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Biology subjects

Zaman, A.

Publications and source records attributed to Zaman, A..

8 recordsLinked to original sources
bioRxiv2026

Nrl expression and promoter activity in developing cone photoreceptors

The MAF family transcription factor Nrl is a key regulator of vertebrate rod photoreceptor formation/differentiation. The expression of Nrl in nascent photoreceptors has been proposed to act as a master regulator to initiate a rod program and to repress a default cone photoreceptor sister fate. The evidence for rod-specific expression of Nrl has been most strongly supported by mouse transgenic models that use a transcriptional promoter element for Nrl. However, this element has not been rigorously evaluated to have rod lineage-specific activity or as a validated proxy for endogenous Nrl expression, despite its wide use under this assumption. Here we identify that the Nrl promoter is not exclusively active in rod photoreceptors but is also transiently active within a high proportion of the differentiating cone photoreceptor population. Thus, the Nrl promoter cannot be used to distinguish rods from cones at developmental timepoints. Furthermore, multiple lines of evidence using immunofluorescence and reanalysis of published single cell RNA-seq/ATAC-seq datasets support the presence of endogenous Nrl gene expression in early differentiating cone photoreceptors. Taken together, these results suggest that proposed gene regulatory networks that position Nrl as a master regulator of rod versus cone fate are inadequate as currently constructed. This impacts our understanding of visual system evolution and has implications for the development of therapeutic strategies of cell replacement for human blindness.

developmental biology↗
bioRxiv2024

Adult-type diffuse gliomas share recurring cell states driven by a common astrocyte-like glioma stem cell population

Adult-type diffuse gliomas are a family of aggressive brain tumours with few effective treatments. Their complex cellular makeup adds to the challenge of finding successful therapies. This intratumoural heterogeneity is fuelled by a subpopulation of glioma stem-like cells (GSCs) that drive tumour growth and resistance to standard treatments. Previous research focused on the three glioma types (astrocytoma, oligodendroglioma, glioblastoma) individually revealed malignant cells mimic the transcriptional profiles of normal brain cell types. Whether these diverse cellular states stem from a shared biological origin is unknown. Here, we show through single-cell RNA sequencing of 40 glioma tumours that all gliomas are described by seven recurring cell states. We also identify a shared astrocyte-like GSC population. Our unique method of identifying GSCs, based on reconstructed tumour phylogenies, repositions astrocyte-like cells at the apex of a differentiation hierarchy in glioma. Our findings indicate the transcriptional heterogeneity observed in gliomas stems from a GSC population recapitulating lineages of healthy adult neural stem cells. These results suggest a shared lineage drives the intratumoural heterogeneity observed in adult-type diffuse gliomas. We anticipate that a deeper understanding of the molecular mechanisms maintaining the GSC state will provide a new framework for future therapeutic development and research into glioma cell biology. HighlightsO_LIRecurring cell states are shared across adult-type diffuse gliomas C_LIO_LIReconstructed tumour phylogenies identify an astrocyte-like glioma stem cell population C_LIO_LITumour subclones are segregated non-randomly across cell states C_LI

cancer biology↗
bioRxiv2024

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis.

The role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Here, the effect of a bioinformatically-rationalized senolytic was tested in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS). Single-cell analysis from brain tissue isolated from mice subjected to EAE identified microglia with a strong senescence signature including the presence of BCL2-family member transcripts. Cells expressing Bcl2l1 had higher expression of pro-inflammatory and senescence genes than their negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were strongly enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune related genes suggesting they may contribute to the active lesion pathology and tissue damage in chronic active lesions. Employing a small molecule BCL2 inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice, decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation. Together, these results provide evidence to support the idea that senescent glia may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease and that removing them may ameliorate disease.

neuroscience↗
bioRxiv2023

Cellular rejuvenation protects neurons from inflammation mediated cell death.

