bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen
Authors: Verma Anita , Ngundi Miriam M. , Price Gregory A. , Takeda Kazuyo , Yu James , Burns Drusilla L. 
Published: February 2018

ABSTRACT
Toxin neutralizing antibodies represent the major mode of protective immunity against a number of toxin-mediated bacterial diseases, including anthrax; however, the cellular mechanisms that lead to optimal neutralizing antibody responses remain ill defined. Here we show that the cellular binding pathway of anthrax protective antigen (PA), the binding component of anthrax toxin, determines the toxin neutralizing antibody response to this antigen. PA, which binds cellular receptors and efficiently enters antigen-presenting cells by receptor-mediated endocytosis, was found to elicit robust anti-PA IgG and toxin neutralizing antibody responses. In contrast, a receptor binding-deficient mutant of PA, which does not bind receptors and only inefficiently enters antigen-presenting cells by macropinocytosis, elicited very poor antibody responses. A chimeric protein consisting of the receptor binding-deficient PA mutant tethered to the binding subunit of cholera toxin, which efficiently enters cells using the cholera toxin receptor rather than the PA receptor, elicited an anti-PA IgG antibody response similar to that elicited by wild-type PA; however, the chimeric protein elicited a poor toxin neutralizing antibody response. Taken together, our results demonstrate that the antigen capture pathway can dictate the magnitudes of the total IgG and toxin neutralizing antibody responses to PA as well as the ratio of the two responses.

IMPORTANCE
Neutralizing antibodies provide protection against a number of toxin-mediated bacterial diseases by inhibiting toxin action. Therefore, many bacterial vaccines are designed to induce a toxin neutralizing antibody response. We have used protective antigen (PA), the binding component of anthrax toxin, as a model antigen to investigate immune mechanisms important for the induction of robust toxin neutralizing antibody responses. We found that the pathway used by antigen-presenting cells to capture PA dictates the robustness of the neutralizing antibody response to this antigen. These results provide new insights into immune mechanisms that play an important role in the induction of toxin neutralizing antibody responses and may be useful in the design of new vaccines against toxin-mediated bacterial diseases.
Coiled-Coil Antagonism Regulates Activity of Venus Flytrap-Domain-Containing Sensor Kinases of the BvgS Family
Authors: Lesne Elodie , Dupré Elian , Lensink Marc F. , Locht Camille , Antoine Rudy , Jacob-Dubuisson Françoise 
Published: February 2018

ABSTRACT

Bordetella pertussis
controls the expression of its virulence regulon through the two-component system BvgAS. BvgS is a prototype for a family of multidomain sensor kinases. In BvgS, helical linkers connect periplasmic Venus flytrap (VFT) perception domains to a cytoplasmic Per-Arnt-Sim (PAS) domain and the PAS domain to the dimerization/histidine phosphotransfer (DHp) domain of the kinase. The two linkers can adopt coiled-coil structures but cannot do so simultaneously. The first linker forms a coiled coil in the kinase mode and the second in the phosphatase mode, with the other linker in both cases showing an increase in dynamic behavior. The intervening PAS domain changes its quaternary structure between the two modes. In BvgS homologues without a PAS domain, a helical “X” linker directly connects the VFT and DHp domains. Here, we used BvgS as a platform to characterize regulation in members of the PAS-less subfamily. BvgS chimeras of homologues with natural X linkers displayed various regulation phenotypes. We identified two distinct coiled-coil registers in the N- and C-terminal portions of the X linkers. Stable coil formation in the C-terminal moiety determines the phosphatase mode, similarly to BvgS; in contrast, coil formation in the N-terminal moiety along the other register leads to the kinase mode. Thus, antagonism between two registers in the VFT-DHp linker forms the basis for activity regulation in the absence of the PAS domain. The N and C moieties of the X linker play roles similar to those played by the two independent linkers in sensor kinases with a PAS domain, providing a unified mechanism of regulation for the entire family.

