bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of oral administration of essential oils on anti-immune stress, antimicrobial properties, and repairing the intestinal damage in broilers challenged by lipopolysaccharide
Authors: Liu S.D. , Song M.H. , Yun W. , Lee J.H. , Kim H.B. , Cho J.H. 
Published: October 2018

The aim of the present study was to evaluate the effects of oral administration of essential oils (carvacrol, thyme, and oregano) on anti-immune stress, antimicrobial properties, and repairing the intestinal damage caused by Salmonella enterica lipopolysaccharides (LPS) in broilers. A total of 100 Ross 308 broilers (21-d-old; 1.10 ± 0.11 kg) were randomly allocated to five groups: T1, basal diet + saline; T2, basal diet + LPS; T3, basal diet + 200 μL carvacrol oils + LPS; T4, basal diet + 200 μL thyme oils + LPS; T5, basal diet + 200 μL oregano oils + LPS, with 20 replicates each, and one chicken per replicate per cage. Those challenged by LPS resulted in an immune stress, which manifests as the abnormal growth (P < 0.05) in immune organs, and the content of immunoglobulin G (P < 0.05), tumor necrosis factor-α (P < 0.05), and the rectum temperature (P < 0.05) increased compared with other groups. The oral administration of essential oils controlled the immune stress to a certain extent. The essential oils could reduce harmful bacteria, such as Escherichia coli (P < 0.05) and Salmonella enumeration (P < 0.05), in vivo of broilers. Meanwhile, the essential oils repaired the intestinal damage, which showed a reduction in the villi height (P < 0.05) and goblet cell (P < 0.05) caused by LPS. In conclusion, the essential oils (carvacrol, thyme, and oregano essential oils) controlled the stress reaction and maintained intestinal health to a certain extent.
Systematic analysis and integrative discovery of active-site subpocket-specific dehydroquinate synthase inhibitors combating antibiotic-resistant Staphylococcus aureus infection
Authors: Liu Quanfeng , Li Liping , Xu Fei 
Published: October 2018

Shikimate pathway plays an essential role in the biosynthesis of aromatic amino acids in various plants and bacteria, which consists of seven key enzymes and they are all attractive targets for antibacterial agent development due to their absence in humans. The Staphylococcus aureus dehydroquinate synthase (SaDHQS) is involved in the second step of shikimate pathway, which catalyzes the NAD[Formula: see text]-dependent conversion of 3-deoxy-D-arabino-heptulosonate-7-phosphate to dehydroquinate via multiple steps. The enzyme active site can be characterized by two spatially separated subpockets 1 and 2, which represent the reaction center of substrate adduct with NAD[Formula: see text] nicotinamide moiety and the assistant binding site of NAD[Formula: see text] adenine moiety, respectively. In silico virtual screening is performed against a biogenic compound library to discover SaDHQS subpocket-specific inhibitors, which were then tested against both antibiotic-sensitive and antibiotic-resistant S. aureus strains by using in vitro susceptibility test. The activity profile of hit compounds has no considerable difference between the antibiotic-sensitive and -resistant strains. The subpocket 1-specific inhibitors exhibit a generally higher activity than subpocket 2-specific inhibitors, and they also hold a strong selectivity between their cognate and noncognate subpockets. Dynamics and energetics analyses reveal that the SaDHQS active site prefers to interact with amphipathic and polar inhibitors by forming multiple hydrogen bonds and van der Waals packing at the complex interfaces of the two subpockets with their cognate inhibitors.
Dehydroepiandrosterone inhibitsICa,Land its window current in voltage-dependent and -independent mechanisms in arterial smooth muscle cells
Authors: Ochi Rikuo , Chettimada Sukrutha , Kizub Igor , Gupte Sachin A. 
Published: October 2018

Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone, which has the highest serum concentration among steroid hormones with DHEA sulfate (DHEAS). DHEA possesses an inhibitory action on glucose-6-phosphate dehydrogenase (G6PD), the first pentose-phosphate pathway enzyme that reduces NADP+to NADPH. DHEA induced relaxation of high K+-induced contraction in rat arterial strips, whereas DHEAS barely induced it. We studied the effects of DHEA on L-type Ca2+current ( ICa,L) of A7r5 arterial smooth muscle cells and compared the mechanism of inhibition with that produced by the 6-aminonicotinamide (6-AN) competitive inhibitor of G6PD. DHEA moderately inhibited ICa,Lthat was elicited from a holding potential (HP) of −80 mV [voltage-independent inhibition (VIDI)] and accelerated decay of ICa,Lduring the depolarization pulse [voltage-dependent inhibition (VDI)]. DHEA-induced VDI decreased peak ICa,Lat depolarized HPs. By applying repetitive depolarization pulses from multiple HPs, novel HP-dependent steady-state inactivation curves ( f∞-HP) were constructed. DHEA shifted f∞-HP to the left and inhibited the window current, which was recorded at depolarized HPs and obtained as a product of current-voltage relationship and f∞-HP. The IC50value of ICa,Linhibition was much higher than serum concentration. DHEA-induced VDI was downregulated by the dialysis of guanosine 5′- O-(2-thiodiphosphate), which shifted f∞-voltage to the right before the application of DHEA. 6-AN gradually and irreversibly inhibited ICa,Lby VIDI, suggesting that the inhibition of G6PD is involved in DHEA-induced VIDI. In 6-AN-pretreated cells, DHEA induced additional inhibition by increasing VIDI and generating VDI. The inhibition of G6PD underlies DHEA-induced VIDI, and DHEA additionally induces VDI as described for Ca2+channel blockers.NEW & NOTEWORTHY Dehydroepiandrosterone, the most abundantly released adrenal steroid hormone with dehydroepiandrosterone sulfate, inhibited L-type Ca2+current and its window current in aortic smooth muscle cells. The IC50value of inhibition decreased with the depolarization of holding potential to 15 µM at −20 mV. The inhibition occurred in a voltage-dependent manner as described for Ca2+channel blockers and in a voltage-independent manner because of the inhibition of glucose-6-phosphate dehydrogenase.
Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats
Authors: Ahmad Shama , Masjoan Juncos Juan Xavier , Ahmad Aftab , Zaky Ahmed , Wei Chih-Chang , Bradley Wayne E. , Zafar Iram , Powell Pamela , Mariappan Nithya , Vetal Nilam , Louch William E. , Ford David A. , Doran Stephen F. , Matalon Sadis , Dell’Italia Louis J. 
Published: October 2018

Halogens are widely used, highly toxic chemicals that pose a potential threat to humans because of their abundance. Halogens such as bromine (Br2) cause severe pulmonary and systemic injuries; however, the mechanisms of their toxicity are largely unknown. Here, we demonstrated that Br2 and reactive brominated species produced in the lung and released in blood reach the heart and cause acute cardiac ultrastructural damage and dysfunction in rats. Br2-induced cardiac damage was demonstrated by acute (3–24 h) increases in circulating troponin I, heart-type fatty acid-binding protein, and NH2-terminal pro-brain natriuretic peptide. Transmission electron microscopy demonstrated acute (3–24 h) cardiac contraction band necrosis, disruption of z-disks, and mitochondrial swelling and disorganization. Echocardiography and hemodynamic analysis revealed left ventricular (LV) systolic and diastolic dysfunction at 7 days. Plasma and LV tissue had increased levels of brominated fatty acids. 2-Bromohexadecanal (Br-HDA) injected into the LV cavity of a normal rat caused acute LV enlargement with extensive disruption of the sarcomeric architecture and mitochondrial damage. There was extensive infiltration of neutrophils and increased myeloperoxidase levels in the hearts of Br2- or Br2 reactant-exposed rats. Increased bromination of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and increased phosphalamban after Br2 inhalation decreased cardiac SERCA activity by 70%. SERCA inactivation was accompanied by increased Ca2+-sensitive LV calpain activity. The calpain-specific inhibitor MDL28170 administered within 1 h after exposure significantly decreased calpain activity and acute mortality. Bromine inhalation and formation of reactive brominated species caused acute cardiac injury and myocardial damage that can lead to heart failure. NEW & NOTEWORTHY The present study defines left ventricular systolic and diastolic dysfunction due to cardiac injury after bromine (Br2) inhalation. A calpain-dependent mechanism was identified as a potential mediator of cardiac ultrastructure damage. This study not only highlights the importance of monitoring acute cardiac symptoms in victims of Br2 exposure but also defines calpains as a potential target to treat Br2-induced toxicity.
A muscle-activity-dependent gain between motor cortex and EMG
Authors: Naufel Stephanie , Glaser Joshua I. , Kording Konrad P. , Perreault Eric J. , Miller Lee E. 
Published: October 2018

