bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dilemma of Addiction and Respiratory Depression in the Treatment of Pain: A Prototypical Endomorphin as a New Approach
Authors: Webster Lynn , Schmidt William K 
Published: April 2019

Abstract

Objective
Although mu-opioid receptor agonists have been the mainstay of analgesic regimens for moderate to severe pain, they are associated with serious side effects, risks, and limitations. We evaluate the most serious risks associated with conventional opioids and compare these with the pharmacology of CYT-1010, a prototypical endomorphin and mu-opioid receptor agonist.

Results
Addiction and respiratory depression are serious risks of traditional mu-opioid analgesics. Mitigation strategies have been inadequate at addressing the opioid crisis and may interfere with the effective treatment of pain. Improved understanding of mu-opioid receptor biology and the discovery in 1997 of an additional and unique family of endogenous opioid peptides (endomorphins) have provided a pathway for dissociating analgesia from opioid-related adverse events and developing new classes of mu-opioid receptor agonists that use biased signaling and/or target novel sites to produce analgesia with reduced side effect liability. Endomorphin-1 and -2 are endogenous opioid peptides highly selective for mu-opioid receptors that exhibit potent analgesia with reduced side effects. CYT-1010 is a cyclized, D-lysine-containing analog of endomorphin-1 with a novel mechanism of action targeting traditional mu- and exon 11/truncated mu-opioid receptor 6TM variants. CYT-1010 preclinical data have demonstrated reduced abuse potential and analgesic potency exceeding that of morphine. In an initial phase 1 clinical study, CYT-1010 demonstrated significant analgesia vs baseline and no respiratory depression at the dose levels tested.

Conclusions
CYT-1010 and other novel mu-opioid receptor agonists in clinical development are promising alternatives to conventional opioids that may offer the possibility of safer treatment of moderate to severe pain.
Silver nanoparticles enter the tree stem faster through leaves than through roots
Authors: Cocozza C , Perone A , Giordano C , Salvatici M C , Pignattelli S , Raio A , Schaub M , Sever K , Innes J L , Tognetti R , Cherubini P 
Published: April 2019

AbstractA major environmental pollution problem is the release into the atmosphere of particulate matter, including nanoparticles (NPs), which causes serious hazards to human and ecosystem health, particularly in urban areas. However, knowledge about the uptake, translocation and accumulation of NPs in plant tissues is almost completely lacking. The uptake of silver nanoparticles (Ag-NPs) and their transport and accumulation in the leaves, stems and roots of three different tree species, downy oak (Quercus pubescens Willd.), Scots pine (Pinus sylvestris L.) and black poplar (Populus nigra L.), were assessed. In the experiment, Ag-NPs were supplied separately to the leaves (via spraying, the foliar treatment) and roots (via watering, the root treatment) of the three species. Uptake, transport and accumulation of Ag were investigated through spectroscopy. The concentration of Ag in the stem was higher in the foliar than in the root treatment, and in poplar more than in oak and pine. Foliar treatment with Ag-NPs reduced aboveground biomass and stem length in poplars, but not in oaks or pines. Species-specific signals of oxidative stress were observed; foliar treatment of oak caused the accumulation of H2O2 in leaves, and both foliar and root treatments of poplar led to increased O2− in leaves. Ag-NPs affected leaf and root bacteria and fungi; in the case of leaves, foliar treatment reduced bacterial populations in oak and poplar and fungi populations in pine, and in the case of roots, root treatment reduced bacteria and increased fungi in poplar. Species-specific mechanisms of interaction, transport, allocation and storage of NPs in trees were found. We demonstrated definitively that NPs enter into the tree stem through leaves faster than through roots in all of the investigated tree species.
Aluminum toxicity could be mitigated with boron by altering the metabolic patterns of amino acids and carbohydrates rather than organic acids in trifoliate orange
Authors: Yan Lei , Riaz Muhammad , Liu Yalin , Zeng Yu , Jiang Cuncang 
Published: April 2019

