Biology subjects

Amini, A.

Publications and source records attributed to Amini, A..

14 recordsLinked to original sources

bioRxiv2026

CXCR3 on transferred T cells enables vaccine-boosted adoptive T-cell therapy in solid tumors

Adoptive T-cell therapy (ACT) has demonstrated marked clinical benefit in hematological malignancies but has limited efficacy against solid tumors. Cancer vaccines can improve ACT, but the mechanisms underlying this combination are poorly understood. Here, we combined ACT with chimpanzee adenovirus ChAdOx1 (ChAd) and modified vaccinia Ankara (MVA) encoding tumor antigens. Whereas PD1 blockade failed to improve ACT, the combination with ChAd/MVA vaccination drove durable regression of established tumors, correlating with expansion of tumor-reactive T cells in lymphoid organs and increased tumor infiltration by T cells. Mechanistically, ChAd priming induced CXCR3 ligands (CXCL10 and CXCL9) in the vaccine-draining lymph node, thereby recruiting transferred T cells to this node independently of cognate antigen. CXCR3 expression on the transferred T cells, but not on host cells, was required for the anti-tumor effect of the combination therapy and favored T-cell accumulation in the vaccine-draining lymph node and the tumor. These findings identify CXCR3 on the transferred T cells as a determinant of ACT plus vaccination synergy and provide a rationale for combining viral-vector vaccines with TCR-T therapies, and for selecting or engineering T cells to retain CXCR3 expression.

immunology↗

bioRxiv2026

The Impact of Smoking Status on the Genomic Landscape of Lung Squamous Cell Carcinoma

PurposeComprehensive genomic profiling (CGP) has changed the treatment paradigm for non-small cell lung cancer (NSCLC) with the advent of molecularly targeted therapies for actionable genomic alterations (AGA). Despite this, the use of CGP is suboptimal, particularly in squamous cell lung cancer (sqNSCLC), which is more closely associated with smoking exposure and a lack of AGAs. We hypothesized that the prevalence of AGAs is inversely correlated with the chronicity and extent of smoking exposure in patients with sqNSCLC. Experimental DesignWe retrospectively evaluated all patients with liquid biopsy testing via Guardant 360CDX or Guardant360 in the context of any sqNSCLC diagnosis at the City of Hope Comprehensive Cancer Center between 10/2020 and 7/2023. The data was obtained on 2/23/24. Social and clinical histories were evaluated to assess the frequency of AGAs in patients with no or remote smoking history. ResultsOf the 56 patients in the initial evaluation, 24% (n=13) were non-smokers or remote smokers (greater than 20 years from cessation). Of these 13 patients, eight (61.5%) harbored AGA. Of these 8 patients, alterations observed included EGFR exon 19 deletion (50%, n=4), MET exon 14 skipping mutation (25%, n=2), EGFR G719S (13%, n=1), EGFR E114K (13%, n=1). Of those patients harboring AGAs that received NCCN-concordant matched targeted therapy, the objective response rate (ORR) with targeted agents was 50% and the clinical benefit rate (CBR) was 83.3%. ConclusionsThese data support the use of CGP in sqNSCLC particularly in patients with remote or no smoking exposure. Statement of translational relevanceThese data demonstrate high frequency of actionable genomic alterations (AGAs) in patients diagnosed with squamous cell lung cancer (sqNSCLC) with remote or no smoking history. Specifically, enrichment of EGFR and MET gene alterations were observed. These findings support the use of comprehensive molecular profiling in sqNSCLC. Furthermore, treatment outcomes demonstrate frequent objective responses and high clinical benefit rate supporting the use of targeted therapies in sqNSCLC harboring AGAs. This analysis provided rationale for further research of larger datasets investigating therapeutic approaches in sqNSCLC, which may have significant implications for consensus guideline recommendations and routine clinical practice.

cancer biology↗

bioRxiv2023

Evolution of a biological thermocouple by adaptation of cytochrome c oxidase in asubterrestrial metazoan

