The nexus of displacement, asset vulnerability and the Right to the City: the case of the refugees and urban poor of Dar es Salaam, Tanzania

This paper examines the asset vulnerability and livelihood strategies of refugees and the urban poor in slum settlements of Dar es Salaam, Tanzania. The Asset Vulnerability Framework is used as the analytical framework of how household’s assets are affected by vulnerability. Using qualitative analysis, factors which impact on the livelihood assets of both groups are examined. The paper focuses on the five main assets as indicated by Moser, while conceptualising further the assets which both populations aspire to accumulate, and which are necessary for them to prosper – rights, in this case the Right to the City. The paper, therefore, attempts to develop linkages between these areas: asset vulnerability, displacement and the Right to the City

CBX7 and miR-9 are part of an autoregulatory loop controlling p16(INK) (4a).

Polycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR-9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR-9-1 and miR-9-2 as part of a regulatory negative feedback loop. The miR-9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin-dependent kinase inhibitor (CDKI) p16(INK4a) during senescence. The ability of the miR-9 family to regulate senescence could have implications for understanding the role of miR-9 in cancer and aging

Classical and nonclassical intercellular communication in senescence and ageing

[Abstract] Intercellular communication refers to the different ways through which cells communicate with each other and transfer a variety of messages. These communication methods involve a number of different processes that occur individually or simultaneously, which change depending on the physiological or pathological context. The best characterized means of intercellular communication is the release of soluble factors that affect the function of neighboring cells. However, there are many other ways by which cells can communicate with each other. Here, we review the different means of intercellular communication including soluble factors in the context of senescence, ageing, and age-related diseases.Biotechnologyand Biological Sciences Research Council (UK); BB/P000223/1Barts Charity Grant; MGU049

NF-κB/IKK Activation by Small Extracellular Vesicles Within the SASP

[Abstract] Cellular senescence plays an important role in different biological and pathological conditions. Senescent cells communicate with their microenvironment through a plethora of soluble factors, metalloproteases and extracellular vesicles (EV). Although much is known about the role that soluble factors play in senescence, the downstream signalling pathways activated by EV in senescence is unknown. To address this, we performed a small molecule inhibitor screen and have identified the IκB kinases IKKε, IKKα and IKKβ as essential for senescence mediated by EV (evSASP). By using pharmacological inhibitors of IKKε, IKKα and IKKβ, in addition to CRISPR/Cas9 targeting their respective genes, we find these pathways are important in mediating senescence. In addition, we find that senescence activation is dependent on canonical NF-κB transcription factors where siRNA targeting p65 prevent senescence. Importantly, these IKK pathways are also relevant to ageing as knockout of IKKA, IKKB and IKKE avoid the activation of senescence. Altogether, these findings open a new potential line of investigation in the field of senescence by targeting the negative effects of the evSASP independent of particular EV contents.AO’s lab is supported by BBSRC (BB/P000223/1) and Bart’s Charity Grant (MGU0497). J.A.F.-L is funded by the Xunta de Galicia Fellowship (ED481B 2017/117)Xunta de Galicia; ED481B 2017/117Reino Unido. Biotechnology and Biological Sciences Research Council; BB/P000223/1Barts Charity (Londres); MGU049

Role for extracellular vesicles in the tumour microenvironment.

Extracellular vesicles (EVs) are small-membrane vesicles secreted by most cells types with the role to provide intercellular communication both locally and systemically. The transfer of their content between cells, which includes nucleic acids, proteins and lipids, confers the means for these interactions and induces significant cellular behaviour changes in the receiving cell. EVs are implicated in the regulation of numerous physiological and pathological processes, including development and neurological and cardiovascular diseases. Importantly, it has been shown that EV signalling is essential in almost all the steps necessary for the progress of carcinomas, from primary tumours to metastasis. In this review, we will focus on the latest findings for EV biology in relation to cancer progression and the tumour microenvironment.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.A.O.'s laboratory is supported by the BBSRC (BB/P000223/1)

The nexus of displacement, asset vulnerability and the Right to the City : the case of the refugees and urban poor of Dar es Salaam, Tanzania.

