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The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that β2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)–binding protein (SREBP)–stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased SPTBN1 and CASPASE-3 expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.

Macrophage plasticity is critical for maintaining immune function and developing solid tumors; however, the macrophage polarization mechanism remains incompletely understood. Our findings reveal that Mg2+ entry through distinct plasma membrane channels is critical to macrophage plasticity. Naïve macrophages displayed a previously unidentified Mg2+ dependent current, and TRPM7-like activity, which modulates its survival. Significantly, in M1 macrophages, Mg2+ entry is facilitated by a novel Mg²-dependent current that relies on extracellular Mg2+, which was crucial for activating iNOS/NFκB pathways and cellular bioenergetics, which drives pro-inflammatory cytokines. Conversely, in M2 macrophages, Mg2+ entry occurs primarily through TRPM7 channels, pivotal for IL-4 and IL-10-mediated anti-inflammatory cytokine secretion. Notably, the Mg2+ deficient diet or addition of TRPM7 agonist Naltriben suppresses the M1 phenotype while promoting angiogenic factors and fostering tumor growth. These findings suggest that Mg2+ flux via specific channels is indispensable for macrophage polarization, with its dysregulation playing a pivotal role in tumor progression. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA's research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC.

Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions. Author summary: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a significant global health issue. Neutrophils, immune cells that rapidly enter the lungs during Mtb infection, contribute both to fighting the infection and exacerbating lung damage. Their metabolic state, especially the way they produce energy, is crucial for their function during TB. However, the specific impact of Mtb on neutrophil metabolism and its role in TB progression has been unclear. In this study, we investigated the roles of glycolysis and fatty acid metabolism in neutrophil responses to Mtb infection. We found that inhibiting glycolysis worsens TB outcomes, while blocking fatty acid oxidation (FAO) provides protection, reducing lung damage, bacterial load, and overall disease severity. Notably, FAO inhibition specifically disrupts the accumulation of an immature neutrophil population that is more susceptible to Mtb, thereby improving infection control. Targeting carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in fatty acid metabolism, impaired neutrophil migration to infection sites and enhanced their antimicrobial activity. These findings suggest that modulating neutrophil metabolism, particularly through FAO inhibition, could be a promising strategy for developing host-directed TB therapies. [ABSTRACT FROM AUTHOR]

The nexus between government spending and economic growth has remained a hot topic of discussion when Wagner (1958) stated about the 'demand following response' hypothesis, whereas Keynes (1936) advocated the 'supply leading response' hypothesis. Other two hypotheses are contemporaneous relationship, and neutrality or independence between government spending and economic growth. In the wake of the recent global economic crisis it is pertinent to analyze the nexus between government spending and economic growth to ascertain the implication of fiscal expansion on economic growth in India. This study tries to assess the influence of government expenditure on economic growth using a production function approach. We examine the influence of government spending, institutional credit and commercial electricity consumption on economic growth using panel data from 14 major (non-special category) sub-national governments in India during the period 1980-81 to 2013-14. After establishing long-run relationship among the variables, panel long-run estimates are drawn by using both Dynamic Ordinary Least Square (DOLS) and Fully-Modified Ordinary Least Square (FMOLS) methods. Results from both the methods suggest positive and statistically significant impact of government spending, institutional credit and commercial electricity consumption on economic growth. Among the three variables the impact of government size on economic growth is found to be highest and the influence of electricity consumption on economic growth is found to be lowest. Dumitrescu-Hurlin pairwise causality test reveals existence of bi-directional causality between government expenditure and economic growth, and between electricity consumption and economic growth. Unidirectional causality running from institutional credit to economic growth is established. The analysis reveals that at sub-national level in India, expansionary fiscal policy through building infrastructure and investing in productive sector, and escalation in credit facility with a lower rate of interest to the private sector will be helpful for the economy in generating higher economic growth. Though the influence of commercial credit consumption on economic growth is found to be low, electrification in India has to be expanded to reap more economies of scale and garner higher economic growth. The conservationist approach cannot be followed because low consumption of electricity can retard economic growth. JEL Classifications: H70, E62, C33 Keywords: State Finance, Economic Growth, Government Expenditure, Institutional Credit, Electricity Consumption, Panel Estimation Corresponding Author's Email Address: bibhutieco@gmail.com, INTRODUCTION The nexus between government spending and economic growth has remained a controversial topic of discussion since more than a century ago, when Wagner (1883/1958) propounded the law of increasing [...]

