Miracle-dz/UniFAR-FTUs huggingface dataset:
3-Phosphoglycerate Dehydrogenase, a Key Enzyme forl-Serine Biosynthesis, Is Preferentially Expressed in the Radial Glia/Astrocyte Lineage and Olfactory Ensheathing Glia in the Mouse Brain

l-Serine is synthesized from glycolytic intermediate 3-phosphoglycerate and is an indispensable precursor for the synthesis of proteins, membrane lipids, nucleotides, and neuroactive amino acids d-serine and glycine. We have recently shown that l-serine and its interconvertible glycine act as Bergmann glia-derived trophic factors for cerebellar Purkinje cells. To investigate whether such a metabolic neuron-glial relationship is fundamental to the developing and adult brain, we examined by in situ hybridization and immunohistochemistry the cellular expression of 3-phosphoglycerate dehydrogenase (3PGDH), the initial step enzyme for de novol-serine biosynthesis in animal cells. At early stages when the neural wall consists exclusively of the ventricular zone, neuroepithelial stem cells expressed 3PGDH strongly and homogeneously. Thereafter, 3PGDH expression was downregulated and eventually disappeared in neuronal populations, whereas its high expression was transmitted to the radial glia and later to astrocytes in the gray and white matters. In addition, 3PGDH was highly expressed throughout development in the olfactory ensheathing glia, a specialized supporting cell that thoroughly ensheathes olfactory nerves. These results establish a fundamental link of the radial glia/astrocyte lineage and olfactory ensheathing glia to l-serine biosynthesis in the brain. We discuss this finding in the context of the hypothesis that 3PGDH expression in these glia cells contributes to energy metabolism in differentiating and differentiated neurons and other glia cells, which are known to be vulnerable to energy loss.
In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor

The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the drug development efforts targeting this pathway with therapeutic interventions have been advanced by academic and industrial groups. However, the clinical outcome is moderate. Combination of inhibition of PI3K/AKT and other targeted agents became a feasible approach. In this study we assessed the combined effect of ARQ 092, a pan-AKT inhibitor, and ARQ 087, a pan-FGFR inhibitor, in vitro and in vivo. In a panel of 45 cancer cell lines, on 24% (11 out of 45) the compounds showed synergistic effect, on 62% (28 out of 45) additive, and on 13% (6 out of 45) antagonistic. The highest percentage of synergism was found on endometrial and ovarian cancer cell lines. Mutational analysis revealed that PIK3CA/PIK3R1 mutations and aberrant activation of FGFR2 predicted synergism, whereas Ras mutations showed a reverse correlation. Pathway analysis revealed that a combination of ARQ 092 and ARQ 087 enhanced the inhibition of both the AKT and FGFR pathways in cell lines in which synergistic effects were found (AN3CA and IGROV-1). Cell cycle arrest and apoptotic response occurred only in AN3CA cell, and was not seen in IGROV-1 cells. Furthermore, enhanced antitumor activity was observed in mouse models with endometrial cancer cell line and patient-derived tumors when ARQ 092 and ARQ 087 were combined. These results from in-vitro and in-vivo studies provide a strong rationale in treating endometrial and other cancers with the activated PI3K/AKT and FGFR pathways.
Temporal requirement of the alternative-splicing factor Sfrs1 for the survival of retinal neurons

Alternative splicing is the primary mechanism by which a limited number of protein-coding genes can generate proteome diversity. We have investigated the role of the alternative-splicing factor Sfrs1, an arginine/serine-rich (SR) protein family member, during mouse retinal development. Loss of Sfrs1 function during embryonic retinal development had a profound effect, leading to a small retina at birth. In addition, the retina underwent further degeneration in the postnatal period. Loss of Sfrs1 function resulted in the death of retinal neurons that were born during early to mid-embryonic development. Ganglion cells, cone photoreceptors, horizontal cells and amacrine cells were produced and initiated differentiation. However, these neurons subsequently underwent cell death through apoptosis. By contrast, Sfrs1 was not required for the survival of the neurons generated later, including later-born amacrine cells, rod photoreceptors, bipolar cells and Müller glia. Our results highlight the requirement of Sfrs1-mediated alternative splicing for the survival of retinal neurons, with sensitivity defined by the window of time in which the neuron was generated.
Estrogen receptor-dependent attenuation of hypoxia-induced changes in the lung genome of pulmonary hypertension rats

