Normal Homeostasis Research Articles

The Neglected Suppressor of Cytokine Signalling (SOCS): SOCS4-7.

SOCS proteins are essential for the regulation of oncogenic, anti-pathogenic, and proinflammatory signalling cascades, including the JAK/STAT and NF-kB pathways, where they act as negative feedback regulators. Given their powerful role in a broad spectrum of biological processes, it is surprising that the functions of many SOCS proteins have not been widely explored. While the mechanisms of action of CIS, SOCS1-3 are well-documented, information regarding SOCS4-7 remains limited. However, recent studies have begun to elucidate the regulatory functions of these proteins during infection and disease, such as influenza infection, cancer and diabetes. Therefore, this review aims to describe and discuss studies detailing our current understanding of SOCS4-7, painting a clearer picture of the biological processes these regulatory proteins maintain. Indeed, our review highlights important evidence proving that all SOCS play a role in biological processes that are essential for normal immunological homeostasis, clearance of infection and avoidance of disease. Understanding how SOCS proteins interact with other proteins or how they are dysregulated in disease is likely to provide valuable insights for advancing therapeutic approaches.

Deciphering the Role of Copper Homeostasis in Atherosclerosis: From Molecular Mechanisms to Therapeutic Targets

Cardiovascular disease (CVD) is a leading cause of death globally, with atherosclerosis (AS) playing a central role in its pathogenesis as a chronic inflammatory condition. Copper, an essential trace element in the human body, participates in various biological processes and plays a significant role in the cardiovascular system. Maintaining normal copper homeostasis is crucial for cardiovascular health, and dysregulation of copper balance is closely associated with the development of CVD. When copper homeostasis is disrupted, it can induce cell death, which has been proposed to be a novel form of “cuproptosis”, distinct from traditional programmed cell death. This new form of cell death is closely linked to the occurrence and progression of AS. This article elaborately describes the physiological mechanisms of copper homeostasis and explores its interactions with signaling pathways related to AS. Additionally, we focus on the process and mechanism of cell death induced by imbalances in copper homeostasis and summarize the relationship between copper homeostasis-related genes and AS. We also emphasize potential therapeutic approaches, such as copper balance regulators and nanotechnology interventions, to adjust copper levels in the body, providing new ideas and strategies for the prevention and treatment of CVD.

7466 The Effects Of Various Forms Of Diabetes On Features Of Tumor Aggressiveness In Thyroid Cancer

Abstract Disclosure: R.D. Paparodis: None. E. Karvounis: None. A. Kapezanou: None. S. Livadas: None. G. Simeakis: None. D.P. Askitis: None. I. Androulakis: None. N.G. Angelopoulos: None. D. Zianni: None. A. Rizoulis: None. A. Boniakos: None. I. Perogamvros: None. D. Bantouna: None. J.C. Jaume: None. Introduction: Diabetes has been linked to increased risk for several cancers and aggressiveness of tumor behavior. A link between thyroid cancer and diabetes appears controversial in the literature as of yet. We designed the present study to assess whether autoimmune (type 1 + LADA = DM1) or type 2 diabetes (DM2) are associated with more aggressive thyroid cancers compared to those found in non-diabetic (non-DM) individuals. Methods: We retrospectively reviewed data from patients undergoing thyroid surgery in 10 Endocrinology and Endocrine Surgery Clinics throughout Greece over 2 years. We collected data on history and type of diabetes, pre-existing to the thyroid surgery, its treatments and duration, the preoperative thyroid function tests and the surgical pathology findings. We compared the incidence of various histological types of thyroid cancer and the features of tumor aggressiveness between patients with diabetes and those with normal glucose homeostasis (non-DM) (DM1 vs. DM2 vs. non-DM). Results: Overall, n=808 subjects with thyroid cancer were included: n=571 were females (70.7%), age 47.3 ± 14.3 years, BMI 27.0 ± 5.0 Kg/m2, mean TSH 1.99 ± 2.21 mIU/L; n= 692 were non-DM, n=10 had DM1 and n=107 had DM2. Histology revealed n=5 poorly differentiated / anaplastic, n=13 medullary, n=12 Hürthle cell, n=17 follicular and n=773 papillary thyroid cancers (PTC); n=20 (2.5%) with aggressive histological subtypes of PTC, n=5 (0.6%) with distant metastases (MET), n=199 (24.6%) with extrathyroidal extension (ETE), n=419 (51.9%) with capsular invasion (CI), n=225 (27.8%) with lymph nodes involvement (LNi) and n=23 with cancer recurrence (CR) (2.8%). The incidence of aggressive histological types, CR, MET or number of I-131 treatments were not different between groups (p>0.05). ETE, CI and LNi were significantly more common in non-DM compared to both diabetes groups, while gross ETE was more common in DM2 over DM1 and non-DM (p<0.001). Conclusions: More DM1 than DM2 seem to confer a protective effect on several features of cancer aggressiveness in affected individuals. On the other hand, more DM2 than DM1 seems to significantly promote gross ETE. No effect was observed pertaining to the risk for more aggressive tumors or histological subtypes of PTC. Although aggressiveness of thyroid cancer seems controlled in DM1 and to a lesser degree in DM2 the complex interplay between autoimmunity, hyperglycemia and thyroid cancer biology requires larger sample size to better determine causative effects. Presentation: 6/2/2024

