bluuebunny/crossref_metadata_2025 huggingface dataset:
Algorithm 1006
Authors: Abergel Rémy , Moisan Lionel
Published: March 2020

We present a computational procedure to evaluate the integral ∫
y
x
s

p
-1

e
-μs
ds
for 0 ≤
x
<
y
≤ +∞,μ = ±1,
p
> 0, which generalizes the lower (
x
=0) and upper (
y
=+∞) incomplete gamma functions. To allow for large values of
x
,
y
, and
p
while avoiding under/overflow issues in the standard double precision floating point arithmetic, we use an explicit normalization that is much more efficient than the classical ratio with the complete gamma function. The generalized incomplete gamma function is estimated with continued fractions, with integrations by parts, or, when
x ≈ y
, with the Romberg numerical integration algorithm. We show that the accuracy reached by our algorithm improves a recent state-of-the-art method by two orders of magnitude, and it is essentially optimal considering the limitations imposed by floating point arithmetic. Moreover, the admissible parameter range of our algorithm (0 ≤
p,x,y
≤ 10
15
) is much larger than competing algorithms, and its robustness is assessed through massive usage in an image processing application.
A Machine Learning Methodology for Cache Memory Design Based on Dynamic Instructions
Authors: Navarro Osvaldo , Yudi Jones , Hoffmann Javier , Hernandez Hector Gerardo Muñoz , Hübner Michael
Published: March 2020

Cache memories are an essential component of modern processors and consume a large percentage of their power consumption. Its efficacy depends heavily on the memory demands of the software. Thus, finding the optimal cache for a particular program is not a trivial task and usually involves exhaustive simulation. In this article, we propose a machine learning–based methodology that predicts the optimal cache reconfiguration for any given application, based on its dynamic instructions. Our evaluation shows that our methodology reaches 91.1% accuracy. Moreover, an additional experiment shows that only a small portion of the dynamic instructions (10%) suffices to reach 89.71% accuracy.
The Five Strands of Living Lab
Authors: Alavi Hamed S. , Lalanne Denis , Rogers Yvonne
Published: March 2020

Since the introduction of the iconic Aware Home project [39] in 1999, the notion of “living laboratory” has been taken up and developed in HCI research. Many of the underpinning assumptions have evolved over the past two decades in various directions, while the same nomenclature is employed—inevitably in ambiguous ways. This contribution seeks to elicit an organized understanding of what we talk about and when we talk about living lab studies in HCI. This is accomplished through the methods of discourse analysis [66, 69], a combination of coding, hypothesis generation, and inferential statistics on the coded data. Analysing the discursive context within which the term living laboratory (or lab) appears in 152 SIGCHI and TOCHI articles, we extracted five divergent strands with overlapping but distinct conceptual frameworks, labeled as “Visited Places,” “Instrumented Places,” “Instrumented People,” “Lived-in Places,” and “Innovation Spaces.” In the first part of this article, we describe in detail the method and outcome of our analysis that draws out the five strands. Building on the results of the first part, in the second part of this article, each of the five types of living lab is discussed using some of the prototypical examples of that kind presented in the literature. Finally, we discuss the raison d’être and future position of the living lab as a method within HCI research and design and in relation to advances in sensing technologies and the emerging world of intelligent built environments (e.g., smart city and smart home).
Countdown Timer Speed
Authors: Ghafurian Moojan , Reitter David , Ritter Frank E.
Published: March 2020

We face delays in a variety of situations. They are either inevitable, e.g., due to system limits, or are intentionally added, e.g., advertisements. In many situations, a visual feedback is provided during the delay to manage expectations. This feedback is usually provided through progress bars, percentages, or countdowns, depending on design limitations such as screen size. In this article, we use 15-second delays and examine (a) how delays affect users’ decision-making and task satisfaction, and (b) how to manipulate time perception to reduce the negative consequences of delays. Experiment 1 (
N
=421) shows that faster countdowns increase task satisfaction and lead to more rational decisions in the subsequent task. In Experiment 2, we investigate the effect of countdown speed on delay perception and recall (
N
=531). We show that faster countdowns lead to shorter perceived delays, while the delay will be recalled as longer after the task. The opposite is obtained for slower countdowns. We also increased the countdown rate and found a limit for the effect of increased speed. Thus, designers have to trade-off between how delays are perceived at the moment of experience and how they are recalled. We discuss the implications of these findings for user interface design.
Molecular Mechanisms of Pollination Biology
Authors: Fattorini Róisín , Glover Beverley J.
Published: March 2020

Pollination is the transfer of pollen grains from the stamens to the stigma, an essential requirement of sexual reproduction in flowering plants. Cross-pollination increases genetic diversity and is favored by selection in the majority of situations. Flowering plants have evolved a wide variety of traits that influence pollination success, including those involved in optimization of self-pollination, attraction of animal pollinators, and the effective use of wind pollination. In this review we discuss our current understanding of the molecular basis of the development and production of these various traits. We conclude that recent integration of molecular developmental studies with population genetic approaches is improving our understanding of how selection acts on key floral traits in taxonomically diverse species, and that further work in nonmodel systems promises to provide exciting insights in the years to come.
Exosomes derived from mmu_circ_0000250-modified adipose-derived mesenchymal stem cells promote wound healing in diabetic mice by inducing miR-128-3p/SIRT1-mediated autophagy
Authors: Shi Rongfeng , Jin Yinpeng , Hu Weiwei , Lian Weishuai , Cao Chuanwu , Han Shilong , Zhao Suming , Yuan Hongxin , Yang Xiaohu , Shi Jiahai , Zhao Hui
Published: March 2020

