bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnosis and management of non-alcoholic fatty liver disease
Authors: Jennison Erica , Patel Janisha , Scorletti Eleonora , Byrne Christopher D 
Published: May 2019

AbstractNon-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western industrialised countries. The prevalence of NAFLD is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. NAFLD represents a spectrum of liver disease severity. NAFLD begins with accumulation of triacylglycerols in the liver (steatosis), and is defined by hepatic fatty infiltration amounting to greater than 5% by liver weight or the presence of over 5% of hepatocytes loaded with large fat vacuoles. In almost a quarter of affected individuals, steatosis progresses with the development of liver inflammation to non-alcoholic steatohepatitis (NASH). NASH is a potentially progressive liver condition and with ongoing liver injury and cell death can result in fibrosis. Progressive liver fibrosis may lead to the development of cirrhosis in a small proportion of patients. With the growing prevalence of NAFLD, there is an increasing need for a robust, accurate and non-invasive approach to diagnosing the different stages of this condition. This review will focus on (1) the biochemical tests and imaging techniques used to diagnose the different stages of NAFLD; and (2) a selection of the current management approaches focusing on lifestyle interventions and pharmacological therapies for NAFLD.
Disruption of the Scaffolding Function of mLST8 Selectively Inhibits mTORC2 Assembly and Function and Suppresses mTORC2-Dependent Tumor Growth In Vivo
Authors: Hwang Yoonha , Kim Laura C. , Song Wenqiang , Edwards Deanna N. , Cook Rebecca S. , Chen Jin 
Published: May 2019

Abstract

mTOR is a serine/threonine kinase that acts in two distinct complexes, mTORC1 and mTORC2, and is dysregulated in many diseases including cancer. mLST8 is a shared component of both mTORC1 and mTORC2, yet little is known regarding how mLST8 contributes to assembly and activity of the mTOR complexes. Here we assessed mLST8 loss in a panel of normal and cancer cells and observed little to no impact on assembly or activity of mTORC1. However, mLST8 loss blocked mTOR association with mTORC2 cofactors RICTOR and SIN1, thus abrogating mTORC2 activity. Similarly, a single pair of mutations on mLST8 with a corresponding mutation on mTOR interfered with mTORC2 assembly and activity without affecting mTORC1. We also discovered a direct interaction between mLST8 and the NH2-terminal domain of the mTORC2 cofactor SIN1. In PTEN-null prostate cancer xenografts, mLST8 mutations disrupting the mTOR interaction motif inhibited AKT S473 phosphorylation and decreased tumor cell proliferation and tumor growth in vivo. Together, these data suggest that the scaffolding function of mLST8 is critical for assembly and activity of mTORC2, but not mTORC1, an observation that could enable therapeutic mTORC2-selective inhibition as a therapeutic strategy.

Significance:
These findings show that mLST8 functions as a scaffold to maintain mTORC2 integrity and kinase activity, unveiling a new avenue for development of mTORC2-specific inhibitors.
Low-Dose IFNγ Induces Tumor Cell Stemness in Tumor Microenvironment of Non–Small Cell Lung Cancer
Authors: Song Mengjia , Ping Yu , Zhang Kai , Yang Li , Li Feng , Zhang Chaoqi , Cheng Shaoyan , Yue Dongli , Maimela Nomathamsanqa Resegofetse , Qu Jiao , Liu Shasha , Sun Ting , Li Zihai , Xia Jianchuan , Zhang Bin , Wang Liping , Zhang Yi 
Published: May 2019