Whether one is delicately placing a contact lens on the surface of the eye or lifting a heavy weight from the floor, the motor system must produce a wide range of forces under different dynamical loads. How does the motor cortex, with neurons that have a limited activity range, function effectively under these widely varying conditions? In this study, we explored the interaction of activity in primary motor cortex (M1) and muscles (electromyograms, EMGs) of two male rhesus monkeys for wrist movements made during three tasks requiring different dynamical loads and forces. Despite traditionally providing adequate predictions in single tasks, in our experiments, a single linear model failed to account for the relation between M1 activity and EMG across conditions. However, a model with a gain parameter that increased with the target force remained accurate across forces and dynamical loads. Surprisingly, this model showed that a greater proportion of EMG changes were explained by the nonlinear gain than the linear mapping from M1. In addition to its theoretical implications, the strength of this nonlinearity has important implications for brain-computer interfaces (BCIs). If BCI decoders are to be used to control movement dynamics (including interaction forces) directly, they will need to be nonlinear and include training data from broad data sets to function effectively across tasks. Our study reinforces the need to investigate neural control of movement across a wide range of conditions to understand its basic characteristics as well as translational implications.NEW & NOTEWORTHY We explored the motor cortex-to-electromyogram (EMG) mapping across a wide range of forces and loading conditions, which we found to be highly nonlinear. A greater proportion of EMG was explained by a nonlinear gain than a linear mapping. This nonlinearity allows motor cortex to control the wide range of forces encountered in the real world. These results unify earlier observations and inform the next-generation brain-computer interfaces that will control movement dynamics and interaction forces.
Human manual control precision depends on vestibular sensory precision and gravitational magnitude
Authors: Rosenberg Marissa J. , Galvan-Garza Raquel C. , Clark Torin K. , Sherwood David P. , Young Laurence R. , Karmali Faisal 
Published: October 2018

Precise motion control is critical to human survival on Earth and in space. Motion sensation is inherently imprecise, and the functional implications of this imprecision are not well understood. We studied a “vestibular” manual control task in which subjects attempted to keep themselves upright with a rotational hand controller (i.e., joystick) to null out pseudorandom, roll-tilt motion disturbances of their chair in the dark. Our first objective was to study the relationship between intersubject differences in manual control performance and sensory precision, determined by measuring vestibular perceptual thresholds. Our second objective was to examine the influence of altered gravity on manual control performance. Subjects performed the manual control task while supine during short-radius centrifugation, with roll tilts occurring relative to centripetal accelerations of 0.5, 1.0, and 1.33 GC(1 GC = 9.81 m/s2). Roll-tilt vestibular precision was quantified with roll-tilt vestibular direction-recognition perceptual thresholds, the minimum movement that one can reliably distinguish as leftward vs. rightward. A significant intersubject correlation was found between manual control performance (defined as the standard deviation of chair tilt) and thresholds, consistent with sensory imprecision negatively affecting functional precision. Furthermore, compared with 1.0 GCmanual control was more precise in 1.33 GC(−18.3%, P = 0.005) and less precise in 0.5 GC(+39.6%, P < 0.001). The decrement in manual control performance observed in 0.5 GCand in subjects with high thresholds suggests potential risk factors for piloting and locomotion, both on Earth and during human exploration missions to the moon (0.16 G) and Mars (0.38 G).NEW & NOTEWORTHY The functional implications of imprecise motion sensation are not well understood. We found a significant correlation between subjects’ vestibular perceptual thresholds and performance in a manual control task (using a joystick to keep their chair upright), consistent with sensory imprecision negatively affecting functional precision. Furthermore, using an altered-gravity centrifuge configuration, we found that manual control precision was improved in “hypergravity” and degraded in “hypogravity.” These results have potential relevance for postural control, aviation, and spaceflight.
Cortical neural modulation by previous trial outcome differentiates fast- from slow-learning rats on a visuomotor directional choice task
Authors: Mao Hongwei , Yuan Yuan , Si Jennie 
Published: October 2018