The nexus between rapid urbanisation and forced migration has in recent years manifested itself in a growing urban refugee phenomenon. The need for integrating the greater mobility of displaced populations with urban development is a humanitarian challenge as governments struggle to develop coherent policies to adequately meet the needs of both indigenous and refugee populations in urban areas. Understanding these needs and the livelihood strategies adopted by both populations are therefore of great importance. This thesis will specifically examine the asset vulnerability and livelihood strategies of the urban refugees and urban poor of Dar es Salaam using an asset vulnerability framework, while linking the framework to the concept of the Right to the City. This dissertation investigates the adaptation strategies of the Tanzanian urban poor and urban refugees to livelihood challenges in Dar es Salaam, the primary city of Tanzania and one of the most rapidly growing cities in the world. The impacts of forced displacement are likely to be challenging for refugee populations as they struggle to adapt to new circumstances. However, the assertion that urban refugees are more vulnerable than their urban poor counterparts is often made as a generalisation and not enough research has been conducted on this topic to develop a robust theory. The research therefore aims to examine the levels of asset vulnerability of both the urban refugees and urban poor Tanzanians and how they claim their Right to the City. In analysing asset vulnerability through the research paradigm of the Right to the City, this research provides analysis of how poor households attempt to reduce their vulnerability, and the institutional factors which help them to succeed or fail in their attempts. This research found that while both groups exert great efforts in attempting to reduce their vulnerability, urban refugees are indeed more disadvantaged overall. In the absence of strong social networks, savings or regular income, they are forced to adopt some negative coping strategies. This study adopts a case study approach and uses institutional analysis with the aid of the conceptual framework developed to examine the extent to which various government institutions and other stakeholders in Dar es Salaam foster an environment which reduces asset vulnerability and allows both groups to claim their Right to the City. The analysis in this research highlights the shortcomings of urban development planning and current refugee policies. The analysis indicates that many of the institutions lack any real vision or common goal for what they are trying to achieve, and instead exist in silos which result in poorly developed policies and ineffective programmes. Analysing the empirical evidence through the lenses of the Right to the City paradigm and asset vulnerability framework, this research reveals that providing more support to NGOs which work with urban refugees could greatly reduce their vulnerability. It also highlights clearly the linkages between asset vulnerability at the micro (household) and macro (city) levels, and how a negative feedback mechanism can develop in the absence of well–developed policies and strong institutions. Municipal and urban governance structures have the ability to create environments at the macro level which will result in less asset vulnerability at the micro level, and thereby increase the resilience of both the urban refugees and Tanzanian populations

When Less Is Best: Female Brown-Headed Cowbirds Prefer Less Intense Male Displays

Sexual selection theory predicts that females should prefer males with the most intense courtship displays. However, wing-spread song displays that male brown-headed cowbirds (Molothrus ater) direct at females are generally less intense than versions of this display that are directed at other males. Because male-directed displays are used in aggressive signaling, we hypothesized that females should prefer lower intensity performances of this display. To test this hypothesis, we played audiovisual recordings showing the same males performing both high intensity male-directed and low intensity female-directed displays to females (N = 8) and recorded the females' copulation solicitation display (CSD) responses. All eight females responded strongly to both categories of playbacks but were more sexually stimulated by the low intensity female-directed displays. Because each pair of high and low intensity playback videos had the exact same audio track, the divergent responses of females must have been based on differences in the visual content of the displays shown in the videos. Preferences female cowbirds show in acoustic CSD studies are correlated with mate choice in field and captivity studies and this is also likely to be true for preferences elucidated by playback of audiovisual displays. Female preferences for low intensity female-directed displays may explain why male cowbirds rarely use high intensity displays when signaling to females. Repetitive high intensity displays may demonstrate a male's current condition and explain why these displays are used in male-male interactions which can escalate into physical fights in which males in poorer condition could be injured or killed. This is the first study in songbirds to use audiovisual playbacks to assess how female sexual behavior varies in response to variation in a male visual display

Genome Wide CRISPR/Cas9 Screen Identifies the Coagulation Factor IX (F9) as a Regulator of Senescence

