bluuebunny/crossref_metadata_2025 huggingface dataset:
The lived experiences of the African middle classes Introduction
Authors: Mercer Claire , Lemanski Charlotte
Published: May 2020

What are the experiences of the African middle classes, and what do their experiences tell us about social change on the continent? While there have been ample attempts to demarcate the parameters of this social group, the necessary work of tracing the social life and social relations of the middle classes is just beginning. The articles in this special issue provide compelling accounts of the ways in which the middle classes are as much made through their social relations and social practices as they are (if indeed they are) identifiable through aggregate snapshots of income, consumption habits and voting behaviours. Rachel Spronk (2018: 316) has argued that ‘the middle class is not a clear object in the sense of an existing group that can be clearly delineated; rather, it is a classification-in-the-making’. We agree, and our aim in bringing these contributions together in this special issue is to develop our understanding ofhowthis process is emerging in different contexts across Africa. In her opening contribution, Carola Lentz suggests that we need more research on ‘the social dynamics of “doing being middle-class”’, or what we term here ‘middle-classness’, which attends to this ‘classification-in-the-making’ through urban–rural changes over intergenerational life courses, multi-class households, kinship and social relations. Such an agenda has recently been opened up by two edited volumes on the African middle classes (Melber 2016; Kroekeret al. 2018). We further develop this agenda here through a series of empirically rich articles by scholars in African studies, anthropology, literature and sociology that explicitly address the question of the lived experiences of the middle classes. Echoing Spronk's unease with taking ‘the middle class’ as an already constituted social group, what emerges across the articles is rather the unstable, tenuous and context-specific nature of middle-class prosperity in contemporary Africa. Social positions shift – or are questioned – as one moves from the suburb to the township (Ndlovu on South Africa) or into state-subsidized high-rise apartments (Gastrow on Angola). Stability gives way over time to precarity (Southall on Zimbabwe). Wealth is not tied to the individual but circulates more widely through social relations. Should one invest in the nuclear or the extended family (Hull on South Africa; Spronk on Ghana)? In a house or a car (Durham on Botswana)? And why does it matter – for the individual, the household, the family, the city, the nation and the continent? To grasp what it means to be middle-class in Africa today necessarily requires an understanding of the historical, social and spatial embeddedness of lived experiences at multiple scales.
Housing middle-classness: formality and the making of distinction in Luanda
Authors: Gastrow Claudia
Published: May 2020

As one of the primary personal sites of financial investment, expression and public performance, housing has stood at the centre of contemporary studies of class in Africa. This article adds to the existing literature on housing and class by exploring residents’ desires for formal housing in post-conflict Luanda, Angola. Luanda's residents increasingly believed that access to formal housing, not necessarily always legally but rather aesthetically defined, was a primary means of affirming middle-class status. By highlighting the links between class, urban formality and the state, the article argues that formal housing became a means for both the state and Luandans to produce middle-classness. Existing beliefs about comportment and urban aesthetics, which anchored subjective understandings of class in the house, intersected with a political economy in which the state played a central role in enabling access to new residences. As such, formality has become a key means through which middle-classness is transforming urban landscapes, opening up discussions about aesthetic belonging, financial stability and the role of the state in the making of Africa's middle classes.
Shuttling between the suburbs and the township: the new black middle class(es) negotiating class and post-apartheid blackness in South Africa
Authors: Ndlovu Thabisani
Published: May 2020

A generation of South Africa's new black middle class shuttles between the suburbs and the townships. This has become the focus of some South African humorous essayists, among them Ndumiso Ngcobo and Fred Khumalo, on whose works this article is based. The article argues that studying the new black middle class should extend to these literary sources and approaches. The humorous essays by these two authors consistently reference metaphors of mobility and the vexed intersection of black middle-classness, consumption, racialized residential zoning and compromised status. Through the mode of humour, the essays evince the psychological burdens borne by those with township roots but who live in the suburbs, as they negotiate status inconsistency in a post-apartheid search for human dignity. Constant visits to the township and the retreat to the suburbs constitute negotiations of spatial, financial and psychic concerns imbricated in the legacies of apartheid's racialized politics of distinction.
Exploring the relationship between the Mediterranean diet and weight loss maintenance: the MedWeight study
Authors: Poulimeneas Dimitrios , Anastasiou Costas A. , Santos Inês , Hill James O. , Panagiotakos Demosthenes B. , Yannakoulia Mary
Published: May 2020