More and more evidence advises that circular RNAs (circRNAs) function critically in regulating different disease microenvironments. Our previous study found that autotransplantation of adipose-derived mesenchymal stem cells (ADSCs) promotes diabetes wound healing. Exosomes derived in ADSCs play an important regulatory role. This study aimed to characterize if mmu_circ_0000250 played a role in ADSC-exosome-mediated full-thickness skin wound repair in diabetic rats. Endothelial progenitor cells (EPCs) were selected to study the therapeutic mechanism of exosomes in high-glucose (HG)-induced cell damage and dysfunction. Analysis and luciferase reporter assay were utilized to explore the interaction among mmu_circ_0000250, miRNA (miR)-128-3p, and sirtuin (SIRT)1. The diabetic rats were used to confirm the therapeutic effect of mmu_circ_0000250 against exosome-mediated wound healing. Exosomes containing a high concentration of mmu_circ_0000250 had a greater therapeutic effect on restoration of the function of EPCs by promotion autophagy activation under HG conditions. Expression of mmu_circ_0000250 promoted SIRT1 expression by miR-128-3p adsorption, which was confirmed via luciferase reporter assay and bioinformatics analysis. In vivo, exosomes containing a high concentration of mmu_circ_0000250 had a more therapeutic effect on wound healing when compared with wild-type exosomes from ADSCs. Immunohistochemistry and immunofluorescence detection showed that mmu_circ_0000250 increased angiopoiesis with exosome treatment in wound skin and suppressed apoptosis by autophagy activation. In conclusion, we verified that mmu_circ_0000250 enhanced the therapeutic effect of ADSC-exosomes to promote wound healing in diabetes by absorption of miR-128-3p and upregulation of SIRT1. Therefore, these findings advocate targeting the mmu_circ_0000250/miR-128-3p/SIRT1 axis as a candidate therapeutic option for diabetic ulcers.
Purinergic signaling, DAMPs, and inflammation
Authors: Di Virgilio Francesco , Sarti Alba Clara , Coutinho-Silva Robson
Published: March 2020

Danger sensing is one of the most fundamental evolutionary features enabling multicellular organisms to perceive potential threats, escape from risky situations, fight actual intruders, and repair damage. Several endogenous molecules are used to “signal damage,” currently referred to as “alarmins” or “damage-associated molecular patterns” (DAMPs), most being already present within all cells (preformed DAMPs), and thus ready to be released, and others neosynthesized following injury. Over recent years it has become overwhelmingly clear that adenosine 5′-triphosphate (ATP) is a ubiquitous and extremely efficient DAMP (thus promoting inflammation), and its main metabolite, adenosine, is a strong immunosuppressant (thus dampening inflammation). Extracellular ATP ligates and activates the P2 purinergic receptors (P2Rs) and is then degraded by soluble and plasma membrane ecto-nucleotidases to generate adenosine acting at P1 purinergic receptors (P1Rs). Extracellular ATP, P2Rs, ecto-nucleotidases, adenosine, and P1Rs are basic elements of the purinergic signaling network and fundamental pillars of inflammation.
The dual phosphodiesterase 3/4 inhibitor RPL554 stimulates rare class III and IV CFTR mutants
Authors: Turner Mark J. , Luo Yishan , Thomas David Y. , Hanrahan John W.
Published: March 2020

Over 2,000 mutations have been reported in the cystic fibrosis transmembrane conductance regulator ( cftr) gene, many of which cause disease but are rare and have no effective treatment. Thus, there is an unmet need for new, mutation-agnostic therapies for cystic fibrosis (CF). Phosphodiesterase (PDE) inhibitors are one such class of therapeutics that have been shown to elevate intracellular cAMP levels and stimulate CFTR-dependent anion secretion in human airway epithelia; however, the number of people with CF that could be helped by PDE inhibitors remains to be determined. Here we used Fisher rat thyroid (FRT) cells stably transduced with rare human CFTR mutants and studied their responsiveness to the dual phosphodiesterase 3/4 inhibitor RPL554 (Verona Pharma). Through its inhibitory effect on PDE4D, we find that RPL554 can elevate intracellular cAMP leading to a potentiation of forskolin-stimulated current mediated by R334W, T338I, G551D, and S549R mutants of CFTR when used alone or in combination with CFTR modulators. We also were able to reproduce these effects of RPL554 on G551D-CFTR when it was expressed in primary human bronchial epithelial cells, indicating that RPL554 would have stimulatory effects on rare CFTR mutants in human airways and validating FRT cells as a model for PDE inhibitor studies. Furthermore, we provide biochemical evidence that VX-809 causes surprisingly robust correction of several class III and IV CFTR mutants. Together, our findings further support the therapeutic potential of RPL554 for patients with CF with class III/IV mutations and emphasize the potential of PDEs as potential drug targets that could benefit patients with CF.
Activation of a nerve injury transcriptional signature in airway-innervating sensory neurons after lipopolysaccharide-induced lung inflammation
Authors: Kaelberer Melanie Maya , Caceres Ana Isabel , Jordt Sven-Eric
Published: March 2020

