bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Necrosis Factor (TNF) Blocking Agents are Associated with Lower Risk for Alzheimer’s Disease in Patients with Rheumatoid Arthritis and Psoriasis
Authors: Zhou Mengshi , Xu Rong , Kaelber David C. , Gurney Mark E. 
Published: September 2019

AbstractThis large, retrospective case-control study of electronic health records from 56 million unique adult patients examined whether or not treatment with a Tumor Necrosis Factor (TNF) blocking agent is associated with lower risk for Alzheimer’s disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases which are mediated in part by TNF and for which a TNF blocker is an approved treatment. The analysis compared the diagnosis of AD as an outcome measure in patients receiving at least one prescription for a TNF blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. Adjusted odds ratios (AORs) were estimated using the Cochran-Mantel-Haenszel (CMH) method and presented with 95% confidence intervals (CIs) and p-values. RA was associated with a higher risk for AD (Adjusted Odds Ratio (AOR) = 2.06, 95% Confidence Interval: (2.02-2.10), P-value <0.0001) as did psoriasis (AOR = 1.37 (1.31-1.42), P <0.0001), ankylosing spondylitis (AOR = 1.57 (1.39-1.77), P <0.0001), inflammatory bowel disease (AOR = 2.46 (2.33-2.59), P < 0.0001), ulcerative colitis (AOR = 1.82 (1.74-1.91), P <0.0001), and Crohn’s disease (AOR = 2.33 (2.22-2.43), P <0.0001). The risk for AD in patients with RA was lower among patients treated with etanercept (AOR = 0.34 (0.25-0.47), P <0.0001), adalimumab (AOR = 0.28 (0.19-0.39), P < 0.0001), or infliximab (AOR = 0.52 (0.39-0.69), P <0.0001). Methotrexate was also associated with a lower risk for AD (AOR = 0.64 (0.61-0.68), P <0.0001), while lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis: AOR = 0.47 (0.30-0.73 and 0.41 (0.20-0.76), respectively. There was no effect of gender or race, while younger patients showed greater benefit from a TNF blocker than did older patients. This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.
Machine learning-based prediction of response to PARP inhibition across cancer types
Authors: Hill Katherine E. , Rattani Ahmed , Lietz Christopher E. , Garbutt Cassandra , Choy Edwin , Cote Gregory M. , Culhane Aedin , Kelly Andrew D. , Haibe-Kains Benjamin , Spentzos Dimitrios 
Published: September 2019

AbstractPARP inhibitors (PARPi) are FDA approved for the treatment of BRCA1/2 deficient breast and ovarian cancer, but a growing body of pre-clinical evidence suggests the drug class holds therapeutic potential in other cancer types, independent of BRCA1/2 status. Large-scale pharmacogenomic datasets offer the opportunity to develop predictors of response to PARPi’s in many cancer types, expanding their potential clinical applicability. Response to the PARPi olaparib was used to identify a multi-gene PARPi response signature in a largein vitrodataset including multiple cancer types, such as breast, ovarian, pancreatic, lung cancer, osteosarcoma and Ewing sarcoma, using machine learning approaches. The signature was validated on multiple independentin vitrodatasets, also testing for response to another PARPi, rucaparib, as well as two clinical datasets using the cisplatin response as a surrogate for PARPi response. Finally, integrative pharmacogenomic analysis was performed to identify drugs which may be effective in PARPi resistant tumors. A PARPi response signature was defined as the 50 most differentially transcribed genes between PARPi resistant and sensitive cell lines from several different cancer types. Cross validated predictors generated with LASSO logistic regression using the PARPi signature genes accurately predicted PARPi response in a training set of olaparib treated cell lines (80-89%), an independent olaparib treatedin vitrodataset (66-77%), and an independent rucaparib treatedin vitrodataset (80-87%). The PARPi signature also significantly predictedin vitrobreast cancer response to olaparib in another separate experimental dataset. The signature also predicted clinical response to cisplatin and survival in human ovarian cancer and osteosarcoma datasets. Robust transcriptional differences between PARPi sensitive and resistant tumors accurately predict PARPi responsein vitroand cisplatin responsein vivofor multiple tumor types with or without known BRCA1/2 deficiency. These signatures may prove useful for predicting response in patients treated with PARP inhibitors.
Differential effects of opioid receptor modulators on motivational and stress-coping behaviors in the back-translational rat IFN-α depression model
Authors: Callaghan Charlotte K. , Rouine Jennifer , Islam Md Nurul , Eyerman David J. , Smith Karen L. , Blumberg Laura , Sanchez Connie , O’Mara Shane M. 
Published: September 2019

