fang , Li Jie , Guo Yan , Zhang Jun , Zhao Qiang , Liu Yuanyuan 
Published: March 2021

AbstractHepatocellular carcinoma (HCC) is one of the most common cancers with an insidious onset, strong invasiveness, insensitivity to chemotherapy, and poor prognosis, thus makes clinical treatment challenging. The mechanisms require further elucidation for developing novel therapies and targeting drug resistance. Here, we observed high Shc3 expression in patients with chemoresistant and recurrent HCCs. Shc3 overexpression induced a significant increase in MDR1/P-glycoprotein expression, whereas Shc3 knockdown impaired this expression. Further, Shc3 inhibition significantly restored HCC cell sensitivity to doxorubicin and sorafenib. Mechanistically, Shc3 interacted with β-catenin, inhibited destruction complex stability, promoted β-catenin release, and dampened β-catenin ubiquitination. Shc3 bound β-catenin and facilitated its nuclear translocation, prompting the β-catenin/TCF pathway to elevate MDR1 transcription. β-catenin blockage abolished the discrepancy in drug resistance between Shc3-depleted HCC cells and control cells, which further validating that β-catenin is required for Shc3-mediated liver chemotherapy. We also determined the effect of Shc3 on the sensitivity of HCC to chemotherapy in vivo. Collectively, this study provides a potential strategy to target these pathways concurrently with systemic chemotherapy that can improve the clinical treatment of HCC.
Sirt1 coordinates with ERα to regulate autophagy and adiposity
Authors: Tao Zhipeng , Shi Limin , Parke Jane , Zheng Louise , Gu Wei , Dong X. Charlie , Liu Dongmin , Wang Zongwei , Olumi Aria F. , Cheng Zhiyong 
Published: March 2021

AbstractSex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.
Human pluripotent stem cell-derived alveolar organoids for modeling pulmonary fibrosis and drug testing
Authors: Kim Jung-Hyun , An Geun Ho , Kim Ji-Young , Rasaei Roya , Kim Woo Jin , Jin Xiong , Woo Dong-Hun , Han Choongseong , Yang Se-Ran , Kim Jong-Hoon , Hong Seok-Ho 
Published: March 2021

AbstractDetailed understanding of the pathogenesis and development of effective therapies for pulmonary fibrosis (PF) have been hampered by lack of in vitro human models that recapitulate disease pathophysiology. In this study, we generated alveolar organoids (AOs) derived from human pluripotent stem cells (hPSCs) for use as an PF model and for drug efficacy evaluation. Stepwise direct differentiation of hPSCs into alveolar epithelial cells by mimicking developmental cues in a temporally controlled manner was used to generate multicellular AOs. Derived AOs contained the expected spectrum of differentiated cells, including alveolar progenitors, type 1 and 2 alveolar epithelial cells and mesenchymal cells. Treatment with transforming growth factor (TGF-β1) induced fibrotic changes in AOs, offering a PF model for therapeutic evaluation of a structurally truncated form (NP-011) of milk fat globule-EGF factor 8 (MFG-E8) protein. The significant fibrogenic responses and collagen accumulation that were induced by treatment with TGF-β1 in these AOs were effectively ameliorated by treatment with NP-011 via suppression of extracellular signal-regulated kinase (ERK) signaling. Furthermore, administration of NP-011 reversed bleomycin-induced lung fibrosis in mice also via ERK signaling suppression and collagen reduction. This anti-fibrotic effect mirrored that following Pirfenidone and Nintedanib administration. Furthermore, NP-011 interacted with macrophages, which accelerated the collagen uptake for eliminating accumulated collagen in fibrotic lung tissues. This study provides a robust in vitro human organoid system for modeling PF and assessing anti-fibrotic mechanisms of potential drugs and suggests that modified MGF-E8 protein has therapeutic potential for treating PF.
2D printed multicellular devices performing digital and analogue computation
Authors: Mogas-Díez Sira , Gonzalez-Flo Eva , Macía Javier 
Published: March 2021

