bluuebunny/crossref_metadata_2025_split huggingface dataset:
DW1 Tidal Enhancements in the Equatorial MLT During 2015 El Niño: The Relative Role of Tidal Heating and Propagation
Authors: Kogure Masaru , Liu Huixin 
Published: June 2021

AbstractGround‐based and satellite observations have shown that the tidal component DW1 in the equatorial mesosphere and lower thermosphere (MLT) was enhanced in July–October 2015, which was an intense El Niño year. This enhancement is reproduced in the 21 years reanalysis‐driven model simulation by the Ground‐to‐topside model of Atmosphere and Ionosphere for Aeronomy (GAIA). Our analysis shows the (1,1) Hough mode dominates this tidal enhancement, and its peak amplitude was 7.4 K (74%) higher than that under neutral (non‐ENSO) conditions at 90 km. The corresponding tidal heating was found to increase by 0.4 mWkg−1 (5%), which can explain 0.5 K (7%) of the (1,1) enhancement. To explain the remaining 6.9 K (93%) of the enhancement, we quantitively examined the upward propagation condition by calculating the vertical wavenumber and the latitudinal shear of the zonal wind. The analysis reveals that the vertical wavenumber between 18 and 60 km was one standard deviation smaller than that under neutral conditions. The latitudinal zonal wind shear also decreased at 18 N/S° in 18–30 km. These results suggest smaller dissipation and damping of the (1,1) mode during its upward propagation, which dominantly contributed to the tidal enhancement at 90 km altitude. This decrease in the vertical wavenumber and the wind shear can be reasonably explained by the eastward phase of the quasi‐biennial oscillation (QBO) in the lower stratosphere. This study suggests that the overlapping of the 2015 El Niño with the eastward phase of the QBO induced the large enhancement of the DW1.
Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies
Authors: Bauer Sebastian , Demetri George D. , Halilovic Ensar , Dummer Reinhard , Meille Christophe , Tan Daniel S. W. , Guerreiro Nelson , Jullion Astrid , Ferretti Stephane , Jeay Sebastien , Van Bree Laurence , Hourcade-Potelleret Florence , Wuerthner Jens U. , Fabre Claire , Cassier Philippe A. 
Published: June 2021

AbstractBackgroundCGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525).MethodsFifty-one patients received oral treatment with CGM097 10–400 mg 3qw (n = 31) or 300–700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics.ResultsNo dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined.ConclusionsDespite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors.Translational relevanceHaematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.
Sulfiredoxin-1 attenuates injury and inflammation in acute pancreatitis through the ROS/ER stress/Cathepsin B axis
Authors: He Jun , Ma Miaomiao , Li Daming , Wang Kunpeng , Wang Qiuguo , Li Qiuguo , He Hongye , Zhou Yan , Li Qinglong , Hou Xuyang , Yang Leping 
Published: June 2021

AbstractAcinar cell injury and the inflammatory response are critical bioprocesses of acute pancreatitis (AP). We investigated the role and underlying mechanism of sulfiredoxin-1 (Srxn1) in AP. Mild AP was induced by intraperitoneal injection of cerulein and severe AP was induced by partial duct ligation with cerulein stimulation or intraperitoneal injection of L-arginine in mice. Acinar cells, neutrophils, and macrophages were isolated. The pancreas was analyzed by histology, immunochemistry staining, and TUNEL assays, and the expression of certain proteins and RNAs, cytokine levels, trypsin activity, and reactive oxygen species (ROS) levels were determined. Srxn1 was inhibited by J14 or silenced by siRNA, and overexpression was introduced by a lentiviral vector. Transcriptomic analysis was used to explore the mechanism of Srxn1-mediated effects. We also evaluated the effect of adeno-associated virus (AAV)-mediated overexpression of Srxn1 by intraductal administration and the protection of AP. We found that Srxn1 expression was upregulated in mild AP but decreased in severe AP. Inhibition of Srxn1 increased ROS, histological score, the release of trypsin, and inflammatory responses in mice. Inhibition of Srxn1 expression promoted the production of ROS and induced apoptosis, while overexpression of Srxn1 led to the opposite results in acinar cells. Furthermore, inhibition of Srxn1 expression promoted the inflammatory response by accumulating and activating M1 phenotype macrophages and neutrophils in AP. Mechanistically, ROS-induced ER stress and activation of Cathepsin B, which converts trypsinogen to trypsin, were responsible for the Srxn1 inhibition-mediated effects on AP. Importantly, we demonstrated that AAV-mediated overexpression of Srxn1 attenuated AP in mice. Taken together, these results showed that Srxn1 is a protective target for AP by attenuating acinar injury and inflammation through the ROS/ER stress/Cathepsin B axis.
Revisiting species and areas of interest for conserving global mammalian phylogenetic diversity
Authors: Robuchon Marine , Pavoine Sandrine , Véron Simon , Delli Giacomo , Faith Daniel P. , Mandrici Andrea , Pellens Roseli , Dubois Grégoire , Leroy Boris 
Published: June 2021

