bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral administration of bacterial Beta cell expansion factor A (BefA) alleviates diabetes in mice with Type 1 and Type 2 diabetes
Authors: Wang Huan , Wei Jing , Hu Hong , Le Fuyin , Wu Heng , Wei Hong , Luo Jie , Chen Tingtao 
Published: October 2021

AbstractDiabetes mellitus (DM) is a group of metabolic diseases, which is of urgent need to develop new therapeutic DM oral drugs with less side effects and sound therapeutic efficacy. In this study, a Beta cell expansion factor A (BefA) production strain of Escherichia Coli BL21-pet 28C-BefA was constructed, and the anti-diabetes effect of BefA was evaluated using type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mice models. The T1DM mice results indicated that BefA significantly reduced the blood glucose level, exerted protective function of islet β cell morphology, down-regulated the TLR-4, p-NFκB/NFκB, Bax/Bcl-2 expressions and the secretion level of IL-1β, TNF-α, increased the expression of PDX-1 protein and insulin secretion in a concentration-dependent manner, and restored the disturbed microbial diversity to normal level. Similar with the T1DM mice, BefA obviously increased islet β cells, reduced inflammatory reaction and apoptosis in T2DM mice, and also improved liver lipid metabolism by down-regulating the expression of CEBP-α, ACC, Fasn and inhibiting the synthesis of triglyceride and induce Cpt-1, Hmgcs2, Pparα in a concentration-dependent manner. In the present study, we verified therapeutic effect and potential mechanisms of BefA in mammal for the first time, providing basic data for its clinical application.
Predominance of clonal propagationconceals extinction risks of the highly endangered floodplain herbCnidium dubium
Authors: Leyer Ilona , Ziegenhagen Birgit , Mengel Christina , Mosner Eva , Liepelt Sascha 
Published: October 2021

AbstractHabitat loss and degradation due to human-induced landscape alterations are considered to be a major threat to biodiversity. The decline of biodiversity may occur with a time delay leading to a so called extinction debt. Therefore, determining extinction risks and conservation status is not always straightforward. Several life history traits might play a role for the accumulation of an extinction debt. Thus, perennial plant species capable of vegetative propagation might be able to persist temporarily in degraded habitats even though sexual and evolutionary processes are effectively halted.We studiedCnidium dubium, which occurs in scattered patches along river corridors in Central Europe and is critically endangered in Germany. It is a perennial species which is able to propagate clonally. Our aims were to reconstruct demographic processes regarding clonal propagation and gene flow along 400 km of river stretch and with respect to the position in the flooplain, i.e. before or behind dykes. We also wanted to determine whether there is evidence for an extinction debt inC. dubiumand to use our insights for conservation recommendations.For this, we used nuclear microsatellites and maternally inherited chloroplast DNA markers and applied a systematic grid based sampling strategy for small scale geographic structures.We observed a high level of clonal propagation. In 935 analysed plants we observed only 121 different genotypes and of 50 studied patches ofC. dubiumthe majority (31 patches) consisted of one single genotype each. Patch size and position were correlated with clonal diversity. Large patches and patches behind dykes exhibited higher clonal diversity. There was no evidence for a large scale genetic substructuring of the study area and no differences in overall genetic diversity between upstream and downstream patches as well as between patches before and behind the dykes. High levels of heterozygosity and a high number of 18 chloroplast DNA haplotypes togetherwith a slightly elevated inbreeding coefficient (Fis) point toward a high level of ancestral polymorphism in an out of equilibrium population due to high levels of clonal propagation and low levels of gene flow and recombination. Therefore, we assume that an extinction debt is present in C. dubium. As a management strategy, we propose to transplant ramets between multiple patches to increase the number of mating partners and therefore restore sexual reproduction.
Shared hotspot mutations in spontaneously arising cancers position dog as an unparalleled comparative model for precision therapeutics
Authors: Rodrigues Lucas , Watson Joshua , Feng Yuan , Lewis Benjamin , Harvey Garrett , Post Gerald , Megquier Kate , Lambert Lindsay , Miller Aubrey , Lopes Christina , Zhao Shaying 
Published: October 2021

