bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons
Authors: Koethe John R. , McDonnell Wyatt , Kennedy Arion , Abana Chike O. , Pilkinton Mark , Setliff Ian , Georgiev Ivelin , Barnett Louise , Hager Cindy C. , Smith Rita , Kalams Spyros A. , Hasty Alyssa , Mallal Simon 
Published: October 2017

Background:
Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially proinflammatory T-cell populations in adipose tissue among persons on long-term antiretroviral therapy and assess whether adipose tissue CD8+ T cells represent an expanded, oligoclonal population.

Methods:
We recruited 10 HIV-infected, non-diabetic, overweight or obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression. We collected fasting blood and subcutaneous abdominal adipose tissue to measure the percentage of CD4+ and CD8+ T cells expressing activation, exhaustion, late differentiation/senescence, and memory surface markers. We performed T-cell receptor (TCR) sequencing on sorted CD8+ cells. We compared the proportion of each T-cell subset and the TCR repertoire diversity, in blood versus adipose tissue.

Results:
Adipose tissue had a higher percentage of CD3+CD8+ T cells compared with blood (61.0% vs. 51.7%, P < 0.01) and was enriched for both activated CD8+HLA-DR+ T cells (5.5% vs. 0.9%, P < 0.01) and late-differentiated CD8+CD57+ T cells (37.4% vs. 22.7%, P < 0.01). Adipose tissue CD8+ T cells displayed distinct TCRβ V and J gene usage, and the Shannon Entropy index, a measure of overall TCRβ repertoire diversity, was lower compared with blood (4.39 vs. 4.46; P = 0.05).

Conclusions:
Adipose tissue is enriched for activated and late-differentiated CD8+ T cells with distinct TCR usage. These cells may contribute to tissue inflammation and impaired adipocyte fitness in HIV-infected persons.
Proof of Concept Study for the Design, Manufacturing, and Testing of a Patient-Specific Shape Memory Device for Treatment of Unicoronal Craniosynostosis
Authors: Borghi Alessandro , Rodgers Will , Schievano Silvia , Ponniah Allan , Jeelani Owase , Dunaway David 
Published: October 2017

Abstract
Treatment of unicoronal craniosynostosis is a surgically challenging problem, due to the involvement of coronal suture and cranial base, with complex asymmetries of the calvarium and orbit. Several techniques for correction have been described, including surgical bony remodeling, early strip craniotomy with orthotic helmet remodeling and distraction. Current distraction devices provide unidirectional forces and have had very limited success. Nitinol is a shape memory alloy that can be programmed to the shape of a patient-specific anatomy by means of thermal treatment.
In this work, a methodology to produce a nitinol patient-specific distractor is presented: computer tomography images of a 16-month-old patient with unicoronal craniosynostosis were processed to create a 3-dimensional model of his skull and define the ideal shape postsurgery. A mesh was produced from a nitinol sheet, formed to the ideal skull shape and heat treated to be malleable at room temperature. The mesh was afterward deformed to be attached to a rapid prototyped plastic skull, replica of the patient initial anatomy. The mesh/skull construct was placed in hot water to activate the mesh shape memory property: the deformed plastic skull was computed tomography scanned for comparison of its shape with the initial anatomy and with the desired shape, showing that the nitinol mesh had been able to distract the plastic skull to a shape close to the desired one.
The shape-memory properties of nitinol allow for the design and production of patient-specific devices able to deliver complex, preprogrammable shape changes.
The Pantheon Variant of the Classic Cathedral Dome Procedure for Parieto-Occipital Skull Deformities
Authors: Eibach Sebastian , Le Hop N. , Zovickian John , Pang Dachling 
Published: October 2017

Objective:
To describe a new technique for the reconstruction of parieto-occipital skull deformities.

Methods and Results:
The technique is a variant of the previously described “cathedral dome procedure” used for frontal skull deformities. The authors apply the same principle of remodeling by making meridional slat craniotomies surrounding the depressed dome of the posterior skull deformity, followed by “green-stick fracture-reshaping” of the meridional slats to elevate and support the excised depressed dome. The authors present an illustrative patient with a follow-up of 2 years and an excellent cosmetic result.