IMPORTANCE
The whooping cough agent
Bordetella pertussis
uses the BvgAS sensory transduction two-component system to regulate production of its virulence factors. BvgS serves as a model for a large family of multidomain bacterial sensor kinases.
B. pertussis
is virulent when BvgS functions as a kinase and avirulent when it switches to phosphatase activity in response to modulating signals. Understanding the molecular regulation of those proteins might lead to new antibacterial strategies. Here, we show that the linker regions between the perception and the enzymatic domains shift between distinct states of conformation in an alternating manner in response to signals and that their antagonistic changes control sensor kinase activity. These linker regions and mechanistic principles appear to be conserved among BvgS homologues, irrespective of the presence or absence of an intervening domain between the perception and the enzymatic domains. This work has thus uncovered general molecular mechanisms that regulate activity of sensor kinases in the BvgS family.
Progressive idiopathic unilateral corneal endothelial failure of unknown aetiology in phakic eyes
Authors: Lee Weng Hon , Tey Adrian , Gales Kevin , Mudhar Hardeep Singh , Figueiredo Francisco C 
Published: February 2018

AimTo describe a cohort of patients with irreversible unilateral bullous keratopathy (BK) of undetermined aetiology.MethodRetrospective, single-centre case series in a tertiary corneal referral centre.ResultsEleven consecutive patients (nine females; mean age 71.7 years) presented from 1999 to 2009 with acute onset unilateral visual loss. At presentation, the best-corrected visual acuity of the affected eyes was 6/9 or worse with mean central corneal thickness (CCT) of 684 (SD 66) μm. Specular microscopy was not possible in the affected eyes. There was no other ocular pathology in the affected eye. The fellow eye remained normal throughout the study (mean endothelial cell density (ECD) of 1980 (SD 736) cells/mm2and CCT of 536 (SD 34) μm). Topical steroid, antiviral treatments (both topical and systemic) or a combination of both did not yield any improvement. After a mean follow-up of 82.2 months, eight eyes had penetrating keratoplasty (PK). One required two regrafts. Histology showed typical BK features, with endothelial cell (EC) loss and thickened Descemet’s membrane (DM). Transmission electron microscopy revealed DM abnormalities in a non-consistent pattern, featuring variable collagen deposition posterior to the non-banded zone. The ECs were degenerated, reduced or absent. Neither viruses nor pseudoexfoliation material was identified.ConclusionWhile medical treatment is not beneficial, PK appears to offer good results. Non-guttate Fuchs’ corneal endothelial dystrophy merits consideration but it would be unusual to see an exclusively unilateral presentation. DM thickening is reflective of a chronic EC loss but the cause of this loss remains elusive.
Single-cell RNAseq reveals seven classes of colonic sensory neuron
Authors: Hockley James R F , Taylor Toni S , Callejo Gerard , Wilbrey Anna L , Gutteridge Alex , Bach Karsten , Winchester Wendy J , Bulmer David C , McMurray Gordon , Smith Ewan St John 
Published: February 2018

ObjectiveIntegration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology and organism behaviour. Colonic sensory neurons activate reflex pathways and give rise to conscious sensation, but the diversity and division of function within these neurons is poorly understood. The identification of signalling pathways contributing to visceral sensation is constrained by a paucity of molecular markers. Here we address this by comprehensive transcriptomic profiling and unsupervised clustering of individual mouse colonic sensory neurons.DesignUnbiased single-cell RNA-sequencing was performed on retrogradely traced mouse colonic sensory neurons isolated from both thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia associated with lumbar splanchnic and pelvic spinal pathways, respectively. Identified neuronal subtypes were validated by single-cell qRT-PCR, immunohistochemistry (IHC) and Ca2+-imaging.ResultsTranscriptomic profiling and unsupervised clustering of 314 colonic sensory neurons revealed seven neuronal subtypes. Of these, five neuronal subtypes accounted for 99% of TL neurons, with LS neurons almost exclusively populating the remaining two subtypes. We identify and classify neurons based on novel subtype-specific marker genes using single-cell qRT-PCR and IHC to validate subtypes derived from RNA-sequencing. Lastly, functional Ca2+-imaging was conducted on colonic sensory neurons to demonstrate subtype-selective differential agonist activation.ConclusionsWe identify seven subtypes of colonic sensory neurons using unbiased single-cell RNA-sequencing and confirm translation of patterning to protein expression, describing sensory diversity encompassing all modalities of colonic neuronal sensitivity. These results provide a pathway to molecular interrogation of colonic sensory innervation in health and disease, together with identifying novel targets for drug development.
Penetrance estimates for BRCA1, BRCA2 (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?
Authors: Evans D Gareth , Woodward Emma , Harkness Elaine F , Howell Anthony , Plaskocinska Inga , Maher Eamonn R , Tischkowitz Marc D , Lalloo Fiona 
Published: February 2018

PurposeThe identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive.MethodsWe assessed the penetrance of BRCA1, BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1/BRCA2.ResultsUsing results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1, 60% (95% CI 49% to 71%) for BRCA2, 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2. There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1.ConclusionWe describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases.
Ab-initio thermodynamic and elastic properties of AlNi and AlNi3intermetallic compounds
Authors: Yalameha Shahram , Vaez Aminollah 
Published: February 2018