12394 "Sugar And Tumors: A Case Report On New-onset Diabetes In Metastatic Pheochromocytoma With Elevated Dopamine Levels"

Abstract Disclosure: B. Agrawal: None. V. mehta: None. R. naseem: None. M. Renzu: None. R. rashid: None. Introduction: Metastatic pheochromocytoma is a rare neuroendocrine tumor with potential complication of new-onset diabetes mellitus (DM). We present a case highlighting the challenges in managing a patient with metastatic pheochromocytoma and concurrent DM. Case presentation: A 66-year-old male with a history of hypertension and gout initially presented in 2010 with an adrenal mass, later identified as pheochromocytoma and resected. In 2018, he presented with bilateral leg pain, revealing metastatic disease-causing spinal cord compression along with metastatic lung nodules and metastasis in adrenalectomy bed. Despite interventions including T6,7,8 laminectomy in 2020 and radiation therapy, metastases persisted. In 2024, he presented with polyuria, polydipsia, and hyperglycemia (blood glucose >500 mg/dL). Laboratory findings showed elevated a1c of 15 in addition to elevated normetanephrines, metanephrines, and dopamine with levels of 3880, 48 and 488 respectively. He was diagnosed with new-onset DM and started on insulin therapy in addition to metformin and jardiance. Discussion: Secondary diabetes mellitus (DM) in secretory pheochromocytoma occurs in approximately 50% of cases, manifesting from mild insulin resistance to severe presentation like DKA. Epinephrine-secreting tumors contribute to glucose intolerance by activating beta receptors, thereby stimulating gluconeogenesis. Patients with higher levels of epinephrine and preoperative glucose intolerance were more prone to developing postoperative hypoglycemia, requiring close monitoring during the postoperative period. Additionally, research by DiSalvo et al. Epinephrine-secreting tumors have a more significant impact on hyperglycemia by impairing insulin secretion and stimulation GLP-1. Tumor resection has been found to be more effective effective in restoring normal glucose homeostasis in these patients. Dopamine-secreting pheochromocytomas are rare neoplasms characterized by the presence of immature catecholamine vesicles that inhibit dopamine conversio owing to localized dopamine beta hydroxylase. Typically presenting around the age of 48, these tumors often lack excess catecholamines, leading to atypical symptoms such as local discomfort or pain from tumor compression. These neoplasms are less detectable on metaiodobenzylguanidine (MIBG) scans, necessitating positron emission tomography (PET) for accurate diagnosis. Surgical resection is the treatment, with preoperative management involving metyrosine instead of alpha blockers. These tumors are frequently diagnosed late, often in a malignant stage, contributing to poor prognosis Conclusion: Overall, understanding the complex interplay between catecholamines and glucose metabolism is crucial for the comprehensive management of patients with pheochromocytoma and secondary DM. Presentation: 6/1/2024