[Abstract] During this last decade, the development of prosenescence therapies has become an attractive strategy as cellular senescence acts as a barrier against tumour progression. In this context, CDK4/6 inhibitors induce senescence and reduce tumour growth in breast cancer patients. However, even though cancer cells are arrested after CDK4/6 inhibitor treatment, genes regulating senescence in this context are still unknown limiting their antitumour activity. Here, using a functional genome-wide CRISPR/Cas9 genetic screen we found several genes that participate in the proliferation arrest induced by CDK4/6 inhibitors. We find that downregulation of the coagulation factor IX (F9) using sgRNA and shRNA prevents the cell cycle arrest and senescent-like phenotype induced in MCF7 breast tumour cells upon Palbociclib treatment. These results were confirmed using another breast cancer cell line, T47D, and with an alternative CDK4/6 inhibitor, Abemaciclib, and further tested in a panel of 22 cancer cells. While F9 knockout prevents the induction of senescence, treatment with a recombinant F9 protein was sufficient to induce a cell cycle arrest and senescence-like state in MCF7 tumour cells. Besides, endogenous F9 is upregulated in different human primary cells cultures undergoing senescence. Importantly, bioinformatics analysis of cancer datasets suggest a role for F9 in human tumours. Altogether, these data collectively propose key genes involved in CDK4/6 inhibitor response that will be useful to design new therapeutic strategies in personalised medicine in order to increase their efficiency, stratify patients and avoid drug resistance.This paper was funded by the BBSRC (BB/P000223/1), the MRC (MR/K501372/1), The Royal Society (RG170399) and Barts Charity (MGU0497 and G-002158) grants to A.O. M.M. was funded by PI19/00145, IN607B2020/12 and 858014. J.F.L. is funded by Xunta de Galicia (ED481B 2017/117). M.B. was funded by MRC (MR/K501372/1). T.P.M. was funded by a QMUL PhD programme and T.D.N.’s lab is currently funded by a Barts Charity project grant (MGU0534). P.C.F. is currently funded by GAIN (IN606C 2021/006) Xunta de GaliciaReino Unido. Biotechnology and Biological Sciences Research Council; BB/P000223/1Reino Unido. Medical Research Council; MR/K501372/1Reino Unido. Royal Society; RG170399Barts Charity (Londres); MGU0497Barts Charity (Londres); G-002158Xunta de Galicia; IN607B2020/12Xunta de Galicia; ED481B 2017/117Barts Charity (Londres); MGU0534Xunta de Galicia; IN606C 2021/00

Small Extracellular Vesicles Are Key Regulators of Non-cell Autonomous Intercellular Communication in Senescence via the Interferon Protein IFITM3

Senescence is a cellular phenotype present in health and disease, characterized by a stable cell-cycle arrest and an inflammatory response called senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behavior of neighboring cells and altering the microenvironment; yet, this role has been mainly attributed to soluble factors. Here, we show that both the soluble factors and small extracellular vesicles (sEVs) are capable of transmitting paracrine senescence to nearby cells. Analysis of individual cells internalizing sEVs, using a Cre-reporter system, show a positive correlation between sEV uptake and senescence activation. We find an increase in the number of multivesicular bodies during senescence in vivo. sEV protein characterization by mass spectrometry (MS) followed by a functional siRNA screen identify interferon-induced transmembrane protein 3 (IFITM3) as being partially responsible for transmitting senescence to normal cells. We find that sEVs contribute to paracrine senescence. Borghesan et al. show that the soluble fraction and small extracellular vesicles (sEVs) mediate paracrine senescence. RNA sequencing and loxP reporter systems confirm sEV-mediated paracrine senescence, while preventing sEV release averts senescence. Mass spectrometry and functional analysis show that the IFN protein, IFITM3, is partially responsible for this phenotype.</p

Evolution of Female Preference for Younger Males

Previous theoretical work has suggested that females should prefer to mate with older males, as older males should have higher fitness than the average fitness of the cohort into which they were born. However, studies in humans and model organisms have shown that as males age, they accumulate deleterious mutations in their germ-line at an ever-increasing rate, thereby reducing the quality of genes passed on to the next generation. Thus, older males may produce relatively poor-quality offspring. To better understand how male age influences female mate preference and offspring quality, we used a genetic algorithm model to study the effect of age-related increases in male genetic load on female mate preference. When we incorporate age-related increases in mutation load in males into our model, we find that females evolve a preference for younger males. Females in this model could determine a male's age, but not his inherited genotype nor his mutation load. Nevertheless, females evolved age-preferences that led them to mate with males that had low mutation loads, but showed no preference for males with respect to their somatic quality. These results suggest that germ-line quality, rather than somatic quality, should be the focus of female preference in good genes models