Biology subjects

Jacobs, R.

Publications and source records attributed to Jacobs, R..

7 recordsLinked to original sources

bioRxiv2026

Sertraline and Carfilzomib Synergize to Target T-cell Malignancies with Serine/Glycine synthesis activity via Cholesterol Dysregulation, Cellular Stress and Immune Modulation

BackgroundT-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphoma (PTCL) are aggressive hematological malignancies requiring novel therapeutic strategies. The majority of T-ALL and PTCL tumors display metabolic activation and addiction to endogenous serine/glycine synthesis (SSP), providing opportunities for targeted therapy with the clinically used antidepressant sertraline, inhibiting SSP enzymes SHMT1/2. However, sertraline monotherapy only induces cell cycle arrest and has limited efficacy in suppressing disease progression in vivo. MethodsDrug synergy of sertraline combined with clinically used proteasome inhibitors carfilzomib and bortezomib was evaluated. Drug effects on cell cycle, proliferation and apoptosis were assessed in T-ALL, PTCL and healthy blood cells using flow cytometry assays. Proteomic, lipidomic and metabolic analyses on drug treated T-ALL cells were performed to elucidate the molecular mechanisms underlying drug synergy, followed by validation of changes of interest, metabolic rescues and shRNA-knockdown of SSP enzymes in T-ALL cells. In vivo therapeutic efficacy and immune remodelling were evaluated in an immunocompetent MYCN-overexpressing PTCL mouse model. ResultsSertraline acted synergistically with clinically used proteasome inhibitor carfilzomib to induce cell cycle arrest and apoptosis in T-ALL and PTCL cells with SSP activity, with minimal effects on SSP-inactive T-ALL cells or healthy blood cells. Adding carfilzomib also enhanced the therapeutic efficacy of sertraline in an aggressive MYCN PTCL model. Sertraline rewired cell metabolism towards increased cholesterol uptake and biosynthesis in SSP-active T-ALL cells, and this effect was not obtained by other means of SSP inhibition. In contrast to sertraline, carfilzomib promoted cholesterol efflux. Moreover, carfilzomib reduced total lipid levels, further restricting nutrients in sertraline - carfilzomib treated cells. Additionally, the drug combination impaired mitochondrial respiration and elevated reactive oxygen species (ROS) levels and DNA damage in SSP-active tumor cells, which was rescued by citrate supplementation. Interestingly, these metabolic changes were associated with microenvironmental changes in our mouse model, where the drug combination elevated natural killer T-cells, neutrophils and eosinophils. ConclusionsOur study identifies synergy of sertraline - carfilzomib combination treatment mediated through metabolic impairment and is associated with remodelling of the immune microenvironment. This invites for further clinical investigation of this drug combination as a therapeutic strategy for SSP-active T-cell malignancies.

cancer biology↗

bioRxiv2026

A rhizarian genome reveals an osmotrophic route to extracellular digestion in eukaryotes

Rhizaria, one of the most species-rich and ecologically important eukaryotic supergroups, accommodates a newly discovered osmotrophic species, yet high-quality genomic resources remain scarce, limiting our understanding of their metabolic diversity and ecological functions. Here, we present the genome of Saccharomycomorpha psychra, the first rhizarian telomere-anchored assembly, to be explored as a model and reference for rhizarian ecology and evolution. The 62 Mb assembly, of which half comprises 22 telomere-to-telomere scaffolds, shows a BUSCO completeness of 94.2%, encodes 17,680 genes, and provides the genomic foundation for investigating rhizarian ecology and evolution. The genome of osmotrophic Saccharomycomorpha psychra reveals a functionally integrated secretome of 1,015 proteins dominated by carbohydrate-active enzymes (CAZymes), proteases, lipases, and oxidoreductases. Taken together with 303 predicted high-confidence membrane transporters of a total of 680, skewed toward H-coupled secondary carriers, these features constitute the genomic signature of an extracellular digestive strategy convergent with saprotrophic fungi. Phenotypic MicroArrayTM assays confirmed active utilization of 17 carbon sources, including all six C5 pentose sugars tested, consistent with the predicted arabinose and ribokinase pathways among the most highly expressed metabolic genes in the transcriptome. These findings demonstrate that osmotrophic saprotrophy has evolved independently in Rhizaria with enzymatic solutions that closely parallel those of evolutionary distant fungal decomposers, highlighting the power of ecological context over phylogenetic heritage in shaping extracellular metabolic architecture.

