bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor
Authors: Adelaiye-Ogala Remi M. , Gryder Berkley , Nguyen Yen Thi Minh , Alilin Aian Neil , Grayson Adlai , Jansson Keith H. , Beshiri Michael L. , Agarwal Supreet , Rodriguez-Nieves Jose Antonio , Capaldo Brian , Kelly Kathleen , VanderWeele David J. 
Published: October 2019

ABSTRACTThe PI3K-AKT pathway has pleiotropic effects, and its inhibition has long been of interest in the management of prostate cancer, where a compensatory increase in PI3K signaling has been reported following Androgen Receptor (AR) blockade. Prostate cancer cells can also bypass AR blockade through induction of other hormone receptors, in particular the glucocorticoid receptor (GR). Here we demonstrate that AKT inhibition significantly decreases cell proliferation through both cytostatic and cytotoxic effects. The cytotoxic effect is enhanced by AR inhibition and is most pronounced in models that induce compensatory GR expression. AKT inhibition increases canonical AR activity and remodels the chromatin landscape, decreasing enhancer interaction at the GR gene (NR3C1) locus. Importantly, it blocks induction of GR expression and activity following AR blockade. This is confirmed in multiplein vivomodels, where AKT inhibition of established xenografts leads to increased canonical AR activity, decreased GR expression, and marked anti-tumor activity. Overall, our results demonstrate that inhibition of the PI3K/AKT pathway can block GR activity and overcome GR-mediated resistance to AR-targeted therapy. Ipatasertib is currently in clinical development, and GR induction may be a biomarker to identify responsive patients or a responsive disease state.SIGNIFICANCEInduced GR expression is compensatory for AR blockade and confers resistance to AR-targeted therapy. Here we show that inhibition of the PI3K/AKT pathway remodels the chromatin landscape, blocks the induction of GR expression and overrides enzalutamide resistance.
The Role of Carbon Nanoparticle in Lymph Node Detection and Parathyroid Gland Protection during Thyroidectomy- a Meta Analysis
Authors: Xu Shao-Wei , Li Zhi-Feng , Xu Man-Bin , Peng Han-Wei 
Published: October 2019

AbstractObjectiveTo assess the efficiency of the carbon nanoparticles (CNs) in lymph node identification and parathyroid gland protection during thyroidectomy.MethodsA systematic literature search for relevant literatures published up to December 2018 in PubMed, Embase, Web of Science and Cochrane Library was performed. Both English and Chinese literatures were retrieved and analyzed. Randomized controlled trials or nonrandomized controlled trials on the use of CNs during thyroidectomy were enrolled in this study. The primary outcomes included the number of lymph nodes harvesed, rate of lymph nodes involvement, and the rates of accidental parathyroidectomy, hypoparathyroidism, and hypocalcemia. Weighted mean differences (WMDs), odds ratios (ORs) and risk differences (RDs) were calculated for the dichotomous outcome variables. Between-study heterogeneity was tested using the Q tests and the I2 statistics. All analyses were performed using Review Manager (version 5.3.5).Results25 studies comprising 3266 patients were included in this analysis. The total number of lymph nodes harvested in the groups of carbon nanoparticles was significant higher than that in the control groups (WMD, 2.36; 95% CI, 1.40 to 3.32; P <0.01). Administrating carbon nanoparticles was associated with a lower incidence of accidental parathyroid gland removal (OR = 0.30, 95% CI = 0.23 to 0.40, P <0.01) and lower rates of both postoperative transient hypoparathyroidism (OR =0.46, 95% CI = 0.33 to 0.64, P <0.01) and transient hypocalcemia (OR =0.55, 95% CI = 0.09 to 3.43, P =0.52). There was no significant difference of identified lymph node metastatic rates between the patients with and without use of carbon nanoparticles. Subgroup analyses indicated that the application of CNs in thyroid cancer reoperation also decreased the rate of transient hypoparathyroidism (OR =0.20, 95% CI = 0.36 to 0.04, P =0.01) and the possibility of accidental parathyroid glands removal (OR = 0.19, 95% CI = 0.05 to 0.73, P<0.05).ConclusionsThe application of CNs for thyroidectomy results in higher number of lymph node harvested and better parathyroid gland protection during initial surgery and reoperation for thyroid cancer.
Single cell transcriptomics of human epidermis reveals basal stem cell transition states
Authors: Wang Shuxiong , Drummond Michael L. , Guerrero-Juarez Christian F. , Tarapore Eric , MacLean Adam L. , Stabell Adam R. , Wu Stephanie C. , Gutierrez Guadalupe , That Bao T. , Benavente Claudia A. , Nie Qing , Atwood Scott X. 
Published: October 2019