AbstractRationaleMany patients respond inadequately to antidepressant drug treatment; the search for alternate pharmacological treatment mechanisms is ongoing. Until the 1950’s, opium was sometimes used to treat depression, but eventually abandoned due to addiction risk. Recent insights into opioid biology have sparked a renewed interest in the potential antidepressant properties of opioids.ObjectiveWe studied how mu (MOR), kappa (KOR) and delta (DOR) opioid receptor ligands affect the dysregulation of motivated behavior (progressive ratio responding; PR), stress-coping behavior (forced swim test; FST) and hippocampal neurogenesis in rats, all induced by the back-translational interferon-alpha (IFN-α)-induced depression model.MethodsMale Wistar rats (3-months old, 8/group) were treated with recombinant human IFN-α (170,000 IU/kg, 3 times/week) or saline. Ligands of the MOR, KOR and DOR receptors were administered as follows: a single subcutaneous dose, 30min before PR and 1h before FST, of the MOR agonist morphine (full agonist; 5mg/kg), the partial agonist RDC 2944 (0.1mg/kg) and the antagonist, cyprodime (10mg/kg); of the KOR agonist, U50 488 (5mg/kg), the antagonist, DIPPA (10mg/kg); and the DOR agonist, SNC 80 (20mg/kg) and antagonist naltrindole (10mg/kg). After 4 days of treatment with the mitotic BrdU marker, hippocampi were harvested and analysed for neurogenesis. Fluoxetine (10 mg/kg/day for 4 weeks, orally) served as control for assay sensitivity in the FST.ResultsThe KOR antagonist, DIPPA, the DOR agonist SNC 80 and fluoxetine reversed the IFN-α-induced immobility increase in the FST. The MOR agonist, morphine, the KOR antagonist DIPPA, and the KOR agonist U50 488 reduced the IFN-α-induced increase in the breakpoint in the PR. The DOR agonist SNC 80 recovered the IFN-α-induced decrease in BrdU+ hippocampal cells.ConclusionOpioid receptors mediate different aspects of the IFN-α-induced dysregulation of motivational and stress-coping behaviors and hippocampal neurogenesis in a back-translational model of depression. KORs and DORs appear to play more prominent roles in torpor–inertia-type behaviors, whereas DORs appear more involved in the regulation of neurogenesis.
Convergent neural representations of acute nociceptive pain in healthy volunteers: A large-scale fMRI meta-analysis
Authors: Xu Anna , Larsen Bart , Baller Erica B. , Scott J. Cobb , Sharma Vaishnavi , Adebimpe Azeez , Basbaum Allan I. , Dworkin Robert H. , Edwards Robert R. , Woolf Clifford J. , Eickhoff Simon B. , Eickhoff Claudia R. , Satterthwaite Theodore D. 
Published: September 2019

ABSTRACTCharacterizing a reliable, pain-related neural signature is critical for translational applications. Many prior fMRI studies have examined acute pain-related brain activation in healthy participants. However, synthesizing these data to identify convergent patterns of activation can be challenging due to the heterogeneity of experimental designs and samples. To address this challenge, we conducted a comprehensive meta-analysis of fMRI studies of stimulus-induced pain in healthy participants. Following pre-registration, two independent reviewers evaluated 4,927 abstracts returned from a search of 8 databases, with 222 fMRI experiments meeting inclusion criteria. We analyzed these experiments using Activation Likelihood Estimation with rigorous type I error control (voxel height p < 0.001, cluster p < 0.05 FWE-corrected) and found a convergent, largely bilateral pattern of pain-related activation in the secondary somatosensory cortex, insula, midcingulate cortex, and thalamus. Notably, these regions were consistently recruited regardless of stimulation technique, location of induction, and participant sex. These findings suggest a highly-conserved core set of pain-related brain areas, encouraging applications as a biomarker for novel therapeutics targeting acute pain.HIGHLIGHTSPain stimulation recruits a core set of pain-related brain regions.This core set includes thalamus, SII, insula and mid-cingulate cortex.These regions were recruited regardless of stimulus modality and stimulus location.
Zinc can counteract selection for ciprofloxacin resistance
Authors: Vos Michiel , Sibleyras Louise , Lo Lai Ka , Hesse Elze , Gaze William , Klümper Uli 
Published: September 2019

