bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspects of Independent Game Production
Authors: Pereira Leônidas S. , Bernardes Maurício M. S.
Published: November 2018

Recent years have witnessed independent game production rise to a prominent position in the digital game industry. Be it by the fresh, innovative take it brought to the scene or by its rebellious attitude towards what is perceived as mainstream, the term “indie game” has become somewhat of a buzzword. The following study displays a series of findings of research fieldwork aiming to advance the study of indie game development by investigating organizational and managerial practices commonly adopted by these developers. Relying on semi-structured interviews conducted with lead developers of seven Brazilian indie game firms, the connections, similarities, and differences among these developers’ firm structure and project management practices and those of the larger game industry is explored, utilizing the lenses of scope, organization, time, cost, and quality management as a starting point. Given the growing and significant relevance of the game industry as a whole, this empirical study offers pragmatic data on the still-niche research topic of indie games.
Fast and Realistic Reflections Using Screen Space and GPU Ray Tracing—A Case Study on Rigid and Deformable Body Simulations
Authors: Macedo Daniel Valente De , Serpa Ygor Rebouças , Rodrigues Maria Andréia Formico
Published: November 2018

The realistic representation of light within a computational domain is not a trivial task. Although several rendering approaches exist, the ray tracing technique is highly regarded as robust and realistic; however, its computational cost is still prohibitive for real-time games and other 3D applications. A modern tradeoff is to pair the ray tracing with the rasterization step, the former being responsible for generating complex lighting interactions, such as reflections, while the latter is used to generate less demanding visual effects, such as diffuse lighting and shadows. The stated framework has been studied by several authors, but it has not been shown to work both efficiently and accurately for highly dynamic scenes with deformable geometry. Stepping in this direction, this work presents a case study whose goal is to generate fast and realistic reflections on rigid and deformable body simulations using a hybrid approach that brings together the Screen Space technique with the GPU ray tracing algorithm and their respective main capabilities. The results show that not only realistic reflections can be generated at interactive rates, but also that the hybrid approach allows to achieve a certain level of scalability with respect to the number of triangles updated on every frame during the simulations.
Overview of PPSN 2018
Authors: Fonseca Carlos M. , Whitley Darrell
Published: November 2018

The PPSN 2018 Conference (Parallel Problem Solving From Nature) was held from September 8 to 12 in the historic city of Coimbra, Portugal. Coimbra is a UNESCO World Heritage site with many architectural structures dating back to the Roman era. PPSN was held at the University of Coimbra, which was established in 1290. The University and much of Coimbra are located on a hill along the Montego River.
RSHSC-Routing Algorithm Based on Simplified Harmony Search and Coding for UWSNs
Authors: Li Meiju , Du Xiujuan , Peng Chunyan
Published: November 2018

With the development of wireless networks and increasingly interest of people in underwater resources and environment, UWSNs are being paid more and more attention. Because of the characteristics of underwater channel and acoustic signal, the protocols used in the terrestrial networks cannot be directly used in UWSNs. In this paper, a reliable and energy-efficient routing protocol based on SHS and coding, called RSHSC, is proposed. Firstly, regular nodes are assigned to cluster heads according to simplified harmony search algorithm. Secondly, partial network encoding is introduced and the next two-hop information is considered when data packets are transmitted to sink nodes from the source node. Only the best next-hop forwards data packets. All data packets from neighbor nodes are used for decoding. Thirdly, two schemes of updating routing are designed and compared. Lastly, extensive simulations prove RSHSC is effective in improving reliability and decreasing energy consumption.
Diagnostic Errors in Tuberculous Patients: A Multicenter Study from a Developing Country
Authors: Neshati Hashem , Sheybani Fereshte , Naderi HamidReza , Sarvghad MohamadReza , Soltani Ahmad Khalifeh , Efterkharpoor Elaheh , Nooghabi Mehdi Jabbari
Published: November 2018

Although there is still much to learn about the types of errors committed in health care and why they occur, enough is known today to recognize that a serious concern exists for patients. Tuberculosis (TB) is an infectious disease that is frequently subject to diagnostic errors. Missed or delayed diagnosis of TB can affect patients and community adversely. Our aim in the present study was at evaluating the type of diagnostic errors in TB patients from symptom onset to diagnosis. This was a multicenter cross-sectional study conducted in three university hospitals in Mashhad, Iran. We showed a long delay in diagnosing TB that is mostly related to the time from first medical visit to diagnosis. Errors in the diagnostic process were identified in 97.5% of patients. The most common type of error in diagnosing TB was failure in hypothesis generation (72%), followed by history taking and physical examination. In conclusion, it seems likely that efforts to improve public awareness of and health literacy for TB, to coordinate the referral and follow-up systems of patients, and to improve physicians’ skills in history taking and physical examination and clinical reasoning will result in reduced delay in diagnosis of TB and, perhaps, improved patient safety and community health.
SIRT3 a Major Player in Attenuation of Hepatic Ischemia‐Reperfusion Injury by Reducing ROS via Its Downstream Mediators: SOD2, CYP‐D, and HIF‐1α
Authors: Katwal Gaurav , Baral Dilip , Fan Xiaoli , Weiyang He , Zhang Xinjiang , Ling Li , Xiong Yan , Ye Qifa , Wang Yanfeng
Published: November 2018