AbstractAluminum (Al) toxicity is the main constraint of root growth and productivity on arable acidic soil. Although boron (B) is used to ameliorate Al stress, the exact mechanisms underlying the effects of B on Al-induced alteration on root metabolites are poorly understood, especially in the trifoliate orange, which is an important rootstock in China. Therefore, a hydroponics experiment was conducted to explore the mechanisms of B mitigates Al toxicity in roots of citrus by metabolomics. A total of 60 metabolites were identified and analyzed in the present study. The 17 amino acids and 8 sugars were up-regulated in Al-treated roots, mainly histidine, cycloleucine, asparagine, citrulline, raffinose and trehalose, and increased by 38.5-, 8.7-, 6.0-, 6.0-, 7.5- and 6.6-fold, respectively. Meanwhile, significant down-regulation of aspartic acid, isoleucine, glutamic acid and six sugars were indicated under Al stress. Aluminum induced a decrease of nine organic acids, especially l-malic acid, citric acid and threonic acid, by 98.2, 93.6 and 95.1%, respectively. Interestingly, in the presence of Al, B application decreased the contents of asparagine, cycloleucine, citrulline and histidine as well as myo-inositol, raffinose, galactinol and 3,6-anhydro-d-galactose by 52.2, 57.4, 46.7, 63.0, 65.4, 74.3, 62.5 and 55.0%, respectively. However, there was no obvious difference in the organic acid contents in Al-stressed roots treated with B. Conclusively, our results show that B regulates the metabolic patterns of amino acids and carbohydrates and reduces Al toxicity. Nevertheless, B addition did not affect the Al-induced changes in the metabolic modes of organic acids.
Dorsal and ventral hippocampus engage opposing networks in the nucleus accumbens
Authors: Sosa Marielena , Joo Hannah R. , Frank Loren M. 
Published: April 2019

AbstractMemories of positive experiences require the brain to link places, events, and reward outcomes. Neural processing underlying the association of spatial experiences with reward is thought to depend on interactions between the hippocampus and the nucleus accumbens (NAc)1–9. Hippocampal projections to the NAc arise from both the ventral hippocampus (vH) and the dorsal hippocampus (dH)6–12, and studies using optogenetic interventions have demonstrated that either vH5, 6 or dH7 input to the NAc can support behaviors dependent on spatial-reward associations. It remains unclear, however, whether dH, vH, or both coordinate memory processing of spatial-reward information in the hippocampal-NAc circuit under normal conditions. Times of memory reactivation within and outside the hippocampus are marked by hippocampal sharp-wave ripples (SWRs)13–19, discrete events which facilitate investigation of inter-regional information processing. It is unknown whether dH and vH SWRs act in concert or separately to engage NAc neuronal networks, and whether either dH or vH SWRs are preferentially linked to spatial-reward representations. Here we show that dH and vH SWRs occur asynchronously in the awake state and that NAc spatial-reward representations are selectively activated during dH SWRs. We performed simultaneous extracellular recordings in the dH, vH, and NAc of rats learning and performing an appetitive spatial task and during sleep. We found that individual NAc neurons activated during SWRs from one subdivision of the hippocampus were typically suppressed or unmodulated during SWRs from the other. NAc neurons activated during dH versus vH SWRs showed markedly different task-related firing patterns. Only dH SWR-activated neurons were tuned to similarities across spatial paths and past reward, indicating a specialization for the dH-NAc, but not vH-NAc, network in linking reward to discrete spatial paths. These temporally and anatomically separable hippocampal-NAc interactions suggest that dH and vH coordinate opposing channels of mnemonic processing in the NAc.
Bioactivity-driven high throughput screening of microbiomes of medicinal plants for discovering new biological control agents
Authors: Iqrar Irum , Shinwari Zabta Khan , El-Sayed Ashraf , Ali Gul Shad 
Published: April 2019