The lungs and the immune and nervous systems functionally interact to respond to respiratory environmental exposures and infections. The lungs are innervated by vagal sensory neurons of the jugular and nodose ganglia, fused together in smaller mammals as the jugular-nodose complex (JNC). Whereas the JNC shares properties with the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG), these sensory structures express differential sets of genes that reflect their unique functionalities. Here, we used RNA sequencing (RNA-seq) in mice to identify the differential transcriptomes of the three sensory ganglia types. Using a fluorescent retrograde tracer and fluorescence-activated cell sorting, we isolated a defined population of airway-innervating JNC neurons and determined their differential transcriptional map after pulmonary exposure to lipopolysaccharide (LPS), a major mediator of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after infection with gram-negative bacteria or inhalation of organic dust. JNC neurons activated an injury response program, leading to increased expression of gene products such as the G protein-coupled receptor Cckbr, inducing functional changes in neuronal sensitivity to peptides, and Gpr151, also rapidly induced upon neuropathic nerve injury in pain models. Unique JNC-specific transcripts, present at only minimal levels in TG, DRG, and other organs, were identified. These included TMC3, encoding for a putative mechanosensor, and urotensin 2B, a hypertensive peptide. These findings highlight the unique properties of the JNC and reveal that ALI/ARDS rapidly induces a nerve injury-related state, changing vagal excitability.
Eye movements as a readout of sensorimotor decision processes
Authors: Fooken Jolande , Spering Miriam
Published: March 2020

Real-world tasks, such as avoiding obstacles, require a sequence of interdependent choices to reach accurate motor actions. Yet, most studies on primate decision making involve simple one-step choices. Here we analyze motor actions to investigate how sensorimotor decisions develop over time. In a go/no-go interception task human observers ( n = 42) judged whether a briefly presented moving target would pass (interceptive hand movement required) or miss (no hand movement required) a strike box while their eye and hand movements were recorded. Go/no-go decision formation had to occur within the first few hundred milliseconds to allow time-critical interception. We found that the earliest time point at which eye movements started to differentiate actions (go versus no-go) preceded hand movement onset. Moreover, eye movements were related to different stages of decision making. Whereas higher eye velocity during smooth pursuit initiation was related to more accurate interception decisions (whether or not to act), faster pursuit maintenance was associated with more accurate timing decisions (when to act). These results indicate that pursuit initiation and maintenance are continuously linked to ongoing sensorimotor decision formation.

NEW & NOTEWORTHY Here we show that eye movements are a continuous indicator of decision processes underlying go/no-go actions. We link different stages of decision formation to distinct oculomotor events during open- and closed-loop smooth pursuit. Critically, the earliest time point at which eye movements differentiate actions preceded hand movement onset, suggesting shared sensorimotor processing for eye and hand movements. These results emphasize the potential of studying eye movements as a readout of cognitive processes.
Plantarflexion force is amplified with sensory stimulation during ramping submaximal isometric contractions
Authors: Pearcey Gregory E. P. , Sun Yao , Zehr E. Paul
Published: March 2020

Stimulating cutaneous nerves, causing tactile sensations, reduces the perceived heaviness of an object, suggesting that either descending commands are facilitated or the perception of effort is reduced when tactile sensation is enhanced. Sensory stimulation can also mitigate decrements in motor output and spinal cord excitability that occur with fatigue. The effects of sensory stimulation applied with coincident timing of voluntary force output, however, are yet to be examined. Therefore, the purpose of this study was to examine effects of sensory enhancement to nerves innervating opposed skin areas of the foot (top or bottom) on force production during voluntary plantarflexion or dorsiflexion contractions. Stimulation trains were applied for 2 s at either a uniform 150 Hz or a modulated frequency that increased linearly from 50 to 150 Hz and were delivered at the initiation of the contraction. Participants were instructed to perform a ramp contraction [~10% maximal voluntary contraction (MVC)/s] to ~20% MVC and then to hold ~20% MVC for 2 s while receiving real-time visual feedback. Cutaneous reflexes were evoked 75 ms after initiating the hold (75 ms after sensory enhancement ended). Force output was greater for all sensory-enhanced conditions compared with control during plantarflexion; however, force output was not amplified during dorsiflexion. Cutaneous reflexes evoked after sensory enhancement were unaltered. These results indicate that sensory enhancement can amplify plantarflexion but not dorsiflexion, likely as a result of differences in neuroanatomical projections to the flexor and extensor motor pools. Further work is required to elucidate the mechanisms of enhanced force during cutaneous stimulation.

NEW & NOTEWORTHY The efficacy of behaviorally timed sensory stimulation to enhance sensations and amplify force output has not been examined. Here we show cutaneous nerve sensory stimulation can amplify plantarflexion force output. This amplification in force occurs irrespective of whether the cutaneous field that is stimulated resides on the surface that is producing the force or the opposing surface. This information may provide insights for the development of technologies to improve performance and/or rehabilitation training.
Acute neurotoxicant exposure induces hyperexcitability in mouse lumbar spinal motor neurons
Authors: Sceniak Michael P. , Spitsbergen Jake B. , Sabo Shasta L. , Yuan Yukun , Atchison William D.
Published: March 2020

