Systems evaluation reveals novel transporter YohJK renders 3-hydroxypropionate tolerance in Escherichia coli

Previously, we have reported that 3-hydroxypropionate (3-HP) tolerance in Escherichia coli W is improved by deletion of yieP, a less-studied transcription factor. Here, through systems analyses along with physiological and functional studies, we suggest that the yieP deletion improves 3-HP tolerance by upregulation of yohJK, encoding putative 3-HP transporter(s). The tolerance improvement by yieP deletion was highly specific to 3-HP, among various C2-C4 organic acids. Mapping of YieP binding sites (ChIP-exo) coupled with transcriptomic profiling (RNA-seq) advocated seven potential genes/operons for further functional analysis. Among them, the yohJK operon, encoding for novel transmembrane proteins, was the most responsible for the improved 3-HP tolerance; deletion of yohJK reduced 3-HP tolerance regardless of yieP deletion, and their subsequent complementation fully restored the tolerance in both the wild-type and yieP deletion mutant. When determined by 3-HP-responsive biosensor, a drastic reduction of intracellular 3-HP was observed upon yieP deletion or yohJK overexpression, suggesting that yohJK encodes for novel 3-HP exporter(s)

Essential oil mixture on rumen fermentation and microbial community – an study

Objective The objective of this study was to investigate the effects of essential oil mixture (EOM) supplementation on rumen fermentation characteristics and microbial changes in an in vitro. Methods Three experimental treatments were used: control (CON, no additive), EOM 0.1 (supplementation of 1 g EOM/kg of substrate), and EOM 0.2 (supplementation of 2 g EOM/kg of substrate). An in vitro fermentation experiment was carried out using strained rumen fluid for 12 and 24 h incubation periods. At each time point, in vitro dry matter digestibility (IVDMD), neutral detergent fiber digestibility (IVNDFD), pH, ammonia nitrogen (NH3-N), and volatile fatty acid (VFA) concentrations, and relative microbial diversity were estimated. Results After 24 h incubation, treatments involving EOM supplementation led to significantly higher IVDMD (treatments and quadratic effect; p = 0.019 and 0.008) and IVNDFD (linear effect; p = 0.068) than did the CON treatment. The EOM 0.2 supplementation group had the highest NH3-N concentration (treatments; p = 0.032). Both EOM supplementations did not affect total VFA concentration and the proportion of individual VFAs; however, total VFA tended to increase in EOM supplementation groups, after 12 h incubation (linear; p = 0.071). Relative protozoa abundance significantly increased following EOM supplementation (treatments, p<0.001). Selenomonas ruminantium and Ruminococcus albus (treatments; p<0.001 and p = 0.005), abundance was higher in the EOM 0.1 treatment group than in CON. The abundance of Butyrivibrio fibrisolvens, fungi and Ruminococcus flavefaciens (treatments; p< 0.001, p<0.001, and p = 0.005) was higher following EOM 0.2 treatment. Conclusion The addition of newly developed EOM increased IVDMD, IVNDFD, and tended to increase total VFA indicating that it may be used as a feed additive to improve rumen fermentation by modulating rumen microbial communities. Further studies would be required to investigate the detailed metabolic mechanism underlying the effects of EOM supplementation

Activation of AMP-activated Protein Kinase Is Essential for Lysophosphatidic Acid-induced Cell Migration in Ovarian Cancer Cells

Lysophosphatidic acid (LPA) is a bioactive phospholipid that affects various biological functions, such as cell proliferation, migration, and survival, through LPA receptors. Among them, the motility of cancer cells is an especially important activity for invasion and metastasis. Recently, AMP-activated protein kinase (AMPK), an energy-sensing kinase, was shown to regulate cell migration. However, the specific role of AMPK in cancer cell migration is unknown. The present study investigated whether LPA could induce AMPK activation and whether this process was associated with cell migration in ovarian cancer cells. We found that LPA led to a striking increase in AMPK phosphorylation in pathways involving the phospholipase C-beta 3 (PLC-beta 3) and calcium/calmodulin-dependent protein kinase kinase beta (CaMKK beta) in SKOV3 ovarian cancer cells. siRNA-mediated knockdown of AMPK beta 1, PLC-beta 3, or (CaMKK beta) impaired the stimulatory effects of LPA on cell migration. Furthermore, we found that knockdown of AMPK beta 1 abrogated LPA-induced activation of the small GTPase RhoA and ezrin/radixin/moesin proteins regulating membrane dynamics as membrane-cytoskeleton linkers. In ovarian cancer xenograft models, knockdown of AMPK significantly decreased peritoneal dissemination and lung metastasis. Taken together, our results suggest that activation of AMPK by LPA induces cell migration through the signaling pathway to cytoskeletal dynamics and increases tumor metastasis in ovarian cancer.close161

