Biology subjects

Farah, H.

Publications and source records attributed to Farah, H..

4 recordsLinked to original sources

bioRxiv2026

Infrapatellar Fat Pad Extracellular Vesicles Induce a Pro-Angiogenic VEGFAhigh/BMP4low Switch in Articular Chondrocytes: Implications for Chondrosarcoma

Chondrosarcoma is a hyper-vascularised, chemoresistant cartilage malignancy driven by VEGF-centred angiogenesis, and local adipose depots are increasingly recognised as paracrine drivers of tumour angiogenesis via adipokines and extracellular vesicles (EVs). The infrapatellar fat pad (IFP), an inflammatory adipose depot within the articular joint in direct cartilage contact, is a key local source of adipose-derived EVs, and thus a candidate driver of angiogenesis in chondrosarcoma. The aim of this study was to determine whether the IFP is a productive source of EVs, and whether IFP-derived EVs induce angiogenesis in articular chondrocytes. The IFP released significantly more EVs than subcutaneous fat (n = 8 per depot; p = 0.027). Treating primary human articular chondrocytes with IFP EVs for 24 h upregulated VEGFA (+1.6-fold, p = 0.036) and downregulated BMP4 (-2.4-fold, p = 0.011), engaging the VEGF/eNOS/ERK axis that drives chondrosarcoma angiogenesis. Re-analysis of a previously published phospho-kinase dataset from the same donor EVs, corroborated by a pooled donor-group analysis (n = 3), supported activation of eNOS, ERK1/2, PLC-{gamma}1 and HSP27. These findings identify the IFP as a dominant source of EVs within the articular joint, which can induce a pro-angiogenic, VEGF-axis switch in articular cartilage cells, supporting a signalling model relevant to chondrosarcoma angiogenesis.

cancer biology↗

bioRxiv2024

Breaking free from the clocks tyranny restores memory to brain damaged flies

The relationship between sleep and memory is an active topic of investigation. In this context, we demonstrate that enhancing sleep restores memory to flies with ablated Mushroom Bodies (MB), a key memory center; this is consistent across several memory assays. Mapping the underlying circuitry reveals circadian modulation of a subset of Dopaminergic neurons (DANs) that modulate aversive learning. Using imaging, we show that MB-ablation disrupts, and sleep restores the time of day these neurons are most responsive. Knocking down the receptor for the clock output signal, Pigment-dispersing factor (Pdfr), in this subset of DANs restores memory to MB-ablated flies. Crucially, MB-ablation does not result in memory impairments in the absence of a functioning clock. Our results reveal neuromodulations key role in cognitive restoration, where sleep aids memory in damaged brains, but a functioning clock unexpectedly hinders this process.

neuroscience↗

bioRxiv2023

Sleep Deprivation, Sleep Fragmentation and Social Jet Lag increase temperature preference in Drosophila

Despite the fact that sleep deprivation substantially affects the way animals regulate their body temperature, the specific mechanisms behind this phenomenon are not well understood. In both mammals and flies, neural circuits regulating sleep and thermoregulation overlap, suggesting an interdependence that may be relevant for sleep function. To investigate this relationship further, we exposed flies to 12 h of sleep deprivation, or 48 h of sleep fragmentation and evaluated temperature preference in a thermal gradient. Flies exposed to 12 h of sleep deprivation chose warmer temperatures after sleep deprivation. Importantly, sleep fragmentation, which prevents flies from entering deeper stages of sleep, but does not activate sleep homeostatic mechanisms nor induce impairments in short-term memory also resulted in flies choosing warmer temperatures. To identify the underlying neuronal circuits, we used RNAi to knock down the receptor for Pigment dispersing factor, a peptide that influences circadian rhythms, temperature preference and sleep. Expressing UAS-PdfrRNAi in subsets of clock neurons prevented sleep fragmentation from increasing temperature preference. Finally, we evaluated temperature preference after flies had undergone a social jet lag protocol which is known to disrupt clock neurons. In this protocol, flies experience a 3 h light phase delay on Friday followed by a 3 h light advance on Sunday evening. Flies exposed to social jet lag exhibited an increase in temperature preference which persisted for several days. Our findings identify specific clock neurons that are modulated by sleep disruption to increase temperature preference. Moreover, our data indicate that temperature preference may be a more sensitive indicator of sleep disruption than learning and memory.

neuroscience↗

bioRxiv2020

Helicobacter pylori diversification during chronic infection within a single host generates sub-populations with distinct phenotypes

Helicobacter pylori chronically infects the stomach of approximately half of the worlds population. Manifestation of clinical diseases associated with H. pylori infection, including cancer, is driven by strain properties and host responses; and as chronic infection persists, both are subject to change. Previous studies have documented frequent and extensive within-host bacterial genetic variation. To define how within-host diversity contributes to phenotypes related to H. pylori pathogenesis, this project leverages a collection of 39 clinical isolates acquired prospectively from a single subject at two time points and from multiple gastric sites. During the six years separating collection of these isolates, this individual, initially harboring a duodenal ulcer, progressed to gastric atrophy and concomitant loss of acid secretion. Whole genome sequence analysis identified 2,232 unique single nucleotide polymorphisms (SNPs) across isolates and a nucleotide substitution rate of 1.3x10-4 substitutions/site/year. Gene ontology analysis identified cell envelope genes among the genes with excess accumulation of nonsynonymous SNPs (nSNPs). A dendrogram based on genetic similarity, clusters isolates from each time point separately. Within time points, there is segregation of subgroups with phenotypic differences in bacterial morphology, ability to induce inflammatory cytokines, and mouse colonization. Higher inflammatory cytokine induction in recent isolates maps to shared polymorphisms in the Cag PAI protein, CagY, while rod morphology in a subgroup of recent isolates mapped to eight mutations in three distinct helical cell shape determining (csd) genes. The presence of subgroups with unique genetic and phenotypic properties suggest complex selective forces and multiple sub-niches within the stomach during chronic infection. Author SummaryHelicobacter pylori, one of the most common bacterial pathogens colonizing humans, is the main agent responsible for stomach ulcers and cancer. Certain strain types are associated with increased risk of disease, however many factors contributing to disease outcome remain unknown. Prior work has documented genetic diversity among bacterial populations within single individuals, but the impact of this diversity for continued bacterial infection or disease progression remains understudied. In our analysis we examined both genetic and functional features of many stomach isolates from a single individual infected over six years. During these six years the subject shifted from having excess acid production and a duodenal ulcer to lower acid production from gastric atrophy. The 39 isolates form sub-populations based on gene sequence changes that accumulated in the different isolates. In addition to having distinguishing genetic features, these sub-populations also have differences in several bacterial properties, including cell shape, ability to activate immune responses, and colonization in a mouse model of infection. This apparent functional specialization suggests that the bacterial sub-populations may have adapted to distinct sub-niches within the stomach during chronic infection.

microbiology↗