ABSTRACTIn a preliminary DNA-based microbiome studies, diverse culturable and unculturable bacterial taxa were identified in the roots and rhizospheres of different medicinal plants. In this report, culturable endophytic bacteria were isolated from four economically important medicinal plants Dodonaea viscosa, Fagonia indica, Caralluma tuberculata and Calendula arvensis. On the basis of initial antimicrobial screening, nine bacterial species in seven different genera, Streptomyces, Pseudomonas, Enterobacter, Bacillus, Pantoea, Pseudarthrobacter and Delftia, were selected for further analyses. These bacteria were identified using 16S rRNA gene sequencing. Antimicrobial assays of these selected bacteria revealed that Pseudomonas taiwanensis has strong anti-Phytophthora activity. Volatiles produced by P. taiwanensis inhibited growth of P. parasitica more than 80%. Ethyl acetate extracts of S. alboniger MOSEL-RD3, P. taiwanensis MOSEL-RD23, E. hormaechei MOSEL-FLS1 and B. tequilensis MOSEL-FLS3 and D. lacustris MB322 also displayed high potency against P. parasitica. All these bacterial extracts showed strong inhibition against P. parasitica at different concentrations (4 µg/mL – 400 µg/mL). Bacterial extracts showing higher bioactivity (>80% inhibition in vitro) were selected for detached-leaf assay against P. parasitica on tobacco. In detached-leaf assay, application of 1% ethyl acetate bacterial extract of MOSE L-RD3, MOSEL-RD23, MOSEL-FLS1, MOSEL-FLS3 and MB322 reduced lesion sizes and lesion frequencies caused by P. parasitica by 68 to 81%. Over all P. taiwenensis MOSEL-RD23 showed positive activities for all the assays. Analysing the potential of bacterial endophytes as biological control agents can potentially lead to the formulation of broad-spectrum biopesticides for sustainable production of crops.
Silencing cryptic specialized metabolism inStreptomycesby the nucleoid-associated protein Lsr2
Authors: Gehrke Emma J. , Zhang Xiafei , Pimentel-Elardo Sheila M. , Johnson Andrew R. , Rees Christiaan A. , Jones Stephanie E. , Hindra  , Gehrke Sebastian S. , Turvey Sonya , Boursalie Suzanne , Hill Jane E. , Carlson Erin E. , Nodwell Justin R. , Elliot Marie A. 
Published: April 2019

ABSTRACTLsr2 is a nucleoid-associated protein conserved throughout the actinobacteria, including the antibiotic-producingStreptomyces.Streptomycesspecies encode paralogous Lsr2 proteins (Lsr2 and Lsr2-like, or LsrL), and we show here that of the two, Lsr2 has greater functional significance. We found that Lsr2 binds AT-rich sequences throughout the chromosome, and broadly represses gene expression. Strikingly, specialized metabolic clusters were over-represented amongst its targets, and the cryptic nature of many of these clusters appears to stem from Lsr2-mediated repression. Manipulating Lsr2 activity in model species and uncharacterized isolates resulted in the production of new metabolites not seen in wild type strains. Our results suggest that the transcriptional silencing of biosynthetic clusters by Lsr2 may protectStreptomycesfrom the inappropriate expression of specialized metabolites, and provide global control overStreptomyces’arsenal of signalling and antagonistic compounds.
The BvgS PAS domain: an independent sensory perception module in theBordetellaBvgAS phosphorelay
Authors: Sobran M. Ashley , Cotter Peggy A. 
Published: April 2019

