bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Pancreatitis and Fluid-Filled Collections
Authors: Lancaster Audrey , Zwijacz Melissa
Published: October 2019

Acute pancreatitis is an inflammatory process of the pancreas, which can range from a localized inflammatory process to a systemic response, resulting in sepsis and multisystem failure. Pancreatic fluid collections are a complication of pancreatitis. Treatment of these fluid collections is dependent on correct classification. The 2012 Atlanta Criteria divides fluid collections into four categories: acute peripancreatic fluid collections, pancreatic pseudocysts, acute necrotic collections, and walled-off necrosis. Endoscopic ultrasound-guided management of chronic fluid collections is currently the preferred treatment modality. Endoscopy nurses need to be aware of their role in this treatment approach. Continued research in this area will lead to both advancements in equipment and treatment options.
Genetic factors influencing a neurobiological substrate for psychiatric disorders
Authors: Andlauer Till F. M. , Mühleisen Thomas W. , Hoffstaedter Felix , Teumer Alexander , Wittfeld Katharina , Teuber Anja , Reinbold Céline S. , Grotegerd Dominik , Bülow Robin , Caspers Svenja , Dannlowski Udo , Herms Stefan , Hoffmann Per , Kircher Tilo , Minnerup Heike , Moebus Susanne , Nenadić Igor , Teismann Henning , Völker Uwe ,   International FTD-Genomics Consortium (IFGC),   The 23andMe Research Team, Etkin Amit , Berger Klaus , Grabe Hans J. , Nöthen Markus M. , Amunts Katrin , Eickhoff Simon B. , Sämann Philipp G. , Müller-Myhsok Bertram , Cichon Sven
Published: October 2019

A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex – areas that constitute hub nodes of the salience network – represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n=2,271), followed by meta-analysis and replication in a fifth cohort (n=865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.
Heat shock response pathways regulate stimulus-specificity and sensitivity of NF-κB signalling to temperature stress
Authors: Paszek Anna , Kardyńska Małgorzata , Bagnall James , Śmieja Jarosław , Spiller David G. , Widłak Piotr , Kimmel Marek , Widlak Wieslawa , Paszek Pawel
Published: October 2019

Ability to adapt to temperature changes trough the Heat Shock Response (HSR) pathways is one of the most fundamental and clinically relevant cellular response systems. Here we report that Heat Shock (HS) induces a temporally-coordinated and stimulus-specific adaptation of the signalling and gene expression responses of the Nuclear Factor κB (NF-κB) transcription factor. We show that exposure of MCF7 breast adenocarcinoma cells to 43°C 1h HS inhibits the immediate signalling response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines. Within 4h after HS treatment IL1β-induced responses return to normal levels, but the recovery of the TNFα-induced responses is delayed. Using siRNA knock-down of Heat Shock Factor 1 and mathematical modelling we show that the stimulus-specificity is conferred via the Inhibitory κB kinase signalosome, with HSR differentially controlling individual cytokine transduction pathways. Finally, using a novel mathematical model we predict and experimentally validate that the HSR cross-talk confers differential cytokine sensitivity of the NF-κB system to a range of physiological and clinically-relevant temperatures. This quantitative understanding of NF-κB and HSR cross-talk mechanisms is fundamentally important for the potential improvement of current hyperthermia protocols.
A combined morphometric and statistical approach to assess non-monotonicity in the developing mammary gland of rats in the CLARITY-BPA study
Authors: Montévil Maël , Acevedo Nicole , Schaeberle Cheryl M. , Bharadwaj Manushree , Fenton Suzanne E. , Soto Ana M.
Published: October 2019

Background

CLARITY-BPA is a rare collaboration of guideline-compliant (core) studies and academic hypothesis-based studies to assess the effects of bisphenol A (BPA).

Objectives

1) determine BPA’s effects on the developing rat mammary gland using new quantitative and established semi-quantitative methods in two labs, 2) develop a software tool for semi-automatic evaluation of quantifiable aspects of the mammary ductal tree, and 3) compare those methods.

Methods

Sprague Dawley rats were exposed to BPA, vehicle, or positive control (ethinyl estradiol, EE2) by oral gavage beginning on gestational day 6 and continuing with direct dosing of the pups after birth. There were two studies; sub-chronic and chronic. The latter used two exposure regimes, one stopping at PND21 the other continuing until tissue harvest. Glands were harvested at multiple time points; whole mounts and histological specimens were analyzed blinded to treatment.

Results

The subchronic study’s semiquantitative analysis revealed no significant differences between control and BPA dose groups at PND21; whereas at PND90 there were significant differences between control and the lowest BPA dose and between control and the lowest EE2 dose in animals in estrus. Quantitative, automatized analysis of the chronic PND21 specimens displayed non-monotonic BPA effects with a breaking point between the 25 and 250μg/kg/day doses. This breaking point was confirmed by a global statistical analysis of chronic study animals at PND90 and 6 months analyzed by the quantitative method. The BPA response was different from the EE2 effect for many features.