Weight loss maintenance is crucial for obesity management, yet optimal dietary patterns for this period are not established. We aimed to explore the relationship between adherence to the Mediterranean diet and weight loss maintenance. Sample includes 565 adults (62 % women) of the MedWeight study. Eligible volunteers were those reporting intentional weight loss of ≥10 %, starting from a BMI ≥ 25 kg/m2, over 12 months prior to enrolment. Based on current weight, participants were characterised as maintainers (≤90 % maximum weight) or regainers (>95 % maximum weight). Socio-demographics and weight history were recorded. Dietary intake was assessed by two non-consecutive 24-h recalls within 10 d and analysed in energy, macronutrient and food group intakes. Adherence to the Mediterranean diet was assessed with the Mediterranean Diet Score (MedDietScore) (range 0–55, greater scores showing higher adherence). Protein intake was higher in maintainers than in regainers (P< 0·001). When MedDietScore quartiles were considered, a linear trend for weight loss maintenance was revealed (P< 0·05). After adjustment for basic demographic characteristics, being in the third or fourth quartile of the MedDietScore (v. first) was associated with 2·30 (95 % CI 1·29, 4·09) and 1·88 (95 % CI 1·10, 3·22) increased odds of maintenance. Regarding individual MedDietScore components, only fruit intake is associated with increased odds for maintenance (1·03 (95 % CI 1·01, 1·06)). The leave-one-out approach revealed that at least six MedDietScore components were essential for the observed relationship. Higher adherence to the Mediterranean diet was associated with 2-fold increased likelihood of weight loss maintenance. Future studies should replicate these findings in non-Mediterranean populations as well.
Movements and habitat use of bottlenose dolphins,Tursiops truncatus, in south-eastern Brazil
Authors: Paschoalini Victor Uber , Santos Marcos César de Oliveira
Published: May 2020

Bottlenose dolphins (Tursiops truncatus) have been surveyed for at least two decades on the southern Brazilian coast. However, little is known about their distribution and habitat use in lower latitudes of the South-western Atlantic Ocean. Aiming to study the movements and distribution of the species along the south-eastern Brazilian coast, we made a comparison of photo-identified individuals of the species catalogued in 21 cruises conducted between 2012 and 2015. Additionally, we performed stable isotope analyses of carbon and nitrogen in skin samples (N = 35) to provide some insights of dolphin habitat use and trophic ecology through comparisons among individuals of distinct surveyed sectors (northern and southern) and sex. A total of 177 individuals were identified. Re-sightings (N = 24) occurred at intervals from 82 to 979 days at distances from 7 to 179 km. No individual was sighted in both sectors, suggesting spatial segregation. Isotopic comparisons showed no significant differences in carbon and nitrogen signatures between distinct sectors. However, ecological divergences were found when we divided the samples by gender. Wider isotopic niches were found for the northern bottlenose dolphinsvsthe southern ones, which could be related to temporal and spatial variation in the availability of resources, as well as possible differences in the home ranges of males and females in each region. This study represents a preliminary evaluation of ecological aspects of bottlenose dolphins along the Brazilian south-eastern coast, however, long-term studies on the feeding ecology and habitat use of this species are important to further improve our knowledge.
BLOCKCHAIN DOUBLE-SPEND ATTACK DURATION
Authors: Brown Mark , Peköz Erol , Ross Sheldon
Published: May 2020

Many cryptocurrencies including Bitcoin are susceptible to a so-called double-spend attack, where someone dishonestly attempts to reverse a recently confirmed transaction. The duration and likelihood of success of such an attack depends on the recency of the transaction and the computational power of the attacker, and these can be related to the distribution of time for counts from one Poisson process to exceed counts from another by some desired amount. We derive an exact expression for this distribution and show how it can be used to obtain efficient simulation estimators. We also give closed-form analytic approximations and illustrate their accuracy.
Thomas Hardy and the Value of Brains
Authors: Lyons Sara
Published: May 2020

This article reads Thomas Hardy'sThe Woodlanders(1887) andJude the Obscure(1895) as ambivalent responses to the new conception of human intelligence that emerged from Victorian psychology and evolutionary theory and which formed the basis of what I describe as the Victorian biopolitics of intelligence. Although these novels reflect Hardy's endorsement of the new biological model of intelligence, they also register his resistance to what many late Victorians assumed to be its corollary: that mental worth can be an object of scientific measurement, classification, and ranking. I suggest that the work of the philosopher Jacques Rancière illuminates the extent to which these novels challenge the scientific reification of intellectual inequality and attempt to vindicate overlooked and stigmatized forms of intelligence.
Virtual Minds, Victorian Novels, and the Question of Modeling
Authors: Cohn Elisha
Published: May 2020

