bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probing apoptosis signaling proteins in single living cells for precision efficacy evaluation of anti-cancer drugs
Authors: Wen Yanrong , Liu Jia , He Hui , Liu Zhen 
Published: June 2019

AbstractIn vitro efficacy evaluation is critical for anti-cancer drug development and precision cancer treatment. Conventional methods, which mainly rely on cell viability and large cell populations, suffer from apparent disadvantages, such as signaling pathway-nonspecific, failing to reflect the real sensitivity of the patient, tedious and time-consuming. Herein, we present a new analytical tool, termed single-cell plasmonic immunosandwich assay (scPISA), for precision efficacy evaluation of anti-cancer drugs. It allows for facilely probing individual signaling proteins as well as protein-protein complexes in single living cells. Based on this approach, two apoptosis signaling proteins, cytochrome C (Cyt C) and caspase-3, were proposed as apoptosis indicators, while three new parameters were proposed as criteria for quantitative efficacy evaluation. Using two typical cytotoxic drugs, actinomycin D (Act D) and staurosporine (STS), as model drugs, the evaluation was found to be consistent among the indicators and parameters. Metformin, a potential anti-cancer drug, was then evaluated using this approach. Interestingly, metformin alone was found to be a less effective anti-cancer drug but its combination with Act D dramatically improved the overall efficacy. The scPISA approach exhibited several unique strengths over conventional assays, including comprehensive and self-consistent evaluation, signaling pathway-specific, simple procedure and high speed. Thus, it holds great promise for personalized drug screening and precision medicine.
Cellular and widefield imaging of sound frequency organization in primary and higher-order fields of the mouse auditory cortex
Authors: Romero Sandra , Hight Ariel E. , Clayton Kameron K. , Resnik Jennifer , Williamson Ross S. , Hancock Kenneth E , Polley Daniel B 
Published: June 2019

AbstractThe mouse auditory cortex (ACtx) contains two core fields – A1 and AAF – arranged in a mirror reversal tonotopic gradient. The best frequency (BF) organization and naming scheme for additional higher-order fields remain a matter of debate, as does the correspondence between smoothly varying global tonotopy and heterogeneity in local cellular tuning. Here, we performed chronic widefield and 2-photon calcium imaging from the ACtx of awake Thy1-GCaMP6s reporter mice. Data-driven parcellation of widefield maps identified five fields, including a previously unidentified area at the ventral posterior extreme of the ACtx (VPAF) and a tonotopically organized suprarhinal auditory field (SRAF) that extended laterally as far as ectorhinal cortex. Widefield maps were stable over time, where single pixel BFs fluctuated by less than 0.5 octaves during a one-month imaging period. After accounting for neuropil signal and frequency tuning strength, BF organization in neighboring layer 2/3 neurons was intermediate to the heterogeneous salt and pepper organization and the highly precise local organization that have each been described in prior studies. Multiscale imaging data suggest there is no ultrasonic field or secondary auditory cortex in the mouse. Instead, VPAF and a dorsoposterior field (DP) emerged as the strongest candidates for higher-order auditory areas.
Arbuscular mycorrhizal fungi, selenium, sulfur, silica-gel and biochar reduce arsenic uptake in plant biomass and improve nutritional quality inPisum sativum
Authors: Alam Mohammad Zahangeer , Hoque Md. Anamul , Ahammed Golam Jalal , Carpenter-Boggs Lynne 
Published: June 2019