In this study we report a naturally evolved temperature-sensing electrical regulator in the cytochrome c oxidase of the Devil Worm, Halicephalobus mephisto. This extremophile metazoan was isolated 1.3 km underground in a South African goldmine, where it adapted to heat and potentially to hypoxia, making its mitochondrial sequence a likely target of adaptational change. We obtained the full mitochondrial genome sequence of this organism, and show through dN/dS analysis statistically robust evidence of positive selection in H. mephisto cytochrome c oxidase subunits. Seventeen of these positively-selected amino acid substitutions were localized in proximity to the H- and K-pathway proton channels of the complex. Surprisingly, the H. mephisto cytochrome c oxidase proton pump completely shuts down at low temperatures (20{degrees}C) leading to approximately a 4.8-fold reduction in the transmembrane proton gradient voltage ({Delta}{Psi}m) compared to optimal temperature (37{degrees}C). Direct measurement of oxygen consumption found a corresponding 4.7-fold drop at 20{degrees}C compared to 37{degrees}C. Correspondingly, the lifecycle of H. mephisto takes four-fold longer at the low temperature compared to higher. This elegant evolutionary adaptation creates a finely-tuned mitochondrial temperature sensor, allowing this ectothermic organism to maximize its reproductive success in varying environmental temperatures. Our study shows that evolutionary innovation may remodel core metabolism to make it more accurately map onto environmental variation.

evolutionary biology↗

bioRxiv2023

A Complex Containing the Na+/K+ ATPase Regulates Epileptogenesis in Drosophilamelanogaster

Epileptogenesis, the process through which the brain becomes seizure-prone, is not well understood. Previous work identified a novel gene in Drosophila, julius seizure (jus), that when mutated or developmentally knocked down, leads to epilepsy in adult Drosophila, providing a useful model for dissecting epileptogenesis. Here we report that when a GFP-tagged version of Jus was used as bait in a co-immunoprecipitation (co-IP) assay, a complex of 23 associated proteins was identified that included ATPalpha and Nervana 3, two subunits of the Na+/K+ ATPase. RNAi-mediated knockdown of ATPalpha, Nervana 3, or any of 8 additional complex proteins enhanced seizure susceptibility. The critical period of Jus expression in epileptogenesis was further defined, occurring between pupal stages P4-7; remarkably, the jus seizure phenotype could be rescued by increasing neural activity of jus-expressing neurons during these mid-pupal stages, suggesting that altered neural activity in these neurons may contribute to the seizure phenotype. Our data support a model that, in wild type flies, a protein complex containing Na+/K+ ATPase and Jus prevents epileptogenesis, possibly by regulating neural activity.

neuroscience↗

bioRxiv2023

Robust memory of face moral values is encoded in the human caudate tail: A simultaneous EEG-fMRI study

Moral judgements about people based on their actions is a key component that guides social decision making. It is currently unknown how positive or negative moral judgments associated with a persons face are processed and stored in the brain. Here, we investigate the long-term memory of moral values associated with human faces using simultaneous EEG-fMRI data acquisition. Results show that only a few exposures to morally charged stories of people, are enough to form long-term memories a day later for a relatively large number of new faces. Event related potentials (ERPs) showed a significant differentiation of remembered good vs bad faces over centerofrontal electrode sites (value ERP). EEG-informed fMRI analysis revealed a subcortical cluster centered on the left caudate tail (CDt) as a correlate of the face value ERP. Importantly neither this analysis nor a conventional whole brain analysis revealed any significant activation in cortical areas in particular the fusiform face area (FFA). Conversely an fMRI-informed EEG source localization using accurate subject-specific EEG head models also revealed activation in the caudate tail. Nevertheless, the detected caudate tail region was found to be functionally connected to the FFA, suggesting FFA to be the source of face-specific information to CDt. These results identify CDt as the main site for encoding the long-term value memories of faces in humans suggesting that moral value of faces activates the same subcortical basal ganglia circuitry involved in processing reward value memory for objects in primates.

neuroscience↗

bioRxiv2022

Further antibody escape by Omicron BA.4 and BA.5 from vaccine and BA.1 serum

The Omicron lineage of SARS-CoV-2, first described in November 2021, spread rapidly to become globally dominant and has split into a number of sub-lineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africas Gauteng region uncovered two new sub-lineages, BA.4 and BA.5 which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences and, although closely related to BA.2, contain further mutations in the receptor binding domain of spike. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by serum from triple AstraZeneca or Pfizer vaccinated individuals compared to BA.1 and BA.2. Furthermore, using serum from BA.1 vaccine breakthrough infections there are likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.

microbiology↗

bioRxiv2022

Human MAIT cells show clonal diversity but transcriptional and functional homogeneity

