Biology subjects

Malik, S.

Publications and source records attributed to Malik, S..

3 recordsLinked to original sources

bioRxiv2018

Ghrelin enhances food odor conditioning in healthy humans: an fMRI study

Vulnerability to obesity includes eating in response to food cues, which acquire incentive value through conditioning. The conditioning process is largely subserved by dopamine, theorized to encode the discrepancy between expected and actual rewards, known as the reward prediction error (RPE). Ghrelin is a gut-derived homeostatic hormone that triggers hunger and eating. Despite extensive evidence that ghrelin stimulates dopamine, it remains unknown in humans if ghrelin modulates food cue learning. Here we show using functional magnetic resonance imaging that intravenously administered ghrelin increased RPE-related activity in dopamine-responsive areas during food odor conditioning in healthy volunteers. Participants responded faster to food odor-associated cues and perceived them to be more pleasant following ghrelin injection. Ghrelin also increased functional connectivity between hippocampus and ventral striatum. Our work demonstrates that ghrelin promotes the ability of cues to acquire incentive salience, and has implications for the development of vulnerability to obesity.

neuroscience↗

bioRxiv2018

Wnt signalling drives context-dependent differentiation or proliferation in neuroblastoma

Neuroblastoma is one of the commonest and deadliest solid tumours of childhood, and is thought to result from disrupted differentiation of the developing sympathoadrenergic lineage of the neural crest. Neuroblastoma exhibits intra-and intertumoural heterogeneity, with high risk tumours characterised by poor differentiation, which can be attributable to MYCN-mediated repression of genes involved in neuronal differentiation. MYCN is known to co-operate with oncogenic signalling pathways such as Alk, Akt and MEK/ERK signalling, and, together with c-MYC has been shown to be activated by Wnt signalling in various tissues. However, our previous work demonstrated that Wnt3a/Rspo2 treatment of some neuroblastoma cell lines can, paradoxically, decrease c-MYC and MYCN proteins. This prompted us to define the neuroblastoma-specific Wnt3a/Rspo2-driven transcriptome using RNA sequencing, and characterise the accompanying changes in cell biology.\n\nHere we report the identification of ninety Wnt target genes, and show that Wnt signalling is upstream of numerous transcription factors and signalling pathways in neuroblastoma. Using live-cell imaging, we show that Wnt signalling can drive differentiation of SK-N-BE(2)-C and SH-SY5Y cell-lines, but, conversely, proliferation of SK-N-AS cells. We show that cell-lines that differentiate show induction of pro-differentiation BMP4 and EPAS1 proteins, which is not apparent in the SK-N-AS cells. In contrast, SK-N-AS cells show increased CCND1, phosphorylated RB and E2F1 in response to Wnt3a/Rspo2, consistent with their proliferative response, and these proteins are not increased in differentiating lines. By meta-analysis of the expression of our 90 genes in primary tumour gene expression databases, we demonstrate discrete expression patterns of our Wnt genes in patient cohorts with different prognosis. Furthermore our analysis reveals interconnectivity within subsets of our Wnt genes, with one subset comprised of novel putative drivers of neuronal differentiation repressed by MYCN. Assessment of {beta}-catenin immunohistochemistry shows high levels of {beta}-catenin in tumours with better differentiation, further supporting a role for canonical Wnt signalling in neuroblastoma differentiation.

cancer biology↗

bioRxiv2018

Identification, expression analysis and molecular modeling of Iron deficiency specific clone 3 (Ids3) like gene in hexaploid wheat

Graminaceous plants secrete iron (Fe) chelators called mugineic acid family phytosiderophores (MAs) from their roots for solubilisation and mobilization of unavailable ferric (Fe3+) ions from the soil. The hydroxylated forms of these phytosiderophores have been found more efficient in chelation and subsequent uptake of minerals from soil which are available in very small quantities. The genes responsible for hydroxylation of phytosiderophores have been recognized as iron deficiency-specific clone 2 (Ids2) and iron deficiency-specific clone 3 (Ids3) in barley but their presence is not reported earlier in hexaploid wheat. Hence, the present investigation was done with the aim:(i) to search for the putative Hordeum vulgare Ids3 (HvIds3) ortholog in hexaploid wheat, (ii) physical mapping of HvIds3 ortholog on wheat chromosome using cytogenetic stocks developed in the background of wheat cultivar Chinese Spring and (iii) to analyze the effect of iron starvation on the expression pattern of this ortholog at transcription level. In the present investigation, a putative ortholog of HvIds3 gene was identified in hexaploid wheat using different bioinformatics tools. Further, protein structure of TaIDS3 was modelled using homology modeling and also evaluated modelled structure behavior on nanoseconds using molecular dynamics based approach. Additionally, the ProFunc results also predict the functional similarity between the proteins of HvIds3 and its wheat ortholog (TaIds3). The physical mapping study with the use of cytogenetic stocks confines TaIds3 in the telomeric region of chromosome 7AS which supports the results obtained by bioinformatics analysis. The relative expression analysis of TaIds3 indicated that the detectable expression of TaIds3 induces after 5th day of Fe-starvation and increases gradually up to 15th day and thereafter decreases till 35th day of Fe-starvation. This reflects that Fe deficiency directly regulates the induction of TaIds3 in the roots of hexaploid wheat.

genomics↗