Spinal motor neurons (MNs) are susceptible to glutamatergic excitotoxicity, an effect associated with lumbar MN degeneration in amyotrophic lateral sclerosis (ALS). MN susceptibility to environmental toxicant exposure, one prospective contributor to sporadic ALS, has not been systematically studied. The goal of this study was to test the ability of a well-known environmental neurotoxicant to induce hyperexcitability in mouse lumbar MNs. Methylmercury (MeHg) causes neurotoxicity through mechanisms involving elevated intracellular Ca2+ concentration ([Ca2+]i), a hallmark of excitotoxicity. We tested whether acute exposure to MeHg induces hyperexcitability in MNs by altering synaptic transmission, using whole cell patch-clamp recordings of lumbar spinal MNs in vitro. Acute MeHg exposure (20 μM) led to an increase in the frequency of both spontaneous excitatory postsynaptic currents (EPSCs) and miniature EPSCs. The frequency of inhibitory postsynaptic currents (IPSCs) was also increased by MeHg. Action potential firing rates, both spontaneous and evoked, were increased by MeHg, despite increases in both EPSCs and IPSCs, indicating a shift toward hyperexcitability. Also consistent with hyperexcitability, fluo 4-AM microfluorimetry indicated that MeHg exposure induced an increase in [Ca2+]i. Spinal cord hyperexcitability is partially mediated by Ca2+-permeable AMPA receptors, as MeHg-dependent increases in EPSCs were blocked by 1-napthyl spermine. Therefore, spinal MNs appear highly susceptible to MeHg exposure, leading to significant increases in spontaneous network excitability and disruption of normal function. Prolonged hyperexcitability could lead to eventual neurodegeneration and loss of motor function as observed in spinal cord after MeHg exposure in vivo and may contribute to MeHg-induced acceleration of ALS symptoms.

NEW & NOTEWORTHY Spinal motor neurons (MN) are susceptible to glutamatergic excitotoxicity, an effect associated with lumbar MN degeneration in amyotrophic lateral sclerosis (ALS). This study investigated MN susceptibility to environmental toxicant exposure, one prospective contributor to sporadic ALS. Spinal MNs appear highly susceptible to methylmercury exposure, leading to significant increases in spontaneous network excitability and disruption of normal function. Prolonged hyperexcitability could lead to neurodegeneration and loss of motor function as observed in ALS spinal cord symptoms.
Prevalence of Anemia and Its Associated Factors in Antiretroviral-Treated HIV/AIDS-Positive Adults from 2013 to 2018 at Debre Berhan Referral Hospital, Ethiopia
Authors: Aynalem Yared Asmare , Shibabaw Shiferaw Wondimeneh , Woldiye Zeleke
Published: March 2020

Introduction. Anemia was defined as a hemoglobin level of less than or equal to 13.9 g/dl for male and less than or equal to 12.2 g/dl for female adults. It is one of the most common hematological abnormalities in people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and is a determining factor for disease progression and death. Among the countries in sub-Saharan Africa, Ethiopia is one of the most affected nations by HIV. Therefore, this study aimed to assess the prevalence of anemia and its associated factors among HIV-positive adults that had received antiretroviral treatment (ART) at Debre Berhan Referral Hospital. Methods. An institution-based, descriptive, cross-sectional study was conducted involving 263 adults with HIV/AIDS that had undergone ART at Debre Berhan Referral Hospital, Ethiopia. Data were collected from patient charts using systematic sampling with a pretested data extraction tool and entered using EpiData 3.1. Variables having a p value ≤0.25 in the bivariate were fitted to a multivariable regression model with a 95% confidence interval. p values ≤0.05 were considered statistically significant in the multivariate analysis. Results. Among the 263 HIV-positive patients, 237 (90.11%) were included in the final analysis. The overall prevalence of anemia was 26.2%. Factors that were significantly associated with anemia were past opportunistic infections, patients being in WHO clinical stage III and IV, and a BMI <18.5. Conversely, those patients who took anti-TB medication were less likely to have anemia. Conclusion. Our study shows that the severity of anemia among HIV/AIDS patients that had undergone ART is lower than most studies conducted in Ethiopia. We also found that opportunistic infection, WHO clinical staging, anti-TB treatment, and low BMI were significantly associated with anemia. Therefore, routine screening of patient nutritional status and opportunistic infections may be useful in predicting and controlling anemia in HIV/AIDS patients.
A Cardiac Pseudoaneurysm as a Thromboembolic Source: Acute Visual Loss due to Cardiac Emboli
Authors: Sá Fernando Montenegro , Fernandes Sara I. L. , Carvalho Rita J. R. , Santos Luís M. G. , Antunes José A. S. , Guardado Joana M. , Morais João C. A.
Published: March 2020

Acute visual loss is rarely caused by a heart condition. This manuscript transcribes a case report of a 36-year-old patient with a 2-year history of aortic valve replacement due to bicuspid aortic valve endocarditis that presents to the emergency department with an acute right eye visual loss. After ophthalmologic investigation identified a central retinal artery occlusion, a transthoracic echocardiography was performed to search for a possible cardiac embolus, despite the patient presenting INR values of 2-2.5 for the last year. A mitral-aortic intervalvular fibrosa pseudoaneurysm was identified. A transoesophageal echocardiography was then performed, identifying a small clot logged inside the pseudoaneurysm that protruded to the left ventricle outflow tract. After INR-adjusted warfarin treatment to levels between 3 and 4, the pseudoaneurysm was surgically closed. This is a rare case since the likely source of embolism to the central retinal artery was the thrombus logged inside the pseudoaneurysm despite a standardly accepted therapeutic INR.
Model Test on Bearing Characteristics of Basalt Fiber‐Reinforced Concrete Lining
Authors: Wang Dao-yuan , Qi Jia-suo , Cui Guang-yao , Yang Yanling , Chang Jie
Published: March 2020