In this paper, thermodynamic and elastic properties of the AlNi and AlNi3were investigated using density functional theory (DFT). The full-potential linearized augmented plane-wave (APW) in the framework of the generalized gradient approximation as used as implemented in the Wien2k package. The temperature dependence of thermal expansion coefficient, bulk modulus and heat capacity in a wide range of temperature (0–1600 K) were investigated. The calculated elastic properties of the compounds show that both intermetallic compounds of AlNi and AlNi3have surprisingly negative Poisson’s ratio (NPR). The results were compared with other experimental and computational data.
Patient-Customized Drug Combination Prediction and Testing for T-cell Prolymphocytic Leukemia Patients
Authors: He Liye , Tang Jing , Andersson Emma I. , Timonen Sanna , Koschmieder Steffen , Wennerberg Krister , Mustjoki Satu , Aittokallio Tero 
Published: February 2018

Abstract
The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway cross-talk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational–experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients. DCPT used drug–target interaction networks to traverse the massive combinatorial search spaces among 218 compounds (a total of 23,653 pairwise combinations) and identified cancer-selective synergies by using differential single-compound sensitivity profiles between patient cells and healthy controls, hence reducing the likelihood of toxic combination effects. A polypharmacology-based machine learning modeling and network visualization made use of baseline genomic and molecular profiles to guide patient-specific combination testing and clinical translation phases. Using T-cell prolymphocytic leukemia (T-PLL) as a first case study, we show how the DCPT platform successfully predicted distinct synergistic combinations for each of the three T-PLL patients, each presenting with different resistance patterns and synergy mechanisms. In total, 10 of 24 (42%) of selective combination predictions were experimentally confirmed to show synergy in patient-derived samples ex vivo. The identified selective synergies among approved drugs, including tacrolimus and temsirolimus combined with BCL-2 inhibitor venetoclax, may offer novel drug repurposing opportunities for treating T-PLL.
Significance: An integrated use of functional drug screening combined with genomic and molecular profiling enables patient-customized prediction and testing of drug combination synergies for T-PLL patients. Cancer Res; 78(9); 2407–18. ©2018 AACR.
STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair
Authors: Maranto Cristina , Udhane Vindhya , Hoang David T. , Gu Lei , Alexeev Vitali , Malas Kareem , Cardenas Karmel , Brody Jonathan R. , Rodeck Ulrich , Bergom Carmen , Iczkowski Ken A. , Jacobsohn Ken , See William , Schmitt Sara M. , Nevalainen Marja T. 
Published: February 2018

Abstract
Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.
Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.
Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.
Conclusions: This work introduces a novel concept of a pivotal role of Jak2–Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2–Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917–31. ©2018 AACR.
Impact of Bystander Automated External Defibrillator Use on Survival and Functional Outcomes in Shockable Observed Public Cardiac Arrests
Authors: Pollack Ross A. , Brown Siobhan P. , Rea Thomas , Aufderheide Tom , Barbic David , Buick Jason E. , Christenson Jim , Idris Ahamed H. , Jasti Jamie , Kampp Michael , Kudenchuk Peter , May Susanne , Muhr Marc , Nichol Graham , Ornato Joseph P. , Sopko George , Vaillancourt Christian , Morrison Laurie , Weisfeldt Myron 
Published: February 2018

Background:
Survival following out-of-hospital cardiac arrest (OHCA) with shockable rhythms can be improved with early defibrillation. Although shockable OHCA accounts for only ≈25% of overall arrests, ≈60% of public OHCAs are shockable, offering the possibility of restoring thousands of individuals to full recovery with early defibrillation by bystanders. We sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public OHCA.

Methods:
From 2011 to 2015, the Resuscitation Outcomes Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander-applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharge with normal or near-normal (favorable) functional status defined as a modified Rankin Score ≤2. Survival to hospital discharge was the secondary outcome measure.

Results:
Among 49 555 OHCAs, 4115 (8.3%) observed public OHCAs were analyzed, of which 2500 (60.8%) were shockable. A bystander shock was applied in 18.8% of the shockable arrests. Patients shocked by a bystander were significantly more likely to survive to discharge (66.5% versus 43.0%) and be discharged with favorable functional outcome (57.1% versus 32.7%) than patients initially shocked by emergency medical services. After adjusting for known predictors of outcome, the odds ratio associated with a bystander shock was 2.62 (95% confidence interval, 2.07–3.31) for survival to hospital discharge and 2.73 (95% confidence interval, 2.17–3.44) for discharge with favorable functional outcome. The benefit of bystander shock increased progressively as emergency medical services response time became longer.