Conclusion:
The authors introduce a new operative technique for the reconstruction of parieto-occipital skull deformities with excellent long-term results. The freshly reconstructed occiput resembles the dome of the pantheon in Rome, Italy, whose unique features inspired us to name this procedure the “Pantheon” variant of the cathedral dome operation.
Untreated Relative Hypotension Measured as Perfusion Pressure Deficit During Management of Shock and New-Onset Acute Kidney Injury—A Literature Review
Authors: Panwar Rakshit 
Published: October 2017

ABSTRACT
Maintaining an optimal blood pressure (BP) during shock is a fundamental tenet of critical care. Optimal BP targets may be different for different patients. In current practice, too often, uniform BP targets are pursued which may result in inadvertently accepting a degree of untreated relative hypotension, i.e., the deficit between patients’ usual premorbid basal BP and the achieved BP, during vasopressor support. Relative hypotension is a common but an under-recognized and an under-treated sign among patients with potential shock state. From a physiological perspective, any relative reduction in the net perfusion pressure across an organ (e.g., renal) vasculature has a potential to overwhelm autoregulatory mechanisms, which are already under stress during shock. Such perfusion pressure deficit may consequently impact organs’ ability to function or recover from an injured state. This review discusses such pathophysiologic mechanisms in detail with a particular focus on the risk of new-onset acute kidney injury (AKI). To review current literature, databases of Medline, Embase, and Google scholar were searched to retrieve articles that either adjusted BP targets based on patients’ premorbid BP levels or considered relative hypotension as an exposure endpoint and assessed its association with clinical outcomes among acutely ill patients. There were no randomized controlled trials. Only seven studies could be identified and these were reviewed in detail. These studies indicated a significant association between the degree of relative hypotension that was inadvertently accepted in real-world practice and new-onset organ dysfunction or subsequent AKI. However, this is not a high-quality evidence. Therefore, well-designed randomized controlled trials are needed to evaluate whether adoption of individualized BP targets, which are initially guided by patient's premorbid basal BP and then tailored according to clinical response, is superior to conventional BP targets for vasopressor therapy, particularly among patients with vasodilatory shock states.
Has molecular imaging delivered to drug development?
Authors: Murphy Philip S. , Patel Neel , McCarthy Timothy J. 
Published: October 2017

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact.
This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Phosphate starvation induces replacement of phospholipids with the betaine lipid diacylglycerol-N,N,N-trimethylhomoserine in the human fungal pathogenCandida albicans
Authors: Naik Surabhi , Cahoon Rebecca , Tripp Bridget , Elowsky Christian , Alvarez Sophie , Liu Kan , Zhang Chi , Riekhof Wayne 
Published: October 2017

AbstractWe have previously demonstrated that phosphate starvation induces replacement of phosphatidylcholine with the betaine lipid diacylglyceryl-N,N,N-trimethylhomoserine (DGTS) in fungi. InNeurospora crassa, theBTA1gene encodes the betaine lipid synthase, which is necessary and sufficient for DGTS synthesis. BTA1 expression and DGTS accumulation are part of the fungal phosphorus (Pi) deprivation (PHO) regulon, mediated by the NUC-1/Pho4p transcription factor. We now demonstrate that the human pathogenCandida albicansencodes aBTA1ortholog (CaBTA1), which is activated during Piscarcity. TheCaBTA1 gene is also induced under certain biofilm-promoting conditions independent of Pistarvation. RNA-seq and qRT-PCR showed a significant increase inCaBTA1 expression in response to Pilimitation. Thin-layer chromatography and LC-ESI-MS/MS confirmed the replacement of PC with DGTS in wild-type under low Piand showed the absence of DGTS in thebta1ΔΔmutant.Pilimitation in the gut of critically ill patients also triggers the switching ofC. albicansinto an invasive filamentous form. To assess the role of BTA1 and DGTS in the pathogenicity ofC. albicans in vitro, we compared the growth and morphology ofbta1ΔΔand wild type in hyphaeinducing media and observed defects in biofilm formation and invasive growth in thebta1ΔΔmutant. This observation is complemented by RNA-seq data demonstrating that Pistarvation in planktonicC. albicanscells induces the expression of virulence-associated cell surface proteins. Taken together, these results show novel functional interactions between lipid metabolism and remodeling, biofilm formation, and the phosphate starvation response ofC. albicans.
Ade novomissense mutation inTUBA1Aresults in reduced neural progenitor survival and differentiation
Authors: Driver Ashley M. , Pitstick Amy L. , Mayhew Chris N. , Kline-Fath Beth , Saal Howard M. , Stottmann Rolf W. 
Published: October 2017

ABSTRACTMutations in tubulins have been implicated in numerous human neurobiological disorders collectively known as “tubulinopathies.” We identified a patient with severe cortical dysgenesis and a novelde novoheterozygous missense mutation inTubulin Alpha 1a(TUBA1A, c.1225 G>T). Induced pluripotent stem cells derived from this individual were differentiated into two dimensional neural rosette clusters to identify underlying mechanisms for the severe cortical dysgenesis phenotype. Patient-derived clones showed evidence of impaired neural progenitor survival and differentiation with abnormal neural rosette formation, increases in cell death, and fewer post-mitotic neurons. These features correlate with the drastically underdeveloped cortical tissues seen in the proband. This is the first experimental evidence in human tissue suggesting a mechanism underlying the role forTUBA1Ain cortical development.SUMMARY STATEMENTVariants in tubulin genes often lead to severe congenital brain malformations. Here we identify a new mutation inTUBA1Aand use iPSCS to show this alters proliferation, differentiation and survival of neural progenitors.
Homeostatic feedback modulates the development of two-state patterned activity in a model serotonin motor circuit inCaenorhabditis elegans
Authors: Ravi Bhavya , Garcia Jessica , Collins Kevin M. 
Published: October 2017