This study empirically investigates the impact of external debt on economic growth, and assesses whether institutional quality matters for this influence, using data from 18 emerging countries during 1996 to 2020. The findings indicate that although an upsurge in external debt negatively affects economic growth, this impact is mitigated when there is an improvement in institutional quality, as reflected by three governance indicators: anti-corruption perception, voice and accountability, and perceptions of the rule of law. However, other three governance indicators (political stability, government effectiveness, and regulatory quality) failed to affect the economic growth favorably. These results have important implications for policymakers in emerging countries who are currently facing major fiscal and external imbalances due to high expenditure on military goods/thigh cost of war, decrease in trade, and financial loss due to the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

The balanced growth theory and the neoclassical growth model predict that certain macroeconomic variables such as output, consumption, and investment grow at a constant rate. Analytically, it indicates that the consumption-output ratio and the investment-output ratio (termed "great ratios") must be stationary. Moreover, consumption and investment must be cointegrated with output. This paper examines these implications with respect to developed (G7) and emerging (E7) countries using data for the period 1970-2019. The validity of the balanced growth hypothesis (BGH) is tested by using unit root tests (univariate analysis) and cointegration techniques (multivariate analysis) that permits endogenously determined structural breaks. The findings of our univariate analysis suggest limited evidence of the BGH in developed and developing countries. The multivariate analysis exhibits more supportive evidence of the BGH in five developed countries and limited evidence for two developing countries. The study also employs the Westerlund (2006) panel cointegration test with structural breaks to examine the validity of the BGH. Empirical findings validate the BGH for the G7 countries, while it is not validated for E7 countries. In sum, the study promulgates the use of structural breaks in a multivariate setup in testing the BGH to find robust evidence. [ABSTRACT FROM AUTHOR]

Introduction Beckwith-Wiedemann syndrome (BWS) is a stem cell overgrowth disorder with an estimated prevalence of 1 in 14,000 (1). Its phenotypic expression includes omphalocele, organomegaly, adrenal cytomegaly, hemihyperplasia, and macrosomia, [...], Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. Epigenetic silencing of β2-spectrin (βL2SP, encoded by SPTBN1), a SMAD adaptor for TGF-β signaling, is causally associated with BWS; however, a role of TGF-β deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous [Sptbn1.sup.+/-] [Smad.3.sup.+/-] mice, which have defective TGF-β signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-β-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-β inducible and facilitates TGF-β-mediated repression of TERT transcription via interactions with β2SP and SMAD3. This regulation was abrogated in TGF-β-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-β pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.

Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disorder involving both upper and lower motor neurons. Interestingly, 15 to 41% of patients with ALS have concomitant frontotemporal dementia (FTD). Approximately, 50% of patients with ALS can copresent with a broader set of neuropsychological pathologies that do not meet FTD diagnostic criteria. This association resulted in revised and expanded criteria establishing the ALS-frontotemporal spectrum disorder (FTSD). In this case report, we review background information, epidemiology, pathophysiology, and structural and molecular imaging features of ALS-FTSD. [ABSTRACT FROM AUTHOR]

Background: Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS. Methods: Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real‐time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS. Results: We provide evidence that loss of Ca2+ signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca2+ homeostasis was mediated by transient receptor potential canonical‐1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro‐inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca2+ homeostasis that inhibited alarmin release thereby reverting the pSS phenotype. Conclusions: These results indicate that loss of Ca2+ signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca2+ signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS. [ABSTRACT FROM AUTHOR]