AbstractMuch effort has been expended on building cellular computational devices for different applications. Despite the significant advances, there are still several addressable restraints to achieve the necessary technological transference. These improvements will ease the development of end-user applications working out of the lab. In this study, we propose a methodology for the construction of printable cellular devices, digital or analogue, for different purposes. These printable devices are designed to work in a 2D surface, in which the circuit information is encoded in the concentration of a biological signal, the so-called carrying signal. This signal diffuses through the 2D surface and thereby interacts with different device components. These components are distributed in a specific spatial arrangement and perform the computation by modulating the level of the carrying signal in response to external inputs, determining the final output. For experimental validation, 2D cellular circuits are printed on a paper surface by using a set of cellular inks. As a proof-of-principle, we have printed and analysed both digital and analogue circuits using the same set of cellular inks but with different spatial topologies. The proposed methodology can open the door to a feasible and reliable industrial production of cellular circuits for multiple applications.
Personalized cancer vaccine strategy elicits polyfunctional T cells and demonstrates clinical benefits in ovarian cancer
Authors: Tanyi Janos L. , Chiang Cheryl L.-L. , Chiffelle Johanna , Thierry Anne-Christine , Baumgartener Petra , Huber Florian , Goepfert Christine , Tarussio David , Tissot Stephanie , Torigian Drew A. , Nisenbaum Harvey L. , Stevenson Brian J. , Guiren Hajer Fritah , Ahmed Ritaparna , Huguenin-Bergenat Anne-Laure , Zsiros Emese , Bassani-Sternberg Michal , Mick Rosemarie , Powell Daniel J. , Coukos George , Harari Alexandre , Kandalaft Lana E. 
Published: March 2021

AbstractT cells are important for controlling ovarian cancer (OC). We previously demonstrated that combinatorial use of a personalized whole-tumor lysate-pulsed dendritic cell vaccine (OCDC), bevacizumab (Bev), and cyclophosphamide (Cy) elicited neoantigen-specific T cells and prolonged OC survival. Here, we hypothesize that adding acetylsalicylic acid (ASA) and low-dose interleukin (IL)-2 would increase the vaccine efficacy in a recurrent advanced OC phase I trial (NCT01132014). By adding ASA and low-dose IL-2 to the OCDC-Bev-Cy combinatorial regimen, we elicited vaccine-specific T-cell responses that positively correlated with patients’ prolonged time-to-progression and overall survival. In the ID8 ovarian model, animals receiving the same regimen showed prolonged survival, increased tumor-infiltrating perforin-producing T cells, increased neoantigen-specific CD8+ T cells, and reduced endothelial Fas ligand expression and tumor-infiltrating T-regulatory cells. This combinatorial strategy was efficacious and also highlighted the predictive value of the ID8 model for future ovarian trial development.
Ligand modulation of the conformational dynamics of the A2A adenosine receptor revealed by single-molecule fluorescence
Authors: Fernandes Dennis D. , Neale Chris , Gomes Gregory-Neal W. , Li Yuchong , Malik Aimen , Pandey Aditya , Orazietti Alexander P. , Wang Xudong , Ye Libin , Scott Prosser R. , Gradinaru Claudiu C. 
Published: March 2021