AbstractAntimicrobial resistance (AMR) has emerged as one of the most pressing global threats to public health. AMR evolution occurs in the clinic but also in the environment, where low concentrations of antibiotics and heavy metals can respectively select and co-select for resistance. While the selective potential for AMR of both antibiotics and metals is increasingly well-characterized, studies exploring the combined effect of both types of selective agents are rare. It has previously been demonstrated that fluoroquinolone antibiotics such as ciprofloxacin can chelate metal ions. To investigate how ciprofloxacin resistance is affected by the presence of metals, we quantified selection dynamics between a ciprofloxacin-susceptible and an isogenic ciprofloxacin-resistantEscherichia coliMG1655 strain across a gradient of ciprofloxacin concentrations in the presence and absence of Zinc cations (Zn2+). The minimal selective concentration (MSC) for ciprofloxacin resistance significantly increased up to 5-fold in the presence of Zn2+. No such effect on the MSC was found for gentamicin, an antibiotic not known to chelate zinc cations. Environmental pollution usually consists of complex mixtures of antimicrobial agents. Our findings highlight the importance of taking antagonistic as well as additive or synergistic interactions between different chemical compounds into account when considering their effect on bacterial resistance evolution.Graphical abstractOne sentence summaryThe minimal selective concentration for a ciprofloxacin resistantE. colistrain increases up to 5-fold in the presence of Zinc cations.
An integrated approach unravels a crucial structural property for the function of the insect steroidogenic Halloween protein Noppera-bo
Authors: Koiwai Kotaro , Inaba Kazue , Morohashi Kana , Enya Sora , Arai Reina , Kojima Hirotatsu , Okabe Takayoshi , Fujikawa Yuuta , Inoue Hideshi , Yoshino Ryunosuke , Hirokawa Takatsugu , Kato Koichiro , Fukuzawa Kaori , Shimada-Niwa Yuko , Nakamura Akira , Yumoto Fumiaki , Senda Toshiya , Niwa Ryusuke 
Published: September 2019

AbstractEcdysteroids are the principal insect steroid hormones essential for insect development and physiology. In the last 18 years, several enzymes responsible for ecdysteroid biosynthesis, encoded by Halloween genes, have been identified and well characterized, both genetically and biochemically. However, none of these proteins have yet been characterized at the tertiary structure level. Here, we report an integratedin silico,in vitro, andin vivoanalyses of the Halloween glutathioneS-transferase (GST) protein, Noppera-bo (Nobo). We determine crystal structures ofDrosophila melanogasterNobo (DmNobo) complexed with glutathione and 17β-estradiol, a DmNobo inhibitor. 17β-estradiol almost fully occupied the putative ligand-binding pocket, and a prominent hydrogen bond formed between Asp113 of DmNobo and 17β-estradiol. Asp113 is essential for inhibiting DmNobo enzymatic activity by 17β-estradiol, as 17β-estradiol does not inhibit and physically interacts less with the Asp113Ala DmNobo point mutant. Asp113 is highly conserved among Nobo proteins, but not among other GSTs, implying that Asp113 is important for endogenous Nobo function. Indeed, a homozygousnoboallele possessing the Asp113Ala point mutation exhibits embryonic lethality with undifferentiated cuticle structure, a phenocopy of complete loss-of-functionnobohomozygotes. These results suggest that thenobofamily of GST proteins has acquired a unique amino acid residue, which seems to be essential for binding an endogenous sterol substrate to regulate ecdysteroid biosynthesis. This is the first study to reveal the structural characteristics of insect steroidogenic Halloween proteins. This study also provides basic insight into applied entomology for developing a new type of insecticides that specifically inhibit ecdysteroid biosynthesis.Significance StatementInsect molting and metamorphosis are drastic and dynamic biological processes and, therefore, have fascinated many scientists. Ecdysteroids represent one class of insect hormones that are indispensable for inducing molting and metamorphosis. It is well known that proteins responsible for catalyzing ecdysteroid biosynthesis reactions are encoded by “Halloween” genes, most of which have names of ghosts and phantoms. However, no studies have focused on the structural properties of these biosynthetic proteins. In this study, we addressed this unsolved issue and successfully unraveled a structural property that is crucial for the function of the fruit fly Halloween protein, Noppera-bo (a Japanese faceless ghost). This is the first study to reveal the structural characteristics of an insect steroidogenic Halloween protein.
Glutamatergic and GABAergic neuronal populations in the dorsolateral Periacqueductual Gray have different functional roles in fear conditioning
Authors: Montardy Quentin , Zhou Zheng , Liu Xuemei , Lei Zhuogui , Zeng Pengyu , Chen Chen , Liu Yuanming , Huang Kang , Wei Mengxia , Wang Liping 
Published: September 2019

