bluuebunny/crossref_metadata_2025 huggingface dataset:
Entanglement distribution in a two-dimensional 5-site frustrated J1−J2 spin system
Authors: Jafarpour Mojtaba , Ghanavati Soghra , Afshar Davood
Published: November 2015

We have studied several ground states and their entanglement structure for a two-dimensional 5-site frustrated [Formula: see text]–[Formula: see text] system in the presence and absence of an external magnetic field. We have used concurrence as a measure of bipartite entanglement and the Meyer–Wallach measure and its generalizations as the measures of multipartite entanglement. They provide a total of eight measures which lead to 30 entanglement quantities for each possible ground state. Computing these 30 quantities for several ground states, we have provided a detailed exposition of the entanglement distribution in each state. We have also categorized them into separable states, not showing entanglement for any bipartition; globally-entangled states, showing entanglement for all the bipartitions, and the states in between. It turns out that by adjusting the external magnetic field, conditioned on the values of the interaction parameters, one may generate specific ground states belonging to a specific class, appropriate for specific tasks in quantum information theory.
Palaeoproductivity linked to monsoon variability in the northern slope of the South China Sea from the last 290 kyr: evidence of benthic foraminifera from Core SH7B
Authors: Zhou Yang , Chen Fang , Wu Cong , Yu Shaohua , Zhuang Chang
Published: November 2015

A benthic foraminiferal proxy record of 290 kyr, acquired from Core SH7B in the northern continental slope of the South China Sea, was studied to identify the bottom-water environment changes since marine isotope stage (MIS) 8. The changes, including oxygenation and types of organic matter flux to the seafloor, reflect the palaeoproductivity fluctuations linked to monsoon variability. Four assemblages, characterizing different palaeoenvironmental changes, have been recognized by factor and cluster analysis with 32 foraminiferal species in 93 samples (>150 µm size fraction). Assemblage
Pyrgo
spp.–
Hoeglundina elegans
mainly dominates during interglacial periods of MIS 7, MIS 5 and MIS 3, suggesting well-oxygenated bottom environments with low sea surface productivity linked to a weak East Asian Winter Monsoon (EAWM). Assemblage
Uvigerina
spp.–
Globocassidulina subglobulosa
is composed of a constantly high percentage of shallow infaunal species, occurring in intervals of MIS 4, MIS 5, MIS 7 and MIS 8, which indicates that an enhanced EAWM led to a low seasonality of palaeoproductivity, a constant high flux of fresh and labile marine-derived organic particles to the seafloor and a low oxygen bottom environment. Assemblage
Melonis barleeanus
–
Clavulina
spp. is characterized by species that depend on seasonal supplies of more altered refractory organic matter and is mainly distributed in interglacial periods (late MIS 5, MIS 3 and MIS 1), suggesting a high seasonality of palaeoproductivity associated with a seasonal intensification of the EAWM. With low benthic foraminiferal diversity and abundance, assemblage
Globobulimina affinis
–
Chilostomella mediterranensis
was identified during the intermediate MIS 8 and early MIS 2. Both substantial input of terrigenous nutrients from an increased river run-off and an increased primary productivity correlated with an enhanced EAWM have led to abundant nutrient supplies and severe bottom-water oxygen depletion. As suggested by the composition of benthic foraminiferal in Core SH7B, changes in bottom-water environments of the northern South China Sea over the last 290 kyr were driven by the fluctuating palaeoproductivity linked to the high variability of the EAWM.
What is the vergence-accommodation conflict and how do we fix it?
Authors: Konrad Robert
Published: November 2015

The next wave of virtual reality technology might turn to light field displays to solve a dizzying problem.
Eccescopy
Authors: Perlin Ken
Published: November 2015

Creating a future where dreams walk among us.
Standards for Tomorrow
Authors: Milojicic Dejan , Nikolich Paul , Leiba Barry
Published: November 2015

Over the decades, standards have been critical for defining how to interconnect computer and networking devices across different vendors so they can seamlessly work together. Standards have been critical, not only in networking and computer interfaces, but also at the operating system and systems software level. There are many examples, such as IEEE 802, POSIX, IETF, and W3C. There was always the question of the right time to standardize (not too early and not too late), and the time to complete a standardization project always seemed too long, but inevitable. However, the contemporary industry seems to be more dynamic and evolving than it has ever been, demanding more agile processes. Open source processes and software defined (networks, storage, data centers, etc.) offer alternatives to standards. In this article we attempt to envision the future role of standards, and how they will complement and enhance alternative choices toward the same goal. We first summarize traditional standards, then discuss alternatives and a couple of use cases, and conclude with some future directions and opportunities for standardization.
The Maturation of a Scientist: An Autobiography
Authors: Roizman Bernard
Published: November 2015