ABSTRACTHow stem cells give rise to human interfollicular epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find at least four spatially distinct stem cell populations that decorate the top and bottom of rete ridge architecture and hold transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling through co-variance of cognate ligand-receptor pairs indicate that the basal cell populations distinctly serve as critical signaling hubs that maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest the “transitional” basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed “transitional” basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.
Deciphering the multi-scale mechanisms ofTephrosia purpureaagainst polycystic ovarian syndrome (PCOS) and its major psychiatric comorbidities: studies from network-pharmacological perspective
Authors: Choudhary Neha , Choudhary Shilpa , Singh Vikram 
Published: October 2019

AbstractTephrosia purpurea (T. purpurea), a plant belonging to Fabaceae (pea) family, is a well-known Ayurvedic herb and is commonly known as Sarapunkha in traditional Indian medicinal system. Described as “Sarwa wranvishapaka”,i.e.having capability to heal all types of wounds, it is particularly recognized for its usage in splenomegaly. Towards exploring the comprehensive effects ofT. purpureaagainst polycystic ovarian syndrome (PCOS), its phytochemicals were extensively reviewed and their network pharmacology evaluation is carried out in this study. The complex regulatory potential of its 76 phytochemicals (PCs) against PCOS are enquired by developing and analyzing high confidence tripartite networks of protein targets of each phytochemical at both pathway and disease association scales. We also developed a high-confidence human PPI sub-network specific to PCOS, explored its modular architecture and probed the drug-like phytochemicals (DPCs) having multi-module regulatory potential. The proteins belonging to endocrine system were identified as major targets of the PCs. The study reports 30 DPCs based on ADMET and drug-like properties. Multi-targeting and synergistic capacities of the 12 DPCs against 10 protein targets were identified and evaluated using molecular docking and interaction analyses. The study concludes by highlighting a couple of DPCs as potential sources of PCOS regulators.
Whole-plant optimality predicts changes in leaf nitrogen under variable CO2 and nutrient availability
Authors: Caldararu Silvia , Thum Tea , Yu Lin , Zaehle Sönke 
Published: October 2019

SummaryVegetation nutrient limitation is essential for understanding ecosystem responses to global change. In particular, leaf nitrogen (N) is known to be plastic under changed nutrient limitation. However, models can often not capture these observed changes, leading to erroneous predictions of whole-ecosystem stocks and fluxes.We hypothesise that an optimality approach can improve representation of leaf N content compared to existing empirical approaches. Unlike previous optimality-based approaches, which adjust foliar N concentrations based on canopy carbon export, we use a maximisation criteria based on whole-plant growth and allow for a lagged response of foliar N to this maximisation criterion to account for the limited plasticity of this plant trait. We test these model variants at a range of Free-Air CO2 Enrichment (FACE) and N fertilisation experimental sites.We show a model solely based on canopy carbon export fails to reproduce observed patterns and predicts decreasing leaf N content with increased N availability. However, an optimal model which maximises total plant growth can correctly reproduce the observed patterns.The optimality model we present here is a whole-plant approach which reproduces biologically realistic changes in leaf N and can thereby improve ecosystem-level predictions under transient conditions.
Conserved serotonergic background of experience-dependent challenge-responding in zebrafish (Danio rerio)
Authors: Varga Zoltán K , Pejtsik Diána , Biró László , Zsigmond Áron , Varga Máté , Tóth Blanka , Salamon Vilmos , Annus Tamás , Mikics Éva , Aliczki Manó 
Published: October 2019