AbstractNeuron activity accompanies synapse formation and maintenance, but how early circuit activity contributes to behavior development is not well understood. Here, we use theCaenorhabditis elegansegg-laying motor circuit as a model to understand how coordinated cell and circuit activity develops and drives a robust two-state behavior in adults. Using calcium imaging in behaving animals, we find the serotonergic Hermaphrodite Specific Neurons (HSNs) and vulval muscles show rhythmic calcium transients in L4 larvae before eggs are produced. HSN activity in L4 is tonic and lacks the alternating burst-firing/quiescent pattern seen in egg-laying adults. Vulval muscle activity in L4 is initially uncoordinated but becomes synchronous as the anterior and posterior muscle arms meet at HSN synaptic release sites. However, coordinated muscle activity does not require presynaptic HSN input. Using reversible silencing experiments, we show that neuronal and vulval muscle activity in L4 is not required for the onset of adult behavior. Instead, the accumulation of eggs in the adult uterus renders the muscles sensitive to HSN input. Sterilization or acute electrical silencing of the vulval muscles inhibits presynaptic HSN activity, and reversal of muscle silencing triggers a homeostatic increase in HSN activity and egg release that maintains ~12-15 eggs in the uterus. Feedback of egg accumulation depends upon the vulval muscle postsynaptic terminus, suggesting a retrograde signal sustains HSN synaptic activity and egg release. Our results show that egg-laying behavior inC. elegansis driven by a homeostat that scales serotonin motor neuron activity in response to postsynaptic muscle feedback.Significance StatementThe functional importance of early, spontaneous neuron activity in synapse and circuit development is not well understood. Here we show that in the nematodeC. elegans, the serotonergic Hermaphrodite Specific Neurons (HSNs) and postsynaptic vulval muscles show activity during circuit development, well before the onset of adult behavior. Surprisingly, early activity is not required for circuit development or the onset of adult behavior, and the circuit remains unable to drive egg laying until fertilized embryos are deposited into the uterus. Egg accumulation potentiates vulval muscle excitability, but ultimately acts to promote burst firing in the presynaptic HSNs during which eggs are laid. Our results suggest that mechanosensory feedback acts at three distinct steps to initiate, sustain, and terminateC. elegansegg-laying circuit activity and behavior.
Virulence evolution of a parasite infecting male and female hosts
Authors: Wardlaw Alison M. , Agrawal Aneil F. 
Published: October 2017

AbstractParasites experience different tradeoffs between transmission and virulence in male and female hosts if the sexes vary in life history or disease-related traits. We determine the evolutionarily stable levels of exploitation by pathogens under two scenarios: an unconstrained pathogen that expresses different exploitation rates within each host type as well as a pathogen constrained to express the same exploitation rate in each sex. We show that an unconstrained horizontally-transmitted parasite evolves to express the same sex-specific exploitation rate within each sex as it would in a host population composed entirely of hosts with that sex’s resistance and intrinsic death rate. In contrast, the ESS exploitation rate of a constrained pathogen is affected by sex-differences in susceptibility and non-random contact patterns between host types that differ in resistance. As the amount of within-sex transmission increases, the ESS shifts closer to the optimum trait value in the more susceptible sex. Allowing for some degree of vertical transmission, the exploitation rate expressed in females (but not males) changes with contact pattern even in unconstrained pathogens. Differences in contact pattern and susceptibility play an important role in determining the ESS exploitation rate by shifting the reproductive value of each host type.
sigQC: A procedural approach for standardising the evaluation of gene signatures
Authors: Dhawan Andrew , Barberis Alessandro , Cheng Wei-Chen , Domingo Enric , West Catharine , Maughan Tim , Scott Jacob G. , Harris Adrian L. , Buffa Francesca M. 
Published: October 2017