AbstractArsenic (As) is a carcinogenic substance. It increased in crop grown in field soil from ground water irrigation. Subsequently As transport into the human body through food chains. The reduction of As transport in root, shoot and grain of pea genotypes is significantly important to protect human health. This research is focused on the biomass growth and alleviation of As accumulation in root, shoot and grain of pea genotypes in high As soil (30mgkg−1) amended with arbuscular mycorrhizal fungi (AMF), biochar (BC) of rice husk and saw dust, selenium (Se), silica- gel (Si), and sulfur (S). Shoot length, root, shoot and pod mass were generally higher in pea crops grown in soil amended with AMF, Se, Si- gel and S. Rice husk and saw dust BC less consistently increased some growth parameters, particularly in genotype BARI Motor 2. However, the BC’s more often reduced growth and pod mass. All treatments significantly reduced As concentration in tissues; As in grains was reduced on average 60% by any of the soil amendments. AMF, Se and Si- gel all were found more effective than BC for the reduction of As uptake in pea crops. As in grains was reduced 77% by AMF, 71% by Se and 69% by Si- gel on average. As in root, shoot, and grain was also affected by variety; in control treatments, total As uptake in plants pot−1of BARI Motor 1 and 3 was found 60 to 70% higher than BARI Motor 2. Comparing the variety and treatment with most As in grains (BARI Motor 1 control, 0.35 mg As kg−1) and least As in grains (BARI motor 1, 2 & 3 with AMF with 0.07 mg As kg−1), the choice of variety and soil amendment could reduce human intake of As through pea by 80%. It is recommended that choice of pea variety and soil amendment with AMF and Se have great potential for improving the nutritional quality of pea grown in As contaminated soil, as well as reducing As transfer to human bodies through food chains in pea crops.
Uveal Melanoma OncogeneCYSLTR2Encodes a Constitutively Active GPCR Highly Biased Toward Gq Signaling
Authors: Ceraudo Emilie , Horioka Mizuho , Mattheisen Jordan M. , Hitchman Tyler D. , Moore Amanda R. , Kazmi Manija A. , Chi Ping , Chen Yu , Sakmar Thomas P. , Huber Thomas 
Published: June 2019

AbstractThe G protein-coupled receptor (GPCR) cysteinyl-leukotriene receptor 2 (CysLTR2) with a single amino acid mutation at position 3.43 (Leu replaced with Gln at position 129 in transmembrane helix 3) causes uveal melanoma in humans. The ability of CysLTR2-L129Q to cause malignant transformation has been hypothesized to result from constitutive activity. We show that CysLTR2-L129Q is a constitutively active mutant (CAM) that strongly drives Gq/11 signaling pathways in melan-a melanocytes and in HEK293T cells in culture. However, the mutant receptor only very weakly recruits beta-arrestins 1 and 2. The mutant receptor displays profound signaling bias while avoiding arrestin-mediated downregulation. The mechanism of the signaling bias results from the creation of a hydrogen-bond network that stabilizes the active G protein signaling state through novel interactions with the highly-conserved NPxxY motif on helix 7. Furthermore, the mutation destabilizes a putative allosteric sodium-binding site that usually stabilizes the inactive state of GPCRs. Thus, the mutation has a dual role of promoting the active state while destabilizing inactivating allosteric networks. The high degree of constitutive activity renders existing orthosteric antagonist ligands of CysLTR2 ineffective as inverse agonists of the mutant. CysLTR2 is the first example of a GPCR oncogene that encodes a GPCR with constitutive highly biased signaling that can escape cellular downregulation mechanisms.
Specialized NADPH diaphorase membrane-related localizations in the brainstem of the pigeons (Columba livia)
Authors: Jia Yunge , Huo Wei , Li Yinhua , Zhang Tianyi , Wang Xinghang , Wen Xiaoxin , Xu Ximeng , Sun Haoran , Wu Xianhui , Rao Chenxu , Wei Zichun , Zhai Zhenhua , Tan Huibing 
Published: June 2019

AbstractNADPH diaphorase (N-d) is used to a histochemical identification of subgroup of neuronal cells. Beside regular intracellular N-d positivity, membrane-related positivity revealed as a specialized staining pattern in the pigeon brain stem. In the investigation of the nervous system of homing pigeons (Columba livia) with N-d staining, we found a specialized structure, which temporally was termed as N-d tubular glomerular body/structure or as T-J body related to the last name of authors. This N-d positive specialization constituted by tubular components bilaterally located in the medial to the lemniscus spinalis in the medulla oblongata. The tubular components were moderate staining. T-J body was a longitudinal oriented structure of 2400 μm with N-d staining. N-d positive tubular components were twisted and intermingled together. Beside the young adult pigeons, T-J body s were also consistently detected in the aged pigeons. Membrane-related staining were also detected in the other rostral nuclei in the brain stem. With discussion and review of related scientific literatures, T-J body was considered as a new anatomical structure or a new feature of the existent nucleus. In summary, beside N-d intracellular distribution, there were other three N-d membrane-related localizations: mini-aggregation, patch-aggregation, and arrangement along tubular unit.
EXOSC10 sculpts the transcriptome during the growth-to-maturation transition in mouse oocytes
Authors: Wu Di , Dean Jurrien 
Published: June 2019