To better understand the neural cortical underpinnings that explain behavioral differences in learning rate, we recorded single-unit activity in primary motor (M1) and secondary motor (M2) areas while rats learned to perform a directional (left or right) operant visuomotor association task. Analysis of neural activity during the early portion of the cue period showed that neural modulation in the motor cortex was most strongly associated with two task factors: the previous trial outcome (success or error) and the current trial’s directional choice (left or right). Furthermore, the fast learners, defined as those who had steeper learning curves and required fewer learning sessions to reach criterion performance, encoded the previous trial outcome factor more strongly than the directional choice factor. Conversely, the slow learners encoded directional choice more strongly than previous trial outcome. These differences in task factor encoding were observed in both the percentage of neurons and the neural modulation depth. These results suggest that fast learning is accompanied by a stronger component of previous trial outcome in the modulation representation present in motor cortex, which therefore may be a contributing factor to behavioral differences in learning rate. NEW & NOTEWORTHY We chronically recorded neural activity as rats learned a visuomotor directional choice task from a naive state. Learning rates varied. Single-unit neural modulation of two motor areas revealed that the fast learners encoded previous trial outcome more strongly than directional choice, whereas the reverse was true for slow learners. This finding provides novel evidence that rat learning rate is strongly correlated with the strength of neural modulation by previous trial outcome in motor cortex.
Nicotine-N′-Oxidation by Flavin Monooxygenase Enzymes
Authors: Perez-Paramo Yadira X. , Chen Gang , Ashmore Joseph H. , Watson Christy J. W. , Nasrin Shamema , Adams-Haduch Jennifer , Wang Renwei , Gao Yu-Tang , Koh Woon-Puay , Yuan Jian-Min , Lazarus Philip 
Published: October 2018

Abstract

Background:
The major mode of metabolism of nicotine is by hydroxylation via cytochrome P450 (CYP) 2A6, but it can also undergo glucuronidation by UDP-glucuronosyltransferases and oxidation by flavin monooxygenases (FMO). The goal of this study was to examine the potential importance of FMOs in nicotine metabolism and assess the potential impact of missense polymorphisms in active FMOs on nicotine-N′-oxide (NOX) formation.

Methods:
Urine samples from 106 current Chinese smokers were analyzed for nicotine metabolites by mass spectrometry. Wild-type FMOs 1–5 and their most prevalent nonsynonymous variants were cloned and overexpressed in HEK293 cells, and were tested in oxidation reactions against nicotine.

Results:
A strong inverse correlation was observed between the ratio of urinary 3′-hydroxycotinine/cotinine, a measure of CYP2A6 activity, and the urinary levels of NOX alone (r = −0.383; P &lt; 0.001) or NOX measured as a ratio of total nicotine metabolites (r = −0.414; P &lt; 0.001) in smokers. In addition to FMO1 and FMO3, the functional FMO2427Q isoform was active against nicotine, whereas FMO4 and FMO5 exhibited low activity against nicotine (Km &gt; 5.0 mmol/L). Significant (P &lt; 0.05) decreases in N′-oxidation activity (Vmax/Km) were observed for the FMO1I303V, FMO3N61S, FMO3D132H, FMO3V257M, and FMO3E308G variants in vitro when compared with their respective wild-type isoforms; the truncated FMO2Q472stop isoform exhibited no enzyme activity.

Conclusions:
These data indicate that increases in nicotine-N′-oxidation occur in subjects with deficient CYP2A6 activity, and that several FMO enzymes are active in nicotine-N′-oxidation.

Impact:
Several common missense FMO variants are associated with altered enzyme activity against nicotine and may play an important role in nicotine metabolism in low-CYP2A6 activity subjects.
Glycoprotein-130 Expression Is Associated with Aggressive Bladder Cancer and Is a Potential Therapeutic Target
Authors: Martin Darryl T. , Shen Hongliang , Steinbach-Rankins Jill M. , Zhu Xi , Johnson Katelyn K. , Syed Jamil , Saltzman W. Mark , Weiss Robert M. 
Published: October 2018