genomics↗

bioRxiv2026

Induction of ferroptotic and amyloidogenic signatures linked to Alzheimers disease by chemically distinct air pollutants

Air pollution (AirP) exposure is associated with increased Alzheimers disease (AD) risk, yet AirP is chemically heterogeneous, complicating identification of shared pathogenic drivers. We examined acute cortical responses to two metal-rich AirP sources, diesel exhaust particles (DEP) and World Trade Center (WTC) dust, and compared them to woodsmoke (WS), a particulate exposure with low metal content. DEP and WTC elicited highly convergent transcriptional responses, sharing over 1200 differentially expressed genes linked to inflammation, ferroptosis, neuronal remodeling, and amyloid processing. These changes were accompanied by impaired antioxidant activity and increased lipid peroxidation within lipid rafts, a membrane microdomain critical for amyloid processing, resulting in increased A{beta} generation. In contrast, WS produced a distinct transcriptional signature and failed to induce ferroptotic priming or lipid peroxidation, consistent with its low metal composition. Together, these findings implicate metals as a shared driver linking diverse AirP exposures to amyloidogenic vulnerability and elevated AD risk. Graphical AbstractAcute AirP exposure converges on ferroptotic priming, amyloidogenic processing, and white-matter vulnerability. Acute exposure to metal-rich AirP, such as DEP or WTC introduces redox-active metals and particulate matter that promote lipid peroxidation, amyloidogenesis, and altered transcriptional regulation in the brain. AirP exposure engages xenobiotic metabolism pathways (AhR/ARNT), activates iron and heme handling through ferritinophagy (NCOA4) and heme oxygenase activity (HMOX1), and blunts lipid peroxide detoxification systems, including glutathione peroxidase 4 (GPx4), ferroptosis suppressor protein 1 (FSP1), and glutathione (GSH) synthesis. These changes promote ferroptotic priming and lipid raft oxidation, facilitating amyloid precursor protein (APP) processing by secretases (ADAM10, BACE1, {gamma}-secretase) and increasing amyloid-{beta} (A{beta}) generation. In parallel, transcriptional and cell-state remodeling involving neuronal and oligodendrocyte responses contribute to selective white-matter vulnerability, particularly within the corpus callosum. Together, these pathways provide a mechanistic framework linking acute AirP exposure to convergent oxidative, amyloidogenic, and microstructural changes relevant to Alzheimers disease pathology. O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/696601v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@3a22dcorg.highwire.dtl.DTLVardef@c6ae26org.highwire.dtl.DTLVardef@1d3412forg.highwire.dtl.DTLVardef@5cb011_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Combined deletion of cytosolic 5'-nucleotidases IA and II lowers glycemia by improving skeletal muscle insulin action and by lowering hepatic glucose production

Obesity and type 2 diabetes (T2D)-linked hyperglycemia, along with their associated complications, have reached pandemic proportions, becoming a major public health issue. Genetic deletion or pharmacological inhibition of purine nucleotide-metabolizing enzymes has emerged as a potential strategy for treating diseases. We previously showed that cytosolic 5-nucleotidase II (NT5C2)-deficient mice were protected against high-fat diet (HFD)-induced insulin resistance. In the present study, we investigated effects of dual deletion of cytosolic 5-nucleotidase IA (NT5C1A) and NT5C2 in mice. We found that NT5C1A/NT5C2 double-knockout (NT5C-dKO) mice exhibited a hypoglycemic phenotype, displaying enhanced skeletal muscle insulin action and reduced hepatic glucose production. In addition to potential involvement of adenosine monophosphate (AMP)-activated protein kinase (AMPK) in their phenotype, NT5C-dKO mice displayed liver and skeletal muscle proteomic alterations most significantly linked to amino acid metabolism. Our findings support the development of novel anti-diabetic treatments using small-molecule cytosolic 5-nucleotidase inhibitors.

physiology↗

bioRxiv2024

Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins

BackgroundDeferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimers disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO, and other chelators do enter the brain despite some contrary reports. ObjectiveLow dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid precursor protein (APP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice. MethodsIron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and APP processing by Western blot. ResultsDFO decreased brain iron by 18% (MRI) and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. APP and secretase enzymes also decreased by 30%. ConclusionsWT mice respond to DFO with decreased APP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered APP and secretase enzymes.