I was shaped by World War II, years of near starvation as a war refugee, postwar chaos, life in several countries, and relative affluence in later life. The truth is that as I was growing up I wanted to be a writer. My aspirations came to an end when, in order to speed up my graduation from college, I took courses in microbiology. It was my second love at first sight—that of my wife preceded it. I view science as an opportunity to discover the designs in the mosaics of life. What initiates my search of discovery is an observation that makes no sense unless there exists a novel design. Once the design is revealed there is little interest in filling all the gaps. I was fortunate to understand that what lasts are not the scientific reports but rather the generations of scientists whose education I may have influenced.
Accelerated cardiac remodeling in desmoplakin transgenic mice in response to endurance exercise is associated with perturbed Wnt/β-catenin signaling
Authors: Martherus Ruben , Jain Rahul , Takagi Ken , Mendsaikhan Uzmee , Turdi Subat , Osinska Hanna , James Jeanne F. , Kramer Kristen , Purevjav Enkhsaikhan , Towbin Jeffrey A.
Published: November 2015

Arrhythmogenic ventricular cardiomyopathy (AVC) is a frequent underlying cause for arrhythmias and sudden cardiac death especially during intense exercise. The mechanisms involved remain largely unknown. The purpose of this study was to investigate how chronic endurance exercise contributes to desmoplakin (DSP) mutation-induced AVC pathogenesis. Transgenic mice with overexpression of desmoplakin, wild-type (Tg-DSPWT), or the R2834H mutant (Tg-DSPR2834H) along with control nontransgenic (NTg) littermates were kept sedentary or exposed to a daily running regimen for 12 wk. Cardiac function and morphology were analyzed using echocardiography, electrocardiography, histology, immunohistochemistry, RNA, and protein analysis. At baseline, 4-wk-old mice from all groups displayed normal cardiac function. When subjected to exercise, all mice retained normal cardiac function and left ventricular morphology; however, Tg-DSPR2834H mutants displayed right ventricular (RV) dilation and wall thinning, unlike NTg and Tg-DSPWT. The Tg-DSPR2834H hearts demonstrated focal fat infiltrations in RV and cytoplasmic aggregations consisting of desmoplakin, plakoglobin, and connexin 43. These aggregates coincided with disruption of the intercalated disks, intermediate filaments, and microtubules. Although Tg-DSPR2834H mice already displayed high levels of p-GSK3-βSer9 and p-AKT1Ser473 under sedentary conditions, decrease of nuclear GSK3-β and AKT1 levels with reduced p-GSK3-βSer9, p-AKT1Ser473, and p-AKT1Ser308 and loss of nuclear junctional plakoglobin was apparent after exercise. In contrast, Tg-DSPWT showed upregulation of p-AKT1Ser473, p-AKT1Ser308, and p-GSK3-βSer9 in response to exercise. Our data suggest that endurance exercise accelerates AVC pathogenesis in Tg-DSPR2834H mice and this event is associated with perturbed AKT1 and GSK3-β signaling. Our study suggests a potential mechanism-based approach to exercise management in patients with AVC.
Melkersson-Rosenthal Syndrome with Orofacial Swelling and Recurrent Lower Motor Neuron Facial Nerve Palsy: A Case Report and Review of the Literature
Authors: Okudo Jerome , Oluyide Yemi
Published: November 2015

Melkersson-Rosenthal Syndrome (MRS) is a rare otoneurologic condition, which is poorly understood and often underdiagnosed. Etiology and incidence are unclear, although infectious, inflammatory, and genetic causes have been implicated. Recurrent facial nerve palsy, facial swelling, and fissured tongue are the symptoms and signs of this condition. However, this triad is not typical in all patients as patients may present with one or more of the symptoms, which makes management of this condition difficult. Steroids may prove to be useful especially in patients who have facial nerve palsy. In this case report, we have described a 46 year-old Caucasian male who presented to the clinic for the evaluation of orofacial swelling and left facial deviation with a history of multiple treatments for recurrent lower motor neuron type facial nerve palsy.
WSNs-Based Mechanical Equipment State Monitoring and Fault Diagnosis in China
Authors: Huang Jianfeng , Chen Guohua , Shu Lei , Zhang Qinghua , Wu Xiaoling
Published: November 2015

Wireless sensor networks (WSNs) have been used in the state monitoring and fault diagnosis (SMFD) of mechanical equipment as a new signal collection and transmission technology, which have attracted a lot of attention recently. By applying the WSNs to the SMFD, many problems existing in conventional wired monitoring are solved. This paper attempts to summarize and review the recent researches and developments of the SMFD in mechanical equipment based on WSNs, providing comprehensive references for researchers concerned about this topic and helping them identify further research topics. Firstly, constraints in the conventional wired monitoring and the superiority of using WSNs in fault detection and diagnosis of mechanical equipment are illustrated. The development process of the SMFD in mechanical equipment is briefly introduced. Then, the recent WSNs applications to the SMFD of mechanical equipment in China are reviewed and summarized in terms of the classifications, such as monitored parameters, monitored objects, and data fusion methods. Finally, the potential future research directions are identified. WSNs are the effective technology to overcome the current bottleneck of the application in the SMFD of mechanical equipment.
Solving Large-Scale TSP Using a Fast Wedging Insertion Partitioning Approach
Authors: Xiang Zuoyong , Chen Zhenyu , Gao Xingyu , Wang Xinjun , Di Fangchun , Li Lixin , Liu Guangyi , Zhang Yi
Published: November 2015