Reactive oxygen species (ROS) production in hepatic ischemia‐reperfusion injury (IRI) is a complex process where multiple cellular and molecular pathways are involved. Few of those molecular pathways are under the direct influence of SIRT3 and its downstream mediators. SIRT3 plays a major role in the mechanism of IRI, and its activation has been shown to attenuate the deleterious effect of ROS during IRI via SOD2‐, CYP‐D‐, and HIF‐1α‐mediated pathways. The objective of this review is to analyze the current knowledge on SIRT3 and its downstream mediators: SOD2, CYP‐D, and HIF‐1α, and their role in IRI. For the references of this review article, we have searched the bibliographic databases of PubMed, Web of Science databases, MEDLINE, and EMBASE with the headings “SIRT3,” “SOD2,” “CYP‐D,” “HIF‐1α,” and “liver IRI.” Priority was given to recent experimental articles that provide information on ROS modulation by these proteins. All the recent advancement demonstrates that activation of SIRT3 can suppress ROS production during IRI through various pathways and few of those are via SOD2, CYP‐D, and HIF‐1α. This effect can improve the quality of the remnant liver following resection as well as a transplanted liver. More research is warranted to disclose its role in IRI attenuation via this pathway.
Antimicrobial Fatty Acids from Green AlgaUlva rigida(Chlorophyta)
Authors: Ismail Amel , Ktari Leila , Ben Redjem Romdhane Yosr , Aoun Brahim , Sadok Saloua , Boudabous Abdellatif , El Bour Monia
Published: November 2018

This study deals with the antimicrobial potential assessment ofUlva rigida,in regard to collection period and sampling site. Besides, we assess the chemical composition of bioactive compounds. For this purpose,Ulva rigidawas seasonally collected from two northern sites in Tunisia, Cap Zebib rocky shore (CZ) and Ghar El Melh lagoon (GEM). Crude organic extracts were prepared using dichloromethane and dichloromethane/methanol and tested against 19 indicator microorganisms using the disk diffusion method and microdilution technique to determine the minimum inhibitory concentration (MIC). Silica gel column and thin layer chromatography were used for purification of active compounds. Nuclear magnetic resonance (NMR) and gas chromatography were used for compounds identification. Samples ofUlva rigidacollected from the two sites have uniform antimicrobial activity throughout the year. Algae collected from the lagoon showed the largest spectrum of activity and were used for subsequent analysis. Bioguided purification of extracts fromUlva rigida,collected at GEM, leads to 16 active fractions with antibacterial effect mainly againstStaphylococcus aureusATCC 25923 andEnterococcus faecalisATCC 29212. These fractions were identified as fatty acids, mainly oleic (C18: 1 w9), linoleic (C18: 2 w6), palmitic (C16: 0), and stearic (C14: 0). MICs values ranged from 10 to 250μg/ml.
3D Reconstruction and Prediction of Sialolith Surgery
Authors: Santos Jamyson Oliveira , da Silva Firmino Brunna , Carvalho Matheus Santos , de Pinho Mendes Jean , Teixeira Lucas Novaes , de Castro Lopes Sérgio Lúcio Pereira , Costa André Luiz Ferreira , Pinto Antonione Santos Bezerra
Published: November 2018

Imaging examinations play an important role in the diagnosis of sialolithiasis, whose symptoms are initially confounded with other diseases. The objective of the present case report is to highlight imaging and processing techniques as well as image analysis for the preoperative assessment and planning of surgical interventions and adequate treatment of massive sialoliths. A 35-year-old male patient presented complaining of pain in the submandibular region and purulent secretions from a lingual caruncle with slightly increased volume in the region. Imaging examinations were ordered as follows: cone beam computed tomography, ultrasonography, and three-dimensional reconstruction, including clinical evaluation. A final diagnosis of sialolithiasis was established. Surgery was indicated and carried out by using a lateral transcervical approach for complete resection of the gland, which was based on the calculation of the total volume of the sialolith, thus increasing the surgery’s success.
A Cadaveric Comparative Study on the Surgical Accuracy of Freehand, Computer Navigation, and Patient-Specific Instruments in Joint-Preserving Bone Tumor Resections
Authors: Bosma Sarah E. , Wong Kwok Chuen , Paul Laurent , Gerbers Jasper G. , Jutte Paul C.
Published: November 2018

Orthopedic oncologic surgery requires preservation of a functioning limb at the essence of achieving safe margins. With most bone sarcomas arising from the metaphyseal region, in close proximity to joints, joint-salvage surgery can be challenging. Intraoperative guidance techniques like computer-assisted surgery (CAS) and patient-specific instrumentation (PSI) could assist in achieving higher surgical accuracy. This study investigates the surgical accuracy of freehand, CAS- and PSI-assisted joint-preserving tumor resections and tests whether integration of CAS with PSI (CAS + PSI) can further improve accuracy. CT scans of 16 simulated tumors around the knee in four human cadavers were performed and imported into engineering software (MIMICS) for 3D planning of multiplanar joint-preserving resections. The planned resections were transferred to the navigation system and/or used for PSI design. Location accuracy (LA), entry and exit points of all 56 planes, and resection time were measured by postprocedural CT. Both CAS + PSI- and PSI-assisted techniques could reproduce planned resections with a mean LA of less than 2 mm. There was no statistical difference in LA between CAS + PSI and PSI resections (p=0.92), but both CAS + PSI and PSI showed a significantly higher LA compared to CAS (p=0.042 and p=0.034, respectively). PSI-assisted resections were faster compared to CAS + PSI (p<0.001) and CAS (p<0.001). Adding CAS to PSI did improve the exit points, however not significantly. In conclusion, PSI showed the best overall surgical accuracy and is fastest and easy to use. CAS could be used as an intraoperative quality control tool for PSI, and integration of CAS with PSI is possible but did not improve surgical accuracy. Both CAS and PSI seem complementary in improving surgical accuracy and are not mutually exclusive. Image-based techniques like CAS and PSI are superior over freehand resection. Surgeons should choose the technique most suitable based on the patient and tumor specifics.
Predictive Factors for Successful Type 1 Big Bubble during Deep Anterior Lamellar Keratoplasty
Authors: Borderie Vincent M. , Touhami Sara , Georgeon Cristina , Sandali Otman
Published: November 2018