Conclusions

Both the semiquantitative and the quantitative methods revealed non-monotonic effects of BPA. The quantitative unsupervised analysis used 91 measurements and produced the most striking non-monotonic dose-response curves. At all-time points, lower doses resulted in larger effects, consistent with the core study which revealed a significant increase of mammary adenocarcinoma incidence in the stop-dose animals at the lowest BPA dose tested.
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

The 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.

SIGNIFICANCE

Induced 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

Objective

To assess the efficiency of the carbon nanoparticles (CNs) in lymph node identification and parathyroid gland protection during thyroidectomy.

Methods

A 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).

Results

25 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).

Conclusions

The 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

How 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

Tephrosia 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

Vegetation 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

Forming 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 statement

The 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.
pH-Dependent Grafting of Cancer Cells with Antigenic Epitopes Promotes Selective Antibody-Mediated Cytotoxicity
Authors: Wehr Janessa , Sikorski Eden L. , Bloch Elizabeth , Feigman Mary S. , Ferraro Noel J. , Baybutt Trevor , Snook Adam E. , Pires Marcos M. , Thévenin Damien
Published: October 2019

A growing class of immunotherapeutic agents work by redirecting components of the immune system to recognize specific markers on the surface of cancer cells and initiate a selective immune response. However, such immunotherapeutic modalities will remain confined to a relatively small subgroup of patients until two major hurdles are overcome: (1) the specific targeting of cancer cells relative to healthy cells, and (2) the lack of common targetable tumor biomarkers among all patients. Here, we designed a unique class of agents that exploit the inherent acidic microenvironment of solid tumors to selectively graft the surface of cancer cells with immuno-engager epitopes for directed destruction by components of the immune system. Specifically, conjugates were assembled using an antigen that recruit antibodies present in human serum, and the pH(Low) Insertion Peptide (pHLIP), a unique peptide that selectively target tumorsin vivoby anchoring onto cancer cell surfaces in a pH-dependent manner. We established that conjugates can recruit antibodies from human serum to the surface of cancer cells, and induce complement-dependent and antibody-dependent cellular cytotoxicity by peripheral blood mononuclear cells and also an engineered NK cell line. These results suggest that these agents have the potential to be applicable to treating a wide range of solid tumors and to circumvent the problem of narrow windows of selectivity.
Connectome Constrained Graphical Models of MEG Coherence
Authors: Wodeyar Anirudh , Srinivasan Ramesh
Published: October 2019

Structural 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

Objective

Neural 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).

Approach

Eight 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 Results

Both 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.

Significance

This 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

Obesity 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

Endoplasmic 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 statement

The 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

Spreading 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

Interleukin-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.
Computationally guided high-throughput design of self-assembling drug nanoparticles
Authors: Reker Daniel , Rybakova Yulia , Kirtane Ameya R. , Cao Ruonan , Yang Jee Won , Navamajiti Natsuda , Gardner Apolonia , Zhang Rosanna M. , Esfandiary Tina , L’Heureux Johanna , von Erlach Thomas , Smekalova Elena M. , Leboeuf Dominique , Hess Kaitlyn , Lopes Aaron , Rogner Jaimie , Collins Joy , Tamang Siddartha M. , Ishida Keiko , Chamberlain Paul , Yun DongSoo , Lytoon-Jean Abigail , Soule Christian K. , Cheah Jaime H. , Hayward Alison M. , Langer Robert , Traverso Giovanni
Published: October 2019

Nanoformulations are transforming our capacity to effectively deliver and treat a myriad of conditions. However, many nanoformulation approaches still suffer from high production complexity and low drug loading. One potential solution relies on harnessing co-assembly of drugs and small molecular excipients to facilitate nanoparticle formation through solvent exchange without the need for chemical synthesis, generating nanoparticles with up to 95% drug loading. However, there is currently no understanding which of the millions of possible combinations of small molecules can result in the formation of these nanoparticles. Here we report the development of a high-throughput screening platform coupled to machine learning to enable the rapid evaluation of such nanoformulations. Our platform identified 101 novel self-assembling drug nanoparticles from 2.1 million pairings derived from 788 candidate drugs with one of 2686 excipients, spanning treatments for multiple diseases and often harnessing well-known food additives, vitamins, or approved drugs as carrier materials – with potential for accelerated approval and translation. Given their long-term stability and potential for clinical impact, we further characterize novel sorafenib-glycyrrhizin and terbinafine-taurocholic acid nanoparticlesex vivoandin vivo. We anticipate that this platform could accelerate the development of safer and more efficacious nanoformulations with high drug loadings for a wide range of therapeutics.
Success of Escherichia coli O25b:H4 ST131 clade C associated with a decrease in virulence
Authors: Duprilot Marion , Baron Alexandra , Blanquart François , Dion Sara , Lettéron Philippe , Flament-Simon Saskia-Camille , Clermont Olivier , Denamur Erick , Nicolas-Chanoine Marie-Hélène
Published: October 2019

