Biology subjects

Abbas, A.

Publications and source records attributed to Abbas, A..

31 records · Page 2Linked to original sources

bioRxiv2020

Cancer cells are sensitive to wild-type IDH1 inhibition under nutrient limitation

Pancreatic cancer cells alter their metabolism to survive cancer-associated stress (1-4). For example, cancer cells must adapt to steep nutrient gradients that characterize the natural tumor microenvironment (TME) (5-7). In the absence of adaptive strategies, harsh metabolic conditions promote the generation of free radicals (8) and impair energy production in tumor cells. Towards this end, wild-type isocitrate dehydrogenase 1 (IDH1) activity is a metabolic requirement for cancer cells living in a harsh metabolic milieu. The cytosolic enzyme interconverts isocitrate and alpha-ketoglutarate, and uses NADP(H) as a cofactor. We show that under low nutrient conditions, the enzymatic reaction favors oxidative decarboxylation to yield NADPH and alpha-ketoglutarate. Metabolic studies showed that the IDH1 products directly support antioxidant defense and mitochondrial function in stressed cancer cells. Genetic IDH1 suppression reduced growth of pancreatic cancer cells in vitro under low nutrient conditions and in mouse models of pancreatic cancer. Surprisingly, allosteric inhibitors of mutant IDH1 proved to be potent wild-type IDH1 inhibitors under conditions specific to the TME, highlighting a natural therapeutic window. The presence of low magnesium enhanced allosteric inhibition by the drug, and ambient low glucose levels enhanced cancer cells dependence on wild-type IDH1. Thus, intrinsic TME conditions sensitized wild-type IDH1 to FDA-approved AG-120 (ivosidenib), and revealed the drug to be a potent single-agent therapeutic in cell culture and diverse in vivo cancer models. This work identified a potentially new repertoire of safe cancer therapies, including a clinically available compound, for the treatment of multiple wild-type IDH1 cancers (e.g., pancreatic).

cancer biology↗

bioRxiv2020

Genomic analyses of high-grade neuroendocrine gynecological malignancies reveal a unique mutational landscape and therapeutic vulnerabilities

The high-grade neuroendocrine carcinoma of gynecologic origin (NEC-GYN) is a highly aggressive cancer affecting young women. The clinical management of NEC-GYN is often extrapolated from their counterpart, small cell carcinoma of the lung (SCLC), but, unfortunately, they have limited effect. In our NEC-GYN cohort, median progression-free survival (PFS) and overall survival (OS) were 1 and 12 months, respectively, indicating their highly lethal nature. Our comprehensive genomic analyses unveiled that NEC-GYN harbors a higher mutational burden with distinct mutational landscapes from SCLC. We identified 14 cancer driver genes (FDR <0.01) including the most frequently altered KMT2C (100%), KNL1 (100%), NCOR2 (100%), and CCDC6 (93%) genes. Transcriptomic analyses identified several novel gene fusions in NEC-GYN. Furthermore, NEC-GYN exhibited a highly immunosuppressive state and uniquely belonged to the YAP1 high molecular subtype that promotes multidrug resistance. Our study suggests an urgent need to reevaluate the therapeutic options and targets for NEC-GYN.

genomics↗

bioRxiv2020

Single-axon level automatic segmentation and feature extraction from immuhistochemical images of peripheral nerves

Quantitative descriptions of the morphology and structure of peripheral nerves is central in the development of bioelectronic devices interfacing the nerves. While histological procedures and microscopy techniques yield high-resolution detailed images of individual axons, automated methods to extract relevant information at the single-axon level are not widely available. We implemented a segmentation algorithm that allows for subsequent feature extraction in immunohistochemistry (IHC) images of peripheral nerves at the single fiber scale. These features include short and long cross-sectional diameters, area, perimeter, thickness of surrounding myelin and polar coordinates of single axons within a nerve or nerve fascicle. We evaluated the performance of our algorithm using manually annotated IHC images of 27 fascicles of the swine cervical vagus; the accuracy of single-axon detection was 82%, and of the classification of fiber myelination was 89%.