AbstractNaturally occurring canine cancers have remarkable similarities to their human counterparts. In order to determine whether these similarities occur at the molecular level, we investigated hotspot mutations in a variety of spontaneously arising canine cancers and found high concordance in oncogenic drivers between cancers in both species. These findings suggest that canines may present a powerful and complementary model for preclinical investigations for targeted cancer therapeutics. Through analysis of 708 client-owned dogs from 96 breeds (plus mixed breeds) with 23 common tumor types, we discovered mutations in 50 well-established oncogenes and tumor suppressors, and compared them to those reported in human cancers. TP53 is the most commonly mutated gene, detected in 30.81% of canine tumors overall and >40% in hemangiosarcoma and osteosarcoma. Canine tumors share mutational hotspots with human tumors in oncogenes including PIK3CA, KRAS, NRAS, BRAF, KIT and EGFR. Hotspot mutations with significant (P<0.0001) association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E in urothelial carcinoma. This work positions canines as excellent spontaneous models of human cancers that can help to investigate a wide spectrum of targeted therapies.
An Unsupervised Machine Learning Paradigm for Artifact Removal from Electrodermal Activity in an Uncontrolled Clinical Setting
Authors: Subramanian Sandya , Tseng Bryan , Barbieri Riccardo , Brown Emery N. 
Published: October 2021

ABSTRACTObjectiveElectrodermal activity (EDA) reflects sympathetic nervous system activity through sweating-related changes in skin conductance. To enable EDA data to be used robustly in clinical settings, we need to develop artifact detection and removal frameworks that can handle the types of interference experienced in clinical settings.MethodsWe collected EDA data from 69 subjects while they were undergoing surgery in the operating room. We then built an artifact removal framework using unsupervised learning methods and informed features to remove the heavy artifact that resulted from the use of surgical electrocautery during the surgery and compared it to other existing methods for artifact removal from EDA data.ResultsOur framework was able to remove the vast majority of artifact from the EDA data across all subjects with high sensitivity (94%) and specificity (90%). In contrast, existing methods used for comparison struggled to be sufficiently sensitive and specific, and none effectively removed artifact even if it was identifiable. In addition, the use of unsupervised learning methods in our framework removes the need for manually labeled datasets for training.ConclusionOur framework allows for robust removal of heavy artifact from EDA data in clinical settings such as surgery. Since this framework only relies on a small set of informed features, it can be expanded to other modalities such as ECG and EEG.SignificanceRobust artifact removal from EDA data is the first step to enable clinical integration of EDA as part of standard monitoring in settings such as the operating room.
Symmetric Inheritance of Histones H3 in Drosophila Male Germline Stem Cell Divisions
Authors: Ray Julie , Maggert Keith A. 
Published: October 2021

ABSTRACTMitotically-stable “epigenetic” memory requires a mechanism for the maintenance of gene-regulatory information through the cell division cycle. Typically DNA-protein contacts are disrupted by DNA replication, but in some cases locus-specific association between DNA and overlying histones may appear to be maintained, providing a plausible mechanism for the transmission of histone-associated gene-regulatory information to daughter cells. Male Drosophila melanogaster testis germ stem cell divisions seem a clear example of such inheritance, as previously chromatin-bound Histone H3.2 proteins (presumably with their post-translational modifications intact) have been reported to be retained in the germ stem cell nuclei, while newly synthesized histones are incorporated into daughter spermatogonial chromosomes. To investigate the rate of errors in this selective partitioning that may lead to defects in the epigenetic identity of germ stem cells, we employed a photoswitchable Dendra2 moiety as a C-terminal fusion on Histones H3 (Histone H3.2 and Histone H3.3); we could thereby discriminate histones translated before photoswitching and those translated after. We found instead that male germ line stem cell divisions show no evidence of asymmetric histone partitioning, even after a single division, and thus no evidence for locus-specific retention of either Histone H3.2 or Histone H3.3. We considered alternative hypotheses for the appearance of asymmetry and find that previous reports of asymmetric histone distribution in male germ stem cells can be satisfactorily explained by asynchrony between subsequent sister stem cell and spermatogonial divisions.
Bioactive constituents ofVerbena officinalisalleviate inflammation and enhance killing efficiency of natural killer cells
Authors: Dai Xiangdong , Zhou Xiangda , Shao Rui , Zhao Renping , Yanamandra Archana K. , Xing Zhimei , Ding Mingyu , Wang Junhong , Zhang Han , Wang Yi , Zheng Qi , Zhang Peng , Qu Bin , Wang Yu 
Published: October 2021

