Biology subjects

Ahmed, M.

Publications and source records attributed to Ahmed, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Nanodomain formation in lipid bilayers II: The influence of mixed-chain saturated lipids

An important class of lipids found in biological membranes are composed of two structurally different hydrocarbon chains. Among these, low-melting lipids possessing both a saturated and unsaturated chain have been intensely studied because of their biological abundance and influence on lipid rafts. In contrast, much less is known about the biophysical effects of mixed chains in high-melting lipids. Here, we investigated two such lipids--MSPC (14:0-18:0 PC) and SMPC (18:0-14:0 PC)--to determine how chain length mismatch and acyl chain position on the glycerol backbone influence lateral organization. We studied the temperature-and composition-dependent phase behavior of liposomes composed of either mixed-chain or symmetric-chain high-melting lipids plus DOPC and cholesterol, using techniques sensitive to domain formation at both microscopic and nanoscopic length scales. All studied mixtures exhibited liquid-ordered (Lo) + liquid-disordered (Ld) phase coexistence with domains that were visible in confocal microscopy experiments. FRET measurements showed that all mixtures also exhibited nanoscopic heterogeneity at temperatures above the microscopic miscibility transition temperature, and cryo-EM imaging further revealed bilayer thickness variation consistent with coexisting Ld and Lo phases. Both the microscopic miscibility transition temperature, m-Tmix, and its nanoscopic counterpart, nm-Tmix, were strongly correlated with the melting transition temperature of the saturated lipid; the sole exception was SMPC/DOPC/Chol, whose m-Tmix showed a significant negative deviation from the expected value, implying an enhanced propensity for nanoscopic phase separation in mixtures containing this high-melting species. These results point to strong effects of acyl chain position within mixed-chain high-TM lipids on the microscopic phase behavior of ternary mixtures.

biophysics↗

bioRxiv2025

JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake

Lung cancer is the leading cause of cancer-related death and is frequently accompanied by reduced food intake and cachexia, a debilitating syndrome characterized by weight loss and skeletal muscle wasting. We sought to identify contributors to cachexia using a murine model of lung cancer that reproduces key features of this syndrome. A multiplex cytokine screening approach, integrated with western blot and transcriptomic analyses, identified tumor-derived inflammatory mediators and downstream signaling pathways associated with cachexia. Notably, IL-6 superfamily members were elevated in the tumor and plasma of mice and patients with cachexia. The JAK-STAT3 signaling was upregulated in liver and skeletal muscle, driving the acute phase response and impairing lipid metabolism. Pharmacologic inhibition of JAK1/2 with ruxolitinib improved body weight, fat mass, and overall survival without altering tumor burden. These effects were driven primarily by blunted hypothalamic leptin receptor signaling, which increased food intake early in the disease course. In the liver, JAK inhibition reduced STAT3 activity, restored fatty acid oxidation, and decreased the production of acute-phase proteins. These findings support JAK inhibition as a therapeutic strategy for lung cancer-associated cachexia. Statement of SignificanceCancer cachexia is a lethal complication of lung cancer that lacks effective treatment. We show that JAK inhibition by ruxolitinib restores weight, fat mass, and prolongs survival in murine models of lung cancer. These effects were independent of tumor burden, underscoring the relevance of addressing cachexia to improve survival in cancer patients and supporting clinical testing of JAK inhibition for cancer cachexia

cancer biology↗

bioRxiv2025

Gsx2 Regulates Oligodendrocyte Precursor Formation in the Zebrafish Spinal Cord

Nervous system development relies on sequential and coordinated formation of diverse neurons and glia from neural progenitor cells (NPCs). In the spinal cord, NPCs of the pMN domain produce neurons early in development followed by oligodendrocyte precursor cells (OPCs), which subsequently differentiate as oligodendrocytes (OLs), the myelinating glia of the central nervous system, later in development. The mechanisms that specify neural progenitor cells to the OL lineage are not yet well understood. Using zebrafish as an experimental model system, we generated single-cell RNA sequencing and single-nuclei ATAC sequencing data that identified a subpopulation of NPCs, called pre-OPCs, that appeared fated to produce OPCs. pre-OPCs uniquely express several genes that encode transcription factors specific to the OL lineage, including Gsx2, which regulates OPC formation in the mouse forebrain. To investigate Gsx2 function in zebrafish OPC specification, we used CRISPR/Cas9 genome editing to create gsx2 loss-of-function alleles. gsx2 homozygous mutant embryos initiated OPC formation prematurely and produced excess OPCs without altering OL differentiation. Using our single-nuclei multi-omics dataset, we predicted a gene regulatory network centered around gsx2 and identified genes that might be transcriptionally regulated by Gsx2. Taken together, our studies suggest that Gsx2 expression in pre-OPCs contributes to the timing of OPC specification.