AbstractG protein-coupled receptors (GPCRs) are the largest class of transmembrane proteins, making them an important target for therapeutics. Activation of these receptors is modulated by orthosteric ligands, which stabilize one or several states within a complex conformational ensemble. The intra- and inter-state dynamics, however, is not well documented. Here, we used single-molecule fluorescence to measure ligand-modulated conformational dynamics of the adenosine A2A receptor (A2AR) on nanosecond to millisecond timescales. Experiments were performed on detergent-purified A2R in either the ligand-free (apo) state, or when bound to an inverse, partial or full agonist ligand. Single-molecule Förster resonance energy transfer (smFRET) was performed on detergent-solubilized A2AR to resolve active and inactive states via the separation between transmembrane (TM) helices 4 and 6. The ligand-dependent changes of the smFRET distributions are consistent with conformational selection and with inter-state exchange lifetimes ≥ 3 ms. Local conformational dynamics around residue 2296.31 on TM6 was measured using fluorescence correlation spectroscopy (FCS), which captures dynamic quenching due to photoinduced electron transfer (PET) between a covalently-attached dye and proximal aromatic residues. Global analysis of PET-FCS data revealed fast (150–350 ns), intermediate (50–60 μs) and slow (200–300 μs) conformational dynamics in A2AR, with lifetimes and amplitudes modulated by ligands and a G-protein mimetic (mini-Gs). Most notably, the agonist binding and the coupling to mini-Gs accelerates and increases the relative contribution of the sub-microsecond phase. Molecular dynamics simulations identified three tyrosine residues (Y112, Y2887.53, and Y2907.55) as being responsible for the dynamic quenching observed by PET-FCS and revealed associated helical motions around residue 2296.31 on TM6. This study provides a quantitative description of conformational dynamics in A2AR and supports the idea that ligands bias not only GPCR conformations but also the dynamics within and between distinct conformational states of the receptor.
Pancancer survival analysis of cancer hallmark genes
Authors: Nagy Ádám , Munkácsy Gyöngyi , Győrffy Balázs 
Published: March 2021

AbstractCancer hallmark genes are responsible for the most essential phenotypic characteristics of malignant transformation and progression. In this study, our aim was to estimate the prognostic effect of the established cancer hallmark genes in multiple distinct cancer types. RNA-seq HTSeq counts and survival data from 26 different tumor types were acquired from the TCGA repository. DESeq was used for normalization. Correlations between gene expression and survival were computed using the Cox proportional hazards regression and by plotting Kaplan–Meier survival plots. The false discovery rate was calculated to correct for multiple hypothesis testing. Signatures based on genes involved in genome instability and invasion reached significance in most individual cancer types. Thyroid and glioblastoma were independent of hallmark genes (61 and 54 genes significant, respectively), while renal clear cell cancer and low grade gliomas harbored the most prognostic changes (403 and 419 genes significant, respectively). The eight genes with the highest significance included BRCA1 (genome instability, HR 4.26, p < 1E−16), RUNX1 (sustaining proliferative signaling, HR 2.96, p = 3.1E−10) and SERPINE1 (inducing angiogenesis, HR 3.36, p = 1.5E−12) in low grade glioma, CDK1 (cell death resistance, HR = 5.67, p = 2.1E−10) in kidney papillary carcinoma, E2F1 (tumor suppressor, HR 0.38, p = 2.4E−05) and EREG (enabling replicative immortality, HR 3.23, p = 2.1E−07) in cervical cancer, FBP1 (deregulation of cellular energetics, HR 0.45, p = 2.8E−07) in kidney renal clear cell carcinoma and MYC (invasion and metastasis, HR 1.81, p = 5.8E−05) in bladder cancer. We observed unexpected heterogeneity and tissue specificity when correlating cancer hallmark genes and survival. These results will help to prioritize future targeted therapy development in different types of solid tumors.
Low dystrophin variability between muscles and stable expression over time in Becker muscular dystrophy using capillary Western immunoassay
Authors: Koeks Z. , Janson A. A. , Beekman C. , Signorelli M. , van Duyvenvoorde H. A. , van den Bergen J. C. , Hooijmans M. T. , Alleman I. , Hegeman I. M. , Verschuuren J. J. G. M. , v. Deutekom J. C. , Spitali P. , Datson N. A. , Niks E. H. 
Published: March 2021