A new partitioning method, called Wedging Insertion, is proposed for solving large-scale symmetric Traveling Salesman Problem (TSP). The idea of our proposed algorithm is to cut a TSP tour into four segments by nodes’ coordinate (not by rectangle, such as Strip, FRP, and Karp). Each node is located in one of their segments, which excludes four particular nodes, and each segment does not twist with other segments. After the partitioning process, this algorithm utilizes traditional construction method, that is, the insertion method, for each segment to improve the quality of tour, and then connects the starting node and the ending node of each segment to obtain the complete tour. In order to test the performance of our proposed algorithm, we conduct the experiments on various TSPLIB instances. The experimental results show that our proposed algorithm in this paper is more efficient for solving large-scale TSPs. Specifically, our approach is able to obviously reduce the time complexity for running the algorithm; meanwhile, it will lose only about 10% of the algorithm’s performance.
Parthenogenesis and Human Assisted Reproduction
Authors: Bos-Mikich Adriana , Bressan Fabiana F. , Ruggeri Rafael R. , Watanabe Yeda , Meirelles Flávio V.
Published: November 2015

Parthenogenetic activation of human oocytes obtained from infertility treatments has gained new interest in recent years as an alternative approach to create embryos with no reproductive purpose for research in areas such as assisted reproduction technologies itself, somatic cell, and nuclear transfer experiments and for derivation of clinical grade pluripotent embryonic stem cells for regenerative medicine. Different activating methods have been tested on human and nonhuman oocytes, with varying degrees of success in terms of parthenote generation rates, embryo development stem cell derivation rates. Success in achieving a standardized artificial activation methodology for human oocytes and the subsequent potential therapeutic gain obtained from these embryos depends mainly on the availability of gametes donated from infertility treatments. This review will focus on the creation of parthenotes from clinically unusable oocytes for derivation and establishment of human parthenogenetic stem cell lines and their potential applications in regenerative medicine.
Novel Action of FSH on Stem Cells in Adult Mammalian Ovary Induces Postnatal Oogenesis and Primordial Follicle Assembly
Authors: Bhartiya Deepa , Parte Seema , Patel Hiren , Sriraman Kalpana , Zaveri Kusum , Hinduja Indira
Published: November 2015

Adult mammalian ovary has been under the scanner for more than a decade now since it was proposed to harbor stem cells that undergo postnatal oogenesis during reproductive period like spermatogenesis in testis. Stem cells are located in the ovary surface epithelium and exist in adult and menopausal ovary as well as in ovary with premature failure. Stem cells comprise two distinct populations including spherical, very small embryonic‐like stem cells (VSELs which express nuclear OCT‐4 and other pluripotent and primordial germ cells specific markers) and slightly bigger ovarian germ stem cells (OGSCs with cytoplasmic OCT‐4 which are equivalent to spermatogonial stem cells in the testes). These stem cells have the ability to spontaneously differentiate into oocyte‐like structures in vitro and on exposure to a younger healthy niche. Bone marrow may be an alternative source of these stem cells. The stem cells express FSHR and respond to FSH by undergoing self‐renewal, clonal expansion, and initiating neo‐oogenesis and primordial follicle assembly. VSELs are relatively quiescent and were recently reported to survive chemotherapy and initiate oogenesis in mice when exposed to FSH. This emerging understanding and further research in the field will help evolving novel strategies to manage ovarian pathologies and also towards oncofertility.
Molecular Structure, Membrane Interactions, and Toxicity of the Islet Amyloid Polypeptide in Type 2 Diabetes Mellitus
Authors: Caillon Lucie , Hoffmann Anais R. F. , Botz Alexandra , Khemtemourian Lucie
Published: November 2015

Human islet amyloid polypeptide (hIAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Mature hIAPP, a 37-aa peptide, is natively unfolded in its monomeric state but forms islet amyloid in T2DM. In common with other misfolded and aggregated proteins, amyloid formation involves aggregation of monomers of hIAPP into oligomers, fibrils, and ultimately mature amyloid deposits. hIAPP is coproduced and stored with insulin by the pancreatic isletβ-cells and is released in response to the stimuli that lead to insulin secretion. Accumulating evidence suggests that hIAPP amyloid deposits that accompany T2DM are not just an insignificant phenomenon derived from the disease progression but that hIAPP aggregation induces processes that impair the functionality and the viability ofβ-cells. In this review, we particularly focus on hIAPP structure, hIAPP aggregation, and hIAPP-membrane interactions. We will also discuss recent findings on the mechanism of hIAPP-membrane damage and on hIAPP-induced cell death. Finally, the development of successful antiamyloidogenic agents that prevent hIAPP fibril formation will be examined.
Nitric Oxide‐Mediated Posttranslational Modifications: Impacts at the Synapse
Authors: Bradley Sophie A. , Steinert Joern R.
Published: November 2015