AbstractVarious prioritisation strategies have been developed to cope with accelerating biodiversity loss and limited conservation resources. These strategies could become more engaging for decision-makers if they reflected the positive effects conservation can have on future projected biodiversity, by targeting net positive outcomes in future projected biodiversity, rather than reflecting the negative consequences of further biodiversity losses only. Hoping to inform the post-2020 biodiversity framework, we here apply this approach of targeting net positive outcomes in future projected biodiversity to phylogenetic diversity (PD) to re-identify species and areas of interest for conserving global mammalian PD. We identify priority species/areas as those whose protection would maximise gains in future projected PD. We also identify loss-significant species/areas as those whose/where extinction(s) would maximise losses in future projected PD. We show that our priority species/areas differ from loss-significant species/areas. While our priority species are mostly similar to those identified by the EDGE of Existence Programme, our priority areas generally differ from previously-identified ones for global mammal conservation. We further highlight that these newly-identified species/areas of interest currently lack protection and offer some guidance for their future management.
Dendritic calcium signals in rhesus macaque motor cortex drive an optical brain-computer interface
Authors: Trautmann Eric M. , O’Shea Daniel J. , Sun Xulu , Marshel James H. , Crow Ailey , Hsueh Brian , Vesuna Sam , Cofer Lucas , Bohner Gergő , Allen Will , Kauvar Isaac , Quirin Sean , MacDougall Matthew , Chen Yuzhi , Whitmire Matthew P. , Ramakrishnan Charu , Sahani Maneesh , Seidemann Eyal , Ryu Stephen I. , Deisseroth Karl , Shenoy Krishna V. 
Published: June 2021

AbstractCalcium imaging is a powerful tool for recording from large populations of neurons in vivo. Imaging in rhesus macaque motor cortex can enable the discovery of fundamental principles of motor cortical function and can inform the design of next generation brain-computer interfaces (BCIs). Surface two-photon imaging, however, cannot presently access somatic calcium signals of neurons from all layers of macaque motor cortex due to photon scattering. Here, we demonstrate an implant and imaging system capable of chronic, motion-stabilized two-photon imaging of neuronal calcium signals from macaques engaged in a motor task. By imaging apical dendrites, we achieved optical access to large populations of deep and superficial cortical neurons across dorsal premotor (PMd) and gyral primary motor (M1) cortices. Dendritic signals from individual neurons displayed tuning for different directions of arm movement. Combining several technical advances, we developed an optical BCI (oBCI) driven by these dendritic signalswhich successfully decoded movement direction online. By fusing two-photon functional imaging with CLARITY volumetric imaging, we verified that many imaged dendrites which contributed to oBCI decoding originated from layer 5 output neurons, including a putative Betz cell. This approach establishes new opportunities for studying motor control and designing BCIs via two photon imaging.
Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer
Authors: Poels Kamrine E. , Schoenfeld Adam J. , Makhnin Alex , Tobi Yosef , Wang Yuli , Frisco-Cabanos Heidie , Chakrabarti Shaon , Shi Manli , Napoli Chelsi , McDonald Thomas O. , Tan Weiwei , Hata Aaron , Weinrich Scott L. , Yu Helena A. , Michor Franziska 
Published: June 2021

AbstractDespite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.
Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma
Authors: Ho Daniel Wai-Hung , Tsui Yu-Man , Chan Lo-Kong , Sze Karen Man-Fong , Zhang Xin , Cheu Jacinth Wing-Sum , Chiu Yung-Tuen , Lee Joyce Man-Fong , Chan Albert Chi-Yan , Cheung Elaine Tin-Yan , Yau Derek Tsz-Wai , Chia Nam-Hung , Lo Irene Lai-Oi , Sham Pak-Chung , Cheung Tan-To , Wong Carmen Chak-Lui , Ng Irene Oi-Lin 
Published: June 2021