AbstractIFNγ is conventionally recognized as an inflammatory cytokine that plays a central role in antitumor immunity. Although it has been used clinically to treat a variety of malignancies, low levels of IFNγ in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy. Accumulating evidence suggests that IFNγ can induce cancer progression, yet the mechanisms underlying the controversial role of IFNγ in tumor development remain unclear. Here, we reveal a dose-dependent effect of IFNγ in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Low levels of IFNγ endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)–PI3K–Akt–Notch1 axis, whereas high levels of IFNγ activated the JAK1–STAT1–caspase pathway to induce apoptosis in non–small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stem-like properties of NSCLC cells induced by the low dose of IFNγ both in vitro and in vivo. This study unveils the role of low levels of IFNγ in conferring tumor stemness and elucidates the distinct signaling pathways activated by IFNγ in a dose-dependent manner, thus providing new insights into cancer treatment, particularly for patients with low expression of IFNγ in the TME.Significance:These findings reveal the dose-dependent effect of IFNγ in inducing tumor stemness and elucidate the distinct molecular mechanisms activated by IFNγ in a dose-dependent manner.
Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors
Authors: Ji Changhua , Roy Marc D. , Golas Jonathan , Vitsky Allison , Ram Sripad , Kumpf Steven W. , Martin Matthew , Barletta Frank , Meier William A. , Hooper Andrea T. , Sapra Puja , Khan Nasir K. , Finkelstein Martin , Guffroy Magali , Buetow Bernard S. 
Published: May 2019

Abstract

Purpose:
Immune checkpoint inhibitors (ICI) targeting PD1, PDL1, or CTLA4 are associated with immune-related adverse events (irAE) in multiple organ systems including myocarditis. The pathogenesis and early diagnostic markers for ICI-induced myocarditis are poorly understood, and there is currently a lack of laboratory animal model to enhance our understanding. We aimed to develop such a model using cynomolgus monkeys.

Experimental Design:
Chinese-origin cynomolgus monkeys were dosed intravenously with vehicle or nivolumab 20 mg/kg plus ipilimumab 15 mg/kg once weekly and euthanized on day 29.

Results:
Multiple organ toxicities were observed in cynomolgus monkeys, and were characterized by loose feces, lymphadenopathy, and mononuclear cell infiltrations of varying severity in heart, colon, kidneys, liver, salivary glands, and endocrine organs. Increased proliferation of CD4+ and CD8+ T lymphocytes as well as an increase in activated T cells and central memory T cells in the blood, spleen, and lymph nodes, were observed. Transcriptomic analysis suggested increased migration and activation of T cells and increased phagocytosis and antigen presentation in the heart. Mononuclear cell infiltration in myocardium was comprised primarily of T cells, with lower numbers of macrophages and occasional B cells, and was associated with minimal cardiomyocyte degeneration as well as increases in cardiac troponin-I and NT-pro-BNP. Morphologically, cardiac lesions in our monkey model are similar to the reported ICI myocarditis in humans.

Conclusions:
We have developed a monkey model characterized by multiple organ toxicities including myocarditis. This model may provide insight into the immune mechanisms and facilitate biomarker identification for ICI-associated irAEs.
Comprehensive Genomic Profiling Identifies Novel Genetic Predictors of Response to Anti–PD-(L)1 Therapies in Non–Small Cell Lung Cancer
Authors: Fang Wenfeng , Ma Yuxiang , Yin Jiani C. , Hong Shaodong , Zhou Huaqiang , Wang Ao , Wang Fufeng , Bao Hua , Wu Xue , Yang Yunpeng , Huang Yan , Zhao Hongyun , Shao Yang W. , Zhang Li 
Published: May 2019

Abstract

Purpose:
Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood.

Experimental Design:
We performed genomic profiling of 78 patients with non–small cell lung cancer (NSCLC) who underwent anti–PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response.

Results:
We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's ρ = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32–4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09–4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types.

Conclusions:
We identified novel genomic biomarkers that were predictive of response to anti–PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.
Análise do Processo de Turistificação de Fernando de Noronha (PE) entre os Anos de 1960 e 2016
Authors: Cordeiro Itamar , Körössy Nathália , Tôrres Edvânia 
Published: May 2019