17β-estradiol (E2) exerts complex and context-dependent effects in pulmonary hypertension. In hypoxia-induced pulmonary hypertension (HPH), E2 attenuates lung vascular remodeling through estrogen receptor (ER)-dependent effects; however, ER target genes in the hypoxic lung remain unknown. In order to identify the genome regulated by the E2-ER axis in the hypoxic lung, we performed a microarray analysis in lungs from HPH rats treated with E2 (75 mcg/kg/day) ± ER-antagonist ICI182,780 (3 mg/kg/day). Untreated HPH rats and normoxic rats served as controls. Using a false discovery rate of 10%, we identified a significantly differentially regulated genome in E2-treated versus untreated hypoxia rats. Genes most upregulated by E2 encoded matrix metalloproteinase 8, S100 calcium binding protein A8, and IgA Fc receptor; genes most downregulated by E2 encoded olfactory receptor 63, secreted frizzled-related protein 2, and thrombospondin 2. Several genes affected by E2 changed in the opposite direction after ICI182,780 co-treatment, indicating an ER-regulated genome in HPH lungs. The bone morphogenetic protein antagonist Grem1 (gremlin 1) was upregulated by hypoxia, but found to be among the most downregulated genes after E2 treatment. Gremlin 1 protein was reduced in E2-treated versus untreated hypoxic animals, and ER-blockade abolished the inhibitory effect of E2 on Grem1 mRNA and protein. In conclusion, E2 ER-dependently regulates several genes involved in proliferative and inflammatory processes during hypoxia. Gremlin 1 is a novel target of the E2-ER axis in HPH. Understanding the mechanisms of E2 gene regulation in HPH may allow for selectively harnessing beneficial transcriptional activities of E2 for therapeutic purposes.
Designed RNAs with Two Peptide‐Binding Units as Artificial Templates for Native Chemical Ligation of RNA‐Binding Peptides

The template effect plays important roles not only in modern synthetic and enzymatic catalysis but also in the ancient “RNA‐polypeptide (RNP) world,” which has been postulated to be a crucial stage in the origin of life. To mimic primitive template catalysis of peptide ligations by RNAs, we previously reported the design and synthesis of a ternary RNP complex in which the ligation of two peptides was significantly facilitated by a template RNA with two peptide‐binding units. However, RNA molecules also promoted the ligation reaction in a nonspecific manner through electrostatic interactions between RNA and basic peptides. In this study, we suppressed this effect by reducing the length of the original template derived from the Tetrahymena intron RNA. This modification, however, decreased the template ability for the specific reaction. As an alternative RNA that was as effective as the original template, we found that a self‐dimerizing RNA was a promising template for peptide ligation without a nonspecific effect.
Coexistence via coevolution driven by reduced allelochemical effects and increased tolerance to competition between invasive and native plants.

Coevolution can promote long-term coexistence of two competing species if selection acts to reduce the fitness inequality between competitors and/or strengthen negative frequency dependence within each population. However, clear coevolution between plant competitors has been rarely documented. Plant invasions offer opportunities to capture the process of coevolution. Here we investigated how the developing relationship between an invasive forb, Alliaria petiolata, and a native competitor, Pilea pumila, may affect their long-term coexistence, by testing the competitive effects of populations of varying lengths of co-occurrence on each other across a chronosequence of invasion history. Alliaria petiolata and P. pumila tended to develop greater tolerance to competition over invasion history. Their coexistence was promoted more by increases in stabilizing relative to equalizing processes. These changes likely stem in part from reductions in allelopathic traits in the invader and evolution of tolerance in the native. These results suggested that some native species can evolve tolerance against the competitive effects of strong invaders, which likely promoted their persistence in invaded communities. However, the potential for coevolutionary rescue of competing populations is likely to vary across native species, and evolutionary processes should not be expected to compensate for the ecological consequences of exotic invasions.
Three Research Strategies of Neuroscience and the Future of Legal Imaging Evidence

