bluuebunny/crossref_metadata_2025_split huggingface dataset:
Free light chains of immunoglobulins in patients with systemic sclerosis: correlations with lung involvement and inflammatory milieu
Authors: Bosello Silvia , Basile Umberto , De Lorenzis Enrico , Gulli Francesca , Canestrari Giovanni , Napodano Cecilia , Parisi Federico , Pocino Krizia , Di Mario Clara , Tolusso Barbara , Ferraccioli Gianfranco , Gremese Elisa 
Published: July 2018

AimHumoral immunity and B cells are thought to play an important role in the pathophysiology of the systemic sclerosis (SSc). The production of free light chains (FLC) of immunoglobulins is abnormally high in several pathological autoimmune conditions and reflects B cell activation. Furthermore, FLCs demonstrated different biological activities including their capability to modulate the immune system, proteolytic activity and complement cascade activation. The aims of this study are to determine the FLC levels in patients with SSc compared with healthy controls (HC) and to study their possible association with organ involvement and disease characteristics.MethodsSixty-five patients with SSc and 20 HC were studied. Clinical and immunological inflammatory characteristics were assessed for all the patients with SSc. κ-FLC and λ-FLC, interleukin 6 (IL-6) and B cell activating factor levels were measured.ResultsThe mean serum κ-FLC levels and FLC ratio were significantly higher in patients with SSc compared with HC, while the serum λ-FLC levels were comparable.The levels of FLC were comparable in patients with diffuse skin disease and limited skin involvement, while κ-FLC levels were increased in patients with restrictive lung (forced vital capacity (FVC) <80%) disease (26.4±7.4 mg/L) when compared with patients with FVC ≥80% (19.6±7.3 mg/L, P=0.009). In patients with SSc, the levels of serum κ-FLC level directly correlated with the IL-6 levels (R=0.3, P=0.001) and disease activity (R=0.4, P=0.003).ConclusionsFLC levels are elevated in SSc and high levels are associated with lung involvement and with a higher degree of inflammation, supporting a possible role of B cell activation in the pathophysiology of the disease.
The South Tibetan Detachment System: history, advances, definition and future directions
Authors: Kellett Dawn A. , Cottle John M. , Larson Kyle P. 
Published: July 2018

Abstract
Recognition and subsequent study of the syn-convergent low-angle normal faults and shear zones – the South Tibetan Detachment System (STDS) – that form the upper boundary of the Himalayan mid-crust fundamentally changed views of how the Himalayan orogenic system developed. This paper reviews the past four decades of discovery and major advances in our understanding of the detachment system. Significantly conflicting maps of the fault trace, as well as proposed extensions of the detachment system up to hundreds of kilometres both up and down dip of the main fault trace, call for a unifying definition of the detachment system based on structural criteria. The different proposed models for the formation of the STDS during tectonic evolution of the Himalayan orogen are compared. Finally, critical outstanding questions about the origin, extent and character of the detachment system are identified and point to future directions for research.
A model of the rat medial gastrocnemius muscle based on inputs to motoneurons and on an algorithm for prediction of the motor unit force
Authors: Raikova R. , Celichowski J. , Angelova S. , Krutki P. 
Published: July 2018

The muscle force is the sum of forces of multiple motor units (MUs), which have different contractile properties. During movements, MUs develop unfused tetani, which result from summation of twitch-shape responses to individual stimuli, which are variable in amplitude and duration. The aim of the study was to develop a realistic muscle model that would integrate previously developed models of MU contractions and an algorithm for the prediction of tetanic forces. The proposed model of rat medial gastrocnemius muscle is based on physiological data: excitability and firing frequencies of motoneurons, contractile properties, and the number and proportion of MUs in the muscle. The MU twitches were modeled by a six-parameter analytical function. The excitability of motoneurons was modeled according to a distribution of their rheobase currents measured experimentally. Processes of muscle force regulation were modeled according to a common drive hypothesis. The excitation signal to motoneurons was modeled by two form types: triangular and trapezoid. The discharge frequencies of MUs, calculated individually for each MU, corresponded to those recorded for rhythmic firing of motoneurons. The force of the muscle was calculated as the sum of all recruited MUs. Participation of the three types of MUs in the developed muscle force was presented at different levels of the excitation signal to motoneurons. The model appears highly realistic and open for input data from various skeletal muscles with different compositions of MU types. The results were compared with three other models with different distribution of the input parameters.NEW & NOTEWORTHY The proposed mathematical model of rat medial gastrocnemius muscle is highly realistic because it is based strictly on experimentally determined motor unit contractile parameters and motoneuron properties. It contains the actual number and proportion of motor units and takes into consideration their different contributions to the whole muscle force, depending on the level of the excitation signal. The model is open for input data from other muscles, and additional physiological parameters can also be included.
CRISPR–Cas13 Precision Transcriptome Engineering in Cancer
Authors: Granados-Riveron Javier T. , Aquino-Jarquin Guillermo 
Published: July 2018