Nitric oxide (NO) is an important gasotransmitter molecule that is involved in numerous physiological processes throughout the nervous system. In addition to its involvement in physiological plasticity processes (long‐term potentiation, LTP; long‐term depression, LTD) which can include NMDAR‐mediated calcium‐dependent activation of neuronal nitric oxide synthase (nNOS), new insights into physiological and pathological consequences of nitrergic signalling have recently emerged. In addition to the canonical cGMP‐mediated signalling, NO is also implicated in numerous pathways involving posttranslational modifications. In this review we discuss the multiple effects of S‐nitrosylation and 3‐nitrotyrosination on proteins with potential modulation of function but limit the analyses to signalling involved in synaptic transmission and vesicular release. Here, crucial proteins which mediate synaptic transmission can undergo posttranslational modifications with either pre‐ or postsynaptic origin. During normal brain function, both pathways serve as important cellular signalling cascades that modulate a diverse array of physiological processes, including synaptic plasticity, transcriptional activity, and neuronal survival. In contrast, evidence suggests that aging and disease can induce nitrosative stress via excessive NO production. Consequently, uncontrolled S‐nitrosylation/3‐nitrotyrosination can occur and represent pathological features that contribute to the onset and progression of various neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Huntington’s.
Cardiac Resynchronization Therapy Outcomes in Type 2 Diabetic Patients: Role of MicroRNA Changes
Authors: Sardu Celestino , Barbieri Michelangela , Rizzo Maria Rosaria , Paolisso Pasquale , Paolisso Giuseppe , Marfella Raffaele
Published: November 2015

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are two growing and related diseases in general population and particularly in elderly people. In selected patients affected by HF and severe dysfunction of left ventricle ejection fraction (LVEF), with left bundle brunch block, the cardiac resynchronization therapy with a defibrillator (CRT) is the treatment of choice to improve symptoms, NYHA class, and quality of life. CRT effects are related to alterations in genes and microRNAs (miRs) expression, which regulate cardiac processes involved in cardiac apoptosis, cardiac fibrosis, cardiac hypertrophy and angiogenesis, and membrane channel ionic currents. Different studies have shown a different prognosis in T2DM patients and T2DM elderly patients treated by CRT-D. We reviewed the literature data on CRT-D effect on adult and elderly patients with T2DM as compared with nondiabetic patients.
Derivation of Pluripotent Cells from Mouse SSCs Seems to Be Age Dependent
Authors: Azizi Hossein , Conrad Sabine , Hinz Ursula , Asgari Behrouz , Nanus Daniel , Peterziel Heike , Hajizadeh Moghaddam Akbar , Baharvand Hossein , Skutella Thomas
Published: November 2015

Here, we aimed to answer important and fundamental questions in germ cell biology with special focus on the age of the male donor cells and the possibility to generate embryonic stem cell‐ (ESC‐) like cells. While it is believed that spermatogonial stem cells (SSCs) and truly pluripotent ESC‐like cells can be isolated from adult mice, it remained unknown if the spontaneous conversion of SSCs to ESC‐like cells fails at some age. Similarly, there have been differences in the literature about the duration of cultures during which ESC‐like cells may appear. We demonstrate the possibility to derive ESC‐like cells from SSC cultures until they reach adolescence or up to 7 weeks of age, but we point out the impossibility to derive these cells from older, mature adult mice. The inability of real adult SSCs to shift to a pluripotent state coincides with a decline in expression of the core pluripotency genes Oct4, Nanog, and Sox2 in SSCs with age. At the same time genes of the spermatogonial differentiation pathway increase. The generated ESC‐like cells were similar to ESCs and express pluripotency markers. In vitro they differentiate into all three germ lineages; they form complex teratomas after transplantation in SCID mice and produce chimeric mice.
Effective Mobilization of Very Small Embryonic‐Like Stem Cells and Hematopoietic Stem/Progenitor Cells but Not Endothelial Progenitor Cells by Follicle‐Stimulating Hormone Therapy
Authors: Zbucka-Kretowska Monika , Eljaszewicz Andrzej , Lipinska Danuta , Grubczak Kamil , Rusak Malgorzata , Mrugacz Grzegorz , Dabrowska Milena , Ratajczak Mariusz Z. , Moniuszko Marcin
Published: November 2015

Recently, murine hematopoietic progenitor stem cells (HSCs) and very small embryonic‐like stem cells (VSELs) were demonstrated to express receptors for sex hormones including follicle‐stimulating hormone (FSH). This raised the question of whether FSH therapy at clinically applied doses can mobilize stem/progenitor cells in humans. Here we assessed frequencies of VSELs (referred to as Lin−CD235a−CD45−CD133+ cells), HSPCs (referred to as Lin−CD235a−CD45+CD133+ cells), and endothelial progenitor cells (EPCs, identified as CD34+CD144+, CD34+CD133+, and CD34+CD309+CD133+ cells) in fifteen female patients subjected to the FSH therapy. We demonstrated that FSH therapy resulted in statistically significant enhancement in peripheral blood (PB) number of both VSELs and HSPCs. In contrast, the pattern of responses of EPCs delineated by different cell phenotypes was not uniform and we did not observe any significant changes in EPC numbers following hormone therapy. Our data indicate that FSH therapy mobilizes VSELs and HSPCs into peripheral blood that on one hand supports their developmental origin from germ lineage, and on the other hand FSH can become a promising candidate tool for mobilizing HSCs and stem cells with VSEL phenotype in clinical settings.
Intermittent Hypoxia Affects the Spontaneous Differentiation In Vitro of Human Neutrophils into Long‐Lived Giant Phagocytes
Authors: Dyugovskaya Larissa , Berger Slava , Polyakov Andrey , Lavie Peretz , Lavie Lena
Published: November 2015