neuroscience↗

bioRxiv2020

An implant for long-term cervical vagus nerve stimulation in mice

Vagus nerve stimulation (VNS) is a neuromodulation therapy with the potential to treat a wide range of chronic conditions in which inflammation is implicated, including type 2 diabetes, obesity and atherosclerosis. Many of these diseases have well-established mouse models, but due to the significant surgical and engineering challenges that accompany a reliable interface for long-term VNS in mice, the therapeutic implications of this bioelectronic therapy remain unexplored. Here, we describe a long-term VNS implant in mice, developed at 3 research laboratories and validated for across-lab reproducibility. Implant functionality was evaluated over 3-8 weeks in 81 anesthetized or behaving mice by determining the stimulus intensity required to elicit a change in heart rate (heart rate threshold, HRT). HRT was also used as a method to standardize stimulation dosing. Overall, 60-90% of implants produced stimulus-evoked physiological responses for at least 4 weeks, with HRT values stabilizing after the second week of implantation. Furthermore, stimulation delivered through 6-week-old implants decreased TNF levels in a subset of mice with acute inflammation caused by endotoxemia. Histological examination of 4- to 6-week-old implants revealed fibrotic encapsulation and no gross fiber loss. This implantation and dosing approach provides a tool to systematically investigate the therapeutic potential of long-term VNS in chronic diseases modeled in the mouse, the most widely used vertebrate species in biomedical research.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioengineering↗

bioRxiv2020

Translational neurophysiological biomarkers of N-methyl-D-aspartate receptor dysfunction in serine racemase knockout mice

Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational pathophysiological and target engagement biomarkers as well as by the lack of animal models that recapitulate the pathophysiological features of Sz. Here, we evaluated the rodent auditory steady state response (ASSR) and long-latency auditory event-related potential (aERP) as potential translational markers. These biomarkers were assessed for their sensitivity to both the N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine (PCP) and to knock-out (KO) of Serine Racemase (SR), which is known to lead to Sz-like alterations in function of parvalbumin (PV)-type cortical interneurons. Both PCP and SRKO led to significant increases of ASSR, consistent with PV interneuron effects. Similar effects were observed in mice with selective NMDAR KO on PV interneurons. By contrast, PCP but not SRKO reduced the amplitude of the rodent analog of the human N1 potential. Overall, these findings support use of rodent ASSR and long-latency aERP, along with previously described measures such as mismatch negativity (MMN), as translational biomarkers, and support SRKO mice as a potential rodent model for PV interneuron dysfunction in Sz.

neuroscience↗

bioRxiv2019

Phytochrome light receptors control metabolic flux, and their action during seedling development sets the trajectory for biomass production

The phytochromes (phys) photoreceptors are known to be major regulators of plastic growth responses to vegetation shade. Recent reports have begun to uncover an important role for phys in carbon resource management. Our earlier work showed that phy mutants had a distinct metabolic profile with elevated levels of metabolites including TCA intermediates, amino acids and sugars. Here we show that in seedlings phy regulates the balance between glucose and starch. Multi-allele phy mutants have excess glucose and low starch levels, which is conducive to hypocotyl elongation. 13C-CO2 labelling demonstrates that metabolic flux balance in adult plants is markedly altered in phy mutants. Phytochrome reduces synthesis rates of stress metabolites, including raffinose and proline and several typical stress-induced biosynthetic genes related to these metabolites show higher expression in phy mutants.\n\nSince growth and metabolism are typically inter-connected, we investigated why phy mutants have severely reduced biomass. Quantification of carbon fixation, biomass accumulation, and 13C labelling of cell wall polysaccharides established that relative growth rate is impaired in multi allele phy mutants for the first 2.5 weeks after germination but equivalent to the WT thereafter. Mathematical modelling predicts that the altered growth dynamics and final biomass deficit can be explained by the smaller cotyledon size of the multiple phy mutants. This indicates that the established role of phy in promoting seedling establishment has enduring effects that govern adult plant biomass.

plant biology↗

bioRxiv2019

Resting brain fluctuations are intrinsically coupled to visual response dynamics

How do intrinsic brain dynamics interact with processing of external sensory stimuli? We sought new insights using functional (f)MRI to track spatiotemporal activity patterns at the whole brain level in lightly anesthetized mice, during both resting conditions and visual stimulation trials. Our results provide evidence that quasiperiodic patterns (QPPs) govern mouse resting brain dynamics. QPPs captured the temporal alignment of global brain fluctuations, anti-correlation of the Default Mode (DMN)- and Task Positive (TPN)-like networks, and activity in neuromodulatory nuclei of the reticular formation. While visual stimulation could trigger a transient spatiotemporal pattern highly similar to intrinsic QPPs, global signal fluctuations and QPPs during rest periods could explain variance in the following visual responses. QPPs and the global signal thus appeared to capture a common arousal-related brain-state fluctuation, orchestrated through neuromodulation. Our findings provide new frontiers to understand the neural processes that shape functional brain states and modulate sensory input processing.