Objective. Big bubble (BB)-deep anterior lamellar keratoplasty (DALK) has become the reference transplantation technique for corneal stromal disorders. Type 1 BB is the desired aspect but it is not constant. We aimed to determine the predictive factors of type 1 BB success.Methods. Observational cohort study including 77 consecutive eyes of 77 patients undergoing DALK by one surgeon at a single reference center without any selection. Clinical and spectral domain optical coherence tomography data were collected pre- and postoperatively.Results. Stromal scars were found in 91.8% of cases and were located in the anterior (90.9%), mid (67.5%), and posterior (36.4%) stroma. Type 1 BB (49.3% of cases) was significantly associated with the absence of scars in the posterior stroma, stage 1–3 keratoconus, and deep trephination. Among eyes with posterior scars, type 1 BB was associated with higher minimal corneal thickness, maximum-minimum corneal thickness < 220 μm, and diagnosis other than keratoconus. Eyes with type 1 BB featured significantly thinner residual stromal bed (22 ± 8 µm versus 61 ± 28 µm), thinner corneas at 12, 24, and 36 months, and better visual acuity at 12 months compared with eyes with no type 1 BB. Conversely, no significant differences between both groups were observed for graft survival, visual acuity at 24 and 36 months, and endothelial cell density at 12 and 36 months.Conclusion. OCT assessment before DALK is useful for choosing trephination depth that should be as deep as possible and for looking for posterior scars. The BB technique may not be the most appropriate method in keratoconus with posterior scars. Follow-up data do not support the need for conversion to penetrating keratoplasty when type 1 BB cannot be obtained nor does it support the need for performing a penetrating keratoplasty as a first-choice procedure in eyes with posterior stromal scars.
Comparison of Biological Properties of Two Medicinal Extracts of the Tehuacan‐Cuicatlan Valley
Authors: Martinez-Elizalde Karla S. , Rodriguez-Monroy Marco A. , Flores Cesar M. , Hernandez-Portilla Luis B. , Barbosa-Cabrera Elizabeth , Canales-Martinez Ma. Margarita
Published: November 2018

In the Valley of Tehuacan‐Cuicatlan, Cyrtocarpa procera and Bursera morelensis are located and are used in traditional medicine. In this research, several biological properties were evaluated. The methanol extracts of C. procera (MeCp) and B. morelensis (MeBm) were obtained by maceration. The antibacterial activities of the extracts were evaluated by the Kirby–Baüer disc‐diffusion method. The wound healing activity was evaluated by histopathological analysis. Both extracts had a bacteriostatic effect in the Staphylococcus aureus (MeCp MIC = 0.25 mg/mL and MeBm MIC = 1 mg/mL) and the Vibrio cholerae (MeCp MIC = 1 mg/mL and MeBm MIC = 4 mg/mL). Both extracts demonstrated a wound healing efficacy similar to the reference standard (Recoveron). They also showed a high antioxidant capacity (MeCp SC50 = 5.75 μg/mL and MeBm SC50 = 4.27 μg/mL). These results are related to the concentration of phenols (MeCp = 166 and MeBm = 236.6 mg GAe/g) and flavonoids of MeCp = 16 and MeBm = 22 μg Qe/g. Both extracts, acting in a similar way in microorganisms that cause infection thanks to their antioxidant activity, favor the healing of wounds. This is the first study in which the biological properties of these two species are compared.
Impact of an In-House Pediatric Surgery Unit and Human Milk Centered Enteral Nutrition on Necrotizing Enterocolitis
Authors: Zamrik Sonja , Giachero Federica , Heldmann Michael , Hensel Kai O. , Wirth Stefan , Jenke Andreas C.
Published: November 2018

The importance for mortality and morbidity of an in-house pediatric surgery unit for premature infants with necrotizing enterocolitis (NEC) remains undefined. Data on 389 consecutive very low birth weight infants with a birth weight <1250 g admitted between 2009 and 2014 was retrospectively analyzed in two almost identical neonatal intensive care units. Epidemiological data (n=172 and n=217, respectively) were comparable. Incidence of NEC stage II+ was significantly higher in center 1 (15.1 versus 5.5%, n=18 versus 6). This correlated with a significantly lower rate of exclusive human milk feeding compared to center 2 (24.2 versus 59.3%). Probiotic treatment did not differ. Importantly, in case of surgery the length of removed intestine (49.9 versus 19.5 cm) and the rate of severe short-bowel syndrome (38.9 versus 0 %) were significantly higher in center 1 (no in-house pediatric surgery). Furthermore, long-term morbidity assessment revealed more impaired motoric (-4.2 versus -2.2 months, p=0.21) and psychologic (-4.3 versus -1.6 months, p=0.09) development in center 1. Mortality was similar in both centers. Conclusions. Short- and possibly also long-term morbidity of NEC is clearly associated with the presence of an on-site pediatric surgery unit. Enteral nutrition with human milk seems to be a strong protective factor against NEC.
An Effective Flocculation Method to the Kaolin Wastewater Treatment by a Cationic Polyacrylamide (CPAM): Preparation, Characterization, and Flocculation Performance
Authors: Zakaria Djibrine Badradine , Zheng Huaili , Wang Moxi , Liu Shuang , Tang Xiaomin , Khan Sarfaraz , Jimenéz Andrea Navarro , Feng Li
Published: November 2018