In multiple sclerosis (MS), the invasion of the central nervous system by peripheral immune cells is followed by the activation of resident microglia and astrocytes. This cascade of events results in demyelination, which triggers neuronal damage and death. The molecular signals in neurons responsible for this damage are not yet fully characterized. In MS, retinal ganglion cell neurons (RGCs) of the central nervous system (CNS) undergo axonal injury and cell death. This phenomenon is mirrored in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. To understand the molecular landscape, we isolated RGCs from mice subjected to the EAE protocol. RNA-sequencing and ATAC-sequencing analyses were performed. Pathway analysis of the RNA-sequencing data revealed that RGCs displayed a molecular signature, similar to aged neurons, showcasing features of senescence. Single-nucleus RNA-sequencing analysis of neurons from human MS patients revealed a comparable senescence-like phenotype., which was supported by immunostaining RGCs in EAE mice. These changes include alterations to the nuclear envelope, modifications in chromatin marks, and accumulation of DNA damage. Transduction of RGCs with an Oct4-Sox2-Klf4 transgene to convert neurons in the EAE model to a more youthful epigenetic and transcriptomic state enhanced the survival of RGCs. Collectively, this research uncovers a previously unidentified senescent-like phenotype in neurons under pathological inflammation and neurons from MS patients. The rejuvenation of this aged transcriptome improved visual acuity and neuronal survival in the EAE model supporting the idea that age rejuvenation therapies and senotherapeutic agents could offer a direct means of neuroprotection in autoimmune disorders.

neuroscience↗
bioRxiv2022

A Framework for Better Sensor-Based Beehive Health Monitoring

Hive bees provide essential pollination services to human agriculture. Managed honey bees in particular pollinate many crops, but also create honey and other bee products that are now of global economic importance. Key aspects of honey bee behaviour can be understood by observing hives. Hence, the limitations of manual observation are increasingly being addressed by new technologies that automate and extend the reach of hive monitoring. Here we propose a framework to classify and clarify the potential for sensor-assisted hive monitoring to inform apiculture and, ultimately, improve hive bee management. This framework considers hive monitoring approaches across three newly proposed categories: Operational monitoring, Investigative monitoring, and Predictive monitoring. These categories constitute a new "OIP Framework" of hive monitoring. Each category has its own requirements for underlying technology that includes sensors and ICT resources we outline. Each category is associated with particular outcomes and benefits for apiculture and hive health monitoring detailed here. Application of these three classes of sensor-assisted hive monitoring can simplify understanding and improve best-practice management of hive bees. Our survey and classification of hive monitoring to date show that it is seldom practiced beyond honey bees, despite the need to understand bumble bees and stingless bees also. Perhaps unsurprisingly, sensor-based hive monitoring is shown to remain primarily a practice of developed nations. Yet we show how all countries, especially developing nations, stand to gain substantially from the benefits improved sensor-based hive monitoring offers. These include a better understanding of environmental change, an increased ability to manage pollination, an ability to respond rapidly to hive health issues such as pests and pathogens, and even an ability to react quickly to the danger posed to insects and humans alike by extreme events such as floods and fires. Finally, we anticipate that the future of hive monitoring lies in the application of Predictive monitoring, such that a hives anticipated future state can be preemptively managed by beekeepers working iteratively with novel hive monitoring technologies.

ecology↗
bioRxiv2019

Global analysis of epigenetic heterogeneity identifies divergent drivers of esophageal squamous cell carcinoma

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome and two-thirds occur in long non-coding (lnc)RNA regions. DNA methylation and epigenetic heterogeneity both coincide with chromosomal topological alterations. Gene body methylation, polycomb repressive complex occupancy, and CTCF binding sites associate with cancer-specific gene regulation. Epigenetically-mediated activation of non-canonical WNT signaling and the lncRNA ESCCAL-1 were validated as potential ESCC driver alterations. Gene-specific cancer driver roles of epigenetic alterations and heterogeneity are identified.

cell biology↗
bioRxiv2017

Evidence for time division multiplexing of multiple simultaneous itemsin a sensory coding bottleneck

How the brain preserves information about multiple simultaneous items is poorly understood. We report that single neurons can represent multiple different stimuli by interleaving different signals across time. We record single units in an auditory region, the inferior colliculus, while monkeys localize 1 or 2 simultaneous sounds. During dual-sound trials, we find that some neurons fluctuate between firing rates observed for each single sound, either on a whole-trial or on a sub-trial timescale. These fluctuations are correlated in pairs of neurons, can be predicted by the state of local field potentials prior to sound onset, and, in one monkey, can predict which sound will be reported first. We find corroborating evidence of fluctuating activity patterns in a separate data set involving responses of inferotemporal cortex neurons to multiple visual stimuli. Alternation between activity patterns corresponding to each of multiple items may therefore be a general strategy to enhance the brain processing capacity, potentially linking such disparate phenomena as variable neural firing, neural oscillations, and limits in attentional/memory capacity.

neuroscience↗