Snagsby's paper shop inBleak House(1853) deals in “all sorts of blank forms of legal process; in skins and rolls of parchment; in paper—foolscap, brief, draft, brown, white, whitey-brown, and blotting; in stamps; in office-quills, pens, India-rubber, pounce, pins, pencils, sealing-wax, and wafers; in red tape, and green ferret; in pocket-books, almanacks, diaries, and law lists; in string boxes, rulers, inkstands—glass and leaden, penknives, scissors, bodkins, and other small office cutlery; in short, in articles too numerous to mention.” While one might imagine this stifling bookish environment as especially inviting for an object-oriented reading, this passage has recently attracted what I might call a newly inflected kind of subject-oriented reading. This description fromBleak Housemakes an appearance in two recent critical monographs concerned with how the reader's cognitive capabilities meet words on the page to transform them into a felt reality. How does a passage like this act on our minds, creating mental images or offering a sense of embeddedness in an unreal “reality”? How does fiction become phenomenological?
Introduction
Authors: Hensley Nathan K.
Published: May 2020

“We saw no issues,” reports the Department of Homeland Security in a self-study of its practices for detaining children at the US–Mexico border, “except one unsanitary bathroom.” The system is working as it should; all is well. “CBP [Customs and Border Protection] facilities we visited,” the report summarizes, “appeared to be operating in compliance with the 2015 National Standards on Transport, Escort, Detention, and Search.” A footnote on page 2 of the September 2018 document defines the prisoners at these facilities, the “unaccompanied alien children,” as “aliens under the age of eighteen with no lawful immigration status in the United States and without a parent or legal guardian in the United States ‘available’ to care and [provide] physical custody for them.” Available is in scare quotes. This tic of punctuation discloses to us that the parents of these children have been arrested and removed. They arenot available, and cannot take physical custody of their children, because they themselves are in physical custody. In a further typographical error, the word “provide” has been omitted: the children arewithout a parent or legal guardian in the United States “available” to care and physical custody for them.The dropped word turns “physical custody” into a verb and sets this new action,to physical custody, in tense relation to “care.”
Awareness of marketing for high fat, salt or sugar foods, and the association with higher weekly consumption among adolescents: a rejoinder to the UK government’s consultations on marketing regulation
Authors: Critchlow Nathan , Bauld Linda , Thomas Christopher , Hooper Lucie , Vohra Jyotsna
Published: May 2020

Objective:

Exposure to marketing for foods high in fat, salt or sugar (HFSS) reportedly influences consumption, nutritional knowledge and diet-related health among adolescents. In 2018/2019, the UK government held two consultations about introducing new restrictions on marketing for HFSS foods. To reinforce why these restrictions are needed, we examined adolescents’ awareness of marketing for HFSS foods, and the association between past month awareness and weekly HFSS food consumption.

Design:

Cross-sectional survey that measured past month awareness of ten marketing activities for HFSS foods (1 = everyday; 6 = not in last month). Frequencies were converted into aggregate past month awareness across marketing activities and grouped into three categories (low/medium/high). Consumption was self-reported for fifteen foods (twelve HFSS) (1 = few times/d; 9 = never). For each food, frequency was divided into higher/lower weekly consumption.

Setting:

United Kingdom.

Participants:

11–19-year-olds (n 3348).

Results:

Most adolescents (90·8 %) reported awareness of a least one marketing activity for HFSS foods, and at least half reported seeing ≥70 instances in the past month. Television, social media and price offers were the marketing activities most frequently reported. Awareness was associated with higher weekly consumption for ten of the twelve HFSS foods. For example, those reporting medium marketing awareness were 1·5 times more likely to report higher weekly consumption of cakes/biscuits compared with those reporting low awareness (AOR = 1·51, P = 0·012). The likelihood of higher weekly HFSS food consumption increased relative to the level of marketing awareness.

Conclusions:

Assuming there is a causal relationship between marketing awareness and consumption, the restrictions proposed by the UK government are likely to help reduce HFSS consumption.
A Nutrition Report Card on food environments for children and youth: 5 years of experience from Canada
Authors: Ferdinands Alexa R , Olstad Dana Lee , Milford Krista M , Maximova Katerina , Nykiforuk Candace IJ , Raine Kim D
Published: May 2020

Objective:

In 2014, a Nutrition Report Card (NRC) was developed as a sustainable, low-cost framework to assess the healthfulness of children’s food environments and highlight action to support healthy eating. We summarise our experiences in producing, disseminating, evaluating and refining an annual NRC in a Canadian province from 2015 to 2019.

Design:

To produce the NRC, children’s food environment indicator data are collected, analyzed and compiled for consensus grading by an Expert Working Group of researchers and practitioners. Knowledge translation activities are tailored annually to the needs of target audiences: researchers, practitioners, policymakers and the public. Evaluation of reach is conducted through diverse strategies, including tracking media coverage and website traffic. Assessment of impact on diets and health outcomes is planned.

Setting:

Alberta, Canada.

Participants:

Not applicable.

Discussion:

The grading process has facilitated refining the NRC to enhance its relevance and utility as a tool for its target audiences. Its public release consistently captures media interest and policymakers’ attention. The importance of partnerships in revealing data sources and in strategising to enhance policy approaches to improve food environments is apparent. The NRC has benchmarked progress and stimulated dialogue regarding healthy food environments for children.