AbstractNatural killer (NK) cells play a key role in eliminating pathogen-infected cells.Verbena officinalis(V. officinalis) has been used as a medical plant in traditional and modern medicine, exhibiting anti-tumor and anti-inflammation activities, but its roles in immune responses still remains largely elusive. In this work, investigated the regulation of inflammation and NK functionsby V. officinalisextract (VO-extract). In an influenza virus infection mouse model, oral administration of VO-extract alleviated lung injury, promoted maturation and activation of NK cells residing in the lung, and decreased the levels of inflammatory cytokines (IL-6, TNF-α and IL-1β) in the serum. We further analyzed the impact of five bioactive components of VO-extract on NK killing functions. Among them, Verbenalin enhanced NK killing efficiency significantly as determined by real-time killing assays based on plate-reader or high-throughput live-cell imaging in 3D using primary human NK cells. Further investigation showed that treatment of Verbenalin accelerated killing processes by reducing the contact time of NK cells with their target cells without affecting NK proliferation, expression of cytotoxic proteins, or lytic granule degranulation. Together, our findings reveal that low doses ofV. officinaliscan achieve a satisfactory anti-inflammation effect against viral infectionin vivo, andV. officinalisregulates activation, maturation and killing functions of NK cells. NK killing efficiency is enhanced by Verbenalin fromV. officinalis, suggesting a promising potential of verbenalin to fight viral infection.
Regulation of Neuroendocrine Plasticity by the RNA-Binding Protein ZFP36L1
Authors: Chen Hsiao-Yun , Durmaz Yavuz T. , Li Yixiang , Sabet Amin H. , Vajdi Amir , Denize Thomas , Walton Emily , Doench John G. , Mahadevan Navin R. , Losman Julie-Aurore , Barbie David A. , Tolstorukov Michael Y. , Rudin Charles M. , Sen Triparna , Signoretti Sabina , Oser Matthew G. 
Published: October 2021

AbstractSome small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine “inflammatory” phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.
A Developmentally Prometastatic Niche to Hepatoblastoma in Neonatal Liver mediated by the Cxcl1/Cxcr2 Axis
Authors: Fan Li , Pan Qingfei , Yang Wentao , Koo Selene C. , Tian Cheng , Li Liyuan , Lu Meifen , Brown Anthony , Ju Bensheng , Easton John , Ranganathan Sarangarajan , Shin Soona , Bondoc Alexander , Yang Jun J. , Yu Jiyang , Zhu Liqin 
Published: October 2021

ABSTRACTBackground and RationaleHepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigating whether the neonatal liver provides a protumorigenic niche to HB development.MethodsHB development was compared between orthotopic transplantation models established in postnatal day 5 and 60 mice (P5Tx and P60Tx models). Single-cell RNA-sequencing was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival.ResultsWe found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in metastatic HB patient tumors there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with HB patient prognosis among pediatric cancers.ConclusionWe demonstrated that the neonatal liver provides a prometastatic niche to HB development via the Cxcl1/Cxcr2 axis.
Environmental DNA analysis needs local reference data to inform taxonomy-based conservation policy – A case study from Aotearoa / New Zealand
Authors: Czechowski Paul , de Lange Michel , Heldsinger Michael , Rayment Will , Hepburn Christopher , Ladds Monique , Knapp Michael 
Published: October 2021

AbstractEffective management of biodiversity requires regular surveillance of multiple species. Analysis of environmental DNA by metabarcoding (eDNA) holds promise to achieve this relatively easily. However, taxonomic inquiries into eDNA data need suitable molecular reference data, which are often lacking. We evaluate the impact of this reference data void in a case study of fish diversity in the remote fiords of New Zealand. We compared eDNA-derived species identifications against Baited Remote Underwater Video (BRUV) data collected at the same time and locations as the eDNA data. Furthermore, we cross referenced both eDNA and BRUV data against species lists for the same region obtained from literature surveys and the Ocean Biodiversity Information System (OBIS). From all four data sources, we obtained a total of 116 species records (106 ray-finned fishes, 10 cartilaginous fishes; 59 from literature, 44 from eDNA, 25 from BRUV, 25 from OBIS). Concordance of taxonomies between the data sources dissolved with lowering taxonomic levels, most decisively so for eDNA data. BRUV agreed with local biodiversity information much better and fared better in detecting regional biodiversity dissimilarities. We provide evidence that eDNA metabarcoding will remain a powerful but impaired tool for species-level biodiversity management without locally generated reference data.
Light-independent regulation of algal photoprotection by CO2availability
Authors: Ruiz-Sola M. Águila , Flori Serena , Yuan Yizhong , Villain Gaelle , Sanz-Luque Emanuel , Redekop Petra , Tokutsu Ryutaro , Kueken Anika , Tsichla Angeliki , Kepesidis Georgios , Allorent Guillaume , Arend Marius , Iacono Fabrizio , Finazzi Giovanni , Hippler Michael , Nikoloski Zoran , Minagawa Jun , Grossman Arthur R. , Petroutsos Dimitris 
Published: October 2021