developmental biology↗

bioRxiv2025

Modulation of serotonergic, dopaminergic and tubulin-associated pathways by tannin-free natural products in Caenorhabditis elegans reveals effective anthelmintic drug targets

Despite of the Southeast Asias rich medicinal flora, Bangladesh behinds in utilizing the Caenorhabditis elegans model for lead anthelmintic compound discovery. Moreover, target-specific resistance (TSR) and non-target-specific resistance (NTSR) surge have influenced the lead compounds bio-discovery over the past decades. To date, prior researches are limited to basic efficacy tests and conventional extraction protocol. Therefore, the study was designed to assess the anthelmintic potency of 19 tannin-free natural products (NPs) induced alterations of neurotransmission in C. elegans. The anthelmintic activity was assessed by examining the motility (head thrashes and body bends), mortality, egg hatch inhibition (EHI) and expression of cat-1, ser-1, dat-1, and tba-1 genes. Eleven (11) plant extracts, Azadirachta indica A. Juss., Cassia alata L., Portulaca oleracea L., Saraca asoca (Roxb.) W.J.de Wilde, Eleusine indica L. Gaertn., Persicaria hydropiper L. Delarbre, Foeniculum vulgare Mill., Clerodendrum infortunatum L., Linum usitatissimum L., Hibiscus rosa-sinensis L., and Vitex negundo L. revealed a significant neurobehavioral and developmental impairments in C. elegans. Persicaria hydropiper L. Delarbre @ 1{square}mg/mL, caused the lowest body bending (31{square}{+/-}{square}1.7, p{square}<{square}0.01), while Eleusine indica L. Gaertn. reduced head thrashing (66.3{square}{+/-}{square}3.0, p{square}<{square}0.01). L. usitatissimum L. exhibited the highest lethality (87.3{square}{+/-}{square}1.8%, p{square}<{square}0.01) and the LD{square}{square} values of Eleusine indica L. Gaertn. (0.40{square}mg/mL) and Linum usitatissimum L. (0.411{square}mg/mL) were the lowest. Interestingly, C. infortunatum L. exhibited the strongest EHI (97.5{square}{+/-}{square}3.0%, p{square}<{square}0.01). Gene expression analysis revealed a significant down-regulation of the dopaminergic and serotonergic pathway indicating the metabolic and reproductive disruptions. This pioneering study underscores the anthelmintic potency of native plant extracts, highlighting their neuromodulatory and developmental impact on C. elegans. Altogether, these findings suggest that the selected genes may serve as potential drug targets, paving the way for lead compounds identification and development to the advance anthelmintic drug discovery from the NPs.

biochemistry↗

bioRxiv2025

Insights into the genetic diversity and population structure of prevalent Theileria orientalis in Bangladesh

Theileria orientalis, an obligatory intracellular blood protozoon, which causes the substantial economic losses to the cattle industry and is widely prevalent throughout Bangladesh. The study was aimed to assess the nationwide prevalence, genetic diversity and evolutionary divergence of T. orientalis parasites in Bangladesh analyzing bovine blood samples. The genetic characterization, haplotype network analysis and Codon-based evolutionary divergence was conducted by targeting the major piroplasm surface protein (MPSP) gene. The overall prevalence of T. orientalis was 63.75% (n = 800), as determined by MPSP-PCR across the eight divisions of Bangladesh with significant regional variation. Subsequent phylogenetic analysis showed that the query MPSP sequences were clustered into two genotypes namely 5 and 7. Genetic diversity indicated high haplotype and moderate nucleotide diversity but consistent with contrasting demographic and selective pressures across regions. The evolutionary divergence analysis revealed the complex genetic landscape of T. orientalis population which shaped by historical expansion, ongoing gene flow and localized diversification. The haplotype network analysis identified total 29 distinct haplotypes, highlighting substantial diversity within the two genotypes. These findings demonstrate the occurrence and genetic richness of T. orientalis in cattle of Bangladesh. Although the pathogenic impact could not be assessed in this study, the presence of diverse genotypes suggests a need for continued surveillance and future research to determine the clinical and economic relevance of this parasite.

