Biology subjects

Kamal, A.

Publications and source records attributed to Kamal, A..

8 recordsLinked to original sources

bioRxiv2026

Leukemic Stem Cell Subtypes Drive Distinct Niche Remodeling in Acute Myeloid Leukemia

Leukemic stem cells (LSCs) sustain acute myeloid leukemia (AML) and are implicated in therapy resistance and relapse. Yet, it remains unknown how LSCs remodel the bone marrow niche. AML is known to alter stromal and vascular microenvironments, but these effects are difficult to separate from bulk leukemic burden and immune inflammation. Here, we use isogenic human AML xenografts with distinct LSC characteristics but comparable engraftment to define LSC-associated niche remodeling in vivo. Single-cell profiling revealed that LSC-high AML shifts the mesenchymal niche toward fibro-inflammatory states, expanding Fmod+ fibroblasts and Cd34+ perivascular fibroblast-like cells while suppressing osteolineage differentiation. The leukemic compartment remained heterogeneous, with a specific MEP-like LSC population expressing niche-remodeling ligands including TGFB1, IL1B, and ANGPT1. LSC-high AML activated a TGF{beta}-responsive, CREB3L1-controlled fibroblast trajectory, and perturbing TGF{beta} signaling or CREB3L1 activation reduced stromal support for AML cells. These findings identify a specific LSC subtype as a source of niche-remodeling cues that shape specialized leukemia-supportive niches.

molecular biology↗

bioRxiv2025

Lemborexant Reduces Infarct Volume and Improves Long-Term Functional Recovery in a Murine Model of Ischemic Stroke

IntroductionRecovery following ischemic stroke is highly variable and often incomplete, underscoring the urgent need to develop novel targeted poststroke treatments. While the mechanisms underlying poststroke recovery remain incompletely understood, sleep fragmentation, a common consequence of stroke, has been linked to worse patient outcomes. Lemborexant is a dual orexin receptor antagonist that promotes sleep by suppressing wakefulness and enhancing sleep continuity. We hypothesized that lemborexant would reduce poststroke sleep disturbances and promote recovery in a rodent model of stroke. MethodsWe examined the effects of lemborexant (10 mg/kg and 30 mg/kg) and zolpidem (30 mg/kg) on sleep macrostructure, fragmentation, and EEG spectra in both healthy mice and in stroke model mice, which underwent photothrombotic ischemia of the forelimb somatosensory cortex. We also evaluated whether 12 days of drug administration altered infarct volume and functional recovery following the experimental induction of stroke in model mice. ResultsLemborexant treatment (30 mg/kg) increased the percentage of NREM sleep, while preserving sleep continuity, in both healthy and stroke model mice. In contrast, zolpidem increased NREM sleep after stroke, but also increased sleep fragmentation in both groups. Lemborexant treatment at 10 mg/kg and 30 mg/kg significantly reduced infarct volume eight weeks after the induction of stroke. In addition, lemborexant-treated mice showed greater use of the impaired limb four weeks after stroke. InterpretationThese preclinical findings suggest that lemborexant stabilizes sleep and promotes structural and functional recovery following the experimental induction of stroke in model mice, supporting its potential as a novel therapeutic intervention following ischemic stroke. Summary for Social Media if PublishedO_LIIf you and/or a co-author has a X handle that you would like to be tagged, please enter it here. (format: @AUTHORSHANDLE). @EricLandsness C_LIO_LIWhat is the current knowledge on the topic? Sleep plays a critical role in structural and functional recovery after stroke, but most pharmacologic sleep aids, such as benzodiazepines and zolpidem, can fragment sleep and impair neuroplasticity. Dual orexin receptor antagonists like lemborexant may offer a newer, mechanistically distinct approach with potential neuroprotective benefits. C_LIO_LIWhat question did this study address? This study investigated whether the dual orexin receptor antagonist lemborexant could improve sleep quality, reduce ischemic injury, and enhance functional recovery following stroke in adult mice, compared with the sleep-promoting agent zolpidem. C_LIO_LIWhat does this study add to our knowledge? Lemborexant increased NREM sleep without causing fragmentation, reduced infarct volume, and improved motor recovery when administered. These findings suggest that modulating sleep architecture through orexin antagonism during the subacute phase after stroke can promote neural repair and functional recovery. C_LIO_LIHow might this potentially impact on the practice of neurology? Since lemborexant is already FDA-approved for insomnia, these results could be rapidly translated into a therapeutic opportunity to improve stroke recovery through targeted sleep modulation. This approach may shift poststroke care toward integrating neurorestorative, sleep-based interventions during the subacute phase. C_LI

neuroscience↗

bioRxiv2025

Preoptic activation induces a torpor-like hypothermic and hypometabolic state that is cerebroprotective

