Biology subjects

Morello, G.

Publications and source records attributed to Morello, G..

4 recordsLinked to original sources

bioRxiv2026

A genetic anemia disentangles the dual effect of chronically reduced thrombopoietin on hematopoietic stem cells and bone marrow niche

Many studies unraveled the reciprocal regulation between hematopoietic stem cells (HSC) and the bone marrow (BM) niche by using transgenic knock-out or reporter mice, often overlooking the pathophysiological relevance and the existence of compensatory mechanisms. Here, we exploit the th3 murine model of a genetic anemia, beta-thalassemia (BThal), to investigate the dual impact of chronically reduced thrombopoietin (TPO) production on HSC and megakaryocytic BM niche. Decreased systemic TPO downregulates stemness programs in HSC and impairs their commitment towards megakaryocytes (Mk). We uncover dysmegakaryopoiesis in the BM from BThal patients and mice with defective Mk maturation and reduced production of niche factors, altering the HSC-niche crosstalk. Notably, in vivo stimulation of the TPO signaling restores HSC quiescence, Mk maturation and niche support. These findings demonstrate that TPO regulates HSC through both direct and niche-mediated routes, underscoring the value of using a genetic disease model to disentangle general molecular mechanisms.

cell biology↗

bioRxiv2025

Give It Time: Green Anacondas Show Prolonged Behavioral Responses to Enclosure Enhancements

Information about green anacondas (Eunectes murinus) in human care is limited, especially concerning their behavior, welfare, and overall well-being. To help bridge this knowledge gap, this study evaluated how exhibit design enhancements influence E. murinus behavior. The aim was to assess immediate behavioral changes following enclosure modifications and investigate potential habituation over time, ultimately evaluating the effectiveness and longevity of the behavioral changes induced by the improved environment. Systematic observations were divided into three phases: before enclosure improvements, immediately after these modifications, and three weeks later. Enclosure modifications focused on areas less frequented by the anacondas during Phase 1. Results revealed decreased inactivity in Phase 2 and more balanced space use in Phase 3, with anacondas occupying previously underutilized areas, including the terrariums vertical dimension. Interaction with exhibit enhancement items increased in the studys final phase, where a decrease in engagement would be anticipated due to habituation. These results suggested the anacondas required additional time to acclimate to the modifications, even though environmental factors may have contributed to these changes. This study highlights how enclosure enhancements may benefit green anacondas welfare while underlining the importance of providing sufficient acclimation time to accurately evaluate the animals complete behavioral response. Simple SummaryGreen anacondas (Eunectes murinus) remain largely understudied, particularly in terms of their behavior and welfare in human care. To address this knowledge gap, improvements were made to the enclosure of green anacondas in captivity, and their behaviors were observed before and after the modifications. The observations were divided into three phases: before the changes (Phase 1), immediately after (Phase 2), and approximately three weeks later (Phase 3). The modifications focused on areas that were rarely utilized during Phase 1. After the improvements, the anacondas became more active and used their enclosure more evenly, including at varying heights. The anacondas interacted more with the new enclosure features after the three weeks, when increased disinterest would have been expected, although environmental conditions may have influenced these changes. These findings show how enclosure modifications may help enhance the welfare of green anacondas and emphasize the need for research that allows enough time for the animals to fully adjust, ensuring a complete understanding of their response.

animal behavior and cognition↗

bioRxiv2024

B cell receptor silencing reveals the origin of high-grade B cell lymphomas with MYC and BCL2 rearrangements