O turismo é uma invenção humana repleta de propósitos e ideologias. Por isso mesmo, o espaço turístico não deve ser assumido enquanto algo natural. Pelo contrário, deve ser questionado em sua essência, de modo a identificar as intenções por trás de sua produção. Este estudo analisa o processo de turistificação de Fernando de Noronha (um dos destinos mais conhecidos e desejados do país) entre os anos de 1960 e 2017. Metodologicamente, este estudo se caracteriza como uma pesquisa descritiva, de natureza qualitativa, realizada a partir de pesquisas bibliográficas e documentais e entrevistas. A análise do processo de turistificação de Fernando de Noronha identificou que, ao longo da sua história e independentemente da gestão que esteve à frente do arquipélago, o espaço insular sempre foi pensado para cumprir o papel de um destino de luxo. Essa tendência, aliás, permanece até os dias de hoje. Constatou-se que essa lógica tem sido responsável pela migração de diversos ilhéus e pela desestruturação do tecido social local.
Palavras-chave: Turismo; Turistificação; Fernando de Noronha.
O uso de infraestruturas verde e azul na revitalização urbana e na melhoria do manejo das águas pluviais
Authors: Guimarães Luciana Fernandes , Oliveira Antonio Krishnamurti Beleño de , Veríssimo Lays De Freitas , Merlo Mylenna Linares , Vérol Aline Pires 
Published: May 2019

A expansão das áreas urbanas e a pressão sobre o uso do solo alteraram as funções ecológicas e ecossistêmicas do ambiente. Estratégias de adaptação como as infraestruturas verde e azul podem reduzir os efeitos negativos das ações antrópicas, além de proporcionarem benefícios para a saúde e qualidade de vida da população. Essas estratégias podem destacar-se como alternativas mais sustentáveis, econômicas, multifuncionais e flexíveis em comparação com as soluções tradicionais. Dentre as diversas funções que as infraestruturas verde e azul podem assumir, o trabalho pretende destacar a capacidade de diminuição do risco hidráulico aliada à promoção da revitalização do ambiente urbano, por meio da implantação de parques urbanos, recomposição da vegetação e interligação de áreas verdes às novas áreas de lazer. Para o desenvolvimento dessa análise, foram propostas intervenções na sub-bacia do Rio Comprido, no Rio de Janeiro, considerando o rio como elemento estruturador da paisagem. Essas intervenções foram simuladas através de um modelo matemático, denominado MODCEL, que permite estimar as alturas de inundação nos cenários atual e de projeto. Como resultado, observa-se que, apesar dos limitados espaços livres, a multifuncionalidade das infraestruturas verde e azul introduz diversas melhorias para a sociedade.
NA ROTA DO ESCÁRNIO E DO MALDIZER: A SÉRIE PORTUGUESA "BICHA DO DEMÓNIO"
Authors: Valentim Jorge Vicente 
Published: May 2019

Este ensaio tem como objetivo a leitura da série portuguesa Bicha do Demónio (2009-2010), produzida exclusivamente para divulgação na rede pelo site Youtube, tomando como ponto de partida a presença de uma veia satírica, observada sob dois aspectos: o primeiro, enquanto continuidade de uma tradição literária e cultural do escárnio e do maldizer; e o segundo, como exposição direta das subjetividades sexuais, bem como das multiplicidades do universo homossexual português.
Differences in flight initiation distance (FID) between rural and urban populations of two species of Australian birds
Authors: Davey Sara , Massaro Melanie , Freire Rafael 
Published: May 2019

Abstract
Although flight initiation distance (FID) has been shown to be shorter in urban compared to rural populations of birds, less is known about how the characteristics of the urban environment, such as the population size and age of the city influences the FID and other aspects of anti-predator behaviour. Urban willie wagtails and magpie larks in a relatively small and new town had shorter FID than rural conspecifics. Both species were more likely to show a short, rather than long, escape flight if the experimenter started walking towards the bird from further away. There was some indication that urban birds may be more likely to show a short escape flight than rural birds. We conclude that anti-predator responses of birds can be influenced by a relatively small, recently established and sparsely-populated town. Additionally, the possibility of the characteristics of the urban centre influencing variation in the FID response is discussed.
On Filipinodiaptomus Lai, Mamaril Sr. & Fernando, 1979 (Calanoida, Diaptomidae): redescription and re-allocation of the Philippine endemic Diaptomus vexillifer Brehm, 1933
Authors: Li Huiming , Guinto Shea K. P. , Papa Rey D. S. , Han Bo-Ping , Magbanua Francis S. , Rizo Eric Z. C. , Dumont Henri J. , Lin Qiuqi 
Published: May 2019