Therapeutic hypothermia for stroke has been limited by shivering, increased metabolic demand, and poor patient tolerance. Engaging endogenous thermoregulatory circuits to lower body temperature may overcome these limitations and modulate metabolism, offering an integrated approach to cerebroprotection. Here, we show that chemogenetic activation of neurons in the preoptic area (POA) elicits a torpor-like state in mice, characterized by sustained hypothermia and hypometabolism. In an animal stroke model, this endogenous hypothermic state significantly reduced infarct volume and improved motor outcomes compared to controls, whereas maintaining normothermia attenuated these protective effects. To explore metabolic mechanisms contributing to this state, we performed untargeted metabolomic profiling 30 minutes after POA activation and identified coordinated shifts in nucleotide, phospholipid, and sphingolipid pathways. These rapid, temperature-dependent changes indicate a metabolically reprogrammed state that may enhance neuronal resilience during ischemic stress. Together, our findings suggest that POA-driven hypothermia confers cerebroprotection through specific metabolic adaptations with translational potential.

neuroscience↗

bioRxiv2025

Bendless-mediated K63 ubiquitination modulates cellular signalling to regulate Drosophila hematopoiesis

Ubiquitination is a reversible modification whose traditional role has been associated with K48-linked poly-ubiquitination involved in proteasomal degradation. However, the role of K63-linked poly-ubiquitination has been explored in various cellular processes like DNA repair, endocytosis, innate immune response, kinase activation, etc. Since K63-linked poly-ubiquitination can regulate the stability, localization, and activity of its target molecules, its regulation and function in various developmental and disease contexts are being explored. Here, we investigate how K63 ubiquitination regulates Drosophila blood cell homeostasis. Ubc13 (UBE2N), an E2 conjugating enzyme, is highly expressed in Acute Myeloid Leukemia (AML), wherein it controls innate immune signalling for the survival of AML cells; however, its role during developmental hematopoiesis is less explored. In Drosophila, Bendless is the functional homolog of Ubc13, whose role in stem cell regulation and particularly hematopoiesis is unknown. Our results indicate that spatial genetic perturbation of Bendless and its associated molecules, namely Uev1a, Effete, and E3 ligase - Traf6, that mediate K63 ubiquitination are critical for maintaining hematopoietic progenitors and regulating their differentiation. We show that Bendless-mediated K63 ubiquitination controls the Wingless signalling pathway by regulating Dishevelled in the larval lymph gland (LG) thereby modulating hematopoietic progenitor maintenance and differentiation. Furthermore, an excess of K63 ubiquitination activates the JNK pathway in the LG, resulting in lamellocyte production. Genetic epistasis analysis shows that activation of the canonical Wingless pathway in the background of Bendless depletion or inactivation of the JNK pathway in Bendless over-expression conditions can restore physiological hematopoiesis. Our findings indicate that regulators of K63 ubiquitination, like Bendless, could act as molecular inter-nodes that are capable of signalling cross-regulation, especially where intricate signalling networks are involved. Our study provides important mechanistic insights into the signalling mechanisms regulated by K63 ubiquitination during stem cell homeostasis.

developmental biology↗

bioRxiv2025

Maternal undernutrition exacerbates microbiota-driven growth stunting through pre and postnatal effects