Mucosal-associated invariant T (MAIT) cells are considered to have limited clonal diversity. In contrast, recent studies suggest the presence of functionally distinct subsets. We investigated this model through single-cell analysis of the MAIT cell TCR repertoire and transcriptional profile in human blood and liver. Further, we developed functional RNA-sequencing (fRNA-seq), an approach to integrate cellular function and TCR clonotype at a single-cell level following differential stimulation. MAIT cells showed surprising clonal diversity, with TCR repertoires shared across tissues but unique to individuals. Functional diversity within resting MAIT cells was low and largely related to tissue site. MAIT cells displayed distinct transcriptional responses to in vitro TCR and cytokine stimulation, with cells positioned along gradients of activation. Clonal origin influenced both resting and activated transcriptional profiles. Overall, MAIT cells exhibit diverse donor-specific TCR repertoires which, along with tissue and activation context, influence their phenotype and function.

immunology↗

bioRxiv2021

Gustatory cortex is involved in evidence accumulation during food choice

Food choice is one of the most fundamental and most frequent value-based decisions for all animals including humans. However, the neural circuitry involved in food-based decisions is only recently being addressed. Given the relatively fast dynamics of decision formation, EEG-informed fMRI analysis is highly beneficial for localizing this circuitry in humans. Here by using the EEG correlates of evidence accumulation in a simultaneously recorded EEG-fMRI dataset, we found a significant role for the right temporal-parietal operculum (PO) and medial insula including gustatory cortex (GC) in binary choice between food items. These activations were uncovered by using the "EEG energy" (power 2) as the BOLD regressor and were missed if conventional analysis with the EEG signal itself were to be used, in agreement with theoretical predictions for EEG and BOLD relations. No significant positive correlations were found with higher powers of EEG (powers 3 or 4) pointing to specificity and sufficiency of EEG energy as the main correlate of the BOLD response. This finding extends the role of cortical areas traditionally involved in palatability processing to value-based decision making and offers the "EEG energy" as a key regressor of BOLD response in simultaneous EEG-fMRI designs.

neuroscience↗

bioRxiv2020

Pattern-based Contractility Screening (PaCS), a reference-free traction force microscopy methodology, reveals contractile differences in breast cancer cells

The sensing and generation of cellular forces are essential aspects of life. Traction Force Microscopy (TFM) has emerged as a standard broadly applicable methodology to measure cell contractility and its role in cell behavior. While TFM platforms have enabled diverse discoveries, their implementation remains limited in part due to various constraints, such as time-consuming substrate fabrication techniques, the need to detach cells to measure null force images, followed by complex imaging and analysis, and the unavailability of cells for post-processing. Here we introduce a reference-free technique to measure cell contractile work in real-time, with basic substrate fabrication methodologies, simple imaging, and analysis with the availability of the cells for post-processing. In this technique, we confine the cells on fluorescent adhesive protein micropatterns of a known area on compliant silicone substrates and use the cell deformed pattern area to calculate cell contractile work. We validated this approach by comparing this Pattern-based Contractility Screening (PaCS) to conventional bead-displacement TFM and show quantitative agreement between the methodologies. Using this platform, we measure the contractile work of highly metastatic MDA-MB-231 breast cancer cells is significantly higher than non-invasive MCF-7 cells. PaCS enables the broader implementation of contractile work measurements in diverse quantitative biology and biomedical applications.

biophysics↗

bioRxiv2019

Object novelty and value coding segregate across functionally connected brain networks

Novel and valuable objects are motivationally attractive for animals including primates. However, little is known about how novelty and value processing is organized across the brain. We used fMRI in macaques to map brain activity to fractal patterns varying in either novelty or value dimensions in the context of functionally connected brain networks determined at rest. Results show unique combinations of novelty and value coding across the brain networks. Networks in the ventral temporal cortex and in the parietal cortex showed preferential coding of novelty and value dimensions, respectively, while a wider network composed of temporal and prefrontal areas (TP network), along with functionally connected portions of the striatum, amygdala, and claustrum, responded to both dimensions with similar activation dynamics. Our results support emergence of a common currency signal in the TP network that may underlie the common attitudes toward novel and valuable objects.

neuroscience↗

bioRxiv2019

Human intestinal tissue-resident memory CD8+ T cells comprise transcriptionally and functionally distinct subsets

Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However transcriptional heterogeneity of human intestinal TRM cells remains undefined, and definitive markers of CD103-TRM cells are lacking. Here, we investigated transcriptional and functional heterogeneity of human TRM cells through the study of donor-derived intestinal TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identified four conventional TRM populations, with two distinct transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We defined a transcriptional signature discriminating the two CD8+ populations, including differential expression of key residency-associated genes and cytotoxic molecules. Flow cytometry of recipient-derived cells infiltrating the graft and intestinal lymphocytes from healthy gut confirmed the two CD8+ TRM phenotypes, with {beta}2-integrin acting as a CD103-CD8+ TRM marker. CD103+ CD8+ TRM cells produced IL-2, and demonstrated greater polyfunctional cytokine production, while {beta}2-integrin+ CD69+ CD103-TRM cells had higher granzyme expression. Phenotypic and functional analysis of intestinal CD4+ T cells identified many parallels, including a distinct {beta}2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal TRM cells, and suggest a role for {beta}2-integrin in TRM development. SummaryHeterogeneity within human tissue-resident memory T (TRM) cells is poorly understood. We show that transcriptionally, phenotypically, and functionally distinct CD4+ and CD8+ TRM subsets exist in the human intestine, and that {beta}2-integrin expression identifies a distinct population of CD8+ TRM cells.

immunology↗

bioRxiv2019

The reliability and heritability of cortical folds and their genetic correlations across hemispheres.

The structure of the brains cortical folds varies considerably in human populations. Specific patterns of cortical variation arise with development and aging, and cortical traits are partially influenced by genetic factors. The degree to which genetic factors affect cortical folding patterning remains unknown, yet may be estimated with large-scale in-vivo brain MRI. Using multiple MRI datasets from around the world, we estimated the reliability and heritability of sulcal morphometric characteristics including length, depth, width, and surface area, for 61 sulci per hemisphere of the human brain. Reliability was assessed across four distinct test-retest datasets. We meta-analyzed the heritability across three independent family-based cohorts (N > 3,000), and one cohort of largely unrelated individuals (N~9,000) to examine the robustness of our findings. Reliability was high (interquartile range for ICC: 0.65-0.85) for sulcal metrics. Most sulcal measures were moderately to highly heritable (heritability estimates = 0.3-0.7). These genetic influences vary regionally, with the earlier forming sulci having higher heritability estimates. The central sulcus, the subcallosal and the collateral fissure were the most highly heritable regions. For some frontal and temporal sulci, left and right genetic influences did not completely overlap, suggesting some lateralization of genetic effects on the cortex.

genetics↗

bioRxiv2019

Activation of MAIT cells plays a critical role in viral vector vaccine immunogenicity

Mucosal-associated invariant T (MAIT) cells can be activated by viruses through a cytokine-dependent mechanism, and thereby protect from lethal infection. Given this, we reasoned MAIT cells may have a critical role in the immunogenicity of replication-incompetent adenovirus vectors, which are novel and highly potent vaccine platforms. In vitro, ChAdOx1 (Chimpanzee Adenovirus Ox1) induced potent activation of MAIT cells. Activation required transduction of monocytes and plasmacytoid dendritic cells to produce IL-18 and IFN-, respectively. IFN--induced monocyte-derived TNF- was identified as a novel intermediate in this activation pathway, and activation required combinatorial signaling of all three cytokines. Furthermore, ChAdOx1-induced in vivo MAIT cell activation in both mice and human volunteers. Strikingly, MAIT cell activation was necessary in vivo for development of ChAdOx1-induced HCV-specific CD8 T cell responses. These findings define a novel role for MAIT cells in the immunogenicity of viral vector vaccines, with potential implications for future design.\n\nOne sentence summaryRobust immunogenicity of candidate adenovirus vaccine vectors requires the activation of unconventional T cells.

immunology↗

bioRxiv2019

Transcranial Pulse Stimulation with Ultrasound in Alzheimer’s disease – A new navigated focal brain therapy

Ultrasound-based brain stimulation techniques offer an exciting potential to modulate the human brain in a highly focal and precisely targeted manner. However, for clinical applications the current techniques have to be further developed. We introduce a new ultrasound stimulation technique, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) and describe a first navigable clinical TPS system. Feasibility, safety and preliminary (uncontrolled) efficacy data in Alzheimers disease (AD) are provided. Simulation data, in vitro measurements with rat and human skulls/brains and clinical data in 35 AD patients were acquired in a multicentric setting (including CERAD scores and functional MRI). Preclinical results show large safety margins and patient results show high treatment tolerability. Neuropsychological scores improved significantly when tested immediately as well as 1 and 3 months after stimulation and fMRI data displayed significant connectivity increases within the memory network. The results encourage broad neuroscientific application and translation of the new method to clinical therapy and randomized sham-controlled studies.

neuroscience↗