P(AM-DMC) (PAD) was synthesized by ultraviolet- (UV-) initiated copolymerization with methacryloxyethyl trimethyl ammonium chloride (DMC) and acrylamide (AM) as the monomers and initiator 2,2-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (VA-044) as the photoinitiator. Parameters that affect the molecular weight were reviewed by using the single-factor approach. The results showed that the molecular weight (MW) of PAD could come to 7.88 × 106 Da with the optimum polymerization conditions as follows: monomer concentration of 30%, monomer mass ratio m(AM) : m(DMC) of 3 : 1, initiator concentration of 0.6‰, illumination time of 80 min, solution pH value of 4.5, and incident light intensity of 1000 μW cm−2. The PAD was represented by several instruments. The results of FTIR and 1H NMR showed that PAD was indeed polymerized by AM and DMC. The results of TGA showed that PAD was very stable at room temperature while the result of SEM revealed that PAD had a porous structure and rough surface. For PAD used as flocculant in kaolin wastewater treatment, the results confirmed that, at optimal conditions, the turbidity and the floc size d50 could reach to 5.9 NTU and 565.936 μm, respectively, at the optimal conditions (pH = 7.0 and dosage = 2 mg l−1). Kaolin wastewater flocculation test outcome reveals that the PAD with high cationic degree and intrinsic viscosity could boost the charge neutralization and bridging capability. Consequently, the result is an excellent flocculation performance of treating kaolin wastewater.
Correlation between Quantitative 13C-Urea Breath Test and Helicobacter pylori Treatment Success in a Population-Based Cohort
Authors: Boltin Doron , Levi Zohar , Perets Tsachi Tsadok , Schmilovitz-Weiss Hemda , Gingold-Belfer Rachel , Dickman Ram , Dotan Iris
Published: November 2018

Background. There are continual efforts to identify factors which influence the success of first-line therapy for Helicobacter pylori (H. pylori) infection. The 13C-urea breath test result (C13-UBT) utilizes H. pylori urease activity and is a highly accurate diagnostic assay. We aimed to determine whether the magnitude of C13-UBT result is related to treatment success. Methods. Adult patients who underwent a first-time 13C-urea breath test between January 2010 and January 2016 were included. In order to isolate a naïve test-and-treat population who were unlikely to have undergone an initial endoscopy-based H. pylori test, we excluded patients > 45 years and those with a previous C13-UBT. Data were extracted from the Clalit Health Services laboratory database. Results. A total of 94,590 subjects (36.1% male, age 28.5 ± 6.0 years) who underwent a first-time C13-UBT during the study period were included. C13-UBT was positive in 48,509 (51.3%) subjects. A confirmatory posttreatment C13-UBT was performed in 18,375 (37.8%), and eradication was successful in 12,018 (65.4%). The mean C13-UBT recording was 20.6 ± 16.2 DOB in subjects with successful eradication and 19.5 ± 13.1 DOB in subjects with treatment failure (OR, 1.01; 95% CI 1.00-1.01, p<0.01). Among patients in the upper quintile of C13-UBT measurement, eradication was achieved in 67.6%, compared to 62.6% in the lower quintile (OR, 1.22; 95% CI 1.11-1.35, p<0.01). Subjects in the top 1 percentile (C13-UBT ≥ 70 DOB) achieved eradication in 75.0%, compared to 65.3% among subjects with C13-UBT < 70 DOB (OR, 1.59; 95% CI 1.05-2.41, p<0.01). Conclusions. The superiority in H. pylori eradication observed in subjects with a higher C13-UBT DOB is small but significant. Further studies should examine the physiological and microbiological basis for this finding.
Impacts of Water Consumption in the Haihe Plain on the Climate of the Taihang Mountains, North China
Authors: Zou Jing , Zhan Chesheng , Zhao Ruxin , Qin Peihua , Hu Tong , Wang Feiyu
Published: November 2018

In this study, the RegCM4 regional climate model was employed to investigate the impacts of water consumption in the Haihe Plain on the local climate in the nearby Taihang Mountains. Four simulation tests of twelve years’ duration were conducted with various schemes of water consumption by residents, industries, and agriculture. The results indicate that water exploitation and consumption in the Haihe Plain causes wetting and cooling of the local land surface and rapid increases in the depth of the groundwater table. These wetting and cooling effects increase atmospheric moisture, which is transported to surrounding areas, including the Taihang Mountains to the west. In a simulation where water consumption in the Haihe Plain was doubled, the wetting and cooling effects in the Taihang Mountains were enhanced but at less than double the amount, because a cooler land surface does not enhance atmospheric convective activities. The impacts of water consumption activities in the Haihe Plain were more obvious during the irrigation seasons (primarily spring and summer). In addition, the land surface variables in the Taihang Mountains, e.g., sensible and latent heat fluxes, were less sensitive to the climatic impacts due to the water consumption activities in the Haihe Plain because they were strongly affected by local surface energy balance.
Long-Pulse Gastric Electrical Stimulation Repairs Interstitial Cells of Cajal and Smooth Muscle Cells in the Gastric Antrum of Diabetic Rats
Authors: Chen Yan , Wang Hongcai , Li Hai , Liu Shi
Published: November 2018