Conclusions:

The NRC may help to foster a supportive climate for improving the quality of children’s food environments. As an engaging and accessible document, the NRC represents a key mechanism for collating data related to children’s food environments and ensuring it reaches the audiences best positioned to use it. Efforts are underway to expand the NRC across Canada.
Exploring the implementation and delivery of primary care services for transgender individuals in Ontario: case study protocol
Authors: Ziegler Erin , Valaitis Ruta , Carter Nancy , Risdon Cathy , Yost Jennifer
Published: May 2020

Background:

Historically transgender adults have experienced barriers in accessing primary care services. In Ontario, Canada, health care for transgender adults is accessed through primary care; however, a limited number of practitioners provide care, and patients are often waiting and/or traveling great distances to receive care. The purpose of this protocol is to understand how primary care is implemented and delivered for transgender adults. The paper presents how the case study method can be applied to explore implementation of health services delivery for the transgender population in primary care.

Methods:

Case study methodology will be used to explore this phenomenon in different primary care contexts. Normalization Process Theory is used as a guide. Three cases known to provide transgender primary care and represent different Ontario primary care models have been identified. Comparing transgender care implementation and delivery across different models is vital to understanding how care provision to this population can be supported. Qualitative interviews will be conducted. Participants will also complete the NoMAD (NOrmalization MeAsure Development) survey, a tool measuring implementation processes. The tool will be modified to explore the implementation of primary care services for transgender individuals. Documentary evidence will be collected. Cross-case synthesis will be completed to compare the cases.

Discussion:

Findings will provide an Ontario perspective on the implementation and delivery of primary care for transgender adults in different primary care models. Results may be applicable to other primary care settings in Canada and other nations with similar systems. Barriers and facilitators in delivery and implementation will be identified. Providing an understanding and increasing awareness of the implementation and delivery of primary care may help to reduce the invisibility and disparities transgender individuals experience when accessing primary care services. Understanding delivery of care could allow care providers to implement primary care services for transgender individuals, improving access to health care for this vulnerable population.
Character Cues Modulate the Affordance Effects during Danger Warning
Authors: Zhao Liang
Published: May 2020

It has been demonstrated that perception of objects automatically evokes potential actions to interact with those objects; this is termed as affordance. The present study investigated how the corresponding affordance effect of graspable objects was modulated by the cue about risk levels of object. Participants were presented with pictures of dangerous graspable objects or neutral graspable objects. The participants were required to perform an upright/upside down discrimination task by pressing different keys. Results showed that both the affordance effects of dangerous object and neutral object in children were enhanced when a cue preceded the object, t(35) = 3.83, p < .01, Cohen’s d = 1.29. These results indicate that the prompt of risk level can improve individual’s appropriate manipulation to the object.
Elevated Hair Mercury Levels Are Associated With Neurodevelopmental Deficits in Children Living Near Artisanal and Small‐Scale Gold Mining in Peru
Authors: Reuben Aaron , Frischtak Helena , Berky Axel , Ortiz Ernesto J. , Morales Ana Maria , Hsu‐Kim Heileen , Pendergast Laura L. , Pan William K.
Published: May 2020

Children living near artisanal and small‐scale gold mining (ASGM) are at risk of exposure to mercury, a neurotoxicant. It is not certain whether such exposures are harming development, as they occur in underresourced contexts entwined with other stressors, such as malnutrition and enteric infection. This study sought to investigate the association between hair‐mercury levels and visual‐motor, cognitive, and physical development among children living near ASGM in the Peruvian Amazon. Total hair‐mercury levels were measured in 164 children ages 5–12 living in Madre de Dios, Peru. Primary outcomes included Visual‐Motor Integration assessed via the Beery‐VMI Developmental Test, General Cognitive Ability assessed via the Batería‐III Woodcock‐Munoz (Spanish‐language Woodcock‐Johnson Tests of Cognitive Abilities), and Physical Health assessed via anthropometry/hemoglobin counts. Mean (SD) hair‐mercury level was 2.06 (2.43) μg/g. Fifty‐four children (32.9%) had hair‐mercury levels above the World Health Organization reference level of 2.0 μg/g. After controlling for sex, child age, maternal education, and family socioeconomic status, each one unit increase in log hair‐mercury level was associated with a 1.01 unit decrease in Visual‐Motor Integration (95%CI: −2.06, 0.05, p = 0.061), a 2.59 unit decrease in General Cognitive Ability (95%CI: −4.52, −0.66, p = 0.012), and a 2.43 unit decrease in Physical Health (95%CI: −5.34, 0.49, p = 0.096). After adjustment for covariates, children with hair‐mercury levels exceeding the World Health Organization reference level scored 4.68 IQ points lower in Cognitive Ability than their peers. Mercury exposures related to ASGM may be harming child development in the Peruvian Amazon. Children in this region may benefit from intervention to reach their full developmental potential.
Assessing California Wintertime Precipitation Responses to Various Climate Drivers
Authors: Allen Robert J. , Lamarque Jean‐Francois , Watson‐Parris Duncan , Olivié Dirk
Published: May 2020