AbstractWith the increase in next generation sequencing generating large amounts of genomic data, gene expression signatures are becoming critically important tools, poised to make a large impact on the diagnosis, management and prognosis for a number of diseases. Increasingly, it is becoming necessary to determine whether a gene expression signature may apply to a dataset, but no standard quality control methodology exists. In this work, we introduce the first protocol, implemented in an R package sigQC, enabling a streamlined methodological and standardised approach for the quality control validation of gene signatures on independent data sets. The emphasis in this work is in showing the critical quality control steps involved in the generation of a clinically and biologically useful, transportable gene signature, including ensuring sufficient expression, variability, and autocorrelation of a signature. We demonstrate the application of the protocol in this work, showing how the outputs created from sigQC may be used for the evaluation of gene signatures on large-scale gene expression data in cancer.
Slower environmental change hinders adaptation from standing genetic variation
Authors: Guzella Thiago S. , Dey Snigdhadip , Chelo Ivo M. , Pino-Querido Ania , Pereira Veronica F. , Proulx Stephen R. , Teotónio Henrique 
Published: October 2017

AbstractEvolutionary responses to environmental change depend on the time available for adaptation before environmental degradation leads to extinction. Explicit tests of this relationship are limited to microbes where adaptation depends on the order of mutation accumulation, excluding standing genetic variation which is key for most natural species. When adaptation is determined by the amount of heritable genotype-by-environment fitness variance then genetic drift and/or maintenance of similarly fit genotypes may deter adaptation to slower the environmental changes. To address this hypothesis, we perform experimental evolution with self-fertilizing populations of the nematode Caenorhabditis elegans and develop a new inference model that follows pre-existing genotypes to describe natural selection in changing environments. Under an abrupt change, we find that selection rapidly increases the frequency of genotypes with high fitness in the most extreme environment. In contrast, under slower environmental change selection favors those genotypes that are worse at the most extreme environment. We further demonstrate with a second set of evolution experiments that, as a consequence of slower environmental change, population bottlenecks and small population sizes lead to the loss of beneficial genotypes, while maintenance of polymorphism impedes their fixation in large populations. Taken together, these results indicate that standing variation for genotype-by-environment fitness interactions alters the pace and outcome of adaptation under environmental change.
Atmospheric CO2availability does not equate to increased nodularin production in diazotrophic cyanobacteria, but does induce varying responses in net photosynthesis and N2fixation rates
Authors: Wannicke Nicola , Gehringer Michelle M. 
Published: October 2017

AbstractIncreasing levels of CO2in the atmosphere are suggested to favour increased incidences of cyanobacterial blooms in water bodies, with a potential concomitant increase in toxin production. As nitrogen fixing cyanobacteria are independent of nitrate and ammonium, this pilot study investigated whether elevated atmospheric CO2levels (eCO2), could increase toxin production and net photosynthesis (NP) rates in both terrestrial and aquatic diazotrophic cyanobacteria. Both toxin and non-toxin producing strains ofNostocandNodulariawere grown at present atmospheric levels (PAL) of CO2or near future elevated (eCO2) and net photosynthesis (NP) determined. Short term responses demonstrated CO2associated increases and decreases in NP, withN. harveyanaSAG44.85 showing little change in its NP at eCO2. Long term responses recorded increases in NP for all species in response to eCO2, except forN. harveyanaon day 7. Nitrogen fixation rates were significantly higher by approx. 10 fold in the aquaticNodulariaspecies compared to the terrestrialNostocspecies tested. Moreover, nitrogen fixation rates were not significantly higher at eCO2, except forN. harveyana. There was no direct correlation between increased nodularin production and eCO2in neither aquatic, nor terrestrial nodularin producing species, however there was a significant correlation between nodularin content and POC:PON ratio for the terrestrialNostocsp. 73.1 not observed for the aquaticNodularia spumigenaCCY9414.
Super-Resolution Ultrasound Bubble Tracking for Preclinical and Clinical Multiparametric Tumor Characterization
Authors: Opacic Tatjana , Dencks Stefanie , Theek Benjamin , Piepenbrock Marion , Ackermann Dimitri , Rix Anne , Lammers Twan , Stickeler Elmar , Delorme Stefan , Schmitz Georg , Kiessling Fabian 
Published: October 2017

AbstractSuper-resolution imaging methods promote tissue characterization beyond the spatial resolution limits of the devices and bridge the gap between histopathological analysis and non-invasive imaging. Here, we introduce Ultrasound Bubble Tracking (UBT) as an easily applicable and robust new tool to morphologically and functionally characterize fine vascular networks in tumors at super-resolution. In tumor-bearing mice and for the first time in patients, we demonstrate that within less than one minute scan time UBT can be realized using conventional preclinical and clinical ultrasound devices. In this context, next to highly detailed images of tumor microvascularization and the reliable quantification of relative blood volume and perfusion, UBT provides access to multiple new functional and morphological parameters that showed superior performance in discriminating tumors with different vascular phenotypes. Furthermore, our initial clinical results indicate that UBT is a highly translational technology with strong potential for the multiparametric characterization of tumors and the assessment of therapy response.