7466 The Effects of Various Forms of Diabetes on Features of Tumor Aggressiveness in Thyroid Cancer

Abstract Disclosure: R.D. Paparodis: None. E. Karvounis: None. A. Kapezanou: None. S. Livadas: None. G. Simeakis: None. D.P. Askitis: None. I. Androulakis: None. N.G. Angelopoulos: None. D. Zianni: None. A. Rizoulis: None. A. Boniakos: None. I. Perogamvros: None. D. Bantouna: None. J.C. Jaume: None. Introduction: Diabetes has been linked to increased risk for several cancers and aggressiveness of tumor behavior. A link between thyroid cancer and diabetes appears controversial in the literature as of yet. We designed the present study to assess whether autoimmune (type 1 + LADA = DM1) or type 2 diabetes (DM2) are associated with more aggressive thyroid cancers compared to those found in non-diabetic (non-DM) individuals. Methods: We retrospectively reviewed data from patients undergoing thyroid surgery in 10 Endocrinology and Endocrine Surgery Clinics throughout Greece over 2 years. We collected data on history and type of diabetes, pre-existing to the thyroid surgery, its treatments and duration, the preoperative thyroid function tests and the surgical pathology findings. We compared the incidence of various histological types of thyroid cancer and the features of tumor aggressiveness between patients with diabetes and those with normal glucose homeostasis (non-DM) (DM1 vs. DM2 vs. non-DM). Results: Overall, n=808 subjects with thyroid cancer were included: n=571 were females (70.7%), age 47.3 ± 14.3 years, BMI 27.0 ± 5.0 Kg/m[2], mean TSH 1.99 ± 2.21 mIU/L; n= 692 were non-DM, n=10 had DM1 and n=107 had DM2. Histology revealed n=5 poorly differentiated / anaplastic, n=13 medullary, n=12 Hürthle cell, n=17 follicular and n=773 papillary thyroid cancers (PTC); n=20 (2.5%) with aggressive histological subtypes of PTC, n=5 (0.6%) with distant metastases (MET), n=199 (24.6%) with extrathyroidal extension (ETE), n=419 (51.9%) with capsular invasion (CI), n=225 (27.8%) with lymph nodes involvement (LNi) and n=23 with cancer recurrence (CR) (2.8%). The incidence of aggressive histological types, CR, MET or number of I-131 treatments were not different between groups (p>0.05). ETE, CI and LNi were significantly more common in non-DM compared to both diabetes groups, while gross ETE was more common in DM2 over DM1 and non-DM (p<0.001). Conclusions: More DM1 than DM2 seem to confer a protective effect on several features of cancer aggressiveness in affected individuals. On the other hand, more DM2 than DM1 seems to significantly promote gross ETE. No effect was observed pertaining to the risk for more aggressive tumors or histological subtypes of PTC. Although aggressiveness of thyroid cancer seems controlled in DM1 and to a lesser degree in DM2 the complex interplay between autoimmunity, hyperglycemia and thyroid cancer biology requires larger sample size to better determine causative effects. Presentation: 6/2/2024

Crocin nano-chitosan-coated compound mitigates hippocampal blood-brain barrier disruption, anxiety, and cognitive deficits in chronic immobilization stress-induced rats

Stressful conditions can disrupt the central nervous system's normal homeostasis and physiological functions, resulting in blood-brain barrier malfunction, memory and learning impairment, anxiety, etc. Crocin is a long-investigated natural compound that has been documented to have anti-inflammation and neuroprotective effects, albeit it comes with some limitations such as low stability and bioavailability. Therefore, we aimed to overcome crocin's limitations by coating crocin with a nano-carrier (chitosan) in the chronic immobilization stress-induced rat model. Crocin was encapsulated into chitosan nanoparticles by a modified method. A total of 35 male Wistar rats were selected as our study subjects (220–250 g) which were randomly divided into 5 groups (control, stress, nanoparticle, crocin, and chitosan). Chronic immobilization stress was induced by placing rats for 2 h into a plastic bottle with specific measurements (for 14 consecutive days) to prevent animals from moving. To evaluate the memory and learning changes, we used the Barnes maze test and the Passive avoidance test followed by the evaluation of the N-methyl-D-aspartate |(NMDA) receptor subunits genes (GRIN1 and GRIN2A) expression. Anxiety levels were evaluated by elevated plus maze test. Furthermore, the changes in the expression of genes responsible for encoding the tight junction proteins of BBB including ZO1, CLDN5, and OCLN were assessed by RT-PCR. Compared to intact crocin, the administration of crocin nano-chitosan-coated compound resulted in significant improvement of specific memory and learning indicators as well as a significant reduction of anxiety levels in chronic immobilization stress-induced rats. Finally, we observed that treatment with the crocin nano-chitosan-coated compound can elevate the expression levels of the genes responsible for encoding NMDA receptor subunits, and the genes responsible for encoding the tight junction proteins of blood-brain barriers in the hippocampus.