Neuroscientific imaging evidence (NIE) has become an integral part of the criminal justice system in the United States. However, in most legal cases, NIE is submitted and used only to mitigate penalties because the court does not recognize it as substantial evidence, considering its lack of reliability. Nevertheless, we here discuss how neuroscience is expected to improve the use of NIE in the legal system. For this purpose, we classified the efforts of neuroscientists into three research strategies: cognitive subtraction, the data-driven approach, and the brain-manipulation approach. Cognitive subtraction is outdated and problematic; consequently, the court deemed it to be an inadequate approach in terms of legal evidence in 2012. In contrast, the data-driven and brain manipulation approaches, which are state-of-the-art approaches, have overcome the limitations of cognitive subtraction. The data-driven approach brings data science into the field and is benefiting immensely from the development of research platforms that allow automatized collection, analysis, and sharing of data. This broadens the scale of imaging evidence. The brain-manipulation approach uses high-functioning tools that facilitate non-invasive and precise human brain manipulation. These two approaches are expected to have synergistic effects. Neuroscience has strived to improve the evidential reliability of NIE, with considerable success. With the support of cutting-edge technologies, and the progress of these approaches, the evidential status of NIE will be improved and NIE will become an increasingly important part of legal practice.
Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells

The Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small-molecule inhibitor of Mdm2–p53 interaction that can induce apoptosis in cancer cells through activation of p53. Although this is a promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal that a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11–Rad50–Nbs1 DNA repair complex. In ovarian cancer cells, where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when used in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53. Implications: Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53. Mol Cancer Res; 13(8); 1197–205. ©2015 AACR.
Hemogenic endothelium specification and hematopoietic stem cell maintenance employ distinct Scl isoforms

Recent studies have shown that nascent hematopoietic stem cells (HSCs) derive directly from the ventral aortic endothelium (VAE) via endothelial to hematopoietic transition (EHT). However, whether EHT initiates from a random or predetermined subpopulation of VAE, as well as the molecular mechanism underlying this process, remain unclear. We previously reported that different zebrafish stem cell leukemia (scl) isoforms are differentially required for HSC formation in the ventral wall of the dorsal aorta. However, the exact stage at which these isoforms impact HSC development was not defined. Here, using in vivo time-lapse imaging of scl isoform-specific reporter transgenic zebrafish lines, we show that prior to EHT scl-β is selectively expressed in hemogenic endothelial cells, a unique subset of VAE cells possessing hemogenic potential, whereas scl-α is expressed later in nascent HSCs as they egress from VAE cells. In accordance with their expression, loss-of-function studies coupled with in vivo imaging analysis reveal that scl-β acts earlier to specify hemogenic endothelium, which is later transformed by runx1 into HSCs. Our results also reveal a previously unexpected role of scl-α in maintaining newly born HSCs in the aorta-gonads-mesonephros. Thus, our data suggest that a defined hemogenic endothelial population preset by scl-β supports the deterministic emergence of HSCs, and unravel the cellular mechanisms by which scl isoforms regulate HSC development.
THERMAL NECROSIS AND PMMA – A CAUSE FOR CONCERN?