Abstract
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated genes (Cas) system has been rapidly harnessed to perform various genomic engineering tasks. Recently, it has been demonstrated that a novel RNA-targeting CRISPR effector protein, called Cas13, binds and cleaves RNA rather than DNA substrates analogously to the eukaryotic RNA interference system. The known Cas13a–Cas13d effectors are able to efficiently cleave complementary target single-stranded RNAs, which represent a potentially safer alternative to deoxyribonuclease Cas9, because it induces loss-of-function phenotypes without genomic loss of the targeted gene. Furthermore, through the improvement in Cas13 effector functionalities, a system called REPAIR has been developed to edit full-length transcripts containing pathogenic mutations, thus providing a promising opportunity for precise base editing. Moreover, advanced engineering of this CRISPR effector also permits nucleic acid detection, allowing the identification of mutations in cell-free tumor DNA through a platform termed Specific High Sensitivity Enzymatic Reporter Unlocking. All of these properties give us a glimpse about the potential of the CRISPR toolkit for precise transcriptome engineering, possibly leading to an expansion of CRISPR technologies for cancer therapeutics and diagnostics. Here, we examine previously unaddressed aspects of the CRISPR-based RNA-targeting approach as a feasible strategy for globally interrogating gene function in cancer in a programmable manner. Cancer Res; 78(15); 4107–13. ©2018 AACR.
A Novel, Fully Human Anti–fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer
Authors: Ponath Paul , Menezes Daniel , Pan Chin , Chen Bing , Oyasu Miho , Strachan Debbie , LeBlanc Heidi , Sun Huadong , Wang Xi-Tao , Rangan Vangipuram S. , Deshpande Shrikant , Cristea Sandra , Park Kwon-Sik , Sage Julien , Cardarelli Pina M. 
Published: July 2018

Abstract
Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1.
Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors.
Results: BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012–mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti–PD-1 or anti-CD137 antibody, therapeutic responses significantly improved.
Conclusions: Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. Clin Cancer Res; 24(20); 5178–89. ©2018 AACR.
Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo
Authors: Kumar Dileep , Rahman Hafeez , Tyagi Ethika , Liu Tong , Li Chelsea , Lu Ran , Lum David , Holmen Sheri L. , Maschek J. Alan , Cox James E. , VanBrocklin Matthew W. , Grossman Douglas 
Published: July 2018

Abstract
There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E2 (PGE2) production and activate 5′-adenosine monophosphate–activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) in vitro at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE2 or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE2 levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE2 in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE2 and activation of AMPK and reduces growth of some melanoma tumors in vivo. This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans. Cancer Prev Res; 11(10); 629–42. ©2018 AACR.
Recurrent Urinary Tract Infections in Women: What Is the Evidence for Investigating with Flexible Cystoscopy, Imaging and Urodynamics?
Authors: Santoni Nicola , Ng Angela , Skews Rachel , Aboumarzouk Omar M. 
Published: July 2018

<b><i>Background/Aims/Objectives:</i></b> Women with recurrent urinary tract infections (UTIs) are commonly referred to urology outpatient clinics. However, there is no clear consensus in existing guidelines as to if, or how, these should be investigated. The primary outcome was to evaluate all available literature to determine the percentage of abnormal findings in non-pregnant women with recurrent simple UTIs. Secondary outcomes were to determine the percentage that were serious, consequential or incidental findings. <b><i>Methods:</i></b> A full literature search was performed of the following databases: MEDLINE; Pubmed; Cochrane Central Register of Controlled Trials-CENTRAL; and ClinicalTrials.gov. Two assessors reviewed the articles independently. Any discrepancy was discussed and an agreement reached. <b><i>Results:</i></b> The literature search yielded 662 titles; 652 were excluded on initial review. A further 13 studies were gathered from references of yielded papers. After full review, 12 were included for analysis. These showed that &#x3c; 1.5% of women investigated for recurrent simple UTIs with imaging or flexible cystoscopy had life-threatening pathology, but up to 67% had abnormal urodynamics. <b><i>Conclusions:</i></b> Women presenting with simple recurrent UTIs should have a flow rate and post-void residual measured. Cystoscopy is not warranted and imaging is unlikely to be of value in the absence of symptoms of upper tract disease or gynaecological problems.
The Effects of Pitch, Gender, and Prosodic Context on the Identification of Creaky Voice
Authors: Davidson Lisa 
Published: July 2018