Previously we identified, for the first time, a new small‐size subset of neutrophil‐derived giant phagocytes (Gϕ) which spontaneously develop in vitro without additional growth factors or cytokines. Gϕ are CD66b+/CD63+/MPO+/LC3B+ and are characterized by extended lifespan, large phagolysosomes, active phagocytosis, and reactive oxygen species (ROS) production, and autophagy largely controls their formation. Hypoxia, and particularly hypoxia/reoxygenation, is a prominent feature of many pathological processes. Herein we investigated Gϕ formation by applying various hypoxic conditions. Chronic intermittent hypoxia (IH) (29 cycles/day for 5 days) completely abolished Gϕ formation, while acute IH had dose‐dependent effects. Exposure to 24 h (56 IH cycles) decreased their size, yield, phagocytic ability, autophagy, mitophagy, and gp91‐phox/p22‐phox expression, whereas under 24 h sustained hypoxia (SH) the size and expression of LC3B and gp91‐phox/p22‐phox resembled Gϕ formed in normoxia. Diphenyl iodide (DPI), a NADPH oxidase inhibitor, as well as the PI3K/Akt and autophagy inhibitor LY294002 abolished Gϕ formation at all oxygen conditions. However, the potent antioxidant, N‐acetylcysteine (NAC) abrogated the effects of IH by inducing large CD66b+/LC3B+ Gϕ and increased both NADPH oxidase expression and phagocytosis. These findings suggest that NADPH oxidase, autophagy, and the PI3K/Akt pathway are involved in Gϕ development.
HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer
Authors: Xu Chun-Fang , Johnson Toby , Wang Xiaojing , Carpenter Chris , Graves Alan P. , Warren Liling , Xue Zhengyu , King Karen S. , Fraser Dana J. , Stinnett Sandy , Briley Linda P. , Mitrica Ionel , Spraggs Colin F. , Nelson Matthew R. , Tada Hiroomi , du Bois Andreas , Powles Thomas , Kaplowitz Neil , Pandite Lini N.
Published: November 2015

Purpose: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury.

Experimental Design: The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted.

Results: The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation [P = 5.0 × 10−5 for maximum on-treatment ALT (MaxALT); P = 4.8 × 10−4 for time to ALT > 3× upper limit of normal (ULN) event; P = 4.1 × 10−5 for time to ALT > 5× ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 × 10−4 for ALT > 3× ULN, P = 9.8 × 10−3 for ALT > 5× ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 × 10−5 for MaxALT, P = 5.1 × 10−6 for time to ALT > 3×ULN event, P = 5.8 × 10−6 for time to ALT > 5× ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3× ULN was 31% and 19%, respectively, and frequency of ALT > 5× ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation.

Conclusions: These data indicate that HLA-B*57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients. Clin Cancer Res; 22(6); 1371–7. ©2015 AACR.
PD-L1 Antibodies to Its Cytoplasmic Domain Most Clearly Delineate Cell Membranes in Immunohistochemical Staining of Tumor Cells
Authors: Mahoney Kathleen M. , Sun Heather , Liao Xiaoyun , Hua Ping , Callea Marcella , Greenfield Edward A. , Hodi F. Stephen , Sharpe Arlene H. , Signoretti Sabina , Rodig Scott J. , Freeman Gordon J.
Published: November 2015

Blocking the programmed death-1 (PD-1) pathway has clinical benefit in metastatic cancer and has led to the approval of the mAbs pembrolizumab and nivolumab to treat melanoma and nivolumab for non–small cell lung cancer. Expression of PD-L1 on the cell surface of either tumor cells or infiltrating immune cells is associated with a higher likelihood of response to PD-1 blockade in multiple studies. Most mAbs to PD-L1 in use are directed to its extracellular domain and immunohistochemically stain tumor tissue with a mixture of cytoplasmic and membrane staining. Cytoplasmic staining obscures the interpretation of a positive reaction on the tumor cell membrane, and thus affects the accuracy of PD-L1 scoring systems. We developed a mAb to the cytoplasmic domain of PD-L1, 405.9A11 (9A11), which is both more selective for membranous PD-L1 and more sensitive in IHC and Western blotting, compared with previous mAbs specific for the PD-L1 extracellular domain. Here, we compare immunohistochemical staining patterns of PD-L1 expression in five types of tumors, using five PD-L1 mAbs: 9A11, 7G11, and three commercially available mAbs. We demonstrate that 9A11, as well as two other cytoplasmic domain-specific mAbs, E1L3N and SP142, can clearly delineate the membrane of PD-L1–positive cells in formalin-fixed paraffin-embedded tissue and facilitate interpretation of staining results. Cancer Immunol Res; 3(12); 1308–15. ©2015 AACR.
Clinical Application of Anti-CCR4 Monoclonal Antibody
Authors: Ueda Ryuzo
Published: November 2015