Thermal damage to bone related to the exothermic polymerisation of bone cement (PMMA) remains a concern. A series of studies were conducted to examine PMMA bone interface during cemented arthroplasty. In vitro and in vivo temperature distributions were performed in the laboratory and human and animal surgery. In vivo (10 patients) measurements of cement temperature during cementing of BHR femoral prosthesis using thermocouples. Intra-operative measurement of cement temperature in BHR in the presence of femoral head cysts was examined in patients. The BHR femoral heads were sectioned to assess cement mantle as well as position of thermocouples. An additional study was performed in sheep with PMMA implanted into cancellous defects. Thermocouples were used to monitor temperature in the cement as well as adjacent bone. Histology and CT was used to assess any thermal damage. The exothermic reaction of PMMA during polymerization does indeed result in an increase in temperature at the interface with bone. The in vivo study recorded a maximum temperature of 49.12C for approximately three minutes in the cancellous bone underneath the BHR prosthesis. This exposure is probably not sufficient to cause significant injury to the femoral head. The maximum temperature of the cement on the surface of the bone was 54.12C, whereas the maximum recorded in the cement in the mixing bowl was 110.2C. In the presence of artificial cysts within the bone, however, temperatures generated within the larger cysts, and even at the bone-cement interface of these cysts, reached levels greater than those previously shown to be harmful to bone. This occurred in one case even in the 1 cc cyst. Routine histology revealed a fibrous layer at the cement bone interface in the sheep study. Fluorescent microscopy demonstrated bone label uptake adjacent to the defect site. Histology did not reveal thermal necrosis in the defects in terms of bony necrosis. CT data was used to measure the amount of PMMA placed into each defect. This analysis revealed a range of volumes that did not seem to influence the histology. The heat of cement polymerisation in resurfacing as performed in our study is not sufficient to cause necrosis. This may reflect the ability of the body to rapidly conduct heat away by acting as a heat sink. The temperature-conducting properties of the metal prosthesis are also likely to be important.
Construction and analysis for differentially expressed long non-coding RNAs and MicroRNAs mediated competing endogenous RNA network in colon cancer

Long non-coding RNA (lncRNA) has been confirmed to act as a key regulatory molecule in different types of cancers and play a significant role in tumors initiation and progression. LncRNA can be as acompeting endogenous RNA(ceRNA) to regulate the expression of targeted genes by sponging miRNA. In the present study, we explore the functional roles and regulatory mechanisms of lncRNAs as ceRNAs in colon cancer and their potential implications for prognosis.The lncRNAs, miRNAs and mRNAs expression profiles of 341 colon cancer tissues and 27 non-tumor colon tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Differential expression of RNAs was identified using the “DESeq” bioconductor package in R. PPI network of differentially expressed genes was constructed using the STRING database. Survival analysis was estimated based on Kaplan-Meier curve analysis. We used KOBAS 3.0 to analyze the KEGG pathway of DEGs. The dysregulated lncRNA-associated ceRNA network was constructed in colon cancer based on bioinformatics generated from miRanda, PicTar, TargetScan, miRDB and miRcode. A total of 791 DElncRNAs and 200 DEmiRNAs were identified in colon cancer compared with matched normal tissues with thresholds of |log2foldChange (FC)| >3.0and adjusted P value<0.05. Twenty DElncRNAs were identified, may be related to tumorigenesis and/or progression of colon cancer. Nine out of 20 dysregulated lncRNA were found to be significantly associated with overall survival (P value<0.05). Finally, we successfully constructed colon cancer-associated ceRNA network, including 9 colon cancer-specific lncRNAs, 13 miRNAS and 70 mRNAs. In conclusion, our study will contribute to improve the understanding of ceRNA network regulatory mechanisms in colon cancer. These identified novel lncRNAs can be as candidate prognostic biomarkers or potential therapeutic targets.
Development of a Testing Machine for Three Point Bending of Ceramics in Controlled Crack Extension.