Adding fiber can improve the brittleness of plain concrete. Compared with plain concrete, basalt fiber‐reinforced concrete has the advantages of strengthening, toughening, and crack resistance. Compared with steel fiber‐reinforced concrete, basalt fiber‐reinforced concrete has better construction performance. Basalt fiber concrete is a type of inorganic material with environmental protection and high mechanical properties, which has an important mechanical advantage for controlling the deformation of the soft surrounding rock tunnel. Through the indoor model test of mechanical behavior of reinforced concrete and basalt fiber‐reinforced concrete lining, the bearing characteristics of basalt fiber‐reinforced concrete lining was studied. The results show that, compared with reinforced concrete, the initial crack load of basalt fiber‐reinforced concrete is increased by 20%; the toughness of lining structure is enhanced by adding basalt fiber, and the lining can still bear large bending moment and deformation after the initial crack appears; after the initial crack appears, the bearing characteristic curve of reinforced concrete lining rises slowly and converges rapidly; the bearing characteristic curve of basalt fiber‐reinforced concrete lining rises slowly, and there is no sign of convergence when it reaches 2 times of initial crack load. For the soft surrounding rock tunnel, it is necessary to seal the rock surface as early as possible, provide support as soon as possible, and have a certain deformation capacity. Basalt fiber‐reinforced concrete can better meet these needs.
Study on Sustainable Development of the Transnational Power Grid Interconnection Projects under Diversified Risks Based on Variable Weight Theory and Bayesian Network
Authors: Wang Hao , Jin Yanan , Tan Xin
Published: March 2020

Transnational power grid interconnection is an important measure to promote the construction of energy Internet. It can meet the global power demand in a clean and green way, promote the UN’s concept of “sustainable energy,” and tackle climate changes. But, transnational power grid projects face many complex and variable risks due to their complex background and lacking experience. According to the characteristics of transnational power grid interconnection projects, a risk assessment index system including 10 indexes such as national relation, public participation, and available transmission capacity is constructed. Then, in order to overcome the shortcomings of traditional risk assessment methods, this paper proposes a risk assessment method combined with risk theory and probabilistic model, which can not only consider the uncertainties but also integrate the probability of accidents with consequences. Therefore, it can effectively assess the transnational power grid interconnection projects under diversified risks. In addition, in order to further magnify the impact of higher risks on such projects, a method combining traditional weighting method with the variable weight theory is proposed. The study in this paper provides certain guidance and decision-making support for different participants such as the government power sector, construction enterprises, and investment enterprises when they launch on sustainable development of the transnational project business, which have obvious practical significance.
Optimization of the Supply Chain in the Production of Ethanol from Agricultural Biomass Using Mixed-Integer Linear Programming (MILP): A Case Study
Authors: León-Olivares Edgar , Minor-Popocatl Hertwin , Aguilar-Mejía Omar , Sánchez-Partida Diana
Published: March 2020

The production of biofuels from agricultural biomass has attracted much attention from researchers in recent years. Biomass residues generated from agricultural production of corn and barley represent an essential source of raw material for the production of biofuels, and a mathematical programming-based approach can be used to establish an efficient supply chain. This paper proposes a model of mixed-integer linear programming (MILP) that seeks to minimize the total cost of the bioethanol supply chain. The proposal allows determining the optimal number and location of storage centers, biorefineries, and mixing plants, as well as the flow of biomass and bioethanol between the facilities. To show the proposed approach, we present a case study developed in the region of Tulancingo, Hidalgo, in Mexico (case study), considering the potential of biomass (corn and barley residues) in the region. The results show the costs for the production of bioethanol, transportation, and refining and total cost of the bioethanol supply chain, besides a sensitivity analysis on the costs of the bioethanol supply chain which is presented by mixing different percentages of bioethanol with fossil fuel to satisfy the demand. We conclude that the proposed approach is viable in the process of configuring the supply chain within the proposed study region.
Extrapolation Algorithm for Computing Multiple Cauchy Principal Value Integrals
Authors: Li Jin , Cheng Yongling
Published: March 2020

In this paper, the computation of multiple (including two dimensional and three dimensional) Cauchy principal integral with generalized composite rectangle rule was discussed, with the density function approximated by the middle rectangle rule, while the singular kernel was analytically calculated. Based on the expansion of the density function, the asymptotic expansion formulae of error functional are obtained. A series is constructed to approach the singular point, then the extrapolation algorithm is presented, and the convergence rate is proved. At last, some numerical examples are presented to validate the theoretical analysis.
Deformation and Acoustic Emission Characteristics of Cracked Granite during Creep
Authors: Wang Chunping , Xie Jingli , Liu Jian
Published: March 2020

A series of multistage creep tests under different confining pressures with acoustic emission monitoring have been performed to investigate the deformation characteristic and failure process of cracked granite during creep. The critical axial strain of cracked sample showed an increasing tendency with the increase of confining pressure. In contrast, critical lateral strain experienced a process of descending first at low confinement and then remaining nearly constant at high confinement. Compared with loading‐cracked specimen, smaller critical axial strain, greater critical lateral strain, and higher lateral creep strain rate were found for unloading‐cracked specimen. Based on the spatial and temporal distribution of acoustic emission events, the cracking process during creep was analysed. The AE events with high energy are mainly concentrated at the final fracture area of the specimen. The higher the confining pressure, the more the AE events with low energy. Compared with the loading‐cracked specimen, the percentage of AE events with high energy is relatively small for the unloading‐cracked specimen.
Enoxaparin Effect on Pregnancy Outcomes in a Patient with Elevated Plasminogen Activator Inhibitor-1
Authors: Minor Kathleen , Leftwich Heidi
Published: March 2020