AbstractBackground/Aims: Creaky voice in American English plays both a prosodic role, as a phrase-final marker, and a sociolinguistic one, but it is unclear how accurately naïve listeners can identify creak, and what factors facilitate or hinder ist identification. Methods: In this study, American listeners are presented with 2 experiments containing stimuli from both high- and low-pitched male and female speakers. Other manipulations include whether the auditory stimulus is a full sentence or a sentence fragment, and whether it is completely modally voiced, completely creaky, or partially creaky (final 40-50% of the utterance). Results: Accuracy is lowest on partial creak, suggesting that creaky voice is least salient when it serves as an utterance-final marker. There are no strong gender effects aside from a weak tendency to identify creak more often in females than males in the whole creak condition in one experiment. In contrast, when no creak is present, listeners false alarm on the low-pitched males. Conclusion: Rates of identifying creak in male and female speakers are similar, suggesting that listeners have a comparable ability to hear creaky voice in all speakers.
F0Timing and Tone Contrasts in Luganda
Authors: Myers Scott , Namyalo Saudah , Kiriggwajjo Anatole 
Published: July 2018

AbstractScholars of Luganda (Bantu, Uganda) have described a contrast between falling and high tone, which is limited to syllables with a long vowel or a coda. The contrast has been represented with H on the first mora of a falling-tone syllable and on both moras in a high-tone syllable. This article explores this contrast through an instrumental study of the timing of f<sub>0</sub> events in Luganda. It was found that the 2-tone classes differed in the timing of both the f<sub>0</sub> rise and the subsequent f<sub>0</sub> fall, supporting a reanalysis of the contrast as one between an early high tone and a late high tone. It was also found that for the speakers in this study, the contrast was limited to syllables with long vowels. The timing of f<sub>0</sub> events was sensitive to the duration of segments in the CVC interval centered on the high-toned syllable, including non-moraic elements and consonants outside the syllable. The association of a tone to a syllable identifies the segments relevant for the timing of the f<sub>0</sub> contour, but that timing is not directly sensitive to the interval of the syllable.
Cardiomyopathy and Preeclampsia
Authors: Gammill Hilary S. , Chettier Rakesh , Brewer Alina , Roberts James M. , Shree Raj , Tsigas Eleni , Ward Kenneth 
Published: July 2018

Background:
Preeclampsia is associated with diastolic dysfunction, peripartum cardiomyopathy, and both pre-existing and subsequent maternal cardiovascular disease. Gene mutations causing idiopathic cardiomyopathy were recently implicated in peripartum cardiomyopathy. We sought to determine whether cardiomyopathy gene mutations are also a contributory factor in preeclampsia.

Methods:
Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of preeclampsia completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with cardiomyopathy. Missense variants were deemed damaging missense if so classified by any of 7 standard function prediction algorithms. Variants were defined as loss-of-function if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from 2 control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33 000 subjects in the Exome Aggregation Consortium. Preeclampsia was not excluded in control groups.

Results:

Of 181 subjects with confirmed preeclampsia, 96% were white. Seventy-two percent had ≥1 preterm preeclampsia delivery <37 weeks. Among preeclampsia subjects, whole exome sequencing demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 cardiomyopathy genes considered. The prevalence of these loss-of-function variants was significantly higher in preeclampsia subjects (5.5%) compared with the local control (2.5%) population (
P
=0.014). Sixty-eight percent of women with preeclampsia carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum cardiomyopathy, most mutations (55%) were found in the TTN gene. Seventy-three percent of preeclampsia subjects had TTN mutations in the preeclampsia cohort versus 48% in local controls (
P
=1.36E-11).

