Biology subjects

Saleh, M.

Publications and source records attributed to Saleh, M..

7 recordsLinked to original sources

bioRxiv2025

The Stmn1-lineage contributes to acinar regeneration but not to neoplasia upon oncogenic Kras expression

BACKGROUND & AIMSThe exocrine pancreas has a limited regenerative capacity, but to what extent all acinar cells are involved in this process is unclear. Nevertheless, the heterogenous nature of acinar cells suggests that cells exhibiting higher plasticity might play a more prominent role in acinar regeneration. In that regard, Stmn1-expressing acinar cells have been identified as potential facultative progenitor-like cells in the adult pancreas. Here, we studied Stmn1-progeny under physiological conditions, during regeneration, and in the context of KrasG12D expression. METHODSWe followed the fate of Stmn1-progenies both under baseline conditions, following caerulein-induced acute or chronic pancreatitis, pancreatic duct ligation, and in the context of KrasG12D expression. RESULTSThe Stmn1-lineage contributes to baseline acinar cell turnover under physiological conditions. Furthermore, these cells rapidly proliferate and repopulate the acinar compartment in response to acute injury in an ADM-independent manner. Moreover, acinar regeneration during chronic pancreatitis progression is in conjunction with a decline in the proliferative capacity of the Stmn1-lineage. Interestingly, newly generated acinar cells display increased susceptibility to additional injury during recurrent acute pancreatitis (RAP). Finally, given their inability to form ADMs, the Stmn1-lineage fails to form PanINs upon oncogenic Kras expression. CONCLUSIONSOur findings establish the Stmn1-lineage as a pivotal subpopulation for acinar regeneration. The ability of these cells to restore acinar tissue in an ADM-independent manner distinguishes them as a critical regenerative population. This study presents a new paradigm for acinar regeneration and repair in the context of pancreatitis and neoplasia.

cell biology↗

bioRxiv2024

Autism and Intellectual Disability-Associated MYT1L Mutation Alters Human Cortical Interneuron Differentiation, Maturation, and Physiology

MYT1L is a neuronal transcription factor highly expressed in the developing and adult brain. While pathogenic MYT1L mutation causes neurodevelopmental disorders, these have not been characterized in human models of neurodevelopment. Here, we defined the consequences of pathogenic MYT1L mutation in human pluripotent stem cell-derived cortical interneurons. During differentiation, mutation reduced MYT1L expression and increased progenitor cell cycle exit and neuronal differentiation and synapse-related gene expression, morphological complexity, and synaptic puncta formation. Conversely, interneuron maturation was compromised, while variant neurons exhibited altered sodium and potassium channel activity and reduced function in electrophysiological analyses. CRISPRi-based knockdown similarly impaired interneuron differentiation and maturation, supporting loss of function-based effects. We further defined MYT1L genome-wide occupancy in interneurons and related this to the transcriptomic dysregulation resulting from MYT1L mutation, to identify direct targets that could mediate these phenotypic consequences. Together, this work delineates contributors to the etiology of neurodevelopmental disorders resulting from MYT1L mutation.

developmental biology↗

bioRxiv2022

TREM1+ regulatory myeloid cells expand in steatohepatitis-HCC and associate with poor prognosis and therapeutic resistance to anti-PD-1 blockade

Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral and non-viral etiologies. Immune checkpoint blockade primarily benefits patients with viral HCC. Expansion of suppressive myeloid cells is a hallmark of chronic inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance in the steatohepatitis setting. Here, we present a high resolution atlas of hepatic innate immune cells from patients with HCC that unravels a steatohepatitis contexture characterized by the emergence of high entropy myeloid cell states and myeloid-biased NK cell differentiation. We identify a discrete population of tumor-infiltrating myeloid cells, predominant in the steatohepatitis setting, that expresses a variety of myeloid lineage-affiliated genes, including granulocyte, macrophage and dendritic cell features, and can be identified in HCC tumors based on selective dual expression of TREM1 and CD163. Functional characterization reveals that TREM1+ CD163+ myeloid cells highly express TGF{beta} and IL-13RA, localize to HCC fibrotic lesions, and potently suppress T cell effector functions ex vivo, a function further potentiated by TREM1 engagement. We refer to this population as TREM1+ CD163+ regulatory myeloid cells (TREM1+CD163+ Mreg). Deconvolution analyses in large cohorts of patients with HCC and other solid tumors reveals that the density of TREM1+ CD163+ Mreg increases in advanced stages, associates with poor prognosis, and therapeutic resistance to PD-1 blockade. Our data support myeloid subset-targeted immunotherapies to treat HCC and identify TREM1 as a therapeutic target. HIGHLIGHTSO_LIAtlas of hepatic innate immune cells (100,000 transcriptomes) from patients with HCC C_LIO_LICore signatures to identify, discriminate and localize innate lymphoid and myeloid cells C_LIO_LIA population of TREM1+CD163+ myeloid cells, referred to as TREM1+CD163+ Mreg, expands in steatohepatitis HCC C_LIO_LITREM1+CD163+ Mreg express granulocyte- and macrophage/dendritic cell-lineage genes C_LIO_LITREM1+CD163+ Mreg potently suppress T cell effector functions, which is potentiated by TREM1 engagement by cognate ligands C_LIO_LITREM1+CD163+ Mreg produce high levels of TGF{beta} and populate fibrotic lesions C_LIO_LIThe density of TREM1+CD163+ Mreg increases in advanced HCC and associate with poor patient survival C_LIO_LIThe density of TREM1+CD163+ Mreg associates with resistance to immune checkpoint blockade in other solid tumors C_LI

immunology↗

bioRxiv2022

MRSCloud: a Cloud-based MR Spectroscopy Tool for Basis Set Simulation

BackgroundAccurate quantification of in vivo proton magnetic resonance spectra involves modeling with a linear combination of known metabolite basis functions. Basis sets can be generated by numerical simulation using the quantum mechanical density-matrix formalism. Accurate simulations for a basis set require correct sequence timings, and pulse shapes and durations. PurposeTo present a cloud-based spectral simulation tool MRSCloud. It allows community users of MRS to simulate a vendor- and sequence-specific basis set online in a convenient and timeefficient manner. This tool can simulate basis sets for 3 major MR scanner vendors (GE, Philips, Siemens), including conventional acquisitions and spectral editing schemes (MEGA, HERMES, HERCULES) with PRESS and semi-LASER localization. Study TypeProspective. SpecimenN/A Field Strength/SequenceSimulations of 3T basis sets for conventional and spectral-editing sequences (MEGA, HERMES, HERCULES) with PRESS and sLASER localizations. AssessmentSimulated metabolite basis functions generated by MRSCloud are compared to those generated by FID-A and MARSS, and a phantom-acquired basis-set from LCModel. Statistical TestsIntraclass correlation coefficients (ICC) were calculated to measure the agreement between individual metabolite basis functions generated using different packages. Statistical analysis was performed using R in RStudio. ResultsSimulation time for a full basis set is approximately 1 hour. ICCs between MRSCloud and FID-A were at least 0.98 and ICCs between MRSCloud and MARSS were at least 0.96. ICCs between simulated MRSCloud basis spectra and acquired LCModel basis spectra were lowest for Gln at 0.68 and highest for NAA at 0.96. Data ConclusionSubstantial reductions in runtime have been achieved by implementing the 1D projection method, coherence-order filtering, and pre-calculation of propagators. High ICC values indicated that the accelerating features are running correctly and produce comparable and accurate basis sets. The generated basis set has been successfully used with LCModel.