Background. Plasminogen activator inhibitor-1 (PAI-1) inhibits tPA and creates a prothrombotic state. Gene polymorphisms of PAI-1 are associated with elevated levels and adverse pregnancy outcomes. Case. A 36-year-old gravida 6, para 1-1-3-1 with elevated prepregnancy PAI-1 levels, a history of early-onset preeclampsia with severe features superimposed on chronic hypertension, intrauterine growth restriction (IUGR), and recurrent pregnancy loss (RPL), presented with a dichorionic-diamniotic twin gestation. She was managed with aspirin and enoxaparin and delivered appropriately grown twins at 36 weeks and 3 days, due to the development of preeclampsia superimposed on chronic hypertension. She was discharged not on enoxaparin and represented with pulmonary edema on postoperative day 8. Conclusion. It is reasonable to consider testing certain patients with recurrent pregnancy loss and/or early preeclampsia with severe features for PAI-1. If levels are elevated, treatment with prophylactic enoxaparin may be beneficial. Further research is needed to determine the effect of this therapy in patients with exceedingly poor perinatal outcomes to better assess for any impact on improved outcomes.
Long Noncoding RNA Lnc-TLN2-4:1 Suppresses Gastric Cancer Metastasis and Is Associated with Patient Survival
Authors: Wu Yuyun , Hao Ningbo , Wang Suming , Yang Xin , Xiao Yufeng , Yang Huan , Yang Shiming , Li Bosheng
Published: March 2020

Gastric cancer (GC) is one of the most common malignancies worldwide, and the tumor metastasis leads to poor outcomes of GC patients. Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules that play a crucial role in tumor metastasis. However, the biological function and underlying mechanism of numerous lncRNAs in GC metastasis remain largely unclear. Here, we report a novel lncRNA, lnc-TLN2-4:1, whose expression is decreased in GC tissue versus matched normal tissue, and its low expression is involved in the lymph node and distant metastases of GC, as well as poor overall survival rates of GC patients. We further found that lnc-TLN2-4:1 inhibits the ability of GC cells to migrate and invade but does not influence GC cell proliferation and confirmed that lnc-TLN2-4:1 is mainly located in the cytoplasm of GC cells. We then found that lnc-TLN2-4:1 increases the mRNA and protein expression of TLN2 in GC cells and there is a positive correlation between the expression of lnc-TLN2-4:1 and TLN2 mRNA in GC tissue. Collectively, we identified a novel lncRNA, lnc-TLN2-4:1, in GC, where lnc-TLN2-4:1 represses cell migration and invasion. The low expression of lnc-TLN2-4:1 is associated with poor overall survival rates of GC patients. These suggest that lnc-TLN2-4:1 may be a tumor suppressor during GC metastasis.
Saponin Facilitates Anti-Robo1 Immunotoxin Cytotoxic Effects on Maxillary Sinus Squamous Cell Carcinoma
Authors: Komatsu Noriko , Komatsu Miku , Ohashi Riuko , Horii Akira , Hoshi Kazuto , Takato Tsuyoshi , Abe Takahiro , Hamakubo Takao
Published: March 2020

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide. The standard treatment of surgery, chemotherapy, and radiotherapy can result in long-term complications which lower the patient’s quality of life, such as eating disorders, speech problems, and disfiguring or otherwise untoward cosmetic issues. Antibody therapy against cancer-specific antigens is advantageous in terms of its lesser side effects achieved by its greater specificity, though the antitumor activity is still usually not enough to obtain a complete cure. Robo1, an axon guidance receptor, has received considerable attention as a possible drug target in various cancers. We have shown previously the enhanced cytotoxic effects of saporin-conjugated anti-Robo1 immunotoxin (IT-Robo1) on the HNSCC cell line HSQ-89 in combination with a photochemical internalization technique. Considering the light source, which has only limited tissue penetrance, we examined the drug internalization effect of saponin. Treatment with saponin facilitated significant cytotoxic effects of IT-Robo1 on HSQ-89 cells. Saponin exerts its own nonspecific cytotoxicity, which may cover the actual extent of the internalization effect. We thus examined whether a flashed treatment with saponin exerted a significant specific cytotoxic effect on cancer cells. The combination of an immunotoxin with saponin also exhibited a significant tumor-suppressive effect on mice HSQ-19 xenografts. These results suggest the utility of saponin treatment as an enhancer of immunotoxin treatment in cancer.
OMTX705, a Novel FAP-Targeting ADC Demonstrates Activity in Chemotherapy and Pembrolizumab-Resistant Solid Tumor Models
Authors: Fabre Myriam , Ferrer Cristina , Domínguez-Hormaetxe Saioa , Bockorny Bruno , Murias Laura , Seifert Oliver , Eisler Stephan A. , Kontermann Roland E. , Pfizenmaier Klaus , Lee So Young , Vivanco María dM. , López-Casas Pedro P. , Perea Sofia , Abbas Muhammad , Richter Wolfgang , Simon Laureano , Hidalgo Manuel
Published: March 2020

Purpose:

The tumor microenvironment plays a key role in cancer development and progression and is involved in resistance to chemo- and immunotherapy. Cancer-associated fibroblast expressing fibroblast-activating protein α (FAPα) is one of the predominant stroma cell types and is involved in resistance to immunotherapy.