ABSTRACTGrowing mammalian oocytes accumulate substantial amounts of RNA, most of which is degraded during subsequent meiotic maturation. The growth-to-maturation transition begins with germinal vesicle or nuclear envelope breakdown (GVBD) and is critical for oocyte quality and early development. The molecular machinery responsible for the oocyte transcriptome transition remains unclear. Here, we report that an exosome-associated RNase, EXOSC10, sculpts the transcriptome to facilitate the growth-to-maturation transition of mouse oocytes. We establish an oocyte-specific conditional knockout ofExosc10in mice using CRISPR/Cas9 which results in female subfertility due to delayed GVBD. By performing multiple single oocyte RNA-seq, we document dysregulation of several types of RNA, and the mRNAs that encode proteins important for endomembrane trafficking and meiotic cell cycle. As expected, EXOSC10-depleted oocytes have impaired endomembrane components including endosomes, lysosomes, endoplasmic reticulum and Golgi. In addition, CDK1 fails to activate, possibly due to persistent WEE1 activity, which blocks lamina phosphorylation and disassembly. Moreover, we identified rRNA processing defects that cause higher percentage of developmentally incompetent oocytes after EXOSC10 depletion. Collectively, we propose that EXOSC10 promotes normal growth-to-maturation transition in mouse oocytes by sculpting the transcriptome to degrade RNAs encoding growth-phase factors and, thus, support the maturation phase of oogenesis.
Interferons drive development of novel interleukin-15-responsive macrophages
Authors: Gordon Scott M. , Nishiguchi Mailyn A. , Chase Julie M. , Mani Sneha , Mainigi Monica A. , Behrens Edward M. 
Published: June 2019

ABSTRACTDisruption in homeostasis of interleukin-15 (IL-15) is linked to poor maternal and fetal outcomes during pregnancy. The only cells described to respond to IL-15 at the early maternal-fetal interface have been natural killer (NK) cells. We now show a novel population of macrophages, evident in several organs but enriched in the uterus of mice and humans, expressing the β chain of the IL-15 receptor complex (CD122) and responding to IL-15. CD122+ macrophages (CD122+Macs) are morphologic, phenotypic, and transcriptomic macrophages that can derive from bone marrow monocytes. CD122+Macs develop in the uterus and placenta with kinetics that mirror interferon (IFN) activity at the maternal-fetal interface. Macrophage colony-stimulating factor (M-CSF) permits macrophages to express CD122, and IFNs are sufficient to drive expression of CD122 on macrophages. Neither Type-I nor Type-II IFNs are required to generate CD122+Macs, however. In response to IL-15, CD122+Macs activate the ERK signaling cascade and enhance production of proinflammatory cytokines after stimulation with the Toll-like receptor 9 agonist CpG. Finally, we provide evidence of human cells that phenocopy murine CD122+Macs in secretory phase endometrium during the implantation window and in first-trimester uterine decidua. Our data support a model wherein IFNs local to the maternal-fetal interface direct novel IL-15-responsive macrophages with the potential to mediate IL-15 signals critical for optimal outcomes of pregnancy.The microarray data presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE132353.
Estimation of immune cell content in tumor using single-cell RNA-seq reference data
Authors: Yu Xiaoqing , Chen Y. Ann , Conejo-Garcia Jose R. , Chung Christine H. , Wang Xuefeng 
Published: June 2019