Understanding how drivers of climate change affect precipitation remains an important area of research. Although several robust precipitation responses have been identified under continued increases in greenhouse gases (GHGs), considerable uncertainty remains. This is particularly the case at regional scales, including the West Coast of the United States and California. Here, we exploit idealized, single forcing simulations from the Precipitation Driver Response Model Intercomparison Project (PDRMIP) to address how climate drivers impact California wintertime precipitation. Consistent with recent work, GHGs including carbon dioxide and methane, as well as solar forcing, yield a robust increase in California wintertime precipitation. We also find robust California precipitation responses to aerosols but with opposite responses for sulfate versus black carbon aerosol. Sulfate aerosol increases California wintertime precipitation, whereas black carbon reduces it. Moreover, California precipitation is more sensitive to aerosols, particularly regional emissions from Europe and Asia, than to GHGs. These precipitation responses are consistent with shifts in the jet stream and altered moisture fluxes. Although the idealized nature of PDRMIP simulations precludes a formal attribution, our results suggest that aerosols can perturb precipitation and fresh water resources along the West Coast of the United States.
Analysis of the Thermodynamic Phase Transition of Tracked Convective Clouds Based on Geostationary Satellite Observations
Authors: Coopman Q. , Hoose C. , Stengel M.
Published: May 2020

Clouds are liquid at temperature greater than 0°C and ice at temperature below −38°C. Between these two thresholds, the temperature of the cloud thermodynamic phase transition from liquid to ice is difficult to predict and the theory and numerical models do not agree: Microphysical, dynamical, and meteorological parameters influence the glaciation temperature. We temporally track optical and microphysical properties of 796 clouds over Europe from 2004 to 2015 with the space‐based instrument Spinning Enhanced Visible and Infrared Imager on board the geostationary METEOSAT second generation satellites. We define the glaciation temperature as the mean between the cloud top temperature of those consecutive images for which a thermodynamic phase change in at least one pixel is observed for a given cloud object. We find that, on average, isolated convective clouds over Europe freeze at −21.6°C. Furthermore, we analyze the temporal evolution of a set of cloud properties and we retrieve glaciation temperatures binned by meteorological and microphysical regimes: For example, the glaciation temperature increases up to 11°C when cloud droplets are large, in line with previous studies. Moreover, the correlations between the parameters characterizing the glaciation temperature are compared and analyzed and a statistical study based on principal component analysis shows that after the cloud top height, the cloud droplet size is the most important parameter to determine the glaciation temperature.
Using Data Assimilation to Reconstruct High‐Latitude Polar Cap Patches
Authors: Negale Michael , Holmes Jeffrey , Parris Richard , Ober Daniel , Dao Eugene , Kelly Ralph , Eccles J. Vincent , Hines Jack , Pedersen Todd
Published: May 2020

Discrete high‐density plasma structures in the Earth's ionosphere that convect across the polar cap from the dayside to nightside are known as polar cap patches. This high‐latitude phenomenon can interfere and disrupt satellite and high‐frequency (HF) communications when the associated sharp electron density gradients are encountered, and therefore, accurate modeling and forecasting of such events would be greatly beneficial. In this study, we have utilized the assimilative Global Positioning System Ionospheric Inversion (GPSII) method to reconstruct the high‐latitude ionosphere utilizing data from Global Navigation Satellite System (GNSS) receivers, vertical ionosondes, the Resolute Bay Incoherent Scatter Radar (RISR‐N), in situ satellite data, and Super Dual Auroral Radar Network (SuperDARN) radars. The novel method of assimilating RISR‐N and SuperDARN ground scatter measurements helps to increase the limited number of observations at high latitudes. The reconstructed polar cap patches are shown to correspond with ground‐ and spaced‐based observations, illustrating the ability of utilizing GPSII to study the complex high‐latitude region.
UHF Propagation Through a Trunk‐Dominated Forest
Authors: Torrico Saúl A. , Utku Cuneyt , Lang Roger H.
Published: May 2020