Effects of the organochlorine pesticide metabolite p,p’-DDE on the gastrointestinal lipidome in fish: A novel toxicity pathway for a legacy pollutant

Though phased out from use in the United States, environmental contamination by organochlorine pesticides (OCPs) remains a widespread issue, especially around intensive agricultural regions. OCPs, such as dichlorodiphenyltrichloroethane (DDT) and its primary metabolite, dichlorodiphenyldichloroethylene (DDE), have been detected in soils, sediments, surface waters, and biota decades after their discontinued use. As OCPs are persistent and can bioaccumulate in fats, these compounds can transfer and magnify across food webs. Freshwater predatory fish and birds can accumulate high OCP concentrations, leading to a myriad of deleterious impacts on organismal health. Studies have found evidence of reproductive disruption in predatory fish, such as the largemouth bass (LMB; Micropterus salmoides), associated with DDT and DDE exposure. DDE can act through estrogenic pathways and induce the expression of estrogenic signals in male animals; however, the molecular mechanism of disruption is unclear. Recently, metabolomics research has revealed corollary relationships between lipid signals and organic pollutant toxicity. Here, a two-month feeding experiment on LMB was conducted to assess the interactions of DDE (as p,p'-DDE) in food with gut and liver lipid signaling. Targeted lipidomic analysis revealed global alterations in the abundance of tissue lipids, especially cholesteryl esters and phospholipids, in LMB exposed to low levels of p,p'-DDE. Results from these studies indicate that p,p'-DDE may act through disruption of normal lipid homeostasis to cause toxicity in freshwater fish.

Microscale marvels: unveiling the macroscopic significance of micropeptides in human health.

Non-coding RNA encodes micropeptides from small open reading frames located within the RNA. Interestingly, these micropeptides are involved in a variety of functions within the body. They are emerging as the resolving piece of the puzzle for complex biomolecular signaling pathways within the body. Recent studies highlight the pivotal role of small peptides in regulating important biological processes like DNA repair, gene expression, muscle regeneration, immune responses, etc. On the contrary, altered expression of micropeptides also plays a pivotal role in the progression of various diseases like cardiovascular diseases, neurological disorders and several types of cancer, including colorectal cancer, hepatocellular cancer, lung cancer, etc. This review delves into the dual impact of micropeptides on health and pathology, exploring their pivotal role in preserving normal physiological homeostasis and probing their involvement in the triggering and progression of diseases.

Transglutaminase 1: Emerging Functions beyond Skin.

Transglutaminase enzymes catalyze Ca2+- and thiol-dependent posttranslational modifications of glutamine-residues that include esterification, hydrolysis and transamidation, which results in covalent protein-protein crosslinking. Among the eight transglutaminase family members in mammals, transglutaminase 1 (TG1) plays a crucial role in skin barrier formation via crosslinking and insolubilizing proteins in keratinocytes. Despite this established function in skin, novel functions have begun merging in normal tissue homeostasis as well as in pathologies. This review summarizes our current understanding of the structure, activation, expression and activity patterns of TG1 and discusses its putative novel role in other tissues, such as in vascular integrity, and in diseases, such as cancer and fibrosis.

Transitions in lung microbiota landscape associate with distinct patterns of pneumonia progression.

The precise microbial determinants driving clinical outcomes in severe pneumonia are unknown. Competing ecological forces produce dynamic microbiota states in health; infection and treatment effects on microbiota state must be defined to improve pneumonia therapy. Here, we leverage our unique clinical setting, which includes systematic and serial bronchoscopic sampling in patients with suspected pneumonia, to determine lung microbial ecosystem dynamics throughout pneumonia therapy. We combine 16S rRNA gene amplicon, metagenomic, and transcriptomic sequencing with bacterial load quantification to reveal clinically-relevant pneumonia progression drivers. Microbiota states are predictive of pneumonia category and exhibit differential stability and pneumonia therapy response. Disruptive forces, like aspiration, associate with cohesive changes in gene expression and microbial community structure. In summary, we show that host and microbiota landscapes change in unison with clinical phenotypes and that microbiota state dynamics reflect pneumonia progression. We suggest that distinct pathways of lung microbial community succession mediate pneumonia progression.