AbstractForming effective responses to threatening stimuli requires the adequate and coordinated emergence of stress-related internal states. Such ability depends on early-life experiences and, in connection, the adequate formation of neuromodulatory systems, particularly serotonergic signaling. Here, we assess the serotonergic background of experience-dependent behavioral responsiveness employing a zebrafish (Danio rerio) model. For the first time, we have characterized a period during the behavioral metamorphosis in which zebrafish are highly reactive to their environment. Absence of social stimuli during this phase established by isolated rearing fundamentally altered the behavioral phenotype of post-metamorphic zebrafish in a challenge-specific manner, partially due to a decline in responsiveness and an inability to develop stress-associated arousal state. In line with this, isolation differently affected whole-brain 5-HT signaling in resting and stress-induced conditions, an effect that was present at the level of the dorsal pallium and was negatively associated with responsiveness. Administration of the 5HT1AR partial agonist buspirone prevented the isolation-induced serotonin response to novelty in the forebrain and rescued stress-induced arousal along with challenge-induced behaviors, which altogether indicates a functional connection between these changes. In summary, there is a consistent negative association between behavioral responsiveness and serotonergic signaling in zebrafish, which is well recognizable through the modifying effects of developmental perturbation and pharmacological manipulations as well. Our results imply a conserved serotonergic mechanism that context-dependently modulates environmental reactivity and is highly sensitive to experiences acquired during a specific early-life time-window, a phenomenon that was previously only suggested in mammals.Significance statementThe ability to respond to challenges is a fundamental factor in survival. We show that zebrafish that lack appropriate social stimuli in a sensitive developmental period show exacerbated alertness in non-stressful conditions while failing to react adequately to stressors. This shift is reflected inversely by central serotonergic signaling, a system that is implicated in numerous mental disorders in humans. Serotonergic changes in brain regions modulating responsivity and behavioral impairment were both prevented by the pharmacological blockade of serotonergic function. These results imply a serotonergic mechanism in zebrafish that transmits early-life experiences to the later phenotype by shaping stress-dependent behavioral reactivity, a phenomenon that was previously only suggested in mammals. Zebrafish provide new insights into early-life-dependent neuromodulation of behavioral stress-responses.
Connectome Constrained Graphical Models of MEG Coherence
Authors: Wodeyar Anirudh , Srinivasan Ramesh 
Published: October 2019

AbstractStructural connectivity by axonal fiber bundles provides the backbone for communication between neural populations. Since axonal transmission occurs on a millisecond time scale, measures of M/EEG functional connectivity sensitive to phase synchronization in a frequency band, such as coherence, are expected to reflect structural connectivity. We develop a complex-valued Gaussian Graphical Model (cGGM) of MEG coherence whose edges are constrained by the structural connectome. The cGGMs’ edge strengths are summarized by partial coherence, a measure of conditional dependence. We made use of the adaptive graphical lasso (AGL) to fit the cGGMs which allows us to perform inference on the hypothesis that the structural connectome is reflected in MEG coherence in a frequency band. In simulations, we demonstrate that the structural connectivity’s influence on the cGGM can be inferred using the AGL. Further, we show that fitting the cGGM is superior to alternative methods at recovering the structural connectome. Graphical modeling of MEG coherence is robust to the source localization estimates required to map MEG from sensors to the cortex. Finally, we show how cG-GMs can be used to explore how distinct parts of the structural connectome contribute to MEG coherence in different frequency bands. We think the cGGM is a useful tool that can improve interpretation of MEG coherence by making a direct link to the structural connectome.
Pavlovian Control of Intraspinal Microstimulation to Produce Over-Ground Walking
Authors: Dalrymple Ashley N , Roszko David A , Sutton Richard S , Mushahwar Vivian K 
Published: October 2019