Escherichia coli of sequence type (ST) 131 resistant to fluoroquinolones and producer of CTX-M-15 is globally one of the major extraintestinal pathogenic E. coli (ExPEC). ST131 phylogenesis showed that multidrug-resistant ST131 strains belong to a clade called C, descending from an ancestral clade called B, comprising mostly antibiotic-susceptible strains. Antibiotic resistance could appear as one of the keys of the clade C global success. We hypothesized that other features of ST131 clade C could contribute to this success since other major global ExPEC clones (ST73, ST95) are mostly antibiotic-susceptible. To test this hypothesis, we measured the growth abilities, early biofilm formation and virulence-factor content of a collection of clade B and clade C strains. Moreover, using competition assays, we measured the capacity of selected representative strains of clades B and C to colonize the mouse intestine and urinary tract, and to kill mice in a septicemia model. Clade B and C strains had similar growth ability. However, clade B strains were more frequently early biofilm producers, expressed mostly faster their type 1 fimbriae and displayed more virulence factor-encoding genes than clade C strains. Clade B outcompeted clade C in the gut and/or urinary tract colonization models and in the septicemia model. These results strongly suggest that clade C strain evolution includes a loss of virulence, i.e. a process that could enhance micro-organism persistence in a given host and thus optimize transmission. This process, associated with acquired antibiotic-resistance, could ensure clade C strain survival in environments under antibiotic pressure.

Importance

Extraintestinal pathogen Escherichia coli (ExPEC) are virulent but mostly antibiotic-susceptible. One worrying exception is ST131, a major multidrug resistant ExPEC clone that has spread worldwide since the 2000s. To contain the emergence of this threatening clone, we need to understand what factors favored its emergence and dissemination. Here, we investigated whether multidrug-resistant ST131 had advantageous phenotypic properties beyond multidrug resistance. To this end, we competed the emergent multidrug-resistant ST131 with its antibiotic-susceptible ancestor in different conditions: biofilm production, in vivo colonization and virulence experiments. In all in vivo competitions, we found that multidrug-resistant ST131 was losing to its ancestor, suggesting a lesser virulence of multidrug-resistant ST131. It was previously described that losing virulence can increase micro-organism persistence in some populations and subsequently its level of transmissibility. Thus, a decreased level of virulence, associated with multidrug resistance, could explain the global success of ST131.
Subordinate effect of −21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin
Authors: Cubero Elia Moreno , Ogbe Ane , Cohen Myron S. , Haynes Barton F. , Borrow Persephone , Peppa Dimitra
Published: October 2019

Natural Killer (NK) cells play an important role in antiviral defence and their potent effector function identifies them as key candidates for immunotherapeutic interventions in chronic viral infections. Their remarkable functional agility is achieved by virtue of a wide array of germline encoded inhibitory and activating receptors ensuring a self-tolerant and tunable repertoire. NK cell diversity is generated by a combination of factors including genetic determinants and infections/environmental factors, which together shape the NK cell pool and functional potential. Recently a genetic polymorphism at position −21 of HLA-B, which influences the supply of HLA-E binding peptides and availability of HLA-E for recognition by the inhibitory NK cell receptor NKG2A, was shown to have a marked influence on NK cell functionality in healthy human cytomegalovirus (HCMV) seronegative Caucasian individuals. In this study, −21 methionine (M)-expressing alleles supplying HLA-E binding peptides were largely poor ligands for inhibitory killer immunoglobulin-like receptors (KIRs), and a bias to NKG2A-mediated education of functionally-potent NK cells was observed. Here, we investigated the effect of this polymorphism on the phenotype and functional capacity of NK cells in a cohort of African individuals with human immunodeficiency virus type 1 (HIV-1)/HCMV co-infection. A similarly profound influence of dimorphism at position −21 of HLA-B on NK cells was not evident in these subjects. They predominantly expressed African specific HLA-B and −C alleles that contribute a distinct supply of NKG2A and KIR ligands, and these genetic differences were compounded by the marked effect of HIV/HCMV coinfection on NK cell differentiation. Together, these factors resulted in a lack of correlation of the HLA-B −21 polymorphism with surface abundance of HLA-E and loss of the NK cell functional advantage in subjects with −21M HLA-B alleles. Instead our data suggest that during HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses. Increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions to overcome the current barriers to enhancing immune-based antiviral control.
Regulation of Bud Emergence by a MAPK Pathway
Authors: Prabhakar Aditi , Chow Jacky , Siegel Alan J. , Cullen Paul J.
Published: October 2019

