bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional imaging of tumor vasculature using iodine and gadolinium-based nanoparticle contrast agents: a comparison of spectral micro-CT using energy integrating and photon counting detectors
Authors: Badea C T , Clark D P , Holbrook M , Srivastava M , Mowery Y , Ghaghada K B 
Published: February 2019

Abstract
Advances in computed tomography (CT) hardware have propelled the development of novel CT contrast agents. In particular, the spectral capabilities of x-ray CT can facilitate simultaneous imaging of multiple contrast agents. This approach is particularly useful for functional imaging of solid tumors by simultaneous visualization of multiple targets or architectural features that govern cancer development and progression. Nanoparticles are a promising platform for contrast agent development. While several novel imaging moieties based on high atomic number elements are being explored, iodine (I) and gadolinium (Gd) are particularly attractive because of their existing approval for clinical use. In this work, we investigate the in vivo discrimination of I and Gd nanoparticle contrast agents using both dual energy micro-CT with energy integrating detectors (DE-EID) and photon counting detector (PCD)-based spectral micro-CT. Simulations and phantom experiments were performed using varying concentrations of I and Gd to determine the imaging performance with optimized acquisition parameters. Quantitative spectral micro-CT imaging using liposomal-iodine (Lip-I) and liposomal-Gd (Lip-Gd) nanoparticle contrast agents was performed in sarcoma bearing mice for anatomical and functional imaging of tumor vasculature. Iterative reconstruction provided high sensitivity to detect and discriminate relatively low I and Gd concentrations. According to the Rose criterion applied to the experimental results, the detectability limits for I and Gd were approximately 2.5 mg ml−1 for both DE-EID CT and PCD micro-CT, even if the radiation dose was approximately 3.8 times lower with PCD micro-CT. The material concentration maps confirmed expected biodistributions of contrast agents in the blood, liver, spleen and kidneys. The PCD provided lower background signal and better simultaneous visualization of tumor vasculature and intratumoral distribution patterns of nanoparticle contrast agent compared to DE-EID decompositions. Preclinical spectral CT systems such as this could be useful for functional characterization of solid tumors, simultaneous quantitative imaging of multiple targets and for identifying clinically-relevant applications that benefit from the use of spectral imaging. Additionally, it could aid in the development nanoparticles that show promise in the developing field of cancer theranostics (therapy and diagnostics) by measuring vascular tumor biomarkers such as fractional blood volume and the delivery of liposomal chemotherapeutics.
Energy delocalization during dynamic rock fragmentation
Authors: Ghaffari H O , Griffith W A , Barber T J 
Published: February 2019

SUMMARYThe formation of fragments due to avalanche-like growth of damage under impulsive forces is a process central to numerous studies ranging from shaped charge jet break up and rock blasting to bolide impacts, and, more recently, earthquake rupture. In the latter case, pulverized rocks found millimetres to tens of metres from the principal slip zones of large faults have been associated with fast, even supershear, rupture propagation. It has been postulated that earthquake source characteristics directly affect the degree of fragmentation, and the study of fragment size distribution may shed light on the energy budget of individual earthquakes as well as long-term effects on fault zone properties. The actual fragmentation process, and the partitioning of dissipated energy at fast loading rates, however, is still enigmatic. We use modified Split Hopkinson Pressure Bar experiments, in which we can control stressing rate, amplitude and duration, as a laboratory analogue for the complex natural prototype source processes. In our experiments, we characterize the velocity distribution of ejected fragments from Westerly Granite specimens resulting in a range of fragmentation states, from weakly fragmented to pulverized. Analysis of the velocity distributions (and the related kinetic energy) reveals spatial domains that are free of ejected fragments; these so-called ‘zero kinetic energy modes’ are related to the fragmentation state: increasing fragmentation corresponds to a reduction of zero mode domains. The evolution of these zero modes with strain rate reveals that the transition from low strain rate fracturing to high strain rate pulverization is a smooth, continuous transition, rather than a sharp boundary. Furthermore, our results yield important insights into the process of fragmentation in earthquake process zones, including how dissipated energy is partitioned during fragmentation, and indicate that delocalization of energy is systematically coupled with source parameters.
Estimating risk of encapsulating peritoneal sclerosis accounting for the competing risk of death
Authors: Lambie Mark , Teece Lucy , Johnson David W , Petrie Michaela , Mactier Robert , Solis-Trapala Ivonne , Belcher John , Bekker Hilary L , Wilkie Martin , Tupling Ken , Phillips-Darby Louise , Davies Simon J 
Published: February 2019