Interdependency of estradiol-mediated ERα activation and subsequent PR and GREB1 induction to control cell cycle progression

Various groups of chemicals that we encounter in every-day life are known to disrupt the endocrine system, such as estrogen mimics that can disturb normal cellular development and homeostasis. To understand the effect of estrogen on intracellular protein dynamics and how this relates to cell proliferation, we aimed to develop a quantitative description of transcription factor complexes and their regulation of cell cycle progression in response to estrogenic stimulation. We designed a mathematical model that describes the dynamics of three proteins, GREB1, PR and TFF1, that are transcriptionally activated upon binding of 17β-estradiol (E2) to estrogen receptor alpha (ERα). Calibration of this model to imaging data monitoring the expression dynamics of these proteins in MCF7 cells suggests that transcriptional activation of GREB1 and PR depends on the association of the E2-ERα complex with both GREB1 and PR. We subsequently combined this ER signaling model with a previously published cell cycle model and compared this to quantification of cell cycle durations in MCF7 cells following nuclei tracking based on images segmented with deep neural networks. The resulting model predicts the effect of GREB1 and PR knockdown on cell cycle progression, thus providing mechanistic insight in the molecular interactions between ERα-regulated proteins and their relation to cell cycle progression. Our findings form a valuable basis to further investigate the pharmacodynamics of endocrine disrupting chemicals and their influence on cellular behavior.

Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.

Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid (PL) metabolism. Cardiolipin (CL), the signature PL of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesised and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to CL biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human CL-related PMDs are not fully characterised. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo CL biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy, and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy, and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterise the molecular defects associated with mutant PTPMT1 and confirm the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterise the functional role of PTPMT1 in CL homeostasis, we established a zebrafish ptpmt1 knockout model associated with abnormalities in body size, developmental alterations, decreased total CL levels, and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired CL metabolism, highlight the contribution of aberrant CL metabolism towards human disease, and emphasise the importance of normal CL homeostasis during neurodevelopment.

Hyd/UBR5 defines a tumor suppressor pathway that links Polycomb repressive complex to regulated protein degradation in tissue growth control and tumorigenesis.

Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as Drosophila have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in Drosophila and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd-Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd-Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, drumstick (drm), which functions as a pseudosubstrate by displacing Bowl from the Hyd-Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd-Lin-Bowl pathway by directly repressing the transcription of the micropeptide drm Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis.

ATP, the 31P Spectral Modulus, and Metabolism.

Adenosine triphosphate (ATP) has a high intracellular millimolar concentration (ca. 2.4 mM) throughout the phylogenetic spectrum of eukaryotes, archaea, and prokaryotes. In addition, the function of ATP as a hydrotrope in the prevention of protein aggregation and maintenance of protein solubilization is essential to cellular, tissue, and organ homeostasis. The 31P spectral modulus (PSM) is a measure of the health status of cell, tissue, and organ systems, as well as of ATP, and it is based on in vivo 31P nuclear magnetic resonance (31P NMR) spectra. The PSM is calculated by dividing the area of the 31P NMR integral curve representing the high-energy phosphates by that of the low-energy phosphates. Unlike the difficulties encountered in measuring organophosphates such as ATP or any other phosphorylated metabolites in a conventional 31P NMR spectrum or in processed tissue samples, in vivo PSM measurements are possible with NMR surface-coil technology. The PSM does not rely on the resolution of individual metabolite signals but uses the total area derived from each of the NMR integral curves of the above-described spectral regions. Calculation is based on a simple ratio of the high- and low-energy phosphate bands, which are conveniently arranged in the high- and low-field portions of the 31P NMR spectrum. In practice, there is essentially no signal overlap between these two regions, with the dividing point being ca. -3 δ. ATP is the principal contributor to the maintenance of an elevated PSM that is typically observed in healthy systems. The purpose of this study is to demonstrate that (1) in general, the higher the metabolic activity, the higher the 31P spectral modulus, and (2) the modulus calculation does not require highly resolved 31P spectral signals and thus can even be used with reduced signal-to-noise spectra such as those detected as a result of in vivo analyses or those that may be obtained during a clinical MRI examination. With increasing metabolic stress or maturation of metabolic disease in cells, tissues, or organ systems, the PSM index declines; alternatively, with decreasing stress or resolution of disease states, the PSM increases. The PSM can serve to monitor normal homeostasis as a diagnostic tool and may be used to monitor disease processes with and without interventional treatment.

Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism

Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.

Generation and characterization of a novel mouse model of Becker Muscular Dystrophy with a deletion of exons 52 to 55.

Becker Muscular Dystrophy (BMD) is a rare X-linked recessive neuromuscular disorder frequently caused by in-frame deletions in the DMD gene that result in the production of a truncated, yet functional, dystrophin protein. The consequences of BMD-causing in-frame deletions on the organism are difficult to predict, especially in regard to long-term prognosis. Here, we employed CRISPR-Cas9 to generate a new Dmd del52-55 mouse model by deleting exons 52-55, resulting in a BMD-like in-frame deletion. To delineate the long-term effects of this deletion, we studied these mice over 52 weeks by performing histology and echocardiography analyses and assessing motor functions. Our results suggest that a truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appears insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon52-55 in-frame deletion, we performed RNA-Seq pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.