ABSTRACTObjectiveNeural interface technologies are more commonly used in people with neural injury. To achieve a symbiotic relationship between device and user, the control system of the device must augment remaining function and adapt to day-to-day changes. The goal of this study was to develop predictive control strategies to produce alternating, over-ground walking in a cat model of hemisection spinal cord injury (SCI) using intraspinal microstimulation (ISMS).ApproachEight cats were anaesthetized and placed in a sling over a walkway. The residual function of a hemisection SCI was mimicked by manually moving one hind-limb through the walking cycle over the walkway. ISMS targeted motor networks in the lumbosacral enlargement to activate muscles in the other limb using low levels of current (< 130 µA). Four different people took turns to move the “intact” limb. Two control strategies, which used ground reaction force and angular velocity information about the manually moved limb to control the timing of the transitions of the other limb, were compared. The first strategy, reaction-based control, used thresholds on the sensor values to initiate state transitions. The other strategy used a reinforcement learning strategy, Pavlovian control, to learn predictions about the sensor values. Thresholds on the predictions were used to initiate transitions.Main ResultsBoth control strategies were able to produce alternating, over-ground walking. Reaction-based control required manual tuning of the thresholds for each person to produce walking, whereas Pavlovian control did not. We demonstrate that learning occurs quickly during walking. Predictions of the sensor signals were learned quickly, initiating transitions in no more than 4 steps. Pavlovian control was resilient to transitions between people walking the limb, between cat experiments, and recovered from mistakes during walking.SignificanceThis work demonstrates that Pavlovian control can augment remaining function and allow for personalized walking with minimal tuning requirements.
Effects of DCM leaf Extract ofGnidia glauca(Fresen) on Locomotor Activity, Anxiety and Exploration-Like Behaviors in High Fat Diet-Induced Obese Rats
Authors: Makori Arika Wycliffe , Kibiti Cromwell Mwiti , Njagi Joan Murugi , Ngugi Mathew Piero 
Published: October 2019

AbstractObesity is the main component of metabolic syndromes involving distinct etiologies which target different underlying behavioral and physiological functions within the brain structures and neuronal circuits. An alteration in the neuronal circuitry stemming from abdominal or central obesity stimulates a cascade of changes in neurochemical signaling that directly or indirectly mediate spontaneously emitted behaviors such as locomotor activity patterns, anxiety and exploration. Pharmacological agents available for the treatment of neurologic disorders have been associated with limited potency and intolerable adverse effects. These have necessitated the upsurge in utilization of herbal prescriptions due to their affordability, easy accessibility and are firmly embedded within wider belief systems of many people.Gnidia glaucahas been used in management of many ailments including obesity and associated symptomatic complications. However, its upsurge in use has not been accompanied with authentication of these folkloric claims. The present study aimed to determine the modulatory effect of Dichloromethane leaf extract ofGnidia glaucaon locomotor activity, exploration and anxiety-like behaviors in high fat diet-induced obese rats in an Open Field Arena. Obesity was experimentally induced by feeding the rats with prepared high fat diet and waterad libitumfor a period of 6 weeks. Thein-vivoanti-obesity effects were determined by oral administration ofG. glaucaat dosage levels of 200, 250 and 300mg/kg body weight in high fat diet-induced obese rats from the 6thto 12thweek. Phytochemical analysis was done using gas chromatography linked to mass spectroscopy. Results indicated thatGnidia glaucashowed anxiolytic effects and significantly increased spontaneous locomotor activity and exploration-like behaviors in HFD-induced obese rats. The plant extract also contained phytocompounds that have been associated with amelioration of the main neurodegenerative mediators viz inflammation and oxidative stress. These findings provide ‘qualified leads’ for the synthesis of new alternative therapeutic agent for management of neurologic disorders. However, there’s need to conduct toxicity studies ofGnidia glaucato establish its safety profiles.
Multiple ER-to-nucleus stress signaling pathways become active duringPlantago asiatica mosaic virusandTurnip mosaic virusinfection inArabidopsis thaliana
Authors: Gayral Mathieu , Gaguancela Omar Arias , Vasquez Evelyn , Herath Venura , Pang Mingxiong , Florez Francisco Javier , Dickman Martin B , Verchot Jeanmarie 
Published: October 2019