molecular biology↗

bioRxiv2025

Psilocybin ameliorates neuropathic pain-like behaviour in mice and facilitates gabapentin-mediated analgesia

Chronic pain states are challenging to control with current drug therapies. Here, we demonstrate that a single dose of psilocybin can produce a sustained anti-nociceptive effect in a model of chronic neuropathic pain in male and female mice. Psilocybin anti-nociceptive effects were mediated by 5-HT2A receptors, although additional mechanisms might also be involved. Furthermore, a single dose of psilocybin caused a significant increase in the anti-nociceptive potential of gabapentin, a widely used treatment for neuropathic pain consistent with the establishment of longer lasting changes in network processing. Overall, these findings present the first preclinical evidence that psilocybin could be a valuable approach for treating chronic pain from nerve injury and serve as a new therapeutic addition for pain management.

neuroscience↗

bioRxiv2025

Integrated Analysis of Glycosylation and Inflammation-Related Genes for Prognostic Risk Modeling and Immunotherapy Response Prediction in Gastric Cancer

BackgroundGastric cancer (GC) continues to be among the most commonly identified cancers worldwide. This study integrates glycosylation and inflammation-related gene features for the first time to construct a prognostic model for gastric cancer, providing new theoretical basis for revealing immune escape mechanisms and personalized treatment strategies. MethodsTranscriptomic and clinical data derived from GC samples were meticulously examined, utilizing resources from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Through differential expression analysis, we successfully identified glycosylation and inflammatory-related differentially expressed genes (GANDIRDEGs). To construct a prognostic gene signature, we applied least absolute shrinkage and selection operator (LASSO) analysis in conjunction with Cox regression analysis. Additionally, we performed somatic mutation (SM) along with copy number variation (CNV) analyses, alongside gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Furthermore, we conducted gene set enrichment analysis (GSEA) along with a comprehensive evaluation of immune infiltration and drug sensitivity. ResultsWe identified and validated a six-gene (INHBA, OLR1, ROS1, EPHA5, TACR1, and IL6) signature, termed GANDIRDEGs, which showed excellent performance in distinguishing overall survival (OS) between high-risk (HR) and low-risk (LR) cohorts. Moreover, we developed a prognostic nomogram utilizing this six-gene signature that provides highly accurate predictions of GC patient outcomes.SM and CNV analyses revealed that MSR1 had the highest mutation rate among the GANDIRDEGs, with a mutation rate of 5%. GO, KEGG, and GSEA revealed significant associations of each pivotal gene with pathways, including cytokine signaling, the inflammatory response, and apoptosis mediated by CDKN1A through TP53, among various biological functions and signal transduction pathways. Our findings offer a novel gene signature, GANDIRDEGs, that correlated with prognosis, immune infiltration, and therapeutic sensitivity in patients with GC. ConclusionThis study establishes a prognostic signature integrating glycosylation and inflammatory pathways in GC, providing valuable insights into the mechanisms of immune evasion and potential personalized treatment approaches.

cell biology↗

bioRxiv2025

Computational Modelling of Resistance to Hormone-Mediated Remission in Childhood Absence Epilepsy

Childhood absence epilepsy (CAE) often resolves during adolescence, a period marked by hormonal and neurosteroid changes associated with puberty. However, remission does not occur in all individuals. To investigate this clinical heterogeneity, we developed a simplified thalamocortical model with a layered cortical structure, using deep-layer intrinsically bursting (IB) neurons to represent frontal cortex and regular spiking (RS) neurons modelling the parietal cortex. By simulating two cortical configurations, we explored how variations in neuronal composition and frontocortical connectivity influence seizure dynamics and the effectiveness of allopregnanolone (ALLO) in resolving pathological spike-wave discharges (SWDs) associated with CAE. While both models exhibited similar physiological and pathological oscillations, only the parietal-dominant network (with a higher proportion of regular spiking neurons in layer 5) recovered from SWDs under increased frontocortical connectivity following ALLO administration. These findings suggest that neuronal composition critically modulates ALLO-mediated resolution of SWDs, providing a mechanistic link between structural connectivity and clinical outcomes in CAE, and highlighting the potential for personalized treatment strategies based on underlying network architecture.