ABSTRACTBackgroundThe rapid development of single-cell RNA sequencing (scRNA-seq) provides unprecedented opportunities to study the tumor ecosystem that involves a heterogeneous mixture of cell types. However, the majority of previous and current studies related to translational and molecular oncology have only focused on the bulk tumor and there is a wealth of gene expression data accumulated with matched clinical outcomes.ResultsIn this paper, we introduce a scheme for characterizing cell compositions from bulk tumor gene expression by integrating signatures learned from scRNA-seq data. We derived the reference expression matrix to each cell type based on cell subpopulations identified in head and neck cancer dataset. Our results suggest that scRNA-Req-derived reference matrix outperforms the existing gene panel and reference matrix with respect to distinguishing immune cell subtypes.ConclusionsFindings and resources created from this study enable future and secondary analysis of tumor RNA mixtures in head and neck cancer for a more accurate cellular deconvolution, and can facilitate the profiling of the immune infiltration in other solid tumors due to the expression homogeneity observed in immune cells.
Environmental harshness is associated with lower investment in collective actions
Authors: Lettinga N. , Jacquet P.O. , André J-B. , Baumard N. , Chevallier C. 
Published: June 2019

AbstractAlthough humans cooperate universally, there is variability across individuals, times and cultures in the amount of resources people invest in cooperative activities. The origins of such variability are not known but recent work highlights that variations in environmental harshness may play a key role. A growing body of experimental work in evolutionary psychology suggests that humans adapt to their specific environment by calibrating their life-history strategy. In this paper, we apply structural equation models to test the association between current and childhood environmental harshness, life-history strategy and adult cooperation in two large-scale datasets (the World Values Survey and the European Values Study). The present study replicates existing research linking a harsher environment (both in adulthood and in childhood) with a modulated reproduction-maintenance trade-off and extends these findings to the domain of collective actions. Specifically, we find that a harsher environment (both in adulthood and in childhood) is associated with decreased involvement in collective action and that this association is mediated by individuals’ life-history strategy.
Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants
Authors: Popp Bernt , Erber Ramona , Kraus Cornelia , Vasileiou Georgia , Hoyer Juliane , Burghaus Stefanie , Hartmann Arndt , Beckmann Matthias W. , Reis André , Agaimy Abbas 
Published: June 2019

ABSTRACTUterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found a FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism.By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7 - 13.9% of females with an FH deficient UL to carry a germline FH variant.Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.
ppGpp Ribosome Dimerization Model for Bacterial Persister Formation and Resuscitation
Authors: Song Sooyeon , Wood Thomas K. 
Published: June 2019

ABSTRACTStress is ubiquitous for bacteria and converts a subpopulation of cells into a dormant state known as persistence, in which cells are tolerant to antimicrobials. These cells revive rapidly when the stress is removed and are likely the cause of many recurring infections such as those associated with tuberculosis, cystic fibrosis, and Lyme disease. However, how persister cells are formed is not understood well. Here we propose the ppGpp ribosome dimerization persister (PRDP) model in which the alarmone guanosine pentaphosphate/tetraphosphate (henceforth ppGpp) generates persister cells directly by inactivating ribosomes via the ribosome modulation factor (RMF) and the hibernation promoting factor (Hpf). We demonstrate both RMF and HpF increase persistence and reduce single-cell persister resuscitation and that ppGpp has no effect on single-cell persister resuscitation. Hence, a direct connection between ppGpp and persistence is shown.
An inducible Cre mouse line to sparsely target nervous system cells, including Remak Schwann cells
Authors: Sapkota Darshan , Dougherty Joseph D. 
Published: June 2019

ABSTRACTNerves of the peripheral nervous system contain two classes of Schwann cells– myelinating Schwann cells that ensheath large caliber axons in myelin, and Remak Schwann cells that surround smaller axons and do not myelinate. While tools exist for genetic targeting of myelinating Schwann cells, such reagents have been challenging to generate for the Remak population in part because many of the genes that mark this population in maturity are also robustly expressed in progenitors of all Schwann cells. To circumvent this challenge, we utilized BAC transgenesis to generate a mouse line expressing a tamoxifen-inducible Cre under the control of a Remak-expressed gene promoter (Egr1). However, as Egr1 is also an activity dependent gene expressed by some neurons, we flanked this Cre by flippase (Flpe) recognition target sites, and coinjected a BAC expressing Flpe under control of a pan-neuronal Snap25 promoter, to excise the Cre transgene from these neuronal cells. Genotyping and inheritance demonstrate that the two BACs co-integrated into a single locus, facilitating maintenance of the line. Anatomical studies following a cross to a reporter line show sparse tamoxifen-dependent recombination in Remak Schwann cells within the mature sciatic nerve. However, depletion of neuronal Cre activity by Flpe is partial, with some neurons and astrocytes also showing evidence of Cre reporter activity in the central nervous system. Thus, this mouse line will be useful in mosaic loss-of-function studies, lineage tracing studies following injury, and live cell imaging studies or other experiment benefiting from sparse labeling.
NF-κB-c-REL impairment drives human stem cells into the oligodendroglial fate
Authors: Ruiz-Perera Lucia M , Greiner Johannes FW , Kaltschmidt Christian , Kaltschmidt Barbara 
Published: June 2019