AbstractTo detect and respond to the diverse environments they encounter, bacteria often use two-component regulatory systems (TCSs) to coordinate essential cellular processes required for survival. In pathogenicBordetellaspecies, the BvgAS TCS regulates expression of hundreds of genes, including those encoding all known protein virulence factors, and its kinase activity is essential for respiratory infection. Maintenance of BvgS kinase activity in the lower respiratory tract (LRT) depends on the function of another TCS, PlrSR. While the periplasmic venus fly-trap domains of BvgS have been implicated in responding to so-called modulating signalsin vitro(nicotinic acid and MgSO4), a role for the cytoplasmic Per-Arnt-Sim (PAS) domain in signal perception has not previously been demonstrated. By comparingB. bronchisepticastrains with mutations in the PAS domain-encoding region ofbvgSwith wild-type bacteriain vitroandin vivo, we found that although the PAS domain is not required to sense modulating signalsin vitro, it is required for the inactivation of BvgS that occurs in the absence of PlrS in the LRT of mice, suggesting that the BvgS PAS domain functions as an independent signal perception domain. Our data also indicate that the BvgS PAS domain is important for controlling absolute levels of BvgS kinase activity and the efficiency of the response to modulating signalsin vitro. Our results indicate that BvgS is capable of integrating sensory inputs from both the periplasm and the cytoplasm to control precise gene expression patterns in diverse environmental conditions.ImportanceDespite high rates of vaccination, Pertussis, a severe, highly contagious respiratory disease, caused by the bacteriumBordetella pertussis, has reemerged as a significant health threat. InBordetella pertussisand the closely related species,Bordetella bronchiseptica, activity of the BvgAS two-component regulatory system is critical for colonization of the human respiratory tract and other mammalian hosts, respectively. Here we show that the cytoplasmic PAS domain of BvgS can function as an independent signal perception domain that is capable of integrating environmental signals that influence overall BvgS activity. Our work is significant as it reveals a critical, yet previously unrecognized role, for the PAS domain in the BvgAS phosphorelay and provides a greater understanding of virulence regulation inBordetella.
Clustering by phenotype and genome-wide association study in autism
Authors: Narita Akira , Nagai Masato , Mizuno Satoshi , Ogishima Soichi , Tamiya Gen , Ueki Masao , Sakurai Rieko , Makino Satoshi , Obara Taku , Ishikuro Mami , Yamanaka Chizuru , Matsubara Hiroko , Kuniyoshi Yasutaka , Murakami Keiko , Ueno Fumihiko , Noda Aoi , Kobayashi Tomoko , Kobayashi Mika , Usuzaki Takuma , Ohseto Hisashi , Hozawa Atsushi , Kikuya Masahiro , Metoki Hirohito , Kure Shigeo , Kuriyama Shinichi 
Published: April 2019

AbstractBackgroundAutism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability.MethodsWe conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a dataset of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC dataset of 712 probands and 354 controls in the replication stage.ResultsIn the preliminary study, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold ofP<5.0×10−8. Some of these loci were located within or near previously reported candidate genes for ASD:CDH5, CNTN5, CNTNAP5, DNAH17, DPP10, DSCAM, FOXK1, GABBR2, GRIN2A5,ITPR1, NTM, SDK1, SNCAandSRRM4.Of these 65 significant chromosomal loci, rs11064685 located within theSRRM4gene had a significantly different distribution in the cases vs. controls in the replication cohort.ConclusionsThese findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies. Further cluster validation and replication studies are warranted in larger cohorts.
Effects of bicycle geometry and riding position on the potential of residual limb muscles to pedaling with a transfemoral prosthesis: a computer simulation study
Authors: Okita Yusuke , Nakamura Takashi 
Published: April 2019

AbstractWe performed musculoskeletal simulations to provide information on the effects of riding position and bicycle geometry on pedaling with a transfemoral prosthesis. Sixty-four models and their corresponding kinematics in one pedaling cycle were generated from the baseline one-leg cycling model by varying one of the six variables (seat height, seat-tube angle, crank length, pelvic tilt, anteroposterior seating position, and thigh length relative to the leg). Induced acceleration analysis was performed to compute the potentials of the residual hip muscles for crank rotation in each model. The simulation results quantified the effects of each variable on the hip and knee kinematics and muscle potential during a pedaling cycle; seat height, crank length, and pelvic tilt were the primary candidates for bicycle fitting considering their accessibility and simple effects on the joint kinematics and muscle potential. The seat-tube angle (similar to pelvic tilt) and the anteroposterior seating position (similar to seat height and seat-tube angle) seemed to have an effect similar to the other variables and thus can be reserved for fine-tuning after gross fitting of the bicycle. Although not considered for adjustment, considering the effects of the thigh length could help as it affects hip kinematics and muscle potentials.
TonB dependent uptake of β-lactam antibiotics in the opportunistic human pathogen Stenotrophomonas maltophilia
Authors: Calvopiña Karina , Dulyayangkul Punyawee , Heesom Kate J. , Avison Matthew B. 
Published: April 2019