AbstractBackgroundRisk of encapsulating peritoneal sclerosis (EPS) is strongly associated with the duration of peritoneal dialysis (PD), such that patients who have been on PD for some time may consider elective transfer to haemodialysis to mitigate the risk of EPS. There is a need to determine this risk to better inform clinical decision making, but previous studies have not allowed for the competing risk of death.MethodsThis study included new adult PD patients in Australia and New Zealand (ANZ; 1990–2010) or Scotland (2000–08) followed until 2012. Age, time on PD, primary renal disease, gender, data set and diabetic status were evaluated as predictors at the start of PD, then at 3 and 5 years after starting PD using flexible parametric competing risks models.ResultsIn 17 396 patients (16 162 ANZ, 1234 Scotland), EPS was observed in 99 (0.57%) patients, less frequently in ANZ patients (n = 65; 0.4%) than in Scottish patients (n = 34; 2.8%). The estimated risk of EPS was much lower when the competing risk of death was taken into account (1 Kaplan–Meier = 0.0126, cumulative incidence function = 0.0054). Strong predictors of EPS included age, primary renal disease and time on PD. The risk of EPS was reasonably discriminated at the start of PD (C-statistic = 0.74–0.79) and this improved at 3 and 5 years after starting PD (C-statistic = 0.81–0.92).ConclusionsEPS risk estimates are lower when calculated using competing risk of death analyses. A patient’s estimated risk of EPS is country-specific and can be predicted using age, primary renal disease and duration of PD.
Hypertonic Saline is Superior to Mannitol for the Combined Effect on Intracranial Pressure and Cerebral Perfusion Pressure Burdens in Patients With Severe Traumatic Brain Injury
Authors: Mangat Halinder S , Wu Xian , Gerber Linda M , Schwarz Justin T , Fakhar Malik , Murthy Santosh B , Stieg Philip E , Ghajar Jamshid , Härtl Roger 
Published: February 2019

Abstract

BACKGROUND
Hypertonic saline (HTS) and mannitol are effective in reducing intracranial pressure (ICP) after severe traumatic brain injury (TBI). However, their simultaneous effect on the cerebral perfusion pressure (CPP) and ICP has not been studied rigorously.

OBJECTIVE
To determine the difference in effects of HTS and mannitol on the combined burden of high ICP and low CPP in patients with severe TBI.

METHODS
We performed a case–control study using prospectively collected data from the New York State TBI-trac® database (Brain Trauma Foundation, New York, New York). Patients who received only 1 hyperosmotic agent, either mannitol or HTS for raised ICP, were included. Patients in the 2 groups were matched (1:1 and 1:2) for factors associated with 2-wk mortality: age, Glasgow Coma Scale score, pupillary reactivity, hypotension, abnormal computed tomography scans, and craniotomy. Primary endpoint was the combined burden of ICPhigh (> 25 mm Hg) and CPPlow (< 60 mm Hg).

RESULTS
There were 25 matched pairs for 1:1 comparison and 24 HTS patients matched to 48 mannitol patients in 1:2 comparisons. Cumulative median osmolar doses in the 2 groups were similar. In patients treated with HTS compared to mannitol, total number of days (0.6 ± 0.8 vs 2.4 ± 2.3 d, P < .01), percentage of days with (8.8 ± 10.6 vs 28.1 ± 26.9%, P < .01), and the total duration of ICPhigh + CPPlow (11.12 ± 14.11 vs 30.56 ± 31.89 h, P = .01) were significantly lower. These results were replicated in the 1:2 match comparisons.