AbstractIt is though that only a subset of brain structures can encode emotional states. This can be investigated though a set of properties, including the ability of neurons to respond to a conditioned stimulus (CS) preceding an aversive unconditioned stimulus (US). The dorsolateral periacqueductal gray (dPAG) is a midbrain structure though to have an essential role in coordinating defensive behaviors in response to aversive stimulation. But its ability of dPAG neurons to encode a CS following fear conditioning as not been sufficiently studied.Here we used calcium imaging by fiber photometry to record the activity of dPAGVGluT2+ and dPAGGAD2+ neuronal populations during unconditioned and conditioned aversive stimulation. Then, following an unconditioned stimulation we performed a retrieval experiment to quantify memory-like responses of dPAG neurons. This shown that whilst both dPAGVGluT2+ and dPAGGAD2+ neuronal populations respond to direct US stimulation, and to CS stimulation during conditioning, only the dPAGVGluT2+ population persisted in responding to the CS stimulation during retrieval. Finally, to better understand dPAGVGluT2+ and dPAGGAD2+ connectivity patterns, we performed a cell specific monosynaptic retrograde rabies virus tracing experiment. This revealed that different patterns of fibers projects to dPAGVGluT2+ and dPAGGAD2+, further complementing our recording showing divergences between PAGVGluT2+ and dPAGGAD2+ populations.
Data-Driven Classification of Spectral Profiles Reveals Brain Region-Specific Plasticity
Authors: Lubinus Christina , Orpella Joan , Keitel Anne , Gudi-Mindermann Helene , Engel Andreas K. , Roeder Brigitte , Rimmele Johanna M. 
Published: September 2019

AbstractCongenital blindness has been shown to result in behavioral adaptation and neuronal reorganization, but the underlying neuronal mechanisms are largely unknown. Brain rhythms are characteristic for anatomically defined brain regions and provide a putative mechanistic link to cognitive processes. In a novel approach, using magnetoencephalography resting state data of congenitally blind and sighted humans, deprivation-related changes in spectral profiles were mapped to the cortex using clustering and classification procedures. Altered spectral profiles in visual areas suggest changes in visual alpha-gamma band inhibitory-excitatory circuits. Remarkably, spectral profiles were also altered in auditory and right frontal areas showing increased power in theta-to-beta frequency bands in blind compared to sighted individuals, possibly related to adaptive auditory and higher-cognitive processing. Moreover, occipital alpha correlated with microstructural white matter properties extending bilaterally across posterior parts of the brain. We provide evidence that visual deprivation selectively modulates spectral profiles, possibly reflecting structural and functional adaptation.
Dynamic reconfiguration, fragmentation and integration of whole-brain modular structure across depths of unconsciousness
Authors: Standage Dominic , Areshenkoff Corson N. , Nashed Joseph Y. , Hutchison R. Matthew , Hutchison Melina , Heinke Dietmar , Menon Ravi S. , Everling Stefan , Gallivan Jason P. 
Published: September 2019