Conclusions:
Bystander automated external defibrillator use before emergency medical services arrival in shockable observed public OHCA was associated with better survival and functional outcomes. Continued emphasis on public automated external defibrillator utilization programs may further improve outcomes of OHCA.
Global Distribution of Snow Precipitation Features and Their Properties from 3 Years of GPM Observations
Authors: Adhikari Abishek , Liu Chuntao , Kulie Mark S. 
Published: February 2018

Abstract
Using a 3-yr Global Precipitation Mission (GPM) Ku-band Precipitation Radar (KuPR) dataset, snow features (SFs) are defined by grouping the contiguous area of nonzero solid precipitation. The near-surface wet bulb temperatures calculated from ERA-Interim reanalysis data are used to verify that SFs are colder than 1°C to omit snowfall that melts before reaching the surface. The properties of SFs are summarized to understand the global distribution and characteristics of snow systems. The seasonal and diurnal variations of SFs and their properties are analyzed over Northern and Southern Hemispheric land and ocean separately.
To quantify the amount of snow missed by the GPM KuPR and the amount of snow underestimated by the CloudSat Cloud Profiling (CPR), 3-yr KuPR pixel-level data are compared with 4-yr CloudSat CPR observations. The overall underestimation of snowfall during heavy snow events by CPR is less than 3% compared to the combined CPR and KuPR estimates. KuPR underestimates about 52% of weak snow. Only a small percentage of SFs have sizes greater than 10 000 km2 (0.35%), maximum near-surface reflectivity above 30 dBZ (5.1%), or echo top above 5 km (1.6%); however, they contribute 40%, 49.5%, or 30.4% of the global volumetric snow detected by KuPR. Snow in the Northern Hemisphere has stronger diurnal and seasonal variation compared to the Southern Hemisphere. Most of the SFs over the ocean are found with relatively smaller, less intense, and shallower echo tops than over land.
A Coupled Ice Sheet–Sea Level Model Incorporating 3D Earth Structure: Variations in Antarctica during the Last Deglacial Retreat
Authors: Gomez Natalya , Latychev Konstantin , Pollard David 
Published: February 2018

Abstract
A gravitationally self-consistent, global sea level model with 3D viscoelastic Earth structure is interactively coupled to a 3D dynamic ice sheet model, and the coupled model is applied to simulate the evolution of ice cover, sea level changes, and solid Earth deformation over the last deglaciation, from 40 ka to the modern. The results show that incorporating lateral variations in Earth’s structure across Antarctica yields local differences in the modeled ice history and introduces significant uncertainty in estimates of both relative sea level change and modern crustal motions through the last deglaciation. An analysis indicates that the contribution of glacial isostatic adjustment to modern records of sea level change and solid Earth deformation in regions of Antarctica underlain by low mantle viscosity may be more sensitive to ice loading during the late Holocene than across the last deglaciation.
Charge in Long-Lasting El Niño Events by Convection-Induced Wind Anomalies over the Western Pacific in Boreal Spring
Authors: Li Zhenning , Yang Song , Hu Xiaoming , Dong Wenjie , He Bian 
Published: February 2018

Abstract
In this study, El Niño events are classified as long El Niño (LE) events and short El Niño (SE) events based on their durations, and the characteristics of the early stages of these events are investigated. Results indicate that LE events tend to start earlier compared to SE events, initiating in boreal spring and peaking in winter. Their early occurrence is attributed to the western equatorial Pacific (WEP) sea surface wind anomalies that benefit the eastward propagation of warm water by forcing the downwelling Kelvin waves. It is also found that the wind anomalies are potentially induced by the convection anomalies over the WEP in spring. Experiments with a fully coupled climate model forced by convection heating anomalies over the WEP show that El Niño events become stronger and longer after introducing anomalous convection heating. The convection anomalies induce an extensive anomalous westerly belt over the WEP, which charges El Niño by eastward-propagating Kelvin waves. Moreover, induced by the anomalously northward-shifted ITCZ heating and the suppressed heating over the Maritime Continent, the equatorially asymmetric westerly belt reduces the meridional shear of mean easterly wind in the lower latitudes, which maintains an anomalous equatorward Sverdrup transport and in turn prolongs the persistence of El Niño events. A case study of the 2015/16 super El Niño and a regression study by using a rainfall index in critical regions support the above results.