AbstractThe β-lactam antibiotic ceftazidime is one of only a handful of drugs with proven clinical efficacy against the opportunistic human pathogen Stenotrophomonas maltophilia, Here, we show that mutations in the energy transducer TonB, encoded by smlt0009 in S. maltophilia, confer ceftazidime resistance. This breaks the dogma that β-lactams enter Gram-negative bacteria only by passive diffusion through outer membrane porins. By confirming cross-resistance of Smlt0009 mutants with a siderophore-conjugated lactivicin antibiotic, we reveal that attempts to improve penetration of antimicrobials into Gram negative bacteria by conjugating them with TonB substrates is likely to select β-lactam resistance in S. maltophilia, increasing its clinical threat. Furthermore, we show that S. maltophilia clinical isolates that have an Smlt0009 mutation already exist. Remarkably, therefore, β-lactam use is already eroding the potential utility of currently experimental siderophore-conjugated antimicrobials against this species.
Revisiting Mitchell’s chemiosmotic theory in light of new stoichiometric reaction equations of ATPase II
Authors: Kushagra Arindam 
Published: April 2019

AbstractChemiosmotic theory has been reining the field of bioenergetics since its inception. As stoichiometric mechanisms of the underlying chemical reactions have now been elucidated, it calls for a revision in the relationships derived by Mitchell in his seminal review paper. Here in this work, new formulation of the relationship between the pH difference and transmembrane potential, as derived in light of modified ATPase II reaction stoichiometry, has been proposed for the first time. This formulation results in accurate estimation of dependence of transmembrane potential on the pH difference across the two sides of the mitochondrial membrane. Thus, this work is of potential interest and will enable researchers working in the field of bioenergetics involving chemiosmotic theory to come-up with more exact mechanistic explanations.
Spinal V2b neurons reveal a role for ipsilateral inhibition in speed control
Authors: Callahan Rebecca A. , Roberts Richard , Sengupta Mohini , Kimura Yukiko , Higashijima Shin-ichi , Bagnall Martha W. 
Published: April 2019

AbstractThe spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These two V2b subclasses make direct synapses onto motor neurons with differential targeting to slower and faster circuits. In vivo, optogenetic suppression of V2b activity leads to increases in locomotor speed. We conclude that V2b neurons exert speed-specific influence over axial motor circuits throughout the rostrocaudal axis. Together, these results indicate a new role for ipsilateral inhibition in speed control.
Comparison of Multi-objective Evolutionary Algorithms to Solve the Modular Cell Design Problem for Novel Biocatalysis
Authors: Garcia Sergio , Trinh Cong 
Published: April 2019

AbstractA large space of chemicals with broad industrial and consumer applications could be synthesized by engineered microbial biocatalysts. However, the current strain optimization process is prohibitively laborious and costly to produce one target chemical and often requires new engineering efforts to produce new molecules. To tackle this challenge, modular cell design based on a chassis strain that can be combined with different product synthesis pathway modules has been recently proposed. This approach seeks to minimize unexpected failure and avoid task repetition, leading to a more robust and faster strain engineering process. The modular cell design problem was mathematically formulated using a multi-objective optimization framework.[1] In this study, we evaluated a library of the state-of-the-art multi-objective evolutionary algorithms (MOEAs) to identify the most effective method to solve the modular cell design problem. Using the best MOEA, we found better solutions for modular cells compatible with many product synthesis modules. Furthermore, the best performing algorithm could provide better and more diverse design options that might help increase the likelihood of successful experimental implementation. We identified key parameter configurations to overcome the difficulty associated with multi-objective optimization problems with many competing design objectives. Interestingly, we found that MOEA performance with a real application problem, e.g., the modular strain design problem, does not always correlate with artificial benchmarks. Overall, MOEAs provide powerful tools to solve the modular cell design problem for novel biocatalysis.