The B cell receptor (BCR) is essential for mature B cell lymphomas, serving as therapeutic target. Here, we show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. HGBCL-DH-BCL2 with undetectable IGH (IGHUND) differ from IGH-expressing counterparts for germinal center-zone gene programs, MYC expression and T cell infiltration. While IGH+ HGBCL-DH-BCL2 prefer IGM/IG-Kappa expression, IGHUND counterparts have completed IGH class-switching, favoring IG-Lambda (IGL) light chains. IGHUND HGBCL-DH-BCL2 preserve IGHV gene integrity, overcoming antigen-driven selection. IGH silencing precedes onset and shapes evolution of HGBCL-DH-BCL2 from Follicular Lymphoma (FL) or FL/HGBCL-DH-BCL2 common precursor. In FL/HGBCL-DH-BCL2 pairs and HGBCL-DH-BCL2 models, BCR silencing promoted RAG1/2-dependent IG light chain editing, causing t(8;22)(q24;q11)/IGL::MYC. IGH silencing protected HGBCL-DH-BCL2 models from killing by CD79B-targeting Polatuzumab-Vedotin. Collectively, HGBCL-DH-BCL2 primarily originate from BCR-silenced isotype-switched t(14;18)/IGH::BCL2-positive (pre)FL cells acquiring IGL::MYC translocations during IG light chain revision, with clinical implications. SignificanceThese findings link BCR silencing in isotype-switched t(14;18)+ Follicular Lymphoma cells (or their precursors) to RAG1/2 re-expression, promoting IGL::MYC translocations responsible for transformation into high-grade B cell lymphomas (HGBCL). Predominant silencing of the BCR complex in HGBCL with MYC and BCL2 rearrangements protects tumor cells from CD79B-directed Polatuzumab-Vedotin killing.

cancer biology↗

bioRxiv2019

Tetrahydrocannabinolic Acid A (THCA-A) Reduces Adiposity And Prevents Metabolic Disease Caused By Diet-Induced Obesity

Cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of {Delta}9-tetrahydrocannabinol ({Delta}9-THC). Surprisingly, the biological profile of the non-narcotic native precursor of {Delta}9-THC ({Delta}9-THC acid A, {Delta}9-THCA-A) is still largely unexplored. We present evidence that {Delta}9-THCA-A is a partial and selective PPAR{gamma} modulator, endowed with lower adipogenic activity than the full PPAR{gamma} agonist rosiglitazone (RGZ) and with an enhanced osteoblastogenic activity in human mesenchymal stem cells. Docking and in vitro functional assays indicated that {Delta}9-THCA-A binds to and activates PPAR{gamma} by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures at inguinal white adipose tissue (iWAT) from mice treated with {Delta}9-THCA-A confirmed its mode of action on PPAR{gamma}. Administration of {Delta}9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with {Delta}9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Altogether, our data validate the potential of {Delta}9-THCA-A as a low adipogenic PPAR{gamma} agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation. These findings suggest that {Delta}9-THCA-A, and perhaps non-decarboxylated Cannabis sativa extracts, are worth considering for addition to our inventory of cannabis medicines.\n\nSIGNIFICANCE STATEMENTThe medicinal use of Cannabis is gaining momentum, despite the adverse psychotropic effects of {Delta}9-THC, the decarboxylation product of its naturally occurring and non-psychotropic precursor {Delta}9-THCA-A. We present evidence that {Delta}9-THCA-A is a partial ligand agonist of PPAR{gamma} with lower adipogenic activity compared to the full PPAR{gamma} agonist rosiglitazone (RGZ). Moreover, chronic administration of {Delta}9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced body weight gain and fat mass, improved glucose intolerance and insulin resistance, and prevented liver steatosis and macrophage infiltration in fat tissues, additionally inducing white adipose tissue browning. Collectively, these observations qualify {Delta}9-THCA-A, a compound devoid of psychotropic effects, as an efficacious pharmacological agent to manage metabolic syndrome and obesity-associated inflammation.\n\nHighlights- {Delta}9-THCA-A is a partial PPAR{gamma} ligand agonist with low adipogenic activity\n- {Delta}9-THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells.\n- {Delta}9-THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice\n- {Delta}9-THCA-A improves glucose tolerance, insulin sensitivity, and insulin profiles in vivo\n- {Delta}9-THCA-A induces browning of iWAT and has a potent anti-inflammatory activity

pharmacology and toxicology↗