AbstractGeneral anesthetics are routinely used to induce unconsciousness, and much is known about their effects on receptor function and single neuron activity. Much less is known about how these local effects are manifest at the whole-brain level, nor how they influence network dynamics, especially past the point of induced unconsciousness. Using resting-state functional magnetic resonance imaging (fMRI) with nonhuman primates, we investigated the dose-dependent effects of anesthesia on whole-brain temporal modular structure, following loss of consciousness. We found that higher isoflurane dose was associated with an increase in both the number and isolation of whole-brain modules, as well as an increase in the uncoordinated movement of brain regions between those modules. Conversely, we found that higher dose was associated with a decrease in the cohesive movement of brain regions between modules, as well as a decrease in the proportion of modules in which brain regions participated. Moreover, higher dose was associated with a decrease in the overall integrity of networks derived from the temporal modules, with the exception of a single, sensory-motor network. Together, these findings suggest that anaesthesia-induced unconsciousness results from the hierarchical fragmentation of dynamic whole-brain network structure, leading to the discoordination of temporal interactions between cortical modules.
LRR-extensins of vegetative tissues are a functionally conserved family of RALF1 receptors interacting with the receptor kinase FERONIA
Authors: Herger Aline , Gupta Shibu , Kadler Gabor , Franck Christina Maria , Boisson-Dernier Aurélien , Ringli Christoph 
Published: September 2019

AbstractPlant cell growth requires the coordinated expansion of the protoplast and the cell wall that confers mechanical stability to the cell. An elaborate system of cell wall integrity sensors monitors cell wall structures and conveys information on cell wall composition and growth factors to the cell. LRR-extensins (LRXs) are cell wall-attached extracellular regulators of cell wall formation and high-affinity binding sites for RALF (rapid alkalinization factor) peptide hormones that trigger diverse physiological processes related to cell growth. RALF peptides are also perceived by receptors at the plasma membrane and LRX4 ofArabidopsis thalianahas been shown to also interact with one of these receptors, FERONIA (FER). Here, we demonstrate that several LRXs, including the main LRX protein of root hairs, LRX1, interact with FER and RALF1 to coordinate growth processes. Membrane association of LRXs correlate with binding to FER, indicating that LRXs represent a physical link between intra- and extracellular compartments via interaction with membrane-localized proteins. Finally, despite evolutionary diversification of the LRR domains of various LRX proteins, many of them are functionally still overlapping, indicative of LRX proteins being central players in regulatory processes that are conserved in very different cell types.Author SummaryCell growth in plants requires the coordinated enlargement of the cell and the surrounding cell wall, which is ascertained by an elaborate system of cell wall integrity sensors, proteins involved in the exchange of information between the cell and the cell wall. InArabidopsis thaliana, LRR-extensins (LRXs) are localized in the cell wall and are binding RALF peptides, hormones that regulate cell growth-related processes. LRX4 also binds the plasma membrane-localized receptor kinase FERONIA (FER), establishing a link between the cell and the cell wall. It is not clear, however, whether the different LRXs of Arabidopsis have similar functions and how they interact with their binding partners. Here, we demonstrate that interaction with FER and RALFs requires the LRR domain of LRXs and several but not all LRXs can bind these proteins. This explains the observation that mutations in several of theLRXsinduce phenotypes comparable to afermutant, establishing that LRX-FER interaction is important for proper cell growth. Some LRXs, however, appear to influence cell growth processes in different ways, which remain to be identified.
Goal-directed action transiently depends on action space
Authors: Bradfield Laura A. , Leung Beatrice K. , Boldt Susan , Balleine Bernard W. 
Published: September 2019

AbstractRats use spatiotemporal features of the environment to navigate to a goal, but whether representations of ‘action space’ are necessary for non-navigational goal-directed actions is unknown. We addressed this question by assessing goal-directed action control across contexts and under hippocampal inactivation and found that such actions do indeed rely on a representation of action space but only immediately after initial acquisition.One Sentence SummaryGoal-directed actions depend on a hippocampal representation of action space immediately after initial encoding but not after a delay.