neuroscience↗

bioRxiv2025

ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation

Mutations in the phosphatase and tensin homolog (PTEN) gene are linked to severe neurodevelopmental disorders. Loss of PTEN causes hyperactivation of both mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2. Recent studies have shown that this dual hyperactivation is required for the neuropathology observed in PTEN-deficient human stem cell-derived neural cells. However, the molecular effectors that integrate these synergistic signals remain unknown. Here, we identify the actin-regulating ARP2/3 complex as a critical point of convergence downstream of mTORC1 and mTORC2. We show that concurrent hyperactivation of both complexes drives increased filamentous actin and elevated levels of the ARP2/3 complex subunits in PTEN-deficient human neural precursors and neurons. Pharmacological or genetic inhibition of ARP2/3 is sufficient to rescue multiple disease-relevant phenotypes, including neural precursor hyperproliferation, neuronal hypertrophy, and electrical hyperactivity, without affecting the upstream mTORC1 or mTORC2 hyperactivation. Together, these findings reveal the PTEN-mTOR-ARP2/3 signaling axis as a core mechanism of neuropathology and highlight ARP2/3 inhibition as a potential therapeutic strategy for PTEN-related neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Hypermutable hotspot enables the rapid evolution of self/non-self recognition genes in Dictyostelium

Cells require highly polymorphic receptors to perform accurate self/non-self recognition. In the amoeba Dicytostelium discoideum, polymorphic TgrB1 & TgrC1 proteins are used to bind sister cells and exclude cheaters, but it remains unknown how cells continually generate this extreme genetic diversity. Here, we created a collection of chromosome-length, whole genome sequences from 10 Dictyostelium discoideum isolates and sister species to understand the evolution of the large tgr gene family. Our dataset includes AX2-214, a widely used D. discoideum lab strain, as well as complete genomes for two Chlamydia-like endosymbionts harbored within amoebae. We find that tgrB1 and C1 lie in a hypermutational hotspot, with haplotypes that undergo repeated intralocus recombination, duplications, transpositions, and inversions. These structural dynamics are highly localized adjacent to tgrB and C, resulting in the gain and loss of dozens of genes. The tgrBC genes themselves frequently duplicate and recombine, leading to the rapid generation of unique tgrBC repertoires. In the broader tgr gene family, some genes (e.g. tgrN) are single copy and syntenic across all the genomes, whereas others (e.g. tgrA) prolifically duplicate at similar rates to Dictyostelium transposons. Thus, the tgr genes are among the most rapidly evolving families genome-wide. We propose that the intense diversification within the tgrBC locus can help explain how these genes acquire such extreme levels of polymorphism, with parallels to the MHC immune genes in mammals and other allorecognition systems. This collection of amoeba genomes is also an ideal dataset for comparative genomics and molecular evolution in Amoebozoa. SignificanceThe ability to distinguish self from non-self is an essential part of innate immunity and multicellularity. In the amoeba Dicytostelium discoideum, cells form transient multicellular structures via aggregation. In the process, they exclude distantly-related cheater strains via highly polymorphic cell surface proteins, TgrB1 and TgrC1. We used this system to ask: how do organisms continually generate new variation in recognition factors? After sequencing a collection of Dictyostelium spp. genomes, we found that the tgrB and tgrC genes lie in an extraordinarily variable locus- a region with such high rates of gene birth and death that genomic similarities are quickly lost, even between closely related isolates. Thus, amoeba cell recognition mirrors self/non-self evolutionary dynamics found across the Tree of Life.

evolutionary biology↗

bioRxiv2025

Voltage-sensor trapping of cardiac Na+ channels by Mg-protoporphyrin impairs cancer cell migration

The human voltage-gated sodium channel hNaV1.5 is essential for cardiac excitability. Though underrecognized, NaV1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNaV1.5 is a therapeutic target but limited isoform specificity presents a risk of side effects via neuronal and skeletal muscle NaV channels. Here we identify Mg2+-protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as inhibitor of hNaV1.5 (IC50 of 1 nM). The activity profile of various metal protoporphyrins correlates with the electrostatic potential at the metal center of the compounds. MgPpIX is specific to hNaV1.5, as no inhibition of other hNaV isoforms (hNaV1.2, 1.4, 1.7, 1.8) was detected. A mutagenesis study and structural modeling reveals that MgPpIX stabilizes the domain-II voltage sensor in the deactivated conformation, with residues E795 and N803 being relevant determinants. MgPpIX also inhibits native NaV channels in breast cancer MDA-MB-231 and colorectal carcinoma SW480 cell lines, and suppresses cell migration. MgPpIX is an exceptionally potent and specific inhibitor of hNaV1.5 and may serve as a lead compound in anti-cancer drug development.