Abstract
The original description of Diaptomus vexillifer Brehm, 1933,
endemic to Lake Danao (Leyte Island), was elementary and lacking taxonomically
satisfactory characters. In this paper, we redescribe the Philippine-endemic
genus Filipinodiaptomus Lai, Mamaril Sr. & Fernando, 1979
and the species D. vexillifer collected from its type locality,
using light and scanning electron microscopy and an analysis of the mtCOI gene
and the ITS of the nuclear 18S operon. We found that D.
vexillifer is the second species under this endemic genus. A
neotype and paraneotypes are hereby designated. Also a detailed morphological
comparison is made between Filipinodiaptomus vexillifer (Brehm,
1933) comb. nov. and Filipinodiaptomus insulanus (Wright,
1928). Their taxonomic characters, interspecies relationship, and biogeography
are likewise discussed.
A report of the free-living freshwater planktonic copepods from an ephemeral pool in Limpopo Province, South Africa, with the description of Microcyclops raynerae n. sp.
Authors: Mnisi Peral , Dippenaar Susan M. 
Published: May 2019

Abstract
Ephemeral pools are biologically important habitats for species adapted to survive through a dry phase. Unfortunately, these pools have been neglected in studies. Copepods are essential in aquatic habitats mainly because of their importance in the food web. Currently there are only 34 species reported from freshwater habitats in South Africa. This study was conducted in an ephemeral pool (Limpopo Province, South Africa). Qualitative sampling was done monthly (December 2014 to June 2015) using a plankton net and specimens were studied through a light microscope. Seven species were collected, three from Calanoida and four from Cyclopoida, including a new species, Microcyclops raynerae. Seven species represent quite a high biodiversity of copepods from a single pool when compared with similar studies previously done in South Africa. The report of Tropocyclops confinis constitutes a new geographical record from South Africa while all other collected species are new records from the Limpopo Province.
Was Zoroastrian Art Invented in Chorasmia?
Authors: Grenet Frantz 
Published: May 2019

Abstract
Before the recent discoveries of the Karakalpak-Australian Expedition to Ancient Chorasmia (KAE) evidence for Zoroastrianism in Chorasmia was scant, coming only from the official use of the Zoroastrian calendar, the onomastics, and the archaeologically documented funerary practices of the region, while the interpretation of remains of temples or fire chapels is subject to discussion.
During the last seasons of work on the material of the KAE excavations at Akchakhan-kala, the royal seat of Chorasmia in the 2nd century BC – 2nd century AD, substantial fragments of wall paintings from the rear wall of the main columned hall of the “Ceremonial Complex” were cleaned and reassembled. It appeared at once that they belong to oversized standing figures, most probably deities. The best preserved image has been identified as Srōsh, god of prayer and protector of the soul after death. The second figure is probably to be identified as a personification of the group of the Fravashis, pre-created souls of the ancestors and protectors of “Aryan people” in battles, also worshipped as deities. A third figure, very partly preserved, perhaps represents Zam-Spandarmad, goddess of the Earth. If these identifications are valid, these deities appear to have been chosen because of their association with the turn of the year. This would be consistent with the possibility that the already known “portrait gallery” of Akchakhan-kala was related to the commemoration of royal and clanic ancestors at the end of the year.
Notwithstanding much still needs to be elucidated, it appears already certain that these paintings, dating about the beginning of the 1st century AD, are the earliest documented attempt to create a Zoroastrian art directly inspired by the Avesta. The identification of some figures in the Toprak-kala “High Palace” (2nd-3rd centuries AD) can perhaps be reconsidered in the light of this new evidence.
The Oxus Route toward the South
Authors: Minardi Michele 
Published: May 2019