Transport theory is used to calculate the intensity of a wave propagating though a trunk‐dominated forest. The trunks are replaced by parallel infinitely long dielectric cylinders, and a vertically polarized plane wave is normally incident on the layer of these randomly distribution parallel cylinders. The problem can be reduced to a two‐dimensional transport problem that can be solved by the eigenvalue technique for the coherent, incoherent, and total intensity of the propagating wave. Using the assumption that the distribution of trunks is sparse and that the trunks locations are independent from one another, the probability density function (PDF) of the total and incoherent intensity as a function of depth into the layer can be found. To verify these results, a Monte Carlo (MC) simulation is performed in the low frequency limit which takes the effect of multiple scattering into account. The results show that there is a very close correspondence between the transport and MC simulation findings; the coherent, incoherent, and the total intensity for these two methods agree very closely as a function of distance into the slab. In addition, the PDFs for these three quantities also agree with the MC based histograms. One sees that as the wave propagates into the layer, the Rician distribution for the magnitude tends to a Rayleigh PDF as the coherent wave decays.
Comparison of Surface Radio Refractivity Variability in the Northern and Southern Parts of Quebec, Canada
Authors: Bettouche Y. , Obeidat H. A. , Agba B. L. , Kouki A. B. , Mosleh M. F. , AlAbdullah A. M. , Abd‐Alhameed R. A.
Published: May 2020

Thirty‐nine years of archived meteorological data measured at two stations located in the northern and southern parts of Quebec, Canada are used to estimate the surface refractivity and its dry and wet components. The results of the comparison of the obtained estimates showed that for all months the values of the dry component are higher in the northern part, whereas the values of the wet component are higher in the southern part. Due to this, for several months of the year, the values of the surface refractivity are higher in the northern part and for the remaining months in the southern part. Moreover, in both parts, August is the month where the highest values of the surface refractivity were recorded. In this particular month, the slope of the surface refractivity trend in the northern part is several times higher than that in the southern part. The obtained results show that the performance of the used direct smoothing forecasting technique depends on the deviation between the values of N in the current year and the previous year.
AP-1 controls the p11-dependent antidepressant response
Authors: Chottekalapanda Revathy U. , Kalik Salina , Gresack Jodi , Ayala Alyssa , Gao Melanie , Wang Wei , Meller Sarah , Aly Ammar , Schaefer Anne , Greengard Paul
Published: May 2020

Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for mood disorders. While the mechanism of SSRI action is still unknown, SSRIs are thought to exert therapeutic effects by elevating extracellular serotonin levels in the brain, and remodel the structural and functional alterations dysregulated during depression. To determine their precise mode of action, we tested whether such neuroadaptive processes are modulated by regulation of specific gene expression programs. Here we identify a transcriptional program regulated by activator protein-1 (AP-1) complex, formed by c-Fos and c-Jun that is selectively activated prior to the onset of the chronic SSRI response. The AP-1 transcriptional program modulates the expression of key neuronal remodeling genes, including S100a10 (p11), linking neuronal plasticity to the antidepressant response. We find that AP-1 function is required for the antidepressant effect in vivo. Furthermore, we demonstrate how neurochemical pathways of BDNF and FGF2, through the MAPK, PI3K, and JNK cascades, regulate AP-1 function to mediate the beneficial effects of the antidepressant response. Here we put forth a sequential molecular network to track the antidepressant response and provide a new avenue that could be used to accelerate or potentiate antidepressant responses by triggering neuroplasticity.
Target identification of natural medicine with chemical proteomics approach: probe synthesis, target fishing and protein identification
Authors: Chen Xiao , Wang Yutong , Ma Nan , Tian Jing , Shao Yurou , Zhu Bo , Wong Yin Kwan , Liang Zhen , Zou Chang , Wang Jigang
Published: May 2020

Natural products are an important source of new drugs for the treatment of various diseases. However, developing natural product-based new medicines through random moiety modification is a lengthy and costly process, due in part to the difficulties associated with comprehensively understanding the mechanism of action and the side effects. Identifying the protein targets of natural products is an effective strategy, but most medicines interact with multiple protein targets, which complicate this process. In recent years, an increasing number of researchers have begun to screen the target proteins of natural products with chemical proteomics approaches, which can provide a more comprehensive array of the protein targets of active small molecules in an unbiased manner. Typically, chemical proteomics experiments for target identification consist of two key steps: (1) chemical probe design and synthesis and (2) target fishing and identification. In recent decades, five different types of chemical proteomic probes and their respective target fishing methods have been developed to screen targets of molecules with different structures, and a variety of protein identification approaches have been invented. Presently, we will classify these chemical proteomics approaches, the application scopes and characteristics of the different types of chemical probes, the different protein identification methods, and the advantages and disadvantages of these strategies.
A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity
Authors: Kostaras Eleftherios , Kaserer Teresa , Lazaro Glorianne , Heuss Sara Farrah , Hussain Aasia , Casado Pedro , Hayes Angela , Yandim Cihangir , Palaskas Nicolaos , Yu Yi , Schwartz Brian , Raynaud Florence , Chung Yuen-Li , Cutillas Pedro R. , Vivanco Igor
Published: May 2020

Background

AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants.

Methods

We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity.

Results

Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations.