Experimental Design:

We generated OMTX705, a novel antibody–drug conjugate from a humanized anti-FAP antibody linked to a new cytolysin. Here, we studied its antineoplastic activity in vitro and in preclinical mouse models alone and in combination with chemotherapy as well as immunotherapy in PD-1–resistant tumors.

Results:

In Avatar models, OMTX705 showed a 100% tumor growth inhibition and prolonged tumor regressions as single agent and in combination with chemotherapy. Treatment rechallenge following treatment discontinuation induced additional tumor regression, suggesting lack of treatment resistance. In a mouse model with a humanized immune system resistant to PD-1 inhibition, OMTX705 increased tumor infiltration by CD8+ T cells, induced complete regressions, and delayed tumor recurrence.

Conclusions:

These data suggest that FAP targeting with OMTX705 represents a novel and potent strategy for cancer treatment, including tumors resistant to immunotherapy, and support its clinical development.
Integrative Analysis of Multi-omics Data Identified EGFR and PTGS2 as Key Nodes in a Gene Regulatory Network Related to Immune Phenotypes in Head and Neck Cancer
Authors: Feng Bohai , Shen Ying , Pastor Hostench Xavier , Bieg Matthias , Plath Michaela , Ishaque Naveed , Eils Roland , Freier Kolja , Weichert Wilko , Zaoui Karim , Hess Jochen
Published: March 2020

Purpose:

Malignant progression exhibits a tightly orchestrated balance between immune effector response and tolerance. However, underlying molecular principles that drive the establishment and maintenance of the tumor immune phenotype remain to be elucidated.

Experimental Design:

We trained a novel molecular classifier based on immune cell subsets related to programmed death-ligand 1 (PD-L1) and interferon γ (IFNγ) expression, which revealed distinct subgroups with higher (cluster A) or lower (subcluster B3) cytotoxic immune phenotypes. Integrative analysis of multi-omics data was conducted to identify differences in genetic and epigenetic landscapes as well as their impact on differentially expressed genes (DEG) among immune phenotypes. A prognostic gene signature for immune checkpoint inhibition (ICI) was established by a least absolute shrinkage and selection operator (LASSO)-Cox regression model.

Results:

Mutational landscape analyses unraveled a higher frequency of CASP8 somatic mutations in subcluster A1, while subcluster B3 exhibited a characteristic pattern of copy-number alterations affecting chemokine signaling and immune effector response. The integrative multi-omics approach identified EGFR and PTGS2 as key nodes in a gene regulatory network related to the immune phenotype, and several DEGs related to the immune phenotypes were affected by EGFR inhibition in tumor cell lines. Finally, we established a prognostic gene signature by a LASSO-Cox regression model based on DEGs between nonprogressive disease and progressive disease subgroups for ICI.

Conclusions:

Our data highlight a complex interplay between genetic and epigenetic events in the establishment of the tumor immune phenotype and provide compelling experimental evidence that a patient with squamous cell carcinoma of the head and neck at higher risk for ICI treatment failure might benefit from a combination with EGFR inhibition.
Preoperative Oral Carbohydrate Reduces Postoperative Insulin Resistance by Activating AMP-Activated Protein Kinase after Colorectal Surgery
Authors: Shi Mengyao , Hu Zunqi , Yang Dejun , Cai Qingping , Zhu Zhenxin
Published: March 2020

Background:Postoperative insulin resistance (PIR) is a common response after colorectal surgery and an independent risk factor for recovery. Preoperative oral carbohydrate (POC) has been known to reduce PIR. Herein, we investigated whether its mechanism of action involves AMP-activated protein kinase (AMPK) and mTOR/S6K1/insulin receptor substrate-1 (IRS-1) pathways. Methods:Patients undergoing colorectal cancer resection were randomly assigned to a POC, fasting, or placebo group. The exclusion criteria were association with diseases or intake of medication affecting insulin sensitivity. Pre- and postoperative insulin resistance, and protein phosphorylation of AMPK, mTOR, and IRS-1 in the rectus abdominis muscle were evaluated. Results:From January 2017 to December 2017, 70 patients were randomized and 63 were evaluated. No difference was found in the clinical and operative characteristics among the 3 groups. In the POC group, the levels of blood glucose, blood insulin, and homeostasis model assessment of insulin resistance were significantly lower in the POC group than the fasting and placebo groups, and the insulin sensitivity index was significantly higher. The phosphorylation of AMPK in the POC group was significantly higher than that in the other 2 groups, whereas the phosphorylation of mTOR and IRS-1 was significantly lower. Conclusion:PIR involves AMPK and mTOR/S6K1/IRS-1 pathways. POC reduces PIR by the stimulation of AMPK, which suppresses the phosphorylation of mTOR/IRS-1 and attenuates PIR after colorectal resection.
Aberrant Gray Matter Volume and Cortical Surface in Paranoid-Type Delusional Disorder
Authors: Wolf Robert Christian , Hildebrandt Viviane , Schmitgen Mike M. , Pycha Roger , Kirchler Erwin , Macina Christian , Karner Martin , Hirjak Dusan , Kubera Katharina M. , Romanov Dmitry , Freudenmann Roland Wolfgang , Huber Markus
Published: March 2020