Linear growth stunting due to undernutrition affects 20% of children under the age of five with far-reaching consequences, including increased susceptibility to infection and altered cognitive development. Current nutritional interventions are largely ineffective in rescuing linear growth. A significant proportion of stunting originates in utero; however, the mechanisms by which maternal undernutrition is transmitted between generations remain poorly characterized. Here we employed a gnotobiotic murine model of intergenerational undernutrition in which offspring are exposed to distinct microbial communities both in utero and after birth. We found that maternal undernutrition exacerbated offspring growth deficits in a microbiota-dependent manner. Maternal undernutrition also altered the offspring microbiome, increasing abundance of Enterococcus species and Escherichia coli. Cross-fostering demonstrated critical roles for the microbiota in growth during both gestation and early life. These findings emphasize the need to target both mother and child in the design of nutritional therapies for undernutrition.

microbiology↗

bioRxiv2024

Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumourigenesis

Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. Regulating cell identity requires gene activation and repression. While master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether unwanted plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternate fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and acted as a tumour suppressor in multiple liver cancer models. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo, and promoted transition of hepatocellular carcinoma to cholangiocarcinoma, conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide mechanistic evidence for PROX1 as a hepatocyte-specific safeguard and support a model where individual cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage choice and prevent disease.

cancer biology↗

bioRxiv2021

GRaNIE and GRaNPA: Inference and evaluation of enhancer-mediated gene regulatory networks applied to study macrophages

Among the biggest challenges in the post-GWAS (genome-wide association studies) era is the interpretation of disease-associated genetic variants in non-coding genomic regions. Enhancers have emerged as key players in mediating the effect of genetic variants on complex traits and diseases. Their activity is regulated by a combination of transcription factors (TFs), epigenetic changes and genetic variants. Several approaches exist to link enhancers to their target genes, and others that infer TF-gene connections. However, we currently lack a framework that systematically integrates enhancers into TF-gene regulatory networks. Furthermore, we lack an unbiased way of assessing whether inferred regulatory interactions are biologically meaningful. Here we present two methods, implemented as user-friendly R packages: GRaNIE (Gene Regulatory Network Inference including Enhancers) for building enhancer-based gene regulatory networks (eGRNs) and GRaNPA (Gene Regulatory Network Performance Analysis) for evaluating GRNs. GRaNIE jointly infers TF-enhancer, enhancer-gene and TF-gene interactions by integrating open chromatin data such as ATAC-Seq or H3K27ac with RNA-seq across a set of samples (e.g. individuals), and optionally also Hi-C data. GRaNPA is a general framework for evaluating the biological relevance of TF-gene GRNs by assessing their performance for predicting cell-type specific differential expression. We demonstrate the power of our tool-suite by investigating gene regulatory mechanisms in macrophages that underlie their response to infection and cancer, their involvement in common genetic diseases including autoimmune diseases, and identify the TF PURA as putative regulator of pro-inflammatory macrophage polarisation. Availability- GRaNIE: https://bioconductor.org/packages/release/bioc/html/GRaNIE.html - GRaNPA: https://git.embl.de/grp-zaugg/GRaNPA Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

genomics↗

bioRxiv2017

Evaluation of anticancer and anti-mitotic properties of quinazoline and quinazolino-benzothiadiazine derivatives

Cancer is one of the major health and social-economic problems despite considerable progress in its early diagnosis and treatment. Owing to the emergence and increase of multi drug resistance to various conventional drugs, and the continuing importance on health-care expenditure, many researchers have focused to develop novel and effective anticancer compounds. In the present study, a series of in-house synthesized quinazoline and quinazolino-benzothiadiazine derivatives were investigated for their anticancer efficacy against a panel of five cancer (DU145, MCF7, HepG2, SKOV3 and MDA-MB-231) and one normal (MRC5) cell lines. Among all the tested compounds, fifteen of them exhibited promising growth-inhibitory effect (0.15 - 5.0 M) and induced cell cycle arrest in G2/M phase. In addition, the selected compounds inhibited the microtubule assembly; altered mitochondrial membrane potential and enhanced the levels of caspase-9 in MCF-7 cells. Furthermore, the active compound with combination of drugs showed synergistic effect at lower concentrations and the drug uptake was mediated through clathrin mediated endocytic pathway. Our results indicated that quinazoline and quinazolino-benzothiadiazine conjugates could serve as potential leads in the development of personalized cancer therapeutics.\n\nSummaryThe present study describes the exploration of small molecules based on heterocyclic scaffolds for tubulin target based development of anticancer agents.

cancer biology↗