Mogamulizumab (KW-0761) is a humanized anti-CCR4 monoclonal antibody with a defucosylated Fc region (Potelligent® Technology), which markedly enhances antibody-dependent cellular cytotoxicity by increasing its binding affinity to the Fcγ receptor expressed on effector cells. It is an effective agent for patients with CCR4-positive adult T-cell leukemia and peripheral T-cell lymphoma, for which no standard therapy exists, and it has an acceptable toxicity profile. In addition, because CCR4 is expressed on CD45RA-FOXP3highCD4+ effector regulatory T (Treg) cells, it is an even more attractive target, because Treg cells involved in the tumor escape from host immunity in the tumor microenvironment. Based on this concept, we conducted a clinical study of mogamulizumab for the treatment of CCR4-negative advanced or recurrent solid cancer, with the aim of depleting effector Treg cells and thus boosting anti-cancer immune responses. In this study, mogamulizumab infusion at doses ranging from 0.1 to 1.0 mg/kg was safe and well tolerated. Four of 10 patients showed stable disease during treatment and showed long-term survival. Mogamulizumab efficiently depleted effector Treg cells even at the lowest dose of 0.1 mg/kg, and an augmentation or induction of specific immune responses to cancer/testis antigens was observed in some patients. In the near future, a novel immunotherapy targeting Treg cells with mogamulizumab will be offered to patients with different types of cancer.
Bringing Leukemia Stem Cells into the Clinic
Authors: Wang Jean C.Y.
Published: November 2015

Outcomes in acute myeloid leukemia (AML) remain poor due to high rates of relapse. Thus, there is an urgent unmet medical need for new therapies that can more effectively kill the leukemia stem cells (LSC) and recently recognized preleukemic hematopoietic stem cells (preL-HSC) that can drive relapsed disease. In order to develop such therapies, a better understanding of the biology of these stem cell populations is required. The best functional assays for stem cells are xenotransplantation models using immunodeficient mouse recipients. Here, we present evidence of the clinical validity of such models for studying the biology of AML stem cells and propose a new paradigm for the development of LSC-targeted agents and biomarker tools for patient selection.
Impaired Eukaryotic Elongation Factor 1A Expression in Alzheimer's Disease
Authors: Beckelman Brenna C. , Zhou Xueyan , Keene C. Dirk , Ma Tao
Published: November 2015

Background/Aims: Recent studies have indicated a link between the impaired capacity of de novo protein synthesis and neurodegenerative diseases including Alzheimer's disease (AD). Moreover, it has been established that eukaryotic elongation factor 1A (eEF1A) plays a critical role in maintaining long-term synaptic plasticity, a cellular model for learning and memory. The aim of the present study is to determine whether brain eEF1A protein levels are dysregulated in brain tissue from AD patients compared with controls. Methods: Postmortem human brain samples collected from patients clinically diagnosed as AD, and from age-matched healthy controls, were utilized for this study. Both Western blot and immunohistochemistry approaches were utilized to investigate the potential alteration of eEF1A protein levels by using a specific antibody. Results: Our data demonstrate that eEF1A expression is reduced in AD patients in the hippocampus, but not in the cerebellum or midfrontal gyrus. Furthermore, immunohistochemical experiments reveal that neuronal eEF1A reduction in the AD hippocampus is localized to the CA1 and dentate gyrus, but not to the CA3. Conclusion: Dysregulation of eEF1A and its associated signaling pathways might represent novel molecular mechanisms underlying AD pathogenesis. Further investigation is necessary to determine whether eEF1A is a viable therapeutic target for AD and other cognitive syndromes.
Genetic Disorders with Tau Pathology: A Review of the Literature and Report of Two Patients with Tauopathy and Positive Family Histories
Authors: Tacik Pawel , Sanchez-Contreras Monica , Rademakers Rosa , Dickson Dennis W. , Wszolek Zbigniew K.
Published: November 2015

Background: Tauopathies are a group of neurodegenerative disorders characterized by the pathological accumulation of hyperphosphorylated and insoluble tau protein within neurons and glia. Although most cases are sporadic, hereditary tauopathies have also been reported. Summary: In this article, we review genetic disorders in which tau pathology has been reported and present two novel families with primary tauopathies. Mutations in the microtubule-associated protein tau gene (MAPT) cause a small subset of primary tauopathies. Mutations in 21 other genes and an 18q deletion syndrome have also been reported to be associated with tau pathology reminiscent of Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease or Pick's disease. In 8 of the 21 genes, tau pathology was only seen in cases with some ‘specific' mutations. In the remaining genes, tau pathology, often in the form of Alzheimer-type neurofibrillary lesions, was a common finding but was ‘not mutation specific'. The probands of the two families were diagnosed with progressive supranuclear palsy based on clinicopathological evaluation. Their family histories were relevant for parkinsonism in 3 siblings of family 1 and 1 brother and the father from family 2, but these were not autopsy-confirmed. DNA from the brains of the probands from these families was screened for MAPT and leucine-rich repeat kinase 2 gene mutations, but no mutations were identified. Key Messages:MAPT mutations are a cause of familial tauopathies, but other genes have also been associated with tau pathology. Novel genes still await discovery.
Tau as the Converging Protein between Chronic Stress and Alzheimer's Disease Synaptic Pathology
Authors: Sotiropoulos Ioannis , Sousa Nuno
Published: November 2015