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Optimal reinsurance with a systemic surplus shock

We examine the optimal reinsurance and asset allocation strategies for an insurer who minimizes the ruin probability and faces a systemic surplus shock. Analytically tractable solutions are obtained when this shock occurs at an uncertain time. We then demonstrate that the systemic surplus shock results in a nonstandard form of market incompleteness, which alters both qualitative and quantitative features of existing strategies without the surplus shock. In particular, a specific form of the marginal value for the insurer's minimized ruin probability plays a key role in the characterization of optimal policies with the systemic surplus shock

The Time Sequence of Gene Expression Changes after Spinal Cord Injury

Gene expression changes following spinal cord injury (SCI) are time-dependent, and an accurate understanding of these changes can be crucial in determining time-based treatment options in a clinical setting. We performed RNA sequencing of the contused spinal cord of rats at five different time points from the very acute to chronic stages (1 hour, 1 day, 1 week, 1 month, and 3 months) following SCI. We identified differentially expressed genes (DEGs) and Gene Ontology (GO) terms at each time point, and 14,257 genes were commonly expressed at all time points. The biological process of the inflammatory response was increased at 1 hour and 1 day, and the cellular component of the integral component of the synaptic membrane was increased at 1 day. DEGs associated with cell activation and the innate immune response were highly enriched at 1 week and 1 month, respectively. A total of 2841 DEGs were differentially expressed at any of the five time points, and 18 genes (17 upregulated and 1 downregulated) showed common expression differences at all time points. We found that interleukin signaling, neutrophil degranulation, eukaryotic translation, collagen degradation, LGI–ADAM interactions, GABA receptor, and L1CAM-ankyrin interactions were prominent after SCI depending on the time post injury. We also performed gene–drug network analysis and found several potential antagonists and agonists which can be used to treat SCI. We expect to discover effective treatments in the clinical field through further studies revealing the efficacy and safety of potential drugs

Abstractive Sentence Compression with Event Attention

Sentence compression aims at generating a shorter sentence from a long and complex source sentence while preserving the important content of the source sentence. Since it provides enhanced comprehensibility and readability to readers, sentence compression is required for summarizing news articles in which event words play a key role in delivering the meaning of the source sentence. Therefore, this paper proposes an abstractive sentence compression with event attention. In compressing a sentence of news articles, event words should be preserved as important information for sentence compression. For this, event attention is proposed which focuses on the event words of the source sentence in generating a compressed sentence. The global information in the source sentence is as significant as event words, since it captures the information of a whole source sentence. As a result, the proposed model generates a compressed sentence by combining both attentions. According to experimental results, the proposed model outperforms both the normal sequence-to-sequence model and the pointer generator on three datasets, namely the MSR dataset, Filippova dataset, and Korean sentence compression dataset. In particular, it shows 122% higher BLEU score than the sequence-to-sequence model. Therefore, the proposed model is effective in sentence compression