bioengineering↗

bioRxiv2021

The Macromolecular MR Spectrum in Healthy Aging

PurposeMobile macromolecules (MMs) from amino acids, cytosolic proteins and mobile lipids contribute a significant spectral background underlying the metabolite signals in the MR spectrum. A recent consensus recommends that MM contributions should be removed or included in modeling basis sets for determination of metabolite concentrations and/or metabolite ratios. The purpose of this study was to acquire the MM spectrum from healthy participants at a range of ages, and to investigate changes in the signals with age and sex groups. MethodsInversion time (TI) series were acquired to determine an optimal inversion time to null the metabolite signals. Experiments were carried out using a single adiabatic hyperbolic-secant inversion pulse. After the preliminary experiment, 102 volunteers (49M/53F) between 20 and 69 years were recruited for in vivo data acquisition in the centrum semiovale (CSO) and posterior cingulate cortex (PCC). The protocol consisted of a T1-weighted MPRAGE for structural images, followed by PRESS localization using a voxel size of 30 x 26 x 26 mm3 with pre-inversion (TR/TI 2000/600 ms) and CHESS water suppression. Metabolite-nulled spectra were modeled using a reduced basis set (NAA, Cr, Cho, Glu) and a flexible spline baseline (0.1 ppm knot spacing) followed by subtraction of the modeled metabolite signals to yield a clean MM spectrum, using the Osprey software. Pearsons correlation coefficient was calculated between integrals and age for the 14 MM signals between 0.9-4.2 ppm. One-way ANOVA was performed to determine differences between age groups. An independent t-test was carried out to determine differences between sexes. Relationships between brain tissues with age and sex groups were also measured. ResultsMM spectra were successfully acquired in 99 (CSO) and 96 (PCC) of 102 subjects. No significant correlations were seen between age and MM integrals. One-way ANOVA also suggested no age-group differences for any MM peak (all p > 0.004). No differences were observed between sex groups. The voxels were segmented as 80 {+/-} 4% white matter, 18 {+/-} 4% gray matter, and 2 {+/-} 1% CSF for CSO and 28 {+/-} 4% white matter, 61 {+/-} 4% gray matter and 11 {+/-} 1% CSF for PCC. WM and GM showed a significant (p < 0.05) negative linear association with age in the WM-predominant CSO (R = -0.29) and GM-predominant PCC regions (R = -0.57) respectively while CSF increased significantly with age in both regions. ConclusionOur findings indicate that the MM spectrum is stable across a large age range and between sexes, suggesting a pre-defined MM basis function can be used for linear combination modeling of metabolite data from different age and sex groups. HighlightsO_LIA large publicly available MM-aging dataset is presented. C_LIO_LIMacromolecule signals do not change with age between 20 and 70. C_LIO_LIThere is no sex difference for macromolecule integrals. C_LI

bioengineering↗

bioRxiv2018

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis

The gut microbiome provides resistance to infection. However, the mechanisms for this are poorly understood. Colonization with the intestinal bacterium Clostridium scindens provided protection from the parasite Entamoeba histolytica via innate immunity. Introduction of C. scindens into the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte-progenitors (GMPs) and provided neutrophil-mediated protection against subsequent challenge with E. histolytica. Adoptive transfer of bone-marrow from C. scindens colonized-mice into naive-mice protected against ameba infection and increased intestinal neutrophils. Because of the known ability of C. scindens to metabolize the bile salt cholate, we measured deoxycholate and discovered that it was increased in the sera of C. scindens colonized mice, as well as in children protected from amebiasis. Administration of deoxycholate alone (in the absence of C. scindens) increased the epigenetic mediator JMJD3 and GMPs and provided protection from amebiasis. In conclusion the microbiota was shown to communicate to the bone marrow via microbially-metabolized bile salts to train innate immune memory to provide antigen-nonspecific protection from subsequent infection. This represents a novel mechanism by which the microbiome protects from disease.\n\nOne Sentence SummaryIntroduction of the human commensal bacteria Clostridium scindens into the intestinal microbiota epigenetically alters bone marrow and protects from future parasite infection.

microbiology↗

bioRxiv2017

Combining optical imaging of cleared tissue with mathematical modelling to predict drug delivery and therapeutic response

Understanding how drugs are delivered to diseased tissue, and their subsequent spatial and temporal distribution, is a key factor in the development of effective, targeted therapies. However, the interaction between the pathophysiology of diseased tissue and individual therapeutic agents can be complex, and can vary significantly between individuals. In cancer, suboptimal dosing resulting from poor delivery can cause reduced treatment efficacy, upregulation of resistance mechanisms and can even stimulate growth. Preclinical tools to better understand drug delivery are therefore urgently required, which incorporate the inherent variability and heterogeneity of human disease. To meet this need, we have combined multiscale mathematical modelling, high-resolution optical imaging of intact, optically-cleared tumour tissue from animal models, and in vivo magnetic resonance imaging (MRI). Our framework, named REANIMATE (REAlistic Numerical Image-based Modelling of biologicAl Tissue substratEs) allows large tissue samples to be investigated as if it were a living sample, in detailed, highly controlled, computational experiments. Specifically, we show that REANIMATE can be used to predict the heterogeneous delivery of specific therapeutic agents, in disparate two murine xenograft models of human colorectal carcinoma. Given the wide adoption of optical clearing equipment in biomedical research laboratories, REANIMATE enables a new paradigm in cancer drug development, which could also be applied to other disease areas.

biophysics↗