SummaryEndoplasmic reticulum (ER) stress due to biotic or abiotic stress activates the unfolded protein response (UPR) to restore ER homeostasis. The UPR relies on multiple ER-to-nucleus signaling factors which mainly induce the expression of cytoprotective ER-chaperones. The inositol requiring enzyme (IRE1) along with its splicing target, bZIP60, restrict potyvirus, and potexvirus accumulation. Until now, the involvement of the alternative UPR pathways and the role of UPR to limit virus accumulation have remained elusive. Here, we used thePlantago asiatica mosaic virus(PlAMV) and theTurnip mosaic virus(TuMV) to demonstrate that the potexvirus triple gene block 3 (TGB3) protein and the potyvirus 6K2 protein activate the bZIP17, bZIP28, bZIP60, BAG7, NAC089 and NAC103 signaling inArabidopsis thaliana. Using the corresponding knock-out mutant lines, we demonstrated that these factors differentially restrict local and systemic virus accumulation. We show that bZIP17, bZIP60, BAG7, and NAC089 are factors in PlAMV infection, whereas bZIP28 and bZIP60 are factors in TuMV infection. TGB3 and 6K2 transient expression in leave reveal that these alternative pathways induce BiPs expression. Finally, using dithiothreitol (DTT) and tauroursodeoxycholic acid (TUDCA) treatment, we demonstrated that the protein folding capacity significantly influences PlAMV accumulation. Together, these results indicate that multiple ER-to-nucleus signaling pathways are activated during virus infection and restrict virus accumulation through increasing protein folding capacity.Significance statementThe IRE1/bZIP60 pathway of unfolded protein response (UPR) is activated by potyviruses and potexviruses, limiting their infection, but the role of alternative UPR pathways is unknown. This study reveals the activation of multiple ER-to-nucleus signaling pathways by thePlantago asiatica mosaic virusand theTurnip mosaic virus.We identify additional signaling pathways serve to restrict virus accumulation through increased protein folding capacity.
Spreading depolarization and repolarization during cardiac arrest as an ultra-early marker of neurological recovery in a preclinical model
Authors: Wilson Robert H. , Crouzet Christian , Lee Donald E. , Donga Dishant P. , Patel Ayushi H. , Bazrafkan Afsheen , Maki Niki , Rafi Masih A. , Moslehyazdi Maziar , Pham Justin H. , Torabzadeh Mohammad , Hjelm Brooke E. , Tromberg Bruce J. , Steward Oswald , Lopour Beth A. , Choi Bernard , Akbari Yama 
Published: October 2019

AbstractSpreading depolarization (SD) accompanies numerous neurological conditions, including migraine, stroke, and traumatic brain injury. There is significant interest in understanding the relationship between SD and neuronal injury. However, characteristics underlying SD and repolarization (RP) induced by global cerebral ischemia (e.g., cardiac arrest (CA)) and reperfusion are not well understood. Quantifying features of SD and RP during CA and cardiopulmonary resuscitation (CPR) may provide important metrics for diagnosis and prognosis of neurological injury from hypoxia-ischemia. We characterized SD and RP in a rodent model of asphyxial CA+CPR using a multimodal platform including electrocorticography (ECoG) and optical imaging. We detected SD and RP by (1) alternating current (AC), (2) direct current (DC), and (3) optical imaging of spreading ischemia, spreading edema, and vasoconstriction. Earlier SD (r=−0.80; p<0.001) and earlier RP (r=−0.71, p<0.001) were associated with better neurological recovery after 24hrs. SD+RP onset times predicted good vs poor neurological recovery with 82% sensitivity and 91% specificity. To our knowledge, this is the first preclinical study to link SD and RP characteristics with neurological recovery post-CA. These data suggest that SD and RP may be ultra-early, real-time prognostic markers of post-CA outcome, meriting further investigation into translational implications during global cerebral ischemia.
Treg cells maintain selective access to IL-2 and immune homeostasis despite substantially reduced CD25 function
Authors: Hayes Erika T. , Hagan Cassidy E. , Campbell Daniel J. 
Published: October 2019

AbstractInterleukin-2 (IL-2) is a critical regulator of immune homeostasis through its impact on both regulatory T (Treg) and effector T (Teff) cells. However, the precise role of IL-2 in the maintenance and function of Treg cells in the adult peripheral immune system remains unclear. Here, we report that neutralization of IL-2 abrogated all IL-2 receptor signaling in Treg cells, resulting in rapid dendritic cell (DC) activation and subsequent Teff cell proliferation. By contrast, despite substantially reduced IL-2 sensitivity, Treg cells maintained selective IL-2 signaling and prevented immune dysregulation following treatment with the inhibitory anti-CD25 antibody PC61, even when CD25hiTreg cells were depleted. Thus, despite severely curtailed CD25 expression and function, Treg cells retain selective access to IL-2 that supports their anti-inflammatory functionsin vivo. Antibody-mediated targeting of CD25 is being actively pursued for treatment of autoimmune disease and preventing allograft rejection, and our findings help inform therapeutic manipulation and design for optimal patient outcomes.