A Closer Look into White Adipose Tissue Biology and the Molecular Regulation of Stem Cell Commitment and Differentiation.

White adipose tissue (WAT) makes up about 20-25% of total body mass in healthy individuals and is crucial for regulating various metabolic processes, including energy metabolism, endocrine function, immunity, and reproduction. In adipose tissue research, "adipogenesis" is commonly used to refer to the process of adipocyte formation, spanning from stem cell commitment to the development of mature, functional adipocytes. Although, this term should encompass a wide range of processes beyond commitment and differentiation, to also include other stages of adipose tissue development such as hypertrophy, hyperplasia, angiogenesis, macrophage infiltration, polarization, etc.… collectively, referred to herein as the adipogenic cycle. The term "differentiation", conversely, should only be used to refer to the process by which committed stem cells progress through distinct phases of subsequent differentiation. Recognizing this distinction is essential for accurately interpreting research findings on the mechanisms and stages of adipose tissue development and function. In this review, we focus on the molecular regulation of white adipose tissue development, from commitment to terminal differentiation, and examine key functional aspects of WAT that are crucial for normal physiology and systemic metabolic homeostasis.

Establishment and transcriptome analysis of single blastomere-derived cell lines from zebrafish

Maintaining chromosome euploidy in zebrafish embryonic cells is challenging because of the degradation of genomic integrity during cell passaging. In this study, we report the derivation of zebrafish cell lines from single blastomeres. These cell lines have a stable chromosome status attributed to BMP4 and exhibit continuous proliferation in vitro. Twenty zebrafish cell lines are successfully established from single blastomeres. Single-cell transcriptome sequencing analysis confirms the fidelity of gene expression profiles throughout long-term culturing of at least 45 passages. The long-term cultured cells are specialized into epithelial cells, exhibiting similar expression patterns validated by integrative transcriptomic analysis. Overall, this work provides a protocol for establishing zebrafish cell lines from single blastomeres, which can serve as valuable tools for in vitro investigations of epithelial cell dynamics in terms of life–death balance and cell fate determination during normal homeostasis.

Advances in Islet Transplantation and the Future of Stem Cell-Derived Islets to Treat Diabetes.

β-Cell replacement for type 1 diabetes (T1D) can restore normal glucose homeostasis, thereby eliminating the need for exogenous insulin and halting the progression of diabetes complications. Success in achieving insulin independence following transplantation of cadaveric islets fueled academic and industry efforts to develop techniques to mass produce β cells from human pluripotent stem cells, and these have now been clinically validated as an alternative source of regulated insulin production. Various encapsulation strategies are being pursued to contain implanted cells in a retrievable format, and different implant sites are being explored with some strategies reaching clinical studies. Stem cell lines, whether derived from embryonic sources or reprogrammed somatic cells, are being genetically modified for designer features, including immune evasiveness to enable implant without the use of chronic immunosuppression. Although hurdles remain in optimizing large-scale manufacturing, demonstrating efficacy, durability, and safety, products containing stem cell-derived β cells promise to provide a potent treatment for insulin-dependent diabetes.

Cell Proliferation and Apoptosis-Key Players in the Lung Aging Process.

Currently, the global lifespan has increased, resulting in a higher proportion of the population over 65 years. Changes that occur in the lung during aging increase the risk of developing acute and chronic lung diseases, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer. During normal tissue homeostasis, cell proliferation and apoptosis create a dynamic balance that constitutes the physiological cell turnover. In basal conditions, the lungs have a low rate of cell turnover compared to other organs. During aging, changes in the rate of cell turnover in the lung are observed. In this work, we review the literature that evaluates the role of molecules involved in cell proliferation and apoptosis in lung aging and in the development of age-related lung diseases. The list of molecules that regulate cell proliferation, apoptosis, or both processes in lung aging includes TNC, FOXM1, DNA-PKcs, MicroRNAs, BCL-W, BCL-XL, TCF21, p16, NOX4, NRF2, MDM4, RPIA, DHEA, and MMP28. However, despite the studies carried out to date, the complete signaling pathways that regulate cell turnover in lung aging are still unknown. More research is needed to understand the changes that lead to the development of age-related lung diseases.