neuroscience↗

bioRxiv2019

Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell cycle arrest

Whether cell forces or extracellular matrix (ECM) can impact genome integrity is largely unclear. Here, acute perturbations (~1hr) to actomyosin stress or ECM elasticity cause rapid and reversible changes in lamin-A, DNA damage, and cell cycle. Embryonic hearts, differentiated iPS-cells, and various nonmuscle cell types all show that actomyosin-driven nuclear rupture causes cytoplasmic mis-localization of DNA repair factors and excess DNA damage. Binucleation and micronuclei increase as telomeres shorten, which all favor cell cycle arrest. Deficiencies in lamin-A and repair factors exacerbate these effects, but lamin-A-associated defects are rescued by repair factor overexpression and by contractility modulators in clinical trials. Contractile cells on stiff ECM normally exhibit low phosphorylation and slow degradation of lamin-A by matrix-metalloprotease-2 (MMP2), and inhibition of this lamin-A turnover and also actomyosin contractility is seen to minimize DNA damage. Lamin-A is thus stress-stabilized to mechano-protect the genome.

cell biology↗

bioRxiv2019

Outcome of radial scar/complex sclerosing lesion associated with epithelial proliferations with atypia diagnosed on breast core biopsy - Results from a multicentric UK based study

AIMS: The clinical significance of radial scar/complex sclerosing lesion (RS/CSL) with high risk lesions (epithelial atypia) diagnosed on needle core biopsy (NCB) is not well defined. We aimed at assessing the upgrade rate to carcinoma in-situ (DCIS) and invasive on the surgical excision specimen in a large cohort of RS/CSL associated with atypia. METHODS: 161 women with NCB diagnosis of a RS/CSL with atypia and follow-up histology were studied. Histological findings including different forms of the atypical lesions and final histological outcome in the excision specimens were retrieved and analysed and the upgrade rate for malignancy and invasive carcinoma calculated. RESULTS: 76% of the cases were associated with an atypical ductal hyperplasia (ADH) whereas lobular neoplasia was seen in 24%. On final histology 38 cases were malignant (overall upgrade rate of 25%); 12 invasive and 27 DCIS. The upgrade differed according to the type of atypia and was highest for ADH (35%). When associated with lobular neoplasia the upgrade rate was 12%. The upgrade rates variability was also considerably lower and showing less variability when considering the upgrade to invasive carcinoma alone. CONCLUSION: The upgrade rate for ADH diagnosed on NCB with RS is similar to that of ADH without RS and therefore should be managed similarly. RS associated with LN is less frequently associated with malignant outcome. Most lesions exhibiting some degree of atypia showed similar upgrade rate to invasive carcinoma. Management of RS should be based on the concurrent atypical lesion.

pathology↗

bioRxiv2018

Quasi-periodic patterns of brain activity in individuals with Attention-Deficit/Hyperactivity Disorder

Individuals with attention-deficit/hyperactivity disorder have been shown to have disrupted functional connectivity in the default mode and task positive networks. Traditional fMRI analysis techniques that focus on static changes in functional connectivity have been successful in identifying differences between healthy controls and individuals with ADHD. However, such analyses are unable to explain the mechanisms behind the functional connectivity differences observed. Here, we study dynamic changes in functional connectivity in individuals with ADHD through investigation of quasi-periodic patterns (QPPs). QPPs are reliably recurring low-frequency spatiotemporal patterns in the brain linked to infra-slow electrical activity. They have been shown to contribute to functional connectivity observed through static analysis techniques. We find that QPPs contribute to functional connectivity specifically in regions that are disrupted during ADHD. Individuals with ADHD also show differences in the spatiotemporal pattern observed within the QPPs. This difference results in a weaker contribution of QPPs to functional connectivity in the default mode and task positive networks. We conclude that quasi-periodic patterns provide insight into the mechanisms behind functional connectivity differences seen in individuals with ADHD. This allows for a better understanding of the etiology of the disorder and development of effective treatments.\n\nHighlights O_LIDefault mode and task positive network connectivity is disrupted in ADHD\nC_LIO_LIQuasi-periodic patterns contribute to typical functional connectivity in the DMN and TPN\nC_LIO_LIThe contribution of QPPs to functional connectivity is diminished in individuals with ADHD\nC_LIO_LIQPPs could explain BOLD dynamics underlying static functional connectivity differences in ADHD\nC_LI