Background/Aims. The damage of interstitial cells of Cajal and smooth muscle cells has far-reaching implications in the pathogenesis of gastroparesis in diabetic patients. Gastric electrical stimulation (GES) is an efficient therapy for gastric motility disorders, but the mechanisms of GES require clarification.Methods. Male rats were randomly divided into the control group, diabetic rat group (DM), diabetic rats with sham GES group (DM + SGES), and diabetic rats with different frequency GES group (DM + GES) (GES1: 5.5 cpm, 100 ms, 4 mA; GES2: 5.5 cpm, 300 ms, 4 mA; and GES3: 5.5 cpm, 550 ms, 2 mA). Gastric contractions were explored using the organ bath technique. The alterations of interstitial cells of Cajal, the SCF/c-kit pathway, and smooth muscle cells were also investigated.Results. (1) Gastric contractions were significantly improved in the DM + GES group compared with those in the DM group. (2) The damage of interstitial cells of Cajal was prevented in the DM + GES group in contrast to the DM group. Moreover, long-pulse GES increased the expression of the SCF/c-kit pathway. More proliferated interstitial cells of Cajal in muscle layers were observed obviously in the DM + GES group. (3) The number of smooth muscle cells in the DM group was not significantly decreased compared with that in the control group. However, ultrastructural changes were distinctly damaged in the DM group. The application of GES protected against the alteration of the ultrastructures of smooth muscle cells.Conclusions. Long-pulse GES improves gastric contraction possibly by enhancing the proliferation of interstitial cells of Cajal and restoring the injury of smooth muscle cells.
A Novel Blind and Robust Video Watermarking Technique in Fast Motion Frames Based on SVD and MR-SVD
Authors: Nouioua Imen , Amardjia Nouredine , Belilita Sarra
Published: November 2018

In this work, a novel and efficient digital video watermarking technique based on the Singular Value Decomposition performed in the Multiresolution Singular Value Decomposition domain is proposed. While most of the existing watermarking schemes embed the watermark in all the video frames, which is time-consuming and also affects the perceptibly of the video quality, the proposed method chooses only the fast motion frames in each shot to host the watermark. In doing so, the number of frames to be processed is consequently reduced and a better quality of the watermarked video is also ensured since the human visual system cannot notice the variations in fast moving regions. The watermark information is embedded by Quantization Index Modulation which is a blind watermarking algorithm. The experimental results demonstrate that the proposed method can achieve a very good transparency, while being robust against various kinds of attacks such as filtering, noising, compression, and frame collusion. Compared with several methods found in the literature, the proposed method gives a better robustness.
Management of Acquired Hemophilia A in Elderly Patients
Authors: Yamaguchi Tomoya , Kudo Naoko , Endo Susumu , Usui Takeo , Imashuku Shinsaku
Published: November 2018

This report describes six elderly patients with acquired hemophilia A (AHA), including four individuals aged ≥90 years. Bleeding symptoms were subcutaneous or intramuscular hemorrhage (n=4), hematuria (n=1), and hemorrhagic shock after tooth extraction (n=1). Factor VIII (FVIII) activity ranged from <1.0% to 3.0%, and anti-FVIII inhibitor titers ranged from 8.8 to 240 BU/mL. Treatment was administered at the discretion of the responsible physician. Hemostatic agents applied in the six patients comprised rFVIIa (NovoSeven®) (n=4), APCC (Feiba®) (n=2), and fresh frozen plasma/plasma exchange (n=1). Agents employed for inhibitor eradication comprised prednisolone only (n=3), prednisolone with cyclophosphamide (n=1), prednisolone with cyclosporine (n=1), and prednisolone with rituximab (n=1). In five patients, management was successful, with complete response. Treatment failed in the patient with the highest inhibitor level (240 BU/mL) in whom treatment with APCC (Feiba®; 100 U/kg/dose, three doses) and prednisolone (0.5 mg/kg/day) was followed by several episodes of relapse. The present data demonstrate that AHA severity shows wide variation in elderly subjects, indicating the necessity of individualized management.
β3‐Adrenoreceptors Control Mitochondrial Dormancy in Melanoma and Embryonic Stem Cells
Authors: Calvani Maura , Cavallini Lorenzo , Tondo Annalisa , Spinelli Valentina , Ricci Luisa , Pasha Amada , Bruno Gennaro , Buonvicino Daniela , Bigagli Elisabetta , Vignoli Marina , Bianchini Francesca , Sartiani Laura , Lodovici Maura , Semeraro Roberto , Fontani Filippo , De Logu Francesco , Dal Monte Massimo , Chiarugi Paola , Favre Claudio , Filippi Luca
Published: November 2018