Complexation between DNA and Hydrophilic-Cationic Diblock Copolymers

We examine connections among polycation composition, DNA-polycation binding thermodynamics, binding strength, and resulting complex properties, for circular and linear DNA and hydrophilic diblock copolymers possessing cationic blocks. Two poly­(2-deoxy-2-methacrylamido glucopyranose)-<i>block</i>-poly­(<i>N</i>-(2-aminoethyl) methacrylamide) (PMAG-<i>b</i>-PAEMA), with block degrees of polymerization of PMAG56-<i>b</i>-PAEMA30 and PMAG52-<i>b</i>-PAEMA63, are employed. DNA binding behavior of these diblocks is also compared with that of a PAEMA homopolymer, in order to evaluate the role of the hydrophilic, charge-neutral PMAG block. In addition, DNA structure was varied, utilizing both circular and linear DNA with the same contour length. The enthalpy change due to DNA-polycation interactions (Δ<i>H</i>_int) is observed via isothermal titration calorimetry (ITC) during titrations of DNA with the polycations. With circular DNA, a higher cationic content is found to result in a completion of binding with a smaller amount of polycation, as well as a larger initial Δ<i>H</i>_int. In contrast to the common understanding that a neutral block simply provides colloidal stability, the PMAG block turns out to significantly impact both the extent of the binding and the size and dispersity of the final complexes. With a lower cationic content, the complex is less compact, but both the size and dispersity are more stable. Changes in circular dichroism spectra of DNA are shown to be correlated with PMAG-to-PAEMA block length ratio. PMAG52-<i>b</i>-PAEMA63 leads to stronger binding with DNA, compared to PMAG56-<i>b</i>-PAEMA30. Better-defined polyplexes and more disruption in the DNA helices are observed when the PMAG-to-PAEMA ratio is lower. All in all, while PMAG itself does not directly interact with DNA, the DNA-polycation binding turns out to be sensitive to the balance between the DNA-PAEMA attraction and PMAG solvation. In addition, it is confirmed that polyelectrolyte complexation is favored both entropically and enthalpically when the ionic strength of the solution is low. While only endothermic interactions occur in the buffered systems, exothermic initial interactions are observed in low-salt, unbuffered cases. Finally, complexes formed with linear DNA show clear bimodal size distributions, distinct from those formed with circular DNA. Collectively, these data provide insights into the controllable parameters in DNA-polycation complexation, which may advance the development of polymeric vehicles for large biomolecules such as nucleic acids

Structures and Protonation States of Hydrophilic–Cationic Diblock Copolymers and Their Binding with Plasmid DNA

Complexation between plasmid DNA (pDNA) and a set of diblock copolymers, each with one cationic block and one hydrophilic, charge-neutral block, is examined. A range of hydrophilic block structures are explored, whereas the cationic block is fixed as poly­(<i>N</i>-(2-aminoethyl) methacrylamide) (PAEMA) with a degree of polymerization of 60 ± 3. The hydrophilic blocks include poly­(ethylene glycol) (PEG45), poly­(oligo­(ethylene glycol) methyl ether methacrylate) (P­(OEGMA)­51), and poly­(2-deoxy-2-methacrylamido glucopyranose) (PMAG52). The numbers represent the degrees of polymerization and are chosen such that the diblock contour lengths are similar (37 ± 2 nm). The three diblock copolymers and a homopolycation control, PAEMA59, are compared with respect to their state of dissolution in aqueous environments, as well as their complexation with pDNA. The diblock copolymers are found to partially aggregate as pH increases above 6, whereas each separate block generally dissolves well over a wide pH range. The hydrophilic block proves to be a critical parameter in determining the structures of pDNA–diblock complexes. When the molar ratio of polycation amines to pDNA phosphates (i.e., N/P) is less than 1, a bulkier hydrophilic block leads to larger resulting complexes. As more polycations are added to the system (N/P > 1.5), colloidal stability becomes an important factor, making more water-soluble systems stabilize at smaller sizes. Further, the charge density effect on the binding thermodynamics is elucidated via calorimetric measurements. P­(OEGMA)­51-<i>b</i>-PAEMA60 exhibits a greater amount of endothermic pDNA binding per charged amine at higher pH, implying that lower cationic charge density promotes more phosphate pairing per amine on average. Also, the colloidal stability and the circular dichroism spectral evolution of the pDNA–PAEMA59 complexes are dependent on pH, showing noticeable differences between pH = 6.0 vs 7.4. To summarize, controlling the solution pH may be crucial in pDNA–polycation complexation, as it impacts polycation solubility, binding characteristics, and the final complex properties. The findings reported herein should aid researchers in drawing more rigorous structure–function correlations in the field of polymeric gene delivery