Abstract
In this contribution, in view of the striking evidence from the site of Akchakhan-kala which is casting a completely new light on the archaeology of the Chorasmian polity and the Central Asian region, I explore relations between Ancient Chorasmia and its neighbouring regions to the south, in particular Bactriana. I will try to argue that the oft-referred to favoured political relations of Chorasmia with the Arsacid empire, considering all the evidence now at our disposal, have been misjudged. The material culture of Ancient Chorasmia, throughout the history of the region, clearly shows the existence of a privileged, albeit not exclusive, exchange route toward the region to its south. Chorasmia has always been, since its birth in the 6th century BC, a bridge from the sedentary world toward the steppes and a polity with a distinctive culture that the scarcity of written sources has often deprived of historical individuality and speciously relegated to the periphery of modern western historiography, in the shadow of the better-known superregional powers that established control over Asia and Iran.
“Long Walls” in Ancient Chorasmia and Central Asia
Authors: Khozhaniyazov Gairatdin 
Published: May 2019

Abstract
The Ancient Chorasmian “long wall” of Dévkesken, part of a larger complex situated on a projection of the semi-arid Ustyurt Plateau in today’s Karakalpakstan, is discussed in this paper in light of similar defensive barriers erected in pre-Islamic Central Asia.
Some New Readings of Chorasmian Inscriptions on Silver Vessels and Their Relevance to the Chorasmian Era
Authors: Lurje Pavel B. 
Published: May 2019

Abstract
The article represents an attempt to read and analyze five of eleven inscriptions in Old Chorasmian language written in cursive Chorasmian script. These inscriptions are incised on silver vessels which were mostly found in the Kama region of the district of Perm in Russia.
The article is divided into sections. Its first section presents a list of the material discussed and the status quaestionis of the article, introduces the variations of the Chorasmian script throughout time. The second section is devoted to the analysis of the words which are recurrent in the inscriptions and to the definition of the formularies used in the inscriptions under scrutiny. The third section provides tentative reading of inscriptions on five vessels kept in the Hermitage museum. It is here assumed that some of the Chorasmian inscriptions indicate that the vessels were votive offerings to Nanaia and probably to other deities.
The fourth and last section of the paper focuses on the indications of weight attested on silver vessels and on the related chronology. It is shown that the value of the unit of weight (ZWZN /stēr/) on most of the vessels (c. 3,6-3,7 grams) corresponds to the silver standard weight used in the coinage of the Chorasmian king Shaushfarn and his less prominent predecessor Shyat. Consequently, it is assumed that the Chorasmian silver vessels were labeled and probably produced during Shaushfarn’s reign about the mid-8th century AD. Since four inscriptions with indication of weight are dated according to the Chorasmian Era (years from 700 to 723(?) of this era), this observation supports the author’s opinion that this indigenous era started towards the mid-1st century AD.
Central Asia and the Interaction between the Iranian Plateau and the Steppes in Late First Millennium BC
Authors: Lhuillier Johanna , Bendezu-Sarmiento Julio 
Published: May 2019

Abstract
Research led by the joint French-Turkmen Archaeological Expedition (MAFTur) at Ulug-depe have brought to light the longest continuous stratigraphic sequence of southern Central Asia, starting from the Late Neolithic up to the Middle Iron Age. During the last fieldwork seasons, a later, still poorly-known occupation has been identified: after its abandonment at the end of the Middle Iron Age period, Ulug-depe was briefly reoccupied during the late 1st millennium BC. The archaeological levels related to this occupation are extremely poorly preserved, and this stage is mainly witnessed by a particular pottery complex. Preliminary and ongoing researches on this pottery complex suggest that it principally includes Hellenistic-period vessels associated with some more unusual shapes. This association of material finds analogies in the area of interaction between the northern and the southern parts of Central Asia (i.e., in Uzbekistan, in a territory stretching from Tashkent to the Aral Sea through the Syr Darya area). In this paper, we will present a first overview of these discoveries, placing Ulug-depe at the crossroads of different cultural groups, sedentary and possibly nomadic, at the end of the 1st millennium BC.