Abstract
Predicting bladder cancer progression is important in selecting the optimal treatment for bladder cancer. Because current diagnostic factors regarding progression are lacking, new factors are needed to further stratify the curative potential of bladder cancer. Glycoprotein-130 (GP130), a transmembrane protein, is central to a number of signal transduction pathways involved in tumor aggressiveness, making it an attractive target. We hypothesize that if GP130 is found in an aggressive population of bladder tumors, then blocking GP130 expression may inhibit bladder cancer growth. Herein, we quantitatively show, using 11 patient samples and four bladder cancer cell lines, that GP130 is expressed in the aggressive human bladder tumors and in high-grade bladder cancer cell lines. Moreover, GP130 is significantly correlated with tumor grade, node category, tumor category, and patient outcome. We demonstrated a tumor-specific GP130 effect by blocking GP130 expression in bladder tumor cells, which resulted in decreased cell viability and reduced cell migration. Furthermore, we reduced tumor volume by approximately 70% compared with controls by downregulating GP130 expression using chitosan-functionalized nanoparticles encapsulating GP130 siRNA in an in vivo bladder cancer xenograft mouse model. Our results indicate that GP130 expression is linked to the aggressiveness of bladder tumors, and blocking GP130 has therapeutic potential in controlling tumor growth.
Identification of the Novel Role of CD24 as an Oncogenesis Regulator and Therapeutic Target for Triple-Negative Breast Cancer
Authors: Chan Shih-Hsuan , Tsai Kuo-Wang , Chiu Shu-Yi , Kuo Wen-Hung , Chen Heng-Yi , Jiang Shih Sheng , Chang King-Jen , Hung Wen-Chun , Wang Lu-Hai 
Published: October 2018

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with unfavorable prognosis and 5-year survival. The purpose of this study was to investigate the underlying mechanisms involved in TNBC progression. We determined that CD24 expression was elevated in highly lung and lymph node metastatic TNBC cells. CD24 depletion inhibited primary tumor growth and lymph node and lung metastasis and reduced the number of blood and lymphatic vessels in the tumor microenvironment. CD24 knockdown impaired EGFR/Met-mediated signaling and reduced lymphangiogenesis- and angiogenesis-related molecules, including vascular endothelial growth factors A and C, by promoting EGFR and Met protein instability via the lysosomal degradation pathway. CD24 monoclonal antibody treatment reduced lung metastasis and prolonged the survival in a lung metastasis mouse model. Clinical analyses revealed that the CD24high/METhigh “double-positive” signature identified a subset of TNBC patients with worst outcomes. We conclude that CD24 could be a therapeutic target by itself and in combination with the Met expression could be a good prognostic biomarker for TNBC patients.
CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory
Authors: Benonisson Hreinn , Altıntaş Işıl , Sluijter Marjolein , Verploegen Sandra , Labrijn Aran F. , Schuurhuis Danita H. , Houtkamp Mischa A. , Verbeek J. Sjef , Schuurman Janine , van Hall Thorbald 
Published: October 2018

AbstractImmunotherapy of cancer with CD3-targeting bispecific antibodies (CD3 bsAb) is a fast developing field, and multiple tumor-associated antigens (TAA) are evaluated for hematologic and solid malignancies. The efficacy of these CD3 bsAb is usually examined in xenograft mouse tumor models with human T cells or in genetically engineered mouse models, where human TAA are introduced. These models often fail to fully recapitulate the natural tumor environment, especially for solid cancers, because of interspecies differences. Here, we investigated the systemic and intratumoral effects of a mouse CD3 bsAb in a fully immune-competent mouse melanoma model. Systemic administration of 0.5 mg/kg antibody induced a brief overall T-cell activation that was selectively sustained in the tumor microenvironment for several days. A fast subsequent influx of inflammatory macrophages into the tumor microenvironment was observed, followed by an increase in the number of CD4+ and CD8+ T cells. Although the capacity to directly kill melanoma cells in vitro was very modest, optimal tumor elimination was observed in vivo, even in the absence of CD8+ T cells, implying a redundancy in T-cell subsets for therapeutic efficacy. Finally, we took advantage of the full immune competence of our mouse model and tested immune memory induction. Despite a strong initial immunity against melanoma, treatment with the CD3 bsAb did not install protective memory responses. The observed mechanisms of action revealed in this immune-competent mouse model might form a rational basis for combinatorial approaches.