AbstractPhotosynthetic algae have evolved mechanisms to cope with suboptimal light and CO2conditions. When light energy exceeds CO2fixation capacity,Chlamydomonas reinhardtiiactivates photoprotection, mediated by LHCSR1/3 and PSBS, and the CO2Concentrating Mechanism (CCM). How light and CO2signals converge to regulate these processes remains unclear. Here, we show that excess light activates photoprotection- and CCM-related genes by altering intracellular CO2concentrations and that depletion of CO2drives these responses, even in total darkness. High CO2levels, derived from respiration or impaired photosynthetic fixation, repressLHCSR3/CCM genes while stabilizing the LHCSR1 protein. Finally, we show that the CCM regulator CIA5 also regulates photoprotection, controllingLHCSR3andPSBStranscript accumulation while inhibiting LHCSR1 protein accumulation. This work has allowed us to dissect the effect of CO2and light on CCM and photoprotection, demonstrating that light often indirectly affects these processes by impacting intracellular CO2levels.
Piezo activity levels need to be tightly regulated to maintain normal morphology and function in pericardial nephrocytes
Authors: Schulz Kristina , Hazelton-Cavill Paris , Alornyo Karl K. , Edenhofer Ilka , Lindenmeyer Maja , Lohr Christian , Huber Tobias B. , Denholm Barry , Koehler Sybille 
Published: October 2021

AbstractDue to their position on glomerular capillaries, podocytes are continuously counteracting biomechanical filtration forces. Most therapeutic interventions known to generally slow or prevent the progression of chronic kidney disease appear to lower these biomechanical forces on podocytes, highlighting the critical need to better understand podocyte mechano-signalling pathways. Here we investigated whether the mechanotransducer Piezo is involved in a mechanosensation pathway inDrosophilanephrocytes, the podocyte homologue in the fly.Loss of function analysis in Piezo depleted nephrocytes reveal a severe morphological and functional phenotype. Further, pharmacological activation of endogenous Piezo with Yoda1 causes a significant increase of intracellular Ca++upon exposure to a mechanical stimulus in nephrocytes, as well as filtration disturbances. Elevated Piezo expression levels also result in a severe nephrocyte phenotype. Interestingly, expression of Piezo which lacks mechanosensitive channel activity, does not result in a severe nephrocyte phenotype, suggesting the observed changes in Piezo wildtype overexpressing cells are caused by the mechanosensitive channel activity. Moreover, blocking Piezo activity using the tarantula toxin GsMTx4 reverses the phenotypes observed in nephrocytes overexpressing Piezo.Taken together, here we provide evidence that Piezo activity levels need to be tightly regulated to maintain normal pericardial nephrocyte morphology and function.
Molecular basis of ocean acidification sensitivity and adaptation in Mytilus galloprovincialis
Authors: Kapsenberg Lydia , Bitter Mark C. , Miglioli Angelica , Pelejero Carles , Gattuso Jean-Pierre , Dumollard Rémi 
Published: October 2021

AbstractOne challenge in global change biology is to identify the mechanisms underpinning physiological sensitivities to environmental change and to predict their potential to adapt to future conditions. Using ocean acidification as the representative stressor, molecular pathways associated with abnormal larval development of a globally distributed marine mussel are identified. The targeted developmental stage was the trochophore stage, which is, for a few hours, pH sensitive and is the main driver of developmental success. RNA sequencing and in situ RNA hybridization were used to identify processes associated with abnormal development, and DNA sequencing was used to identify which processes evolve when larvae are exposed to low pH for the full duration of their larval stage. Trochophores exposed to low pH exhibited 43 differentially expressed genes. Thirteen genes, none of which have previously been identified in mussel trochophores, including three unknown genes, were expressed in the shell field. Gene annotation and in situ hybridization point to two core processes associated with the response to low pH: development of the trochophore shell field and the cellular stress response. Encompassing both of these processes, five genes demonstrated changes in allele frequency that are indicative of rapid adaptation. Thus, genes underpinning the most pH-sensitive developmental processes also exhibit scope to adapt via genetic variation currently maintained in the mussel population. These results provide evidence that protecting species’ existing genetic diversity is a critical management action to maximize the potential for rapid adaptation under a changing environment.