AbstractMolecular mechanisms underlying fate decisions of human neural stem cells (NSCs) between neurogenesis and gliogenesis are critical during neuronal development and progression of neurodegenerative diseases. Despite its crucial role in murine nervous system development, the potential role of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) in fate shifts of human stem cells is poorly understood.Facing this challenge, we demonstrate here that NF-κB-c-REL drives glutamatergic differentiation of adult human stem cells, while its impairment results in a shift towards the oligodendroglial fate. We particularly observed an opposing balance switch from NF-κB-RELB/p52 to NF-κB-c-REL during early neuronal differentiation of NSCs originating from neural crest-derived stem cells. Exposure of differentiating human NSCs to the c-REL inhibiting approved drug pentoxifylline (PTXF) resulted in elevated levels of cell death and significantly decreased amounts of NF200+/VGLUT2+ neurons. PTXF-mediated inhibition of c-REL further drove human NSCs into the oligodendrocyte fate, as demonstrated by a complete switch to OLIG2+/O4+ oligodendrocytes, which also showed PDGFRα, NG2 and MBP transcripts.In summary, we present here a novel human cellular model of neuronal differentiation with an essential role of NF-κB-c-REL in fate choice between neurogenesis and oligodendrogenesis potentially relevant for multiple sclerosis and schizophrenia.
Expression of nitric oxide synthase and nitric oxide levels in peripheral blood cells and oxidized low-density lipoprotein levels in saliva as early markers of severe dengue
Authors: Hapugaswatta Harsha , Wimalasekara Ruwani L. , Perera Suharshi S. , Premaratna Ranjan , Seneviratne Kapila N. , Jayathilaka Nimanthi 
Published: June 2019

ABSTRACTBackgroundSevere dengue (SD), experienced by only a fraction of dengue patients can be lethal. Due to lack of early markers that can predict the evolution of SD, all dengue patients have to be monitored under hospital care. We discovered early oxidative stress markers of SD to identify patients who can benefit from early intervention before the symptoms appear.MethodsExpression of inducible nitric oxide synthase (iNOS) in peripheral blood cells (PBC), nitric oxide (NO) and oxidized low-density lipoprotein (oxLDL) levels in plasma and saliva collected at early stages of dengue infection from 20 non-severe dengue fever (DF) patients and 20 patients who later developed SD were analyzed in a retrospective nested case-control study.ResultsExpression of iNOS is significantly (P<0.05) lower in patients who developed SD than in DF patients at admission within 4 days from fever onset. Median plasma NO concentration within 4 days from fever onset is also significantly (P<0.05) lower in patients who developed SD (17.9±1.6 μM) than DF (23.0±2.1 μM). Median oxLDL levels in plasma within 3 days from fever onset is significantly (P<0.05) lower in patients who developed SD (509.4±224.1 ng/mL) than DF (740.0±300.0 ng/mL). Median salivary oxLDL levels are also significantly (P<0.05) lower in patients who developed SD (0.8±0.5 ng/mL) than DF (3.6±2.6 ng/mL) within 4 days from fever onset.ConclusionsThese findings suggest that the expression of iNOS (73% sensitivity, 86% specificity) and plasma NO (96% sensitivity, 61% specificity at 22.3 μM; P<0.05) may serve as early markers of SD within 3 days from fever onset. Salivary oxLDL levels may serve as early non-invasive markers of SD with a sensitivity and specificity respectively of 57% and 91% at 0.9 ng/mL, 76% and 55% at 2.3 ng/mL and 100% and 50% at 4.6 ng/mL; P<0.05) within 4 days from fever onset.