CONCLUSION
HTS bolus therapy appears to be superior to mannitol in reduction of the combined burden of intracranial hypertension and associated hypoperfusion in severe TBI patients.
Phase dependence of response curves to stimulation and their relationship: from a Wilson-Cowan model to essential tremor patient data
Authors: Duchet Benoit , Weerasinghe Gihan , Cagnan Hayriye , Brown Peter , Bick Christian , Bogacz Rafal 
Published: February 2019

AbstractEssential tremor manifests predominantly as a tremor of the upper limbs. One therapy option is high-frequency deep brain stimulation, which continuously delivers electrical stimulation to the ventral intermediate nucleus of the thalamus at about 130 Hz. Investigators have been looking at stimulating less, chiefly to reduce side effects. One strategy, phase-locked deep brain stimulation, consists of stimulating according to the phase of the tremor, once per period. In this study, we aim to reproduce the phase dependent effects of stimulation seen in patient data with a biologically inspired Wilson-Cowan model. To this end, we first analyse patient data, and conclude that half of the datasets have response curves that are better described by sinusoidal curves than by straight lines, while an effect of phase cannot be consistently identified in the remaining half. Using the Hilbert phase we derive analytical expressions for phase and amplitude responses to phase-dependent stimulation and study their relationship in the linearisation of a stable focus model, a simplification of the Wilson-Cowan model in the stable focus regime. Analytical results provide a good approximation for response curves observed in patients with consistent significance. Additionally, we fitted the full non-linear Wilson-Cowan model to these patients, and we show that the model can fit in each case to the dynamics of patient tremor as well as the phase response curve, and the best fits are found to be stable foci for each patients (tied best fit in one instance). The model provides satisfactory prediction of how patient tremor will react to phase-locked stimulation by predicting patient amplitude response curves although they were not explicitly fitted. This can be partially explained by the relationship between the response curves in the model being compatible with what is found in the data. We also note that the non-linear Wilson-Cowan model is able to describe response to stimulation more precisely than the linearisation.
Label-free Method for Classification of T cell Activation
Authors: Walsh Alex J. , Mueller Katie , Jones Isabel , Walsh Christine M. , Piscopo Nicole , Niemi Natalie N. , Pagliarini David J. , Saha Krishanu , Skala Melissa C. 
Published: February 2019

AbstractT cells have a range of cytotoxic and immune-modulating functions, depending on activation state and subtype. However, current methods to assess T cell function use exogenous labels that often require cell permeabilization, which is limiting for time-course studies of T cell activation and non-destructive quality control of immunotherapies. Label-free optical imaging is an attractive solution. Here, we use autofluorescence imaging of NAD(P)H and FAD, co-enzymes of metabolism, to quantify optical imaging endpoints in quiescent and activated T cells. Machine learning classification models were developed for label-free, non-destructive determination of T cell activation state. T cells were isolated from the peripheral blood of human donors, and a subset were activated with a tetrameric antibody against CD2/CD3/CD28 surface ligands. NAD(P)H and FAD autofluorescence intensity and lifetime of the T cells were imaged using a multiphoton fluorescence lifetime microscope. Significant differences in autofluorescence imaging end-points were observed between quiescent and activated T cells. Feature selection methods revealed that the contribution of the short NAD(P)H lifetime (α1) is the most important feature for classification of activation state, across multiple donors and T cell subsets. Logistic regression models achieved 97-99% accuracy for classification of T cell activation from the autofluorescence imaging endpoints. Additionally, autofluorescence imaging revealed NAD(P)H and FAD autofluorescence differences between CD3+CD8+and CD3+CD4+T cells, and random forest models of the autofluorescence imaging endpoints achieved 97+% accuracy for four-group classification of quiescent and activated CD3+CD8+and CD3+CD4+T cells. Altogether these results indicate that autofluorescence imaging of NAD(P)H and FAD is a powerful method for label-free, non-destructive determination of T cell activation and subtype, which could have important applications for the treatment of cancer, autoimmune, infectious, and other diseases.
Hypertrophic cardiomyopathy mutations at the folded-back sequestered β-cardiac myosin S1-S2 and S1-S1 interfaces release sequestered heads and increase myosin enzymatic activity
Authors: Adhikari Arjun S. , Trivedi Darshan V. , Sarkar Saswata S. , Song Dan , Kooiker Kristina B. , Bernstein Daniel , Spudich James A. , Ruppel Kathleen M. 
Published: February 2019

AbstractHypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart. Nearly 40 percent of HCM-causing mutations are found in human β-cardiac myosin. Previous studies looking at the effect of HCM mutations on the force, velocity and ATPase activity of the catalytic domain of human β-cardiac myosin have not shown clear trends leading to hypercontractility at the molecular scale. Here we present functional data showing that four separate HCM mutations located at the myosin head-tail (R249Q, H251N) and head-head (D382Y, R719W) interfaces of a folded-back sequestered state referred to as the interacting heads motif lead to a significant increase in the number of heads functionally accessible for interaction with actin. These results provide evidence that HCM mutations can modulate myosin activity by disrupting intramolecular interactions within the proposed sequestered state, thereby leading to hypercontractility at the molecular level.
Impact of population structure in the design of RNA-based diagnostics for antibiotic resistance in Neisseria gonorrhoeae
Authors: Wadsworth Crista B. , Sater Mohamad R.A. , Bhattacharyya Roby P. , Grad Yonatan H. 
Published: February 2019

ABSTRACTQuantitative assessment of antibiotic-responsive RNA transcripts holds promise for a rapid point of care (POC) diagnostic tool for antimicrobial susceptibility testing. These assays aim to distinguish susceptible and resistant isolates by transcriptional differences upon drug exposure. However, an often-overlooked dimension of designing these tests is that the genetic diversity within a species may yield differential transcriptional regulation independent of resistance phenotype. Here, we use a phylogenetically diverse panel of Neisseria gonorrhoeae and transcriptome profiling coupled with RT-qPCR to test this hypothesis, to identify azithromycin responsive transcripts and evaluate their potential diagnostic value, and to evaluate previously reported diagnostic markers for ciprofloxacin resistance (porB and rpmB). Transcriptome profiling confirmed evidence of population structure in transcriptional response to azithromycin. Taking this population structure into account, we found azithromycin-responsive transcripts overrepresented in susceptible strains compared to resistant strains, and selected four candidate diagnostic transcripts (rpsO, rplN, omp3, and NGO1079) that were the most significantly differentially regulated between phenotypes across drug exposure. RNA signatures for these markers categorically predicted resistance in 19/20 cases, with the one incorrect categorical assignment for an isolate at the threshold of reduced susceptibility. Finally, we found that porB and rpmB expression were not diagnostic of ciprofloxacin resistance in a panel of isolates with unbiased phylogenetic sampling. Overall, our results suggest that RNA signatures as a diagnostic tool are promising for future POC diagnostics; however, development and testing should consider representative genetic diversity of the target pathogen.
Fetal stage melanopsin (OPN4) and GNAQ (Gαq) signaling regulates vascular development of the eye
Authors: Vemaraju Shruti , Nayak Gowri , Miller William E. , Copenhagen David R. , Lang Richard A. 
Published: February 2019

AbstractMaturation of sensory systems in mammals is regulated by appropriate sensory stimulation. Developmental refinement of the eye and visual system is regulated by light and visual stimulation. One compelling example is that fetal mouse pups deprived of light exhibit altered vascular development in their eyes. Previous work demonstrated that light activation of the photopigment melanopsin (Opn4), an atypical opsin expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs), is crucial to normal vascular development. This suggested the unusual hypothesis that vascular development of the eye was regulated by ipRGC responses in the fetal eye by light that traveled through the body wall of the mother. Here, we test the requirement of OPN4 during fetal stages using genetic approaches. The G-protein GNAQ (Gαq) is a candidate mediator of melanopsin signaling. We show that ipRGC-specific deletion of Gnaq phenocopies both hyaloid and retinal vascular development of the Opn4 null mouse. Furthermore, GNAQ gain-of-function in Opn4-expressing cells only during late gestation was sufficient to reverse the consequences for vascular development of either dark rearing or Opn4 loss-of-function. We conclude that melanopsin-dependent signaling in the fetal mouse eye is necessary and sufficient for vascular maturation.
Increasing molar activity by HPLC purification improves 68Ga-DOTA-NAPamide tumor accumulation in a B16/F1 melanoma xenograft model
Authors: Hacht Jan Lennart von , Erdmann Sarah , Niederstadt Lars , Prasad Sonal , Wagener Asja , Exner Samantha , Beindorff Nicola , Brenner Winfried , Grötzinger Carsten 
Published: February 2019