physiology↗

bioRxiv2025

The efficacy and accuracy of ribosomal RNA depletion methods

The depletion of ribosomal RNA (rRNA) is a critical step in RNA-sequence analyses, used to enhance the detection of non-rRNA molecules, such as messenger RNAs and non-coding RNAs. However, the efficiency and potential biases introduced by different rRNA depletion methods remain poorly characterized. Here, we evaluated three commercially available rRNA depletion kits - QIAseq FastSelect, riboPOOL, Zymo-Seq RiboFree - for their performance with the parasitic nematode Strongyloides ratti. We assessed the kits efficiency in rRNA removal, the recovery of expressed genes and transposable elements, and the detection of spliced leader sequences and genes operonic organization. Zymo-Seq demonstrated the highest sensitivity and minimal bias in a measure of gene expression, while QIAseq showed the least rRNA depletion and significant differential expression biases. Our findings underscore the importance of empirical validation of rRNA depletion methods, particularly for parasites and non-model organisms, and we suggest that Zymo-Seq as the optimal choice for S. ratti and related nematodes.

genomics↗

bioRxiv2025

A Novel Mouse Model Reveals a Role for Mitochondria in EarlyLineage Specification and Gastrulation

Mitochondria are increasingly recognised as regulators of developmental state, but how mitochondrial dysfunction influences lineage transitions during mammalian embryogenesis remains poorly understood. Here, we generate a conditional mouse model expressing a mitochondrially targeted, attenuated variant of the DNA ADP-ribosyltransferase DarT (mitoAtDarT). Early activation of mitoAtDarT reduced mitochondrial membrane potential and mitochondrial area, altered mitochondrial morphology, and caused embryonic lethality, without detectable increases in nuclear {gamma}H2AX. Developmental defects were evident before implantation: mitoAtDarT expressing blastocysts contained fewer cells and an increased proportion of CDX2/SOX2 double-positive cells, consistent with delayed or incomplete resolution of trophectoderm and inner-cell-mass identities. Following implantation, embryos showed progressive growth retardation and reduced proliferation without widespread apoptosis. By E7.5, Brachyury-positive posterior mesoderm was retained and expanded despite failure of allantoic morphogenesis, while broad SOX2- and SOX17-positive compartments remained recognisable. These defects were accompanied by increased PKM2 expression. Together, our findings suggest that mitochondrial dysfunction can compromise the resolution and progression of developmental states. The conditional mitoAtDarT model provides a means to determine whether mitochondrial state represents a general requirement for lineage transitions or whether particular developmental programmes are selectively vulnerable.

developmental biology↗

bioRxiv2025

Hidden in Plain Sight: A Novel Symbiotic Haplosclerid Sponge Species Revealed by its Mitochondrial Genome

An unusual third mitochondrial genome was discovered in the genomic data from the symbiotic association between two sponges, Haliclona plakophila (Haplosclerida, Demospongiae) and Plakortis symbiotica (Homoscleromorpha). This mitogenome exhibited an unusually high GC content, lacked the cox2 gene, and could not be reliably positioned among animals based on phylogenetic analysis of the sequence data. Nevertheless, conserved gene clusters and the presence of atp9 indicated that this species is a sponge, while phylogenetic analysis using 18S and 28S places it in the order Haplosclerida of Demospongiae. Since no tissue of the cryptic sponge was found in the investigated association, its relationship with other sponges remained unclear. Therefore, we sampled 10 additional samples assumed to be H. plakophila - P. symbiotica associations in the field to search for the mysterious third sponge. PCR analysis revealed that one of the collected samples contained the novel sponge, but not H. plakophila. A follow-up morphological investigation revealed that this sponge, Haplosclerida sp. nov., while superficially indistinguishable from H. plakophila, differs in skeletal organization and spicule composition. Here, we report the unusual mitochondrial genome of the new species, along with a phylogenetic analysis using 18S and 28S sequences, and demonstrate that Haplosclerida sp. nov. belongs to a new clade of Haplosclerida. We also report the mitogenome of Xestospongia deweerdtae, another haplosclerid species described in association with multiple Plakortis species, including P. symbiotica. Our results support multiple origins of Haplosclerida-Plakortis symbiosis and open new avenues for its investigation.

evolutionary biology↗

bioRxiv2025

Innervation and cargo-specific axonal transport impairments in FUS-ALS mice with gain and loss of function