本研究では, 試験片試験機系の自由エネルギーの議論に基づき。 セラミックスの破壊じん性試験におけるき裂の安定条件を検討し, その結果に基づいて, SEN三点曲げ試験片の安定破壊が可能な卓上型試験装置を開発した. この装置は, 試験片の準備や試験手順を簡単にするため, 製作が容易なJIS R 1607型の曲げ試験片を用いるとともに, クラックスタビライザ等の付加装置を必要としない設計にした. 一般的なエンジニアリングセラミックス4種 (Al2O3, Y-PSZ, SiC, Si3N4) を試験片として, その性能を確認したところ, すべての材質において安定なき裂進展を実現することができ, 荷重変位曲線の記録に成功した. 水晶式力変換器を用いた荷重測定は, 一般には長時間の安定性が保証されないが, 本実験における誤差は5～10%以下と推定されるので実用上許容される範囲であると認められた.
Words' Burstiness in Language Models

Good estimation of the probability of a single word is a crucial part of language modelling. It is based on raw frequency of the word in a training corpus. Such computation is a good estimation for functional words and most very frequent words, but it is a poor estimation for most content words because of words' tendency to occur in clusters. This paper provides an analysis of words' burstiness and propose a new unigram language model which handles bursty words much better. The evaluation of the model on two data sets shows consistently lower perplexity and cross-entropy in the new model.
A Forward GPS Multipath Simulator Based on the Vegetation Radiative Transfer Equation Model

Global Navigation Satellite Systems (GNSS) have been widely used in navigation, positioning and timing. Nowadays, the multipath errors may be re-utilized for the remote sensing of geophysical parameters (soil moisture, vegetation and snow depth), i.e., GPS-Multipath Reflectometry (GPS-MR). However, bistatic scattering properties and the relation between GPS observables and geophysical parameters are not clear, e.g., vegetation. In this paper, a new element on bistatic scattering properties of vegetation is incorporated into the traditional GPS-MR model. This new element is the first-order radiative transfer equation model. The new forward GPS multipath simulator is able to explicitly link the vegetation parameters with GPS multipath observables (signal-to-noise-ratio (SNR), code pseudorange and carrier phase observables). The trunk layer and its corresponding scattering mechanisms are ignored since GPS-MR is not suitable for high forest monitoring due to the coherence of direct and reflected signals. Based on this new model, the developed simulator can present how the GPS signals (L1 and L2 carrier frequencies, C/A, P(Y) and L2C modulations) are transmitted (scattered and absorbed) through vegetation medium and received by GPS receivers. Simulation results show that the wheat will decrease the amplitudes of GPS multipath observables (SNR, phase and code), if we increase the vegetation moisture contents or the scatters sizes (stem or leaf). Although the Specular-Ground component dominates the total specular scattering, vegetation covered ground soil moisture has almost no effects on the final multipath signatures. Our simulated results are consistent with previous results for environmental parameter detections by GPS-MR.
An adjoint method for design optimization of ship hulls

We present a design optimization method for reducing the wave resistance (drag) of surface piercing hulls. Since this component of the drag is directly related to the energy contained in the wave structure that extends behind the ship, a fully coupled calculation of the flow field and wave evolution equation is required. The method combines the authors’ efficient automatic shape optimization technique based on control theory, and non-linear free surface solver. In this approach an evaluation of the gradient of a cost function is computed by solving an adjoint system of partial differential equations, which enables to account for an arbitrary number of design variables (degrees of freedom).
Probing the Surface Tension of Ionic Liquids Using the Langmuir Principle

At 298 K, the surface tension of ionic liquids (ILs) of the 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide series, [CnC1Im][NTf2], ranges from around 35 mN·m–1 for [C2C1Im][NTf2] to just below 30 mN·m–1 for [C12C1Im][NTf2]. However, the decrease rate along the series is not constant: a large decrease from [C2C1Im][NTf2] to [C8C1Im][NTf2] is followed by almost constant values from [C8C1Im][NTf2] to [C12C1Im][NTf2]. Such behavior is hard to interpret from a molecular point of view without suitable information about the free-surface structure of the different ILs. In this work, we have successfully used the Langmuir principle in combination with structural data obtained from angle-resolved X-ray photoelectron spectroscopy experiments and molecular dynamics simulations, to predict the correct surface tension trend along the IL series. The concepts unveiled for this particular homologous IL family can be easily extended to other systems.