AbstractBecker muscular dystrophy (BMD) is the milder allelic variant of Duchenne muscular dystrophy, with higher dystrophin levels. To anticipate on results of interventions targeting dystrophin expression it is important to know the natural variation of dystrophin expression between different muscles and over time. Dystrophin was quantified using capillary Western immunoassay (Wes) in the anterior tibial (TA) muscle of 37 BMD patients. Variability was studied using two samples from the same TA biopsy site in nine patients, assessing nine longitudinal TA biopsies, and eight simultaneously obtained vastus lateralis (VL) muscle biopsies. Measurements were performed in duplicate with two primary antibodies. Baseline dystrophin levels were correlated to longitudinal muscle strength and functional outcomes. Results showed low technical variability and high precision for both antibodies. Dystrophin TA levels ranged from 4.8 to 97.7%, remained stable over a 3–5 year period, and did not correlate with changes in longitudinal muscle function. Dystrophin levels were comparable between TA and VL muscles. Intra-muscle biopsy variability was low (5.2% and 11.4% of the total variability of the two antibodies). These observations are relevant for the design of clinical trials targeting dystrophin production, and may urge the need for other biomarkers or surrogate endpoints.
Ants modulate stridulatory signals depending on the behavioural context
Authors: Masoni A. , Frizzi F. , Nieri R. , Casacci L. P. , Mazzoni V. , Turillazzi S. , Santini G. 
Published: March 2021

AbstractInsect societies require an effective communication system to coordinate members’ activities. Although eusocial species primarily use chemical communication to convey information to conspecifics, there is increasing evidence suggesting that vibroacoustic communication plays a significant role in the behavioural contexts of colony life. In this study, we sought to determine whether stridulation can convey information in ant societies. We tested three main hypotheses using the Mediterranean ant Crematogaster scutellaris: (i) stridulation informs about the emitter’caste; (ii) workers can modulate stridulation based on specific needs, such as communicating the profitability of a food resource, or (iii) behavioural contexts. We recorded the stridulations of individuals from the three castes, restrained on a substrate, and the signals emitted by foragers workers feeding on honey drops of various sizes. Signals emitted by workers and sexuates were quantitatively and qualitatively distinct as was stridulation emitted by workers on different honey drops. Comparing across the experimental setups, we demonstrated that signals emitted in different contexts (restraining vs feeding) differed in emission patterns as well as certain parameters (dominant frequency, amplitude, duration of chirp). Our findings suggest that vibrational signaling represents a flexible communication channel paralleling the well-known chemical communication system.
Green propolis extract attenuates acute kidney injury and lung injury in a rat model of sepsis
Authors: Silveira Marcelo Augusto Duarte , Capcha José Manuel Condor , Sanches Talita Rojas , de Sousa Moreira Roberto , Garnica Margot S. , Shimizu Maria Heloisa , Berretta Andresa , Teles Flávio , Noronha Irene L. , Andrade Lúcia 
Published: March 2021

AbstractSepsis is the leading cause of acute kidney injury (AKI) and lung injury worldwide. Despite therapeutic advances, sepsis continues to be associated with high mortality. Because Brazilian green propolis (GP) has promising anti-inflammatory, antioxidant, and immunomodulatory properties, we hypothesized that it would protect kidneys and lungs in rats induced to sepsis by cecal ligation and puncture (CLP). Male Wistar rats were divided into groups—control (sham-operated); CLP (CLP only); and CLP + GP (CLP and treatment with GP at 6 h thereafter)—all receiving volume expansion and antibiotic therapy at 6 h after the procedures. By 24 h after the procedures, treatment with GP improved survival, attenuated sepsis-induced AKI, and restored renal tubular function. Whole-blood levels of reduced glutathione were higher in the CLP + GP group. Sepsis upregulated the Toll-like receptor 4/nuclear factor-kappa B axis in lung and renal tissues, as well as increasing inflammatory cytokine levels and macrophage infiltration; all of those effects were attenuated by GP. Treatment with GP decreased the numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in renal and lung tissue, as well as protecting the morphology of the renal mitochondria. Our data open the prospect for clinical trials of the use of GP in sepsis.