The early phases of embryonic development and cancer share similar strategies to improve their survival in an inhospitable environment: both proliferate in a hypoxic and catecholamine‐rich context, increasing aerobic glycolysis. Recent studies show that β3‐adrenergic receptor (β3‐AR) is involved in tumor progression, playing an important role in metastasis. Among β‐adrenergic receptors, β3‐AR is the last identified member of this family, and it is involved in cancer cell survival and induction of stromal reactivity in the tumor microenvironment. β3‐AR is well known as a strong activator of uncoupling protein 1 (UCP1) in brown fat tissue. Interestingly, β3‐AR is strongly expressed in early embryo development and in many cancer tissues. Induction of uncoupling protein 2 (UCP2) has been related to cancer metabolic switch, leading to accelerated glycolysis and reduced mitochondrial activity. In this study, for the first time, we demonstrate that β3‐AR is able to promote this metabolic shift in both cancer and embryonic stem cells, inducing specific glycolytic cytoplasmic enzymes and a sort of mitochondrial dormancy through the induction of UCP2. The β3‐AR/UCP2 axis induces a strong reduction of mitochondrial activity by reducing ATP synthesis and mitochondrial reactive oxygen species (mtROS) content. These effects are reverted by SR59230A, the specific β3‐AR antagonist, causing an increase in mtROS. The increased level of mtROS is neutralized by a strong antioxidant activity in embryonic stem cells, but not in cancer stem cells, where it causes a dramatic reduction in tumor cell viability. These results lead to the possibility of a selective antitumor therapeutic use of SR59230A. Notably, we demonstrate the presence of β3‐AR within the mitochondrial membrane in both cell lines, leading to the control of mitochondrial dormancy.
Strength Characteristics and the Reaction Mechanism of Stone Powder Cement Tailings Backfill
Authors: Hu Jianhua , Ren Qifan , Jiang Quan , Gao Rugao , Zhang Long , Luo Zhouquan
Published: November 2018

Stone powder cement (SPC) is widely used as a novel cement substitute material in concrete for its good gelling performance and low cost. In order to reduce the backfilling cost and assess the potential of SPC backfilling materials, a series of experiments were conducted to analyze the strength and hydration reaction mechanism of stone powder cement tailings backfill (SPCTB). The analysis was based on SPC and tailings, which were used as the gelling agent and the aggregate, respectively. The results showed that the strength of the backfill was greatly reduced at an early stage and slightly reduced in the final stages. The stone powder content was less than 15%, which met the requirement of mining procedure. The addition of stone powder reduced the content of adsorbed water and capillary water in the early stages, while it increased in the middle stages. The SiO2 contained in stone powder reacted with the hydration products at later stages, which is the reason why the growth of strength is rapid between the groups with the addition of stone powder. The addition of stone powder improved the microstructure of backfill and produced a denser three‐dimensional (3D) network structure; however, the plane porosities of Groups A and B gradually increased with the increase in the content of stone powder. The cement powder mixed appropriately with the stone power could meet the strength requirement and reduce the cost of backfilling materials.
Synthesis of Some Pyrimidine, Pyrazole, and Pyridine Derivatives and Their Reactivity Descriptors
Authors: Abd El-Sattar Nour E. A. , Badawy Eman H. K. , Abdel-Mottaleb M. S. A.
Published: November 2018

A series of novel pyrimidine (2, 3), pyrazole (4, 5), and pyridine (6) derivatives were synthesized using a chalcone-bearing thiophene nucleus (1). The target compounds were synthesized by reaction of compound (1) with urea, thiourea, malononitrile, hydrazine hydrate, and 2,4-dinitrophenyl hydrazine, respectively. Molecular electronic structures have been modeled within density functional theory framework (DFT). Reactivity indices and electrostatic surface potential maps (ESP maps) allow us to establish trends that enable making predictions about chemical characteristics of the newly synthesized molecules and their proton transfer tautomers. Proton transfer is generally more favored in solution than in the gas phase. In acetonitrile, keto-form tautomers and thione-form tautomers become more energetically stable than the corresponding enol or thiol tautomers due to solvent-induced enhancement in the molecular polarity identified by computed dipole moment.
Simultaneous Determination of Cr, As, Se, and Other Trace Metal Elements in Seawater by ICP-MS with Hybrid Simultaneous Preconcentration Combining Iron Hydroxide Coprecipitation and Solid Phase Extraction Using Chelating Resin
Authors: Itoh Akihide , Ono Masato , Suzuki Kota , Yasuda Takumi , Nakano Kazuhiko , Kaneshima Kimika , Inaba Kazuho
Published: November 2018

In the present study, ICP-MS with a new hybrid simultaneous preconcentration combining solid phase extraction using chelating resin and iron hydroxide coprecipitation in one batch at a single pH adjustment (pH 6.0) were developed for multielement determination of trace metal ions in seawater. In multielement determination, the present method makes it possible to determine Cr(III), As(V), Se (IV), and other 14 trace metal elements (Ti, V, Co, Ni, Cu, Zn, Zr, Ge, Cd, Sb, Sn, W, Pb, and U) in seawater. Moreover, for speciation analyses of Cr, As, and Se, the pH dependence on recovery for the different chemical forms of Cr, As, and Se was investigated. In speciation analyses, Cr, As, and Se were determined as the total of Cr (III) and a part of Cr (VI), total of As (III) and As (V), and Se(IV), respectively. Determination of total of Se and Cr(VI) remains as future task to improve. Nevertheless, the present method would have possibility to develop as the analytical method to determine comprehensively most metal elements in all standard and guideline values in quality standard in environmental water in Japan, that is, most toxic metal elements in environmental water.
Supporting Technology Research in Deep Well Based on Modified Terzaghi Formula
Authors: Peng Wen-qing , Wang Wei-jun , Yuan Chao
Published: November 2018