All cells establish and maintain an axis of polarity that is critical for cell shape and progression through the cell cycle. A well-studied example of polarity establishment is bud emergence in yeast, where the Rho GTPase Cdc42p regulates symmetry breaking at bud sites and the establishment of polarity by interacting with effector proteins. The prevailing view of bud emergence does not account for regulation by extrinsic cues or signal transduction pathways. Here, we show that the MAPK pathway that controls filamentous growth (fMAPK pathway), which also requires Cdc42p and the effector p21 activated kinase (PAK) Ste20p, regulates bud emergence under nutrient-limiting conditions that favor filamentous/invasive growth. The fMAPK pathway regulated the expression of polarity targets that included the gene encoding a direct effector of Cdc42p, Gic2p. The fMAPK pathway also stimulated GTP-Cdc42p levels, which is a critical determinant of polarity establishment. The fMAPK pathway activity was spatially restricted to bud sites and highest at a period in the cell cycle that coincided with bud emergence. Time-lapse fluorescence microscopy showed that the fMAPK pathway stimulated the rate of bud emergence during filamentous growth. Unregulated activation of the fMAPK pathway induced growth at multiple sites that resulted from multiple rounds of symmetry breaking inside the growing bud. Collectively, our findings identify a new regulatory aspect of bud emergence that sensitizes this essential cellular process to external cues.
Revisiting biogeography of livestock animal domestication
Authors: Žliobaitė Indrė
Published: October 2019

Human society relies on four main livestock animals – sheep, goat, pig and cattle, which all were domesticated at nearly the same time and place. Many arguments have been put forward to explain why these animals, place and time were suitable for domestication, but the question – why only these, but not other animals, still does not have a clear answer. Here we offer a biogeographical perspective: we survey global occurrence of large mammalian herbivore genera around 15 000 – 5 000 years before present and compile a dataset characterising their ecology, habitats and dental traits. Using predictive modelling we extract patterns from this data to highlight ecological differences between domesticated and nondomesticated genera. The most suitable for domestication appear to be generalists adapted to persistence in marginal environments of low productivity, largely corresponding to cold semi-arid climate zones. Our biogeographic analysis shows that even though domestication rates varied across continents, potentially suitable candidate animals were rather uniformly distributed across continents. We interpret this pattern as a result of an interface between cold semi-arid and hot semi-arid climatic zones. We argue that hot Semi-arid climate was most suitable for plant domestication, cold Semi-arid climate selected for animals most suitable for domestication as livestock. We propose that the rates of domestication across biogeographic realms largely reflect how much intersection between hot and cold Semi-arid climatic zones was available at each continent.
The sensory representation of causally controlled objects
Authors: Clancy Kelly B. , Mrsic-Flogel Thomas D.
Published: October 2019

Intentional control over external objects is informed by our sensory experience of them. To study how causal relationships are learned and effected, we devised a brain machine interface (BMI) task utilising wide-field calcium signals. Mice learned to entrain activity patterns in arbitrary pairs of cortical regions to guide a visual cursor to a target location for reward. Brain areas that were normally correlated could be rapidly reconfigured to exert control over the cursor in a sensory feedback-dependent manner. Higher visual cortex was more engaged when expert but not naïve animals controlled the cursor. Individual neurons in higher visual cortex responded more strongly to the cursor when mice controlled it than when they passively viewed it, with the greatest response boosting as the cursor approached target location. Thus, representations of causally-controlled objects are sensitive to intention and proximity to the subject’s goal, potentially strengthening sensory feedback to allow more fluent control.
Light-Inducible Recombinases for Bacterial Optogenetics
Authors: Sheets Michael B. , Wong Wilson W. , Dunlop Mary J.
Published: October 2019

Optogenetic tools can provide direct and programmable control of gene expression. Light-inducible recombinases, in particular, offer a powerful method for achieving precise spatiotemporal control of DNA modification. However, to-date this technology has been largely limited to eukaryotic systems. Here, we develop optogenetic recombinases for Escherichia coli which activate in response to blue light. Our approach uses a split recombinase coupled with photodimers, where blue light brings the split protein together to form a functional recombinase. We tested both Cre and Flp recombinases, Vivid and Magnet photodimers, and alternative protein split sites in our analysis. The optimal configuration, Opto-Cre-Vvd, exhibits strong blue light-responsive excision and low ambient light sensitivity. For this system we characterize the effect of light intensity and the temporal dynamics of light-induced recombination. These tools expand the microbial optogenetic toolbox, offering the potential for precise control of DNA excision with light-inducible recombinases in bacteria.