neuroscience↗

bioRxiv2018

Integrating Hi-C and FISH data for modeling 3D organizations of chromosomes

The new advances in various experimental techniques that provide complementary in-formation about the spatial conformations of chromosomes have inspired researchers to develop computational methods to fully exploit the merits of individual data sources and combine them to improve the modeling of chromosome structure. In this paper, we propose GEM-FISH, a first method for reconstructing the 3D models of chromosomes through systematically integrating both Hi-C and FISH data with the prior biophysical knowledge of a polymer model. Comprehensive tests on a set of chromosomes for which both Hi-C and FISH data were available have demonstrated that GEM-FISH can reconstruct the 3D models of chromosomes with more accurate spatial organizations of TADs and compartments than using only Hi-C data. In addition, GEM-FISH can accurately capture the spatial proximity of loop loci and the colocalization of loci from the same sub-compartments. Moreover, our reconstructed 3D models of chromosomes revealed novel patterns of spatial distributions of super-enhancers which can provide useful insights into understanding the functional roles of these super-enhancers in gene regulation. All these results demonstrated that, through integrating both Hi-C and FISH data into a unified framework, GEM-FISH can provide a better tool for modeling the 3D organizations of chromosomes than using the Hi-C data alone.

bioinformatics↗

bioRxiv2018

Quasi-periodic patterns contribute to functional connectivity in the brain

Functional connectivity is widely used to study the coordination of activity between brain regions over time. Functional connectivity in the default mode and task positive networks is particularly important for normal brain function. However, the processes that give rise to functional connectivity in the brain are not fully understood. It has been postulated that low-frequency neural activity plays a key role in establishing the functional architecture of the brain. Quasi-periodic patterns (QPPs) are a reliably observable form of low-frequency neural activity that involve the default mode and task positive networks. Here, QPPs from resting-state and working memory task-performing individuals were acquired. The spatiotemporal pattern, strength, and frequency of the QPPs between the two groups were compared and the contribution of QPPs to functional connectivity in the brain was measured. In task-performing individuals, the spatiotemporal pattern of the QPP changes, particularly in task-relevant regions, and the QPP tends to occur with greater strength and frequency. Differences in the QPPs between the two groups could partially account for the variance in functional connectivity between resting-state and task-performing individuals. The QPPs contribute strongly to connectivity in the default mode and task positive networks and to the strength of anti-correlation seen between the two networks. Many of the connections affected by QPPs are also disrupted during several neurological disorders. These findings contribute to understanding the dynamic neural processes that give rise to functional connectivity in the brain and how they may be disrupted during disease.\n\nHighlightsO_LIQuasi-periodic patterns (QPPs) of low-frequency activity contribute to functional connectivity\nC_LIO_LIThe spatiotemporal pattern of QPPs differs between resting-state and task-performing individuals\nC_LIO_LIQPPs account for significant functional connectivity in the DMN and TPN during rest and task performance\nC_LIO_LIChanges in functional connectivity in these networks may reflect differences in QPPs\nC_LI

neuroscience↗

bioRxiv2017

Instantaneous Brain Dynamics Mapped to a Continuous State Space

Measures of whole-brain activity, from techniques such as functional Magnetic Resonance Imaging, provide a means to observe the brains dynamical operations. However, interpretation of whole-brain dynamics has been stymied by the inherently high-dimensional structure of brain activity. The present research addresses this challenge through a series of scale transformations in the spectral, spatial, and relational domains. Instantaneous multispectral dynamics are first developed from input data via a wavelet filter bank. Voxel-level signals are then projected onto a representative set of spatially independent components. The correlation distance over the instantaneous wavelet-ICA state vectors is a graph that may be embedded onto a lower-dimensional space to assist the interpretation of state-space dynamics. Applying this procedure to a large sample of resting and task data (acquired through the Human Connectome Project), we segment the empirical state space into a continuum of stimulus-dependent brain states. We also demonstrate that resting brain activity includes brain states that are very similar to those adopted during some tasks, as well as brain states that are distinct from experimentally-defined tasks. Back-projection of segmented brain states onto the brains surface reveals the patterns of brain activity that support each experimental state.

neuroscience↗