In order to solve the difficult problem of supporting roadway with large cross section and broken surrounding rock, the large‐section inclined shaft of Pingdingshan Coal Mine is taken as the research instance. In this paper, a modified formula for the Terzaghi ultimate bearing capacity of a foundation is established based on rock mass strength criteria. As per the engineering practice, the maximum roof pressure of the inclined shaft is calculated to be 2.7 MPa, and the minimum pressure value from the modified formula is only 0.3 MPa. In order to control the floor heave of the roadway, a U‐type steel inverted arch and bolts support scheme was designed. After calculating through the mechanical model of the inverted arch, its bearing capacity is 0.56 Mpa. Through comparison and analysis of various supporting schemes, finally, the “U‐type steel + inverted arch + pouring concrete + backwall grouting” technology is selected, and the engineering practice shows that the supporting scheme can effectively improve surrounding rock stability.
miR-146a Controls Immune Response in the Melanoma Microenvironment
Authors: Mastroianni Justin , Stickel Natalie , Andrlova Hana , Hanke Kathrin , Melchinger Wolfgang , Duquesne Sandra , Schmidt Dominik , Falk Martina , Andrieux Geoffroy , Pfeifer Dietmar , Dierbach Heide , Schmitt-Graeff Annette , Meiss Frank , Boerries Melanie , Zeiser Robert
Published: November 2018

MicroRNAs (miR) are small noncoding RNAs that regulate gene expression, posttranscription, and manipulate immune responses in different types of cancers. In this study, we identify miR-146a as a negative regulator of immune activation, comparable to immune-checkpoint molecules. miR-146a levels were increased in melanoma microenvironmental tissue, and miR-146a−/− mice survived longer and developed less metastases in comparison with wild-type melanoma-bearing mice. T cells isolated from miR-146a−/− mice revealed higher expression levels of the miR-146a target gene Stat1 and the Stat1-regulated cytokine IFNγ. Neutralization of IFNγ in miR-146a−/− mice decreased survival and increased melanoma metastasis patterns to those of wild-type mice. In vitro, IFNγ reduced melanoma cell migration, cell-cycle activity, and basal metabolic rate. Conversely, IFNγ also increased PD-L1 levels on the melanoma cells, which may counterbalance some of the beneficial effects increasing immune escape in vivo. Combined treatment with a miR-146a antagomiR and anti–PD-1 resulted in improved survival over isotype control or anti–PD-1 treatment alone. In summary, these data show that miR-146a plays a central role within the STAT1/IFNγ axis in the melanoma microenvironment, affecting melanoma migration, proliferation, and mitochondrial fitness as well as PD-L1 levels. Additionally, combined inhibition of PD-1 and miR-146a could be a novel strategy to enhance antitumor immune response elicited by checkpoint therapy.

Significance:

These findings identify a microRNA–based mechanism by which melanoma cells escape the immune system, providing a new therapeutic strategy to improve the current management of patients with melanoma.
Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer
Authors: Rachner Tilman D. , Kasimir-Bauer Sabine , Göbel Andy , Erdmann Kati , Hoffmann Oliver , Browne Andrew , Wimberger Pauline , Rauner Martina , Hofbauer Lorenz C. , Kimmig Rainer , Bittner Ann-Kathrin
Published: November 2018

Purpose:

We assessed serum concentrations of the receptor activator of NFκB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), two proteins implicated in the development and progression of breast cancer, in 509 patients with primary, nonmetastatic breast cancer. Then the results were evaluated with regards to the occurrence of bone metastases, the presence of disseminated tumor cells (DTC) in the bone marrow, survival, and risk of developing metastatic disease.

Experimental Design:

Before surgery, two bone marrow aspirates were analyzed for DTC using density centrifugation followed by immunocytochemistry (pan-cytokeratin antibody A45-B/B3). RANKL and OPG levels in the serum were measured by ELISA.

Results:

RANKL levels were significantly lower in women >60 years (P < 0.0001) and RANKL/OPG ratios higher in lymph node–positive patients (P < 0.05). High OPG serum levels were associated with a higher risk of death from breast cancer [HR 1.94; 95% confidence interval (CI) 1.23–3.07; P = 0.005] and OPG was an independent prognostic marker for breast cancer–specific survival (BCSS; multivariate analyses, P = 0.035). RANKL levels were 33% higher (P < 0.0001) in DTCpos patients (41%), whereas high levels were associated with a significantly better BCSS in DTCneg patients as compared with low levels (HR 0.524; 95% CI 0.30–0.95; P = 0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (P = 0.01) and patients within the highest quartile of RANKL had a significantly increased risk of developing bone metastases compared with those in the lowest (HR 4.62; 95% CI 1.49–14.34; P = 0.03).