Background: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex physiopathology and still undefined initiators. Several risk factors have been suggested for AD with recent evidence supporting an etiopathogenic role of chronic environmental stress and glucocorticoids (GCs, stress hormones) in the development of the disease. Indeed, both AD and chronic stress are associated with neuronal atrophy, synaptic loss and cognitive impairment. Our previous studies have demonstrated the aggravating role of stress and GCs on AD pathology, including Tau hyperphosphorylation and aggregation and cognitive deficits in various AD models. In light of the suggested involvement of Tau missorting in AD synaptotoxity and the dual cytoplasmic and synaptic role of Tau, our recent studies focused on the possible role of Tau in the underlying cascades of stress/GC neuronal malfunction/atrophy in wild-type animals by monitoring the intracellular localization of Tau and its phosphorylation status in different cellular compartments. Summary: Biochemical, ultrastructural, behavioral and neurostructural analysis have helped demonstrate that prolonged GC administration leads to dendritic remodeling and spine atrophy and loss in the rat hippocampus triggering Tau missorting at hippocampal synapses with the participation of specific phosphorylated Tau isoforms in this synaptic accumulation. Key Messages: The above findings suggest that Tau plays an essential role in mediating the neurodegenerative effects of stress and GCs towards the development of AD pathology. In addition, they highlight the involvement of Tau missorting in mechanism(s) of synaptic atrophy, beyond AD adding to our limited knowledge of the mechanisms through which stress causes brain pathology.
Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia
Authors: Jantzie Lauren L. , Winer Jesse L. , Corbett Christopher J. , Robinson Shenandoah
Published: November 2015

Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies.
Efficacy and Feasibility of Salvage Living Donor Liver Transplantation after Initial Liver Resection in Patients with Hepatocellular Carcinoma
Authors: Abe Tomoyuki , Tashiro Hirotaka , Teraoka Yoshifumi , Hattori Minoru , Tanimine Naoki , Kuroda Shintaro , Tahara Hiroyuki , Ohira Masahiro , Tanaka Yuka , Kobayashi Tsuyoshi , Ide Kentaro , Ishiyama Kohei , Ohdan Hideki
Published: November 2015

Background/Aims: Liver transplantation (LT) is promising method of treatment for hepatocellular carcinoma (HCC) patients, but is limited by donor organ shortages and tumor progression during long wait periods. This study investigated the efficacy of salvage living donor LT (LDLT) after initial liver resection (LR) in HCC patients. Methods: Sixty patients with HCC who underwent primary LDLT (n = 45) or salvage LDLT after initial LR (n = 15) were enrolled. Significant prognostic variables determined by univariate analysis were subjected to multivariate analysis using a Cox proportional hazard regression model. Cox proportional hazards models with inverse probability of treatment weighting (IPTW) based on propensity score were used to adjust for selection bias between groups. Results: The salvage group had significantly higher Child-Pugh class A (p = 0.003), ≥3 pretransplant treatments (p = 0.007), and reoperation rates for postoperative bleeding (p = 0.032) than the primary LDLT group, whereas overall and recurrence-free survival rates were comparable. After IPTW matching, the salvage LDLT group had significantly more reoperations for postoperative bleeding (hazard ratio 7.948, p = 0.017). Conclusions: First-line LR followed by salvage LDLT allows survival equal to that of primary LDLT. Salvage LDLT following primary LR could be an effective therapy.
A Study of Ecological Corridors in Two Quarters of Lima: Chorrillos and Villa El Salvador
Authors: Sabogal Ana , Martinez Maria Isabel
Published: November 2015

The city of Lima does not have enough green areas. The origin and the aim of the green areas and parks is diverse, in this way we can identify a profile and propose a typology for parks. The tree species and their distribution have a correspondence with the decade their creation. Two spaces—one in the quarter of Chorrillos and the other in Villa El Salvador—have been analyzed. The distribution of the green areas and quality of the parks has been defined. The existence and distribution of the ecological corridors will be described in the correspondent study areas. The proposal of a new ecological corridor that will be used as a connection for the bird life will be presented for the quarter of Chorrillos. Finally, new ecological corridors will by proposed for the Chorrillos quarter. A park will be implemented as a corridor for the quarter of Villa El Salvador.
Factors of E-book Use Intentions: Perspective of Students in a Developing Country
Authors: Maduku Daniel K.
Published: November 2015

E-books are regarded as a new, digital way to access reading material and as a learning tool for students. Therefore, South African institutions of higher learning are spending increasing amounts of money on the provision of e-books for use by students. However, the extent to which students will accept e-books remains unclear. This paper is aimed at examining the factors of e-book use intentions among students in tertiary education, based on theoretical considerations rooted inutaut. Data used in the analysis was sourced from 544 participating students from five institutions of higher learning using a structured questionnaire. Results of the analysis identified performance expectancy, social influence and facilitating conditions as salient factors of e-book use intentions among tertiary students. Interestingly, gender and e-book use experience had no significant moderating effect of the factors of use intention examined in this study. The implications of these findings on the efforts aimed at promoting a more enthusiastic acceptance of e-books among tertiary students are highlighted in this paper.
Use of Mobile Telephones among Small-Scale Goods and Service Providers in Shillong, India
Authors: Choudhury Devomitra
Published: November 2015