Conclusions

These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options.
Racial differences in prostate cancer: does timing of puberty play a role?
Authors: Hur Jinhee , Giovannucci Edward
Published: May 2020

The burden of prostate cancer has a remarkably disproportionate distribution across racial groups. For example, in the USA, African Americans are twice as likely as individuals of European ancestry to develop or die from prostate cancer, and have a more aggressive disease nature at diagnosis. In contrast, Asian American men have the lowest incidence and mortality rates of prostate cancer. That considerable racial disparities exist even in the subclinical stage of prostate cancer among young men in their 20–30s suggests that patterns of prostate carcinogenesis start to diverge even earlier, perhaps during puberty, when the prostate matures at its most rapid rate. Mendelian randomisation studies have provided strong population-based evidence supporting the hypothesis that earlier onset of puberty increases the risk of prostate cancer—particularly of high grade—and prostate cancer-specific mortality later in life, observations which correspond to the epidemiology of the disease in African Americans. Notably, African American boys initiate genital development ~1 year earlier and thus go through longer periods of pubertal maturation compared with European American boys. In this perspective, bringing together existing evidence, we point to puberty as a potential critical window of increased susceptibility to prostate carcinogenesis that could account for the marked prevailing racial differences in the burden of prostate cancer.
Omental adipocytes promote peritoneal metastasis of gastric cancer through the CXCL2–VEGFA axis
Authors: Natsume Makoto , Shimura Takaya , Iwasaki Hiroyasu , Okuda Yusuke , Hayashi Kazuki , Takahashi Satoru , Kataoka Hiromi
Published: May 2020

Background

Gastric cancer (GC) patients frequently develop peritoneal metastasis; however, the underlying mechanism remains unknown. We hypothesised that omental adipocytes (OmAd) trigger GC cells towards malignant activity to induce peritoneal metastasis.

Methods

We analysed interactions among human GC cells, endothelial cells and OmAd using a 3D co-culture system. We also employed a multipronged animal study, including subcutaneous and orthotopic tumours, and humanised omental adipose tissue models. Urinary levels of CXCL2 were analysed in human GC patients with and without peritoneal metastasis.

Results

Conditioned media derived from OmAd (OmAd-CM) promoted the proliferation, migration and capacity to induce angiogenesis of GC cells through AKT phosphorylation and VEGFA overexpression, whereas silencing CXCL2 in OmAd cancelled OmAd-induced effects. In an orthotopic tumour model using SCID mice, omentectomy suppressed GC growth and peritoneal dissemination, and reduced serum levels of CXCL2. OmAd promoted GC growth in a humanised omental adipose tissue model using NSG mice, but silencing CXCL2 in OmAd cancelled OmAd-induced tumour growth. Finally, urinary levels of CXCL2 were significantly higher in GC patients with peritoneal metastasis than in those without.

Conclusion

Omental adipocytes trigger GC cells to an aggressive phenotype through CXCL2 secretion, which induces angiogenesis followed by cell growth and peritoneal metastasis.
Defining COMMD4 as an anti-cancer therapeutic target and prognostic factor in non-small cell lung cancer
Authors: Suraweera Amila , Duff Alex , Adams Mark N. , Jekimovs Christian , Duijf Pascal H. G. , Liu Cheng , McTaggart Matthew , Beard Sam , O’Byrne Kenneth J. , Richard Derek J.
Published: May 2020

Background

Non-small cell lung cancers (NSCLC) account for 85–90% of all lung cancers. As drug resistance critically impairs chemotherapy effectiveness, there is great need to identify new therapeutic targets. The aims of this study were to investigate the prognostic and therapeutic potential of the copper-metabolism-domain-protein, COMMD4, in NSCLC.

Methods

The expression of COMMD4 in NSCLC was investigated using bioinformatic analysis, immunoblotting of immortalised human bronchial epithelial (HBEC) and NSCLC cell lines, qRT-PCR and immunohistochemistry of tissue microarrays. COMMD4 function was additionally investigated in HBEC and NSCLC cells depleted of COMMD4, using small interfering RNA sequences.

Results

Bioinformatic analysis and in vitro analysis of COMMD4 transcripts showed that COMMD4 levels were upregulated in NSCLC and elevated COMMD4 was associated with poor prognosis in adenocarcinoma (ADC). Immunoblotting demonstrated that COMMD4 expression was upregulated in NSCLC cells and siRNA-depletion of COMMD4, decreased cell proliferation and reduced cell viability. Cell death was further enhanced after exposure to DNA damaging agents. COMMD4 depletion caused NSCLC cells to undergo mitotic catastrophe and apoptosis.