Conclusions:

These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.
Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors
Authors: de Moel Emma C. , Rozeman Elisa A. , Kapiteijn Ellen H. , Verdegaal Els M.E. , Grummels Annette , Bakker Jaap A. , Huizinga Tom W.J. , Haanen John B. , Toes René E.M. , van der Woude Diane
Published: November 2018

Immune-checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre- and posttreatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival. Autoantibodies developed in 19.2% (19/99) of patients who were autoantibody-negative pretreatment. A nonsignificant association was observed between development of any autoantibodies and any irAEs [OR, 2.92; 95% confidence interval (CI) 0.85–10.01]. Patients with antithyroid antibodies after ipilimumab had significantly more thyroid dysfunction under subsequent anti–PD-1 therapy: 7/11 (54.6%) patients with antithyroid antibodies after ipilimumab developed thyroid dysfunction under anti–PD1 versus 7/49 (14.3%) patients without antibodies (OR, 9.96; 95% CI, 1.94–51.1). Patients who developed autoantibodies showed a trend for better survival (HR for all-cause death: 0.66; 95% CI, 0.34–1.26) and therapy response (OR, 2.64; 95% CI, 0.85–8.16). We conclude that autoantibodies develop under ipilimumab treatment and could be a potential marker of ICI toxicity and efficacy.
Recent Advances in Experimental Allergy
Authors: Adams Olivia Joan , von Gunten Stephan
Published: November 2018

Atopic disorders are on the rise and pose a great burden on society. A better understanding of the underlying mechanisms is required for the development of improved or novel therapeutic strategies. Here we aim to highlight recent advances in experimental allergy, with a particular focus on proposed treatment alternatives for airway disorders, atopic dermatitis, and food allergy. Furthermore, we discuss recent work focusing on molecular and cellular mechanisms that might offer candidates for future preventive or therapeutic intervention.
Global mRNA and Long Non-Coding RNA Expression in the Placenta and White Adipose Tissue of Mice Fed a High-Fat Diet During Pregnancy
Authors: Huang Chen , Huang Bin-bin , Niu Jian-min , Yu Yan , Qin Xiao-yun , Yang Ya-li , Xiao Tian-xia , Chen Jie , Ren Li-rong  , Zhang Jian V.
Published: November 2018

Background/Aims: Gestational diabetes mellitus (GDM) is a common complication of pregnancy, but the mechanisms underlying the disorders remain unclear. The study aimed to identify mRNA and long non-coding RNA (lncRNA) profiles in placenta and gonadal fat of pregnant mice fed a high-fat diet and to investigate the transcripts and pathways involved in the development of gestational diabetes mellitus. Methods: Deep and broad transcriptome profiling was performed to assess the expression of mRNAs and lncRNAs in placenta and gonadal fat from 3 mice fed an HFD and chow during pregnancy. Then, differentially expressed mRNAs and lncRNAs were validated by quantitative real-time PCR. The function of the differentially expressed mRNAs was determined by pathway and Gene Ontology (GO) analyses, and the physical or functional relationships between the lncRNAs and the corresponding mRNAs were determined. Results: Our study revealed that 82 mRNAs and 52 lncRNAs were differentially expressed in the placenta of mice fed an HFD during pregnancy, and 202 mRNAs and 120 lncRNAs were differentially expressed in gonadal fat. GO and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed differentially expressed mRNAs of placenta were closely related to extracellular matrix interactions, digestion, adhesion, and metabolism, whereas the differentially expressed mRNAs in adipose tissue were related to metabolic and insulin signalling pathways. The gene network demonstrated that Actg2, Cnfn, Muc16, Serpina3k, NONMMUT068202, and NONMMUT068203, were the core of the network in placental tissue, and the genes Tkt, Acss2, and Elovl6 served as the core of the network in gonadal fat tissue. Conclusion: These newly identified key genes and pathways in mice might provide valuable information regarding the pathogenesis of GDM and might be used to improve early diagnosis, prevention, drug design, and clinical treatment.
Ca2+ Signaling Triggered by Shear-Autocrine P2X Receptor Pathway in Rat Atrial Myocytes
Authors: Kim Joon-Chul , Son Min-Jeong , Woo Sun-Hee
Published: November 2018

Background/Aims: The atrium is exposed to high shear stress during heart failure and valvular diseases. We aimed to understand atrial shear-induced Ca2+ signaling and its underlying mechanisms. Methods: Pressurized micro-flow was applied to single rat atrial myocytes, and Ca2+ signal, membrane potential, and ATP release were assessed using confocal imaging, patch clamp technique, and luciferin-luciferase assay, respectively. Results: Shear stress (∼16 dyn/cm2) induced global Ca2+ waves (∼0.1 events/s) from the periphery to the center of cells in a transverse direction (“T-wave”; ∼145 μm/s). Pharmacological interventions and simultaneous recording of membrane potential and Ca2+ demonstrated that shear-induced T-waves resulted from action potential (AP)-triggered Ca2+ release from the sarcoplasmic reticulum. T-waves were not sensitive to inhibitors of known shear signaling mechanisms except connexin hemichannels and ATP release. Shear stress caused ATP release from these myocytes (∼1.1x10-17 moles/unit membrane, µm2); ATP release was increased by enhancement of connexin hemichannels and suppressed by inhibition of the hemichannels, but not affected by inhibitors of other ATP release pathways. Blockade of P2X receptor, but not pannexin or the Na+-Ca2+ exchanger, eliminated shear-induced T-wave initiation. Conclusion: Our data suggest that shear stress triggers APs and concomitant Ca2+ signaling via activation of P2X receptors by connexin hemichannel-mediated ATP release in atrial myocytes.