TrkB isoforms differentially modulate amyloid precursor protein metabolism

Alzheimer’s disease (AD) is a complex neurodegenerative disease determined by the combination of environmental and genetic factors. The prevalence of the disease is rapidly increasing with the aging of the population in the Western world. The main genetic contributors to the disease are still unclear and no cure is available yet. The complete picture of the molecular pathologic mechanisms involved in the disease are also not resolved yet. The current hypothesis is that the disease is caused by accumulation of a toxic fragment of amyloid precursor protein (APP) called Aβ in the neurons. This accumulation causes synaptic dysfunction and neuronal death.Our study aims at investigating the role of TrkB in modulating APP metabolism. TrkB is a receptor expressed on neurons and important in synaptic function, neuronal survival and long-term potentiation. This receptor has a functional relevance in AD and a genetic relevance since some studies associated single nucleotide polymorphisms on this gene to AD. We hypothesized that TrkB isoforms can affect APP metabolism in different ways and we tested this hypothesis in different human cell lines.We found that TrkB isoforms can alter APP glycosylation and processing and that the TrkB isoforms can interact with each other and alter their effect on APP. We also showed for the first time that TrkB SHC, one of the TrkB truncated isoforms, regulates the full-length isoform differently from TrkB T.Our work demonstrates the potential importance of TrkB in AD pathogenesis and lays ground for designing better AD therapies based on the natural TrkB ligand BDNF (Brain Derived Neurotrophic Factor).Ph.D., Biological Sciences -- Drexel University, 201

Mobility issues and multidimensional inequalities: exploring the limits of the National Strategy for Immigration and Asylum during the COVID-19 pandemic in Morocco

In December 2019, the severe respiratory syndrome coronavirus-2 was discovered in China. The virus spread rapidly and, by March 2020, the World Health Organization (WHO) declared COVID-19 to be a global pandemic. Scientists expected the African continent to be among the worst affected by the sanitary emergency in terms of prevalence, incidence and mortality. This prediction was refuted by evidence, considering that Africa reported the least number of cases and deaths compared to Europe, Asia and America. The first case in Africa was registered in Egypt on February 14, 2020. By the end of 2021, the continent recorded a cumulative of 7,110,817 cases and 155,505 deaths. Nonetheless, estimates are likely to be distorted due to the lack of available data about the impact of COVID-19 and the limited documentary capacity of most African countries. There are several theories to explain why, contrary to the expected trend, Africa had the fewest COVID-19 incidences compared to other continents. Africa is characterized by a young population, which is notoriously less susceptible to COVID-19, with an average age of 19.7 years. In addition, most of the Africans (59%) live in rural areas, with few opportunities to travel or get in contact with outsiders. Moreover, governments enforced outstanding measures to contain the spread of the virus and safeguard the national economy, such as strengthening their documentary capacity and enforcing effective social safety nets. However, most of these policies have aggravated entrenched patterns of discrimination, making certain populations uniquely vulnerable. Indeed, mobility restrictions and border closures severely affected people with mobile livelihoods. In Morocco, the emergency measures compromised the resilience capacity of sub-Saharan migrants, particularly women and girls. To study the phenomenon of African migration to Morocco, we conducted fieldwork research from October to December 2021, interrupted by the closure of the kingdom's borders, and continued remotely thanks to key informants

TrkB Isoforms Differentially Affect AICD Production through Their Intracellular Functional Domains

We report that NTRK2, the gene encoding for the TrkB receptor, can regulate APP metabolism, specifically AICD levels. Using the human neuroblastoma cell line SH-SY5Y, we characterized the effect of three TrkB isoforms (FL, SHC, T) on APP metabolism by knockdown and overexpression. We found that TrkB FL increases AICD-mediated transcription and APP levels while it decreases sAPP levels. These effects were mainly mediated by the tyrosine kinase activity of the receptor and partially by the PLC-γ- and SHC-binding sites. The TrkB T truncated isoform did not have significant effects on APP metabolism when transfected by itself, while the TrkB SHC decreased AICD-mediated transcription. TrkB T abolished TrkB FL effects on APP metabolism when cotransfected with it while TrkB SHC cotransfected with TrkB FL still showed increased APP levels. In conclusion, we demonstrated that TrkB isoforms have differential effects on APP metabolism

MicroRNAs Can Regulate Human APP Levels

A number of studies have shown that increased APP levels, resulting from either a genomic locus duplication or alteration in APP regulatory sequences, can lead to development of early-onset dementias, including Alzheimer's disease (AD). Therefore, understanding how APP levels are regulated could provide valuable insight into the genetic basis of AD and illuminate novel therapeutic avenues for AD. Here we test the hypothesis that APP protein levels can be regulated by miRNAs, evolutionarily conserved small noncoding RNA molecules that play an important role in regulating gene expression. Utilizing human cell lines, we demonstrate that miRNAs hsa-mir-106a and hsa-mir-520c bind to their predicted target sequences in the APP 3'UTR and negatively regulate reporter gene expression. Over-expression of these miRNAs, but not control miRNAs, results in translational repression of APP mRNA and significantly reduces APP protein levels. These results are the first to demonstrate that levels of human APP can be regulated by miRNAs

MicroRNAs can regulate human APP levels

A number of studies have shown that increased APP levels, resulting from either a genomic locus duplication or alteration in APP regulatory sequences, can lead to development of early-onset dementias, including Alzheimer's disease (AD). Therefore, understanding how APP levels are regulated could provide valuable insight into the genetic basis of AD and illuminate novel therapeutic avenues for AD. Here we test the hypothesis that APP protein levels can be regulated by miRNAs, evolutionarily conserved small noncoding RNA molecules that play an important role in regulating gene expression. Utilizing human cell lines, we demonstrate that miRNAs hsa-mir-106a and hsa-mir-520c bind to their predicted target sequences in the APP 3'UTR and negatively regulate reporter gene expression. Over-expression of these miRNAs, but not control miRNAs, results in translational repression of APP mRNA and significantly reduces APP protein levels. These results are the first to demonstrate that levels of human APP can be regulated by miRNAs

The miR-430 locus with extreme promoter density forms a transcription body during the minor wave of zygotic genome activation

In anamniote embryos, the major wave of zygotic genome activation starts during the mid-blastula transition. However, some genes escape global genome repression, are activated substantially earlier, and contribute to the minor wave of genome activation. The mechanisms underlying the minor wave of genome activation are little understood. We explored the genomic organization and cis -regulatory mechanisms of a transcrip-tion body, in which the minor wave of genome activation is first detected in zebrafish. We identified the miR-430 cluster as having excessive copy number and the highest density of Pol-II-transcribed promoters in the genome, and this is required for forming the transcription body. However, this transcription body is not essential for, nor does it encompasse, minor wave transcription globally. Instead, distinct minor-wave -specific promoter architecture suggests that promoter-autonomous mechanisms regulate the minor wave of genome activation. The minor-wave-specific features also suggest distinct transcription initiation mecha-nisms between the minor and major waves of genome activation

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London