AbstractPurposeMelanocortin receptor 1 is overexpressed in melanoma and may be a molecular target for imaging and peptide receptor radionuclide therapy. 68Gallium labeling of DOTA-conjugated peptides is an established procedure in the clinic for use in positron emission tomography imaging. Aim of this study was to compare a standard labeling protocol against the 68Ga-DOTA peptide purified from the excess of unlabeled peptide.ProceduresThe MC1R ligand DOTA-NAPamide was labeled with 68Ga using a standard clinical protocol. Radioactive peptide was separated from the excess of unlabeled DOTA-NAPamide by HPLC. Immediately after the incubation of peptide and 68Ga (95 °C, 15 min), the reaction was loaded on a C18 column and separated by a water/acetonitrile gradient, allowing fractionation in less than 20 minutes. Radiolabeled products were compared in biodistribution studies and PET imaging using nude mice bearing MC1R-expressing B16/F1 xenograft tumors.ResultsIn biodistribution studies, the non-purified 68Ga-DOTA-NAPamide did not show significant uptake in the tumor at 1 h post injection (0.78% IA/g). By the additional HPLC step, the molar activity was raised around 10,000-fold by completely removing unlabeled peptide. Application of this rapid purification strategy led to a more than 8-fold increase in tumor uptake (7.0% IA/g). The addition of various amounts of unlabeled DOTA-NAPamide to the purified product led to a blocking effect and a decreased specific tumor uptake, similar to the result seen with non-purified radiopeptide. PET imaging was performed using the same tracers for biodistribution. Purified 68Ga-DOTA-NAPamide, in comparison, showed superior tumor uptake.ConclusionsWe demonstrated that chromatographic separation of radiolabeled from excess unlabeled peptide is technically feasible and beneficial, even for short-lived isotopes such as 68Ga. Unlabeled peptide molecules compete with receptor binding sites in the target tissue. Purification of the radiopeptide therefore improved tumor uptake.
Conformational and dynamical plasticity in substrate-binding proteins underlies selective transport in ABC importers
Authors: de Boer Marijn , Gouridis Giorgos , Vietrov Ruslan , Begg Stephanie L. , Schuurman-Wolters Gea K. , Husada Florence , Eleftheriadis Nikolaos , Poolman Bert , McDevitt Christopher A. , Cordes Thorben 
Published: February 2019

ABSTRACTSubstrate-binding proteins (SBPs) are associated with ATP-binding cassette importers and switch from an open-to a closed-conformation upon substrate binding providing specificity for transport. We investigated the effect of substrates on the conformational dynamics of six SBPs and the impact on transport. Using single-molecule FRET, we reveal an unrecognized diversity of plasticity in SBPs. We show that a unique closed SBP conformation does not exist for transported substrates. Instead, SBPs sample a range of conformations that activate transport. Certain non-transported ligands leave the structure largely unaltered or trigger a conformation distinct from that of transported substrates. Intriguingly, in some cases similar SBP conformations are formed by both transported and non-transported ligands. In this case, the inability for transport arises from slow opening of the SBP or the selectivity provided by the translocator. Our results reveal the complex interplay between ligand-SBP interactions, SBP conformational dynamics and substrate transport.
Conservation of N-hydroxy-pipecolic acid-mediated systemic acquired resistance in crop plants
Authors: Holmes Eric C. , Chen Yun-Chu , Sattely Elizabeth , Mudgett Mary Beth 
Published: February 2019

SUMMARYSignal propagation and the coordination of whole-organism responses in plants rely heavily on small molecules. Systemic acquired resistance (SAR) is one such process in which long-distance signaling activates immune responses in uninfected tissue as a way to limit the spread of a primary, localized infection. Recently, N-hydroxy pipecolic acid (NHP) was discovered and shown to coordinate SAR in Arabidopsis. Here, we provide metabolic and biochemical evidence that NHP is conserved across the plant kingdom and demonstrate a role for NHP in mediating SAR responses in tomato and pepper. We reconstituted the NHP biosynthetic pathway in planta and show that transient expression of two NHP biosynthetic genes in tomato induces enhanced resistance to a bacterial pathogen in distal tissue. Our results suggest engineering strategies to induce NHP-mediated SAR are a promising route to improve broad-spectrum pathogen resistance in crops.IN BRIEFEngineering NHP production is a promising strategy to enhance disease resistance in crops.HIGHLIGHTSArabidopsis N-hydroxy-pipecolic acid (NHP) pathway is conserved across the plant kingdomApplication of NHP to tomato and pepper plants induces a robust SAR responseMetabolic engineering of the Arabidopsis NHP pathway in Solanum lycopersicum leads to enhanced NHP production and defense primingGenetic engineering for enhanced NHP production is a promising strategy to protect crop plants from multiple pathogens