Discussion:
Women who develop preeclampsia are more likely to carry protein-altering mutations in genes associated with cardiomyopathy, particularly in TTN. Mutations promoting cardiomyopathy are prevalent in preeclampsia, idiopathic cardiomyopathy, and peripartum cardiomyopathy, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.
Lipoprotein Particle Profiles, Standard Lipids, and Peripheral Artery Disease Incidence
Authors: Aday Aaron W. , Lawler Patrick R. , Cook Nancy R. , Ridker Paul M , Mora Samia , Pradhan Aruna D. 
Published: July 2018

Background:
Despite strong and consistent prospective associations of elevated low-density lipoprotein (LDL) cholesterol concentration with incident coronary and cerebrovascular disease, data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle (LDL-P) concentration, rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein (HDL) cholesterol (HDL-C), may be the primary lipid driver of PAD risk.

Methods:
The study population was a prospective cohort study of 27 888 women ≥45 years old free of cardiovascular disease at baseline and followed for a median of 15.1 years. We tested whether standard lipid concentrations, as well as nuclear magnetic resonance spectroscopy–derived lipoprotein measures, were associated with incident symptomatic PAD (n=110) defined as claudication and/or revascularization.

Results:

In age-adjusted analyses, while LDL cholesterol was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very LDL (VLDL) particle (VLDL-P) subclasses, increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle (HDL-P) concentration (all
P
for extreme tertile comparisons <0.05). Findings persisted in multivariable-adjusted models comparing extreme tertiles for elevated total LDL-P (adjusted hazard ratio [HR
adj
] 2.03; 95% CI, 1.14–3.59), small LDL-P (HR
adj
2.17; 95% CI, 1.10–4.27), very large VLDL-P (HR
adj
1.68; 95% CI, 1.06–2.66), medium VLDL-P (HR
adj
1.98; 95% CI, 1.15–3.41), and TC:HDL-C (HR
adj
, 3.11; 95% CI, 1.67–5.81). HDL was inversely associated with risk; HR
adj
for extreme tertiles of HDL-C and HDL-P concentration were 0.30 (
P
trend < 0.0001) and 0.29 (
P
trend < 0.0001), respectively. These components of atherogenic dyslipidemia, including small LDL-P, medium and very large VLDL-P, TC:HDL-C, HDL-C, and HDL-P, were more strongly associated with incident PAD than incident coronary and cerebrovascular disease. Finally, the addition of LDL-P and HDL-P concentration to TC:HDL-C measures identified women at heightened PAD risk.

Conclusions:
In this prospective study, nuclear magnetic resonance–derived measures of LDL-P, but not LDL cholesterol, were associated with incident PAD. Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and nuclear magnetic resonance–derived measures of HDL, were significant risk determinants. These data help clarify prior inconsistencies and may elucidate a unique lipoprotein signature for PAD compared to coronary and cerebrovascular disease.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov/
. Unique Identifier: NCT00000479.
Spiking Elementary Motion Detector in Neuromorphic Systems
Authors: Milde M. B. , Bertrand O. J. N. , Ramachandran H. , Egelhaaf M. , Chicca E. 
Published: July 2018

Apparent motion of the surroundings on an agent's retina can be used to navigate through cluttered environments, avoid collisions with obstacles, or track targets of interest. The pattern of apparent motion of objects, (i.e., the optic flow), contains spatial information about the surrounding environment. For a small, fast-moving agent, as used in search and rescue missions, it is crucial to estimate the distance to close-by objects to avoid collisions quickly. This estimation cannot be done by conventional methods, such as frame-based optic flow estimation, given the size, power, and latency constraints of the necessary hardware. A practical alternative makes use of event-based vision sensors. Contrary to the frame-based approach, they produce so-called events only when there are changes in the visual scene. We propose a novel asynchronous circuit, the spiking elementary motion detector (sEMD), composed of a single silicon neuron and synapse, to detect elementary motion from an event-based vision sensor. The sEMD encodes the time an object's image needs to travel across the retina into a burst of spikes. The number of spikes within the burst is proportional to the speed of events across the retina. A fast but imprecise estimate of the time-to-travel can already be obtained from the first two spikes of a burst and refined by subsequent interspike intervals. The latter encoding scheme is possible due to an adaptive nonlinear synaptic efficacy scaling. We show that the sEMD can be used to compute a collision avoidance direction in the context of robotic navigation in a cluttered outdoor environment and compared the collision avoidance direction to a frame-based algorithm. The proposed computational principle constitutes a generic spiking temporal correlation detector that can be applied to other sensory modalities (e.g., sound localization), and it provides a novel perspective to gating information in spiking neural networks.