neuroscience↗

bioRxiv2024

Tcf12 controls dynamic calvarial bone growth and motor learning in mice

Heterozygous loss-of-function mutations of TCF12 and TWIST1 can each cause craniosynostosis and neurodevelopmental delay in humans. Twist1-Tcf12 interaction plays an important role in regulating suture development. Although the molecular and cellular mechanisms underlying craniosynostosis and neurocognitive dysfunctions in Twist1+/- mice have been studied, less information on the role of Tcf12 in these defects is available. To investigate the functional mechanism of Tcf12 in regulating skull and brain development, we analyzed the skull shape of Wnt1-Cre;Mesp1-Cre;Tcf12fl/fl mice and found that, despite mild coronal synostosis, their skull shape appears to be similar to that of controls. We also found evidence of impaired motor learning ability in Tcf12 mutant mice. Furthermore, loss of Tcf12 in neural crest lineage leads to upregulated Runx2 expression in the calvarial mesenchyme and posterior expansion of the frontal bone in Wnt1-Cre;Tcf12fl/fl mice. Mechanistically, we show that Lmx1b is a direct downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during embryonic development. Importantly, overexpression of Lmx1b inhibits osteogenic differentiation in the calvarial mesenchyme of Wnt1-Cre;Tcf12fl/fl mice, indicating Tcf12s regulation of Lmx1b expression is crucial for controlling osteogenesis during calvarial bone development. Our study suggests that Tcf12 expression in the brain is crucial for motor learning. Moreover, this study establishes a new molecular mechanism underlying regulation of calvarial bone formation. Author SummaryCraniosynostosis is characterized by premature fusion of cranial sutures and associated with abnormal skull growth, delayed brain development, and often impaired brain functions. Loss-of-function mutation of TCF12 can cause coronal synostosis and neurodevelopmental delay in humans. In developing mouse sutures, Tcf12 is essential for maintaining the boundary between sutural and osteogenic cells. However, roles of Tcf12 in skull formation and brain development have not been fully investigated. In this study, we show that loss of Tcf12 leads to brain abnormalities even in the absence of coronal synostosis and that frontal bone expansion results from upregulated osteogenic differentiation in the calvarial mesenchyme in mice. Furthermore, we identify Lmx1b as a downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during frontal bone development. Our findings highlight the role of Tcf12 in the development of calvarial bones and provide new insight into molecular mechanisms for regulation of calvarial bone formation.

developmental biology↗

bioRxiv2019

Contrast-Enhanced, Molecular Imaging of Vascular Inflammation in the Mouse Model by Simultaneous PET/MRI

Despite advances in diagnosis and management, cardiovascular diseases (CVDs) remain the leading cause of death in the US. Atherosclerosis is the most common form of CVD and the vulnerability of atherosclerotic plaques to rupture is a primary determinant for risk of catastrophic ischemic events. Current imaging of atherosclerotic disease focuses on assessing plaque size and the degree of luminal stenosis, which are not good predictors of plaque stability. Functional methods to identify biomarkers of inflammation in plaques could facilitate assessment of plaque instability to allow early intervention. In this study, we validate the use of a purpose-built, magnetic resonance imaging (MRI)-compatible positron emission tomography (PET) insert for multimodal, molecular imaging of vulnerable plaques in mice. We illustrate the application of PET to screen for inflamed regions to guide the application of MRI. Molecular MRI visualizes regions of vascular inflammation and is coupled with anatomical MRI to generate detailed maps of the inflammatory marker within the context of an individual vessel. As a testbed for this imaging methodology, we developed a multimodal, iron oxide nanoparticle (NP) targeting vascular cell adhesion molecule-1 (VCAM-1) for simultaneous PET/MRI of vascular inflammation performed on a mouse carotid ligation model. In vitro cell studies confirmed that the NPs are not cytotoxic to liver cells. In vivo simultaneous PET/MRI imaging identified regions of inflammation. Three-dimensional rendering of the MRI data facilitated high-resolution visualization of patterns of inflammation along the injured vessel. Histology validated the co-localization of the NPs with VCAM-1 expression at sites of induced inflammation. The results of this work validate the utility of the simultaneous PET/MR insert as a research tool for small animals and lays groundwork to further advance the potential clinical utility of integrated imaging systems.

bioengineering↗