Mutations in the RNA-binding protein FUS lead to nuclear depletion and cytoplasmic mislocalisation of the protein and cause amyotrophic lateral sclerosis (ALS). Using a novel FUS-ALS mouse model, we found that adult mutant mice develop loss of function transcriptomic alterations, along with aberrant cytoplasmic partitioning associated with translatome deficits. Neuromuscular junction innervation was selectively impaired in FUS-ALS females; however, reinnervation following sciatic nerve crush was equally perturbed in both sexes. Additionally, we observed cargo-specific axonal transport alterations, a process critical for neuronal maintenance. In vivo mitochondrial transport was impaired across FUS-ALS mice, whereas the transport of signalling endosomes was selectively disrupted in mutant females. Altogether, our findings identify broader and sex-dependent motor neuron dysfunction in FUS-ALS, emphasise the link between endosomal transport impairments and denervation in disease, and establish FUS-ALS mice as a valuable model for investigating early cellular impairments driving ALS pathology.

neuroscience↗

bioRxiv2025

A New Pathway for the Decussation of Corticospinal Tracts

Each brain hemisphere controls the movements of the opposite side of the body because the motor axons cross the midline, known as CST decussation. The current theory on CST decussation suggests CSTs decussate as a single tract at the junction between medulla and spinal cord. Although this theory is widely accepted, this theory is based on selective analyses and is therefore incomplete. Here, we employed new approaches, including the horizontal analyses and a non-invasive anterograde tracing method to examine CST decussation thoroughly. We analyzed all CS axons in 3 planes. These approaches led to the discovery of a new pathway for CST decussation. We found CSTs turned back to medulla, moving anteriorly and decussated in an oval structure. In this structure, each CST split into 4 fascicle groups and interdigitated with the corresponding groups from the opposite CST to cross the midline. The significance of this pathway was apparent after decussation where these 4 groups reversed direction, moving posteriorly toward spinal cord. While moving, the motor axons gradually separated at different locations and subsequently turned and occupied the correct positions in the dorsal funiculus for proper limb control. In addition to CSTs, we also characterized several components in the oval structure.

neuroscience↗

bioRxiv2025

C9orf72 polyGA knock-in mice exhibit mild motor and proteomic changes consistent with ALS/FTD

A GGGGCC repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion is translated into five different dipeptide repeat proteins: polyGA, polyGP, polyGR, polyAP and polyPR. To investigate the effect of polyGA, which is the most abundant dipeptide repeat protein in patient brains, we used CRISPR/Cas9 to insert 400 codon-optimized polyGA repeats immediately downstream of the mouse C9orf72 start codon. This generated (GA)400 knock-in mice driven by the endogenous mouse C9orf72 promoter, coupled with heterozygous C9orf72 reduction. (GA)400 mice develop subtle pathology including mild motor dysfunction characterized by impaired rotarod performance. Quantitative proteomics revealed polyGA expression caused protein alterations in the spinal cord, including changes in previously identified polyGA interactors. Our findings show that (GA)400 mice are a complementary in vivo model to better understand C9ALS/FTD pathology and determine the specific role of single DPRs in disease.

neuroscience↗

bioRxiv2025

Sustained Glucose Turnover Flux Distinguishes Cancer Cachexia from Nutrient Limitation

Cancer cachexia is an involuntary weight loss condition characterized by systemic metabolic disorder. A comprehensive flux characterization of this condition however is lacking. Here, we systematically isotope traced eight major circulating nutrients in mice bearing cachectic C26 tumors (cxC26) and food intake-matched mice bearing non-cachectic C26 tumors (ncxC26). We found no difference in whole-body lipolysis and proteolysis, ketogenesis, or fatty acid and ketone oxidation by tissues between the two groups. In contrast, compared to ncxC26 mice ad libitum, glucose turnover flux decreased in food intake-controlled ncxC26 mice but not in cxC26 mice. Similarly, sustained glucose turnover flux was observed in two autochthonous cancer cachexia models despite reduced food intake. We identified glutamine and alanine as responsible for sustained glucose production and tissues with altered use of glucose and lactate in cxC26 mice. We provide a comprehensive view of metabolic alterations in cancer cachexia revealing those distinct from decreased nutrient intake. HighlightsO_LIQuantitative fluxomics of cancer cachexia under matched food intake and body weight C_LIO_LIIntact lipolysis, proteolysis, ketogenesis, and lipid oxidation in cachectic mice C_LIO_LISustained glucose consumption in cachectic mice despite reduced food intake C_LIO_LIIncreased glucose production from glutamine and alanine in cachectic mice C_LI

cancer biology↗