The study, carried out in Shillong, the capital of Meghalaya, was selected as a case study of the use of mobile telephones among small-scale goods and service providers in a relatively slowly moving urban place like Shillong. The study attempts to observe different sectors of traders and goods and service providers of perishable and non-perishable items using mobile telephones. The attempt is to see if the mobile device has evolved as a grand tool to overcome various obstacles in the expansion and extension of livelihood and business opportunities, and understand the how changes in communication technology have an enabling influence in people’s business lives—as a resource for increasing clientele, improving sales, and connecting to new markets, buyers and vendors. Differences are greatly found to lie in the type of goods and service provider, types of clientele being targeted (local versus international) and scale of operations.
Review of the Hemyda Robineau-Desvoidy of China (Diptera: Tachinidae)
Authors: WANG QIANG , ZHANG CHUNTIAN , WANG XINHUA
Published: November 2015

The Chinese species of Hemyda Robineau-Desvoidy (Phasiinae, Cylindromyiini) are revised. Five species are recognized, consisting of the previously recorded species H. hertingi Ziegler & Shima, H. obscuripennis (Meigen) and H. vittata (Meigen), one new species from NW Yunnan, Hemyda deqinensis sp. nov., and one new record for China, H. dominikae Draber-Mońko. A generic diagnosis of Hemyda is provided, each of the previously described species is diagnosed, the new species is described, and a key is given to the five Chinese species.
The occurrence of Pandalopsis spinosior Hanamura, Kohno & Sakaji, 2000 (Crustacea: Decapoda: Caridea: Pandalidae) in Hokkaido, northern Japan, and reassessment of its diagnostic characters
Authors: HIBINO MAI , MATSUZAKI KOJI , KOMAI TOMOYUKI
Published: November 2015

Pandalopsis spinosior Hanamura, Kohno & Sakaji, 2000 (Decapoda: Caridea: Pandalidae) was originally described on the basis of material collected in the Urup Strait, South Kurile Islands, but there have been no subsequent records of the species since the original description. The Marine Science Museum, Fukushima Prefecture (Aquamarine Fukushima) has carried out investigations on deep-water animals in the Nemuro Strait, off Shiretoko Peninsula, Hokkaido, Japan, amongst the collections a large, commercially important pandalid shrimp routinely identified with P. coccinata Urita, 1941. Examination of the specimens from the collections, however, resulted in an unexpected identification with P. spinosior, instead of P. coccinata. In this short article, diagnostic characters of P. spinosior are reassessed, and comparison with P. coccinata is made. The validity of P. zarenkovi Ivanov & Sokolov, 2001, for which possible synonymy with P. spinosior was suggested, is maintained for the time being.
The prevalence and age of onset of psychiatric disorders in Australian men
Authors: Williams Lana J , Jacka Felice N , Pasco Julie A , Coulson Carolyn E , Quirk Shae E , Stuart Amanda L , Berk Michael
Published: November 2015

Objective:

Given the burden of common psychiatric disorders and their consequent service and planning requirements, it is important to have a thorough knowledge of their distribution and characteristics in the population. Thus, we aimed to report the prevalence and age of onset of mood, anxiety and substance-use disorders in an age-stratified representative sample of Australian men.

Method:

Psychiatric disorders (mood, anxiety and substance-use disorders) were diagnosed utilising a structured clinical interview (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition, Non-Patient Edition) for 961 men aged 24–98 years enrolled in the Geelong Osteoporosis Study. The lifetime and current prevalence of these disorders was determined from the study population and standardised to 2006 census data for Australia.

Results:

Approximately one in three men (28.8%, 95% confidence interval [CI] = [26.8%, 30.8%]) reported a lifetime history of any psychiatric disorder, with mood disorders (18.2%, 95% CI = [15.2%, 21.2%]) being more prevalent than anxiety (7.2%, 95% CI = [5.0%, 9.4%]) and substance-use disorders (12.9%, 95% CI = [9.7%, 16.0%]). Approximately 8.7% (95% CI = [7.5%, 10.0%]) were identified as having a current disorder, with 3.8% (95% interquartile range [IQR] = [2.2%, 5.4%]), 2.4% (95% CI = [1.1%, 3.8%]) and 3.4% (95% CI = [1.8%, 4.9%]) meeting criteria for current mood, anxiety and substance-use disorders, respectively. The median age of onset for mood disorders was 37.5 years (IQR = 27.0–48.0 years), 25.0 years (IQR = 20.0–40.3 years) for anxiety and 22.0 years (IQR = 18.0–34.3 years) for substance-use disorders.

Conclusion:

This study reports the lifetime and current prevalence of psychiatric disorders in the Australian male population. These findings emphasise the extent of the burden of these disorders in the community.