AbstractInteraction between tumor cells and immune cells in the tumor microenvironment is important in cancer development. Immune cells interact with the tumor cells to shape this process. Here, we use single-cell RNA sequencing analysis to delineate the immune landscape and tumor heterogeneity in a cohort of patients with HBV-associated human hepatocellular carcinoma (HCC). We found that tumor-associated macrophages suppress tumor T cell infiltration and TIGIT-NECTIN2 interaction regulates the immunosuppressive environment. The cell state transition of immune cells towards a more immunosuppressive and exhaustive status exemplifies the overall cancer-promoting immunocellular landscape. Furthermore, the heterogeneity of global molecular profiles reveals co-existence of intra-tumoral and inter-tumoral heterogeneity, but is more apparent in the latter. This analysis of the immunosuppressive landscape and intercellular interactions provides mechanistic information for the design of efficacious immune-oncology treatments in hepatocellular carcinoma.
Hypoxia-induced SETX links replication stress with the unfolded protein response
Authors: Ramachandran Shaliny , Ma Tiffany S. , Griffin Jon , Ng Natalie , Foskolou Iosifina P. , Hwang Ming-Shih , Victori Pedro , Cheng Wei-Chen , Buffa Francesca M. , Leszczynska Katarzyna B. , El-Khamisy Sherif F. , Gromak Natalia , Hammond Ester M. 
Published: June 2021

AbstractTumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.
Longevity and germination of Juniperus communis L. pollen after storage
Authors: Kormuťák Andrej , Bolecek Peter , Galgóci Martin , Gömöry Dušan 
Published: June 2021

AbstractPollen storage belongs among the most important activities associated with pollen handling. It overcomes the differences in pollen shedding and ovule receptivity during controlled pollination experiments. It is especially important for species like common juniper (Juniperus communis L.) with an extremely low quality of seeds due to pollination failure. Additionally, it is a substantial part of germplasm preservation programmes in pollen banks. In the present paper, the effect of short-term storage of pollen was studied using pollen samples from five shrubs in an in vitro germination test. Two temperature regimes were tested. The pollen viability of freshly collected pollen varied considerably between individual shrubs, exhibiting 67.3–88.6% germination rate and 248.0–367.3 µm of pollen tubes. Storage at + 4 °C for four months was accompanied by a profound decline in pollen viability. The germination percentage was reduced to 49.2–75.2% and the pollen tube length to 32.5–69.0%, depending on individual shrubs. The corresponding decline in pollen viability characteristics during storage at − 20 °C was only negligible in two of the tested shrubs. In the remaining three shrub samples, an increase in germination percentage was observed. Pollen tube growth responded more sensitively to freezing, but, on average, the decrease in length was lower than that at + 4 °C. The rate of reduction in pollen tube length varied between 11.5 and 45.4%. Cytological events accompanying in vitro germination of freezer-stored pollen exhibited some delay in releasing the exine from pollen grains during the early stages of germination as compared with freshly collected pollen. In conclusion, short-term storage of the common juniper pollen in a freezer is better for the preservation of its viability than storage at + 4 °C.
Persistent symptoms and lab abnormalities in patients who recovered from COVID-19
Authors: Varghese Julian , Sandmann Sarah , Ochs Kevin , Schrempf Inga-Marie , Frömmel Christopher , Dugas Martin , Schmidt Hartmut H. , Vollenberg Richard , Tepasse Phil-Robin 
Published: June 2021

AbstractWith increasing numbers of patients recovering from COVID-19, there is increasing evidence for persistent symptoms and the need for follow-up studies. This retrospective study included patients without comorbidities, who recovered from COVID-19 and attended an outpatient clinic at a university hospital for follow-up care and potential convalescent plasma donation. Network analysis was applied to visualize symptom combinations and persistent symptoms. Comprehensive lab-testing was ascertained at each follow-up to analyze differences regarding patients with vs without persistent symptoms. 116 patients were included, age range was 18–69 years (median: 41) with follow-ups ranging from 22 to 102 days. The three most frequent persistent symptoms were Fatigue (54%), Dyspnea (29%) and Anosmia (25%). Lymphopenia was present in 13 of 112 (12%) cases. Five of 35 cases (14%) had Lymphopenia in the later follow-up range of 80–102 days. Serum IgA concentration was the only lab parameter with significant difference between patients with vs without persistent symptoms with reduced serum IgA concentrations in the patient cohort of persistent symptoms (p = 0.0219). Moreover, subgroup analyses showed that patients with lymphopenia experienced more frequently persistent symptoms. In conclusion, lymphopenia persisted in a noticeable percentage of recovered patients. Patients with persistent symptoms had significantly lower serum IgA levels. Furthermore, our data provides evidence that lymphopenia is associated with persistence of COVID-19 symptoms.
Ginsenoside Rg1 can restore hematopoietic function by inhibiting Bax translocation-mediated mitochondrial apoptosis in aplastic anemia
Authors: Cao Huiqin , Wei Wei , Xu Ruirong , Cui Xing 
Published: June 2021