Introduction: Delusions are core symptoms of schizophrenia-spectrum and related disorders. Despite their clinical relevance, the neural correlates underlying such phenomena are unclear. Recent research suggests that specific delusional content may be associated with distinct neural substrates. Objective: Here, we used structural magnetic resonance imaging to investigate multiple parameters of brain morphology in patients presenting with paranoid type delusional disorder (pt-DD, n = 14) compared to those of healthy controls (HC, n = 25). Methods: Voxel- and surface-based morphometry for structural data was used to investigate gray matter volume (GMV), cortical thickness (CT) and gyrification. Results: Compared to HC, patients with pt-DD showed reduced GMV in bilateral amygdala and right inferior frontal gyrus. Higher GMV in patients was found in bilateral orbitofrontal and in left superior frontal cortices. Patients also had lower CT in frontal and temporal regions. Abnormal gyrification in patients was evident in frontal and temporal areas, as well as in bilateral insula. Conclusions: The data suggest the presence of aberrant GMV in a right prefrontal region associated with belief evaluation, as well as distinct structural abnormalities in areas that essentially subserve processing of fear, anxiety and threat in patients with pt-DD. It is possible that cortical features of distinct evolutionary and genetic origin, i.e. CT and gyrification, contribute differently to the pathogenesis of pt-DD.
Impact of Anterior Kidney Calyx Involvement of Complex Stones on Outcomes for Patients Undergoing Percutaneous Nephrolithotomy
Authors: Kalkanli Arif , Cilesiz Nusret Can , Fikri Onur , Ozkan Arif , Gezmis Cem Tugrul , Aydin Memduh , Tandoğdu Zafer
Published: March 2020

Introduction: A number of factors that can impact the outcomes of percutaneous nephrolithotomy (PCNL) procedures have previously been investigated. Complex stones that extend to the anterior calyx could affect the success and complication rates of PCNL. Objective: We analyzed the effect of anterior calyx involvement on the outcomes of patients with complex stones treated with PCNL. Methods: A total of 132 consecutive patients who underwent PCNL due to complex stones (multiple, partial staghorn, or staghorn stones) between 2015 and 2017 were enrolled in this study. They were stratified into two groups based on whether the stone extended to the anterior calyx (group 1, n = 45) or not (group 2, n = 87). The stratification was achieved through contrast-enhanced computerized tomography (CT). Demographics, laboratory tests, and peri- and postoperative findings (operation and fluoroscopy duration, hospital stay, utilization of flexible instruments, access numbers, total blood count change, stone-free rate [SFR], and complications) were compared between the groups. The SFR was evaluated by plain kidney-ureter-bladder radiography or CT. Results: The demographics, operation and fluoroscopy duration, access number, and hospital stay were similar between the groups (p < 0.05). A higher drop in the hemoglobin level in group 1 was identified (group 1 [2.14 ± 1.49 g/dL] vs. group 2 [1.43 ± 1.31 g/dL]) (p = 0.006). The SFR among the patients with extension to the anterior calyx was 60%, compared to 77% among the patients with no extension to the anterior calyx (p = 0.041). Flexible instruments were utilized in 60% of the patients of group 1, which was a higher rate than for group 2 (36%) (p = 0.007). Complication rates were similar in the two groups according to the Clavien-Dindo classification (p > 0.05). Conclusions: Our study demonstrated that complicated stones with extension to the anterior calyx are more challenging than cases without extension to the anterior calyx. This was noted by a lower SFR, a more prominent drop in total blood count, and more frequent utilization of flexible scopes.
Prognostic Impact of Postoperative Complications following Salvage Esophagectomy for Esophageal Cancer after Definitive Chemoradiotherapy
Authors: Sugimura Keijiro , Miyata Hiroshi , Shinno Naoki , Ushigome Hajime , Asukai Kei , Hara Hisashi , Hasegawa Shinichiro , Yamada Daisaku , Yamamoto Kazuyoshi , Haraguchi Naotsugu , Nishimura Junichi , Motoori Masaaki , Wada Hiroshi , Takahashi Hidenori , Yasui Masayoshi , Omori Takeshi , Ohue Masayuki , Yano Masahiko
Published: March 2020

Background: Recent studies have reported that the occurrence of postoperative complications after esophagectomy for esophageal cancer has a negative impact on long-term survival. Although salvage esophagectomy is associated with higher rates of morbidity and mortality, the impact of postoperative complications on long-term survival following salvage esophagectomy has not been fully investigated. Methods: We retrospectively analyzed 73 patients with thoracic esophageal cancer who underwent salvage esophagectomy between January 1997 and December 2017 after definitive chemoradiotherapy. We investigated the clinical impact of postoperative complications on long-term survival after salvage esophagectomy. Results: Postoperative complications, pulmonary complications, and anastomotic leakage occurred in 34 (47%), 14 (13%), and 14 (19%) of the patients, respectively. Patients with complications had significantly poorer survival than patients who did not have complications (HR [hazard ratio], 2.06; p = 0.017), but there were no significant differences in overall survival between patients with and those without pulmonary complications or anastomotic leakage (HR, 1.48, p = 0.318, and HR, 1.37, p = 0.377, respectively). Multivariate analysis revealed that pathological T3–4 disease (HR, 4.63; p = 0.001), residual disease (HR, 5.09; p = 0.001), and postoperative complications (HR, 3.85; p = 0.001) were significant independent prognostic factors. In particular, the frequency of death from other diseases among patients with postoperative complications was nonsignificantly higher than among patients without postoperative complications (26 vs. 10%; p = 0.071). Conclusion: The occurrence of complications leads to a poor prognosis for patients with esophageal cancer after salvage esophagectomy. Prevention of postoperative complications and long-term postoperative general supportive care might be important for improving patients’ prognosis.