Conclusions

Our data indicate that COMMD4 may function as a prognostic factor in ADC NSCLC. Additionally, COMMD4 is a potential therapeutic target for NSCLC, as its depletion induces cancer cell death.
Inhibition of soluble epoxide hydrolase attenuates renal tubular mitochondrial dysfunction and ER stress by restoring autophagic flux in diabetic nephropathy
Authors: Jiang Xu-shun , Xiang Xing-yang , Chen Xue-mei , He Jun-ling , Liu Ting , Gan Hua , Du Xiao-gang
Published: May 2020

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD), and renal tubular cell dysfunction contributes to the pathogenesis of DN. Soluble epoxide hydrolase (sEH) is an enzyme that can hydrolyze epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs) into the less biologically active metabolites. Inhibition of sEH has multiple beneficial effects on renal function, however, the exact role of sEH in hyperglycemia-induced dysfunction of tubular cells is still not fully elucidated. In the present study, we showed that human proximal tubular epithelial (HK-2) cells revealed an upregulation of sEH expression accompanied by the impairment of autophagic flux, mitochondrial dysfunction, ubiquitinated protein accumulation and enhanced endoplasmic reticulum (ER) stress after high glucose (HG) treatment. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which resulted in excessive reactive oxygen species (ROS) generation, Bax translocation, cytochrome c release, and apoptosis. However, t-AUCB, an inhibitor of sEH, partially reversed these negative outcomes. Moreover, we also observed increased sEH expression, impaired autophagy flux, mitochondrial dysfunction and enhanced ER stress in the renal proximal tubular cells of db/db diabetic mice. Notably, inhibition of sEH by treatment with t-AUCB attenuated renal injury and partially restored autophagic flux, improved mitochondrial function, and reduced ROS generation and ER stress in the kidneys of db/db mice. Taken together, these results suggest that inhibition of sEH by t-AUCB plays a protective role in hyperglycemia-induced proximal tubular injury and that the potential mechanism of t-AUCB-mediated protective autophagy is involved in modulating mitochondrial function and ER stress. Thus, we provide new evidence linking sEH to the autophagic response during proximal tubular injury in the pathogenesis of DN and suggest that inhibition of sEH can be considered a potential therapeutic strategy for the amelioration of DN.
High glucose mediates NLRP3 inflammasome activation via upregulation of ELF3 expression
Authors: Wang Jing , Shen Xuefang , Liu Jing , Chen Wankun , Wu Fengfeng , Wu Weifei , Meng Zhipeng , Zhu Minmin , Miao Changhong
Published: May 2020

Microtubule affinity regulating kinase 4 (MARK4) plays a crucial role in the regulation of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome activation, which leads to the generation of bioactive interleukin (IL)-1β and IL-18. E74-like ETS transcription factor 3 (ELF3) participates in endothelial inflammatory processes. We hypothesized that ELF3 modulates MARK4 expression in vascular endothelial cells, thus contributing to high glucose-mediated NLRP3 inflammasome activation. Plasma IL-1β, IL-18, NLRP3 inflammasome and MARK4 expression was increased in diabetic patients and rats. An in vitro study indicated that high glucose increased IL-1β and IL-18 expression and activated the NLRP3 inflammasome via upregulation of MARK4 in human umbilical vein endothelial cells (HUVECs). Furthermore, high glucose increased ELF3 expression. ELF3 downregulation reversed the effects of high glucose treatment. Accordingly, the effects of ELF3 overexpression were similar to those of high glucose treatment and were counteracted by siMARK4. Furthermore, ELF3 was found to interact with SET8. High glucose inhibited SET8 expression and histone H4 lysine 20 methylation (H4K20me1), a downstream target of SET8. Overexpression of SET8 inhibited high glucose-induced MARK4 expression and NLRP3 inflammasome activation. The effects of shSET8 were similar to those of high glucose treatment and were counteracted by siMARK4. A mechanistic study found that ELF3 and H4K20me1 were enriched in the MARK4 promoter region. si-ELF3 attenuated MARK4 promoter activity and augmented the inhibitory effect of SET8 on MARK4 promoter activity. Furthermore, SET8 downregulation and ELF3 upregulation were confirmed in diabetic patients and rats. In conclusion, ELF3 interacted with SET8 to modulate MARK4 expression, which participated in hyperglycaemia-mediated endothelial NLRP3 inflammasome activation.
CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts
Authors: Lu Hong-Ting , Feng Ren-Qian , Tang Jia-Kun , Zhou Jing-Jun , Gao Feng , Ren Jun
Published: May 2020

Previous studies indicated that Ca2+/calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca2+-regulated protease μ-calpain to promote myocardial ischemia/reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca2+-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca2+ flux using ryanodine and thapsigargin failed to prevent Ca2+ paradox-induced heart injury. In contrast, the Ca2+ paradox increased CaMKII auto-phosphorylation at Thr287, while the CaMKII inhibitor KN-62 and the Na+/Ca2+ exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of μ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca2+ leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.