AbstractThe present study investigated, the anti-apoptotic activity of Ginsenoside Rg1 (Rg1) via inhibition of Bax translocation and the subsequent recovery of hematopoietic function. Mitochondrial apoptosis in bone marrow mononuclear cells (BMNCs) was observed in aplastic anemia (AA) patients. To establish a mouse model of AA, BALB/c mice were transplanted with lymph node cells from DBA/2 donor mice via vein injection after treatment with Co60 γ-radiation. After treatment with Rg1 for 14 days, the peripheral blood and Lin–Sca-1 + c-Kit + (LSK) cell counts of the treated group were increased compared with those of the untreated model mice. In in vivo and in vitro tests of LSKs, Rg1 was found to increase mitochondrial number and the ratio of Bcl-2/Bax and to decrease damage to the mitochondrial inner and outer membranes, the mitochondrial Bax level and the protein levels of mitochondrial apoptosis-related proteins AIF and Cyt-C by decreasing the ROS level. Rg1 also improved the concentration–time curve of MAO and COX and levels of ATP, ADP and AMP in an in vitro test. In addition, high levels of Bax mitochondrial translocation could be corrected by Rg1 treatment. Levels of markers of mitochondrial apoptosis in the Rg1-treated group were significantly better than those in the AA model group, implying that Rg1 might improve hematopoietic stem cells and thereby restore hematopoietic function in AA by suppressing the mitochondrial apoptosis mediated by Bax translocation.
Photoperiodically driven transcriptome-wide changes in the hypothalamus reveal transcriptional differences between physiologically contrasting seasonal life-history states in migratory songbirds
Authors: Sharma Aakansha , Das Subhajit , Sur Sayantan , Tiwari Jyoti , Chaturvedi Khushboo , Agarwal Neha , Malik Shalie , Rani Sangeeta , Kumar Vinod 
Published: June 2021

AbstractWe investigated time course of photoperiodically driven transcriptional responses in physiologically contrasting seasonal life-history states in migratory blackheaded buntings. Birds exhibiting unstimulated winter phenotype (photosensitive state; responsive to photostimulation) under 6-h short days, and regressed summer phenotype (photorefractory state; unresponsiveness to photostimulation) under 16-h long days, were released into an extended light period up to 22 h of the day. Increased tshβ and dio2, and decreased dio3 mRNA levels in hypothalamus, and low prdx4 and high il1β mRNA levels in blood confirmed photoperiodic induction by hour 18 in photosensitive birds. Further, at hours 10, 14, 18 and 22 of light exposure, the comparison of hypothalamus RNA-Seq results revealed transcriptional differences within and between states. Particularly, we found reduced expression at hour 14 of transthyretin and proopiomelanocortin receptor, and increased expression at hour 18 of apolipoprotein A1 and carbon metabolism related genes in the photosensitive state. Similarly, valine, leucine and isoleucine degradation pathway genes and superoxide dismutase 1 were upregulated, and cocaine- and amphetamine-regulated transcript and gastrin-releasing peptide were downregulated in the photosensitive state. These results show life-history-dependent activation of hypothalamic molecular pathways involved in initiation and maintenance of key biological processes as early as on the first long day.
OpiumPlex is a novel microsatellite system for profiling opium poppy (Papaver somniferum L.)
Authors: Vašek Jakub , Čílová Daniela , Melounová Martina , Svoboda Pavel , Zdeňková Kamila , Čermáková Eliška , Ovesná Jaroslava 
Published: June 2021

AbstractOpium poppy (Papaver somniferum L.) is a versatile plant exploited by the pharmaceutical and food industries. Unfortunately, it is also infamously known as a source of highly addictive narcotics, primarily heroin. Drug abuse has devastating consequences for users and also has many direct or indirect negative impacts on human society as a whole. Therefore, developing a molecular genetic tool for the individualization of opium poppy, raw opium or heroin samples could help in the fight against the drug trade by retrieving more information about the source of narcotics and linking isolated criminal cases. Bioinformatic analysis provided insight into the distribution, density and other characteristics of roughly 150 thousand microsatellite loci within the poppy genome and indicated underrepresentation of microsatellites with the desired attributes. Despite this fact, 27 polymorphic STR markers, divided into three multiplexed assays, were developed in this work. Internal validation confirmed species-specific amplification, showed that the optimal amount of DNA is within the range of 0.625–1.25 ng per reaction, and indicate relatively well balanced assays according to the metrics used. Moreover, the stutter ratio (mean + 3 SD 2.28–15.59%) and allele-specific stutters were described. The analysis of 187 individual samples led to the identification of 158 alleles in total, with a mean of 5.85 alleles and a range of 3–14 alleles per locus. Most of the alleles (151) were sequenced by the Sanger method, which enabled us to propose standardized nomenclature and create three allelic ladders. The OpiumPlex system discriminates most of the varieties from each other and pharmaceutical varieties from the others (culinary, dual and ornamental).