Towards sustainable resource management: A short and long-run dynamics of mineral production on ecological footprint.

The effect of mineral production on ecological footprint is examined in this study while controlling for economic growth, renewable energy consumption, and trade openness as additional determinants for Pakistan. On the empirical front, the study uses the "Dynamic Autoregressive Distributed Lag (DYNARDL)" simulations for the data collected between 1990 and 2021. The result portrays movement to the long-run equilibrium relationship when considering the ecological footprint as the outcome variable amidst mineral production, economic growth, renewable energy consumption, and trade openness as the covariates. Further, the finding shows temporal dynamics of mineral production on environmental quality with a short-term degradation versus long-term amelioration, which suggests that mineral production can be conducted more sustainably over time with an implication towards taking measures such as technological advancements, improved efficiency, and better waste management practices. Additionally, it failed to find evidence for the conventional "Environmental Kuznets Curve," implying a need for policy reevaluation, reassessment of economic development models and accounting for environmental externalities in economic decision-making. Besides, as expected, the outcome demonstrates that using renewable energy lowers the ecological footprint both in long and short terms, which indicates that utilization of renewable energy sources reduces reliance on fossil fuels, resulting in decreased environmental degradation, thereby fostering the need for emphasis on the importance of continued technological innovation in renewable energy technologies to reduce the ecological footprint further. Moreover, it shows that trade openness improves the environmental quality in the short run (worsens it in the long run), thereby highlighting that trade openness may lead to short-term environmental benefits by promoting cleaner technologies and increasing resource efficiency. However, in the long term, trade openness can exacerbate environmental degradation due to economic priorities often taking precedence over environmental concerns.

Editorial: Acute Hepatitis of Unknown Origin in Children. Is Autoimmunity at Play?

A recent global outbreak of cases of acute hepatitis of unknown origin in children has raised health alerts. Increasing numbers of cases are being reported in most countries, mainly in the United Kingdom (UK). Although the cause remains unknown, several viruses have been isolated from affected children, including adenovirus, severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2), Epstein-Barr virus (EBV), and rhinovirus. Notably, the cause is not from common hepatitis viruses, as serology for hepatitis viruses A, B, C, D, and E has been negative. Current causal hypotheses include possible infection with a new adenovirus variant that affects immunocompetent children, a new pediatric manifestation of COVID-19, or coinfection with enteric adenovirus type F41. This Editorial aims to present current hypotheses regarding the etiology of acute hepatitis of unknown origin in children, including the role of autoimmune hepatitis secondary to viral infection.

Editorial: Treatment with Dual Incretin Receptor Agonists to Maintain Normal Glucose Levels May Also Maintain Normal Weight and Control Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD).

Worldwide, metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. MAFLD is associated with insulin resistance, type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Early diagnosis and management are vital to improving hepatic and cardiometabolic outcomes. Dietary change, weight loss, and structured exercise are the main treatment approaches for fatty liver disease. Since 2010, several investigational drug treatments failed to achieve regulatory approval due to mixed and unsatisfactory results. Although glucagon-like peptide 1 receptor agonists (GLP1-RAs) showed initial promise as therapeutic agents, metabolic liver damage can recur after monotherapy cessation. Dual incretin receptor agonists target the receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). Importantly, on May 13, 2022, the US Food and Drug Administration (FDA) approved tirzepatide as the first dual GLP-1 and GIP receptor agonist for the treatment of T2DM. Dual incretin receptor agonists induce weight loss and enhance hepatic lipid metabolism and systemic insulin sensitivity. Insulin resistance and hepatic steatosis are the main contributors to the development of MAFLD. Treatment with dual incretin analogs reduces hepatic steatosis, lobular inflammation, liver cell damage, fibrosis, and total liver triglyceride levels. The availability of dual incretin receptor agonists for patients with MAFLD may result in weight control, normalizing insulin sensitivity, and reducing or even reversing metabolic dysfunction and liver damage. This Editorial aims to provide an update and discuss how treatment with dual incretin receptor agonists may maintain normal glucose levels and weight and control MAFLD.

Identification of Hepatic Dendritic Cells in Liver Biopsies Showing Steatosis in Patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Associated with Obesity.

BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the term used for hepatic steatosis in patients who are overweight or obese, have type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation. The prevalence of MAFLD among morbidly obese subjects is 65-93%. Hepatic dendritic cells (hDCs) are antigen-presenting cells that induce T cell-mediated immunity. MAFLD pathogenesis involves numerous immune cell-mediated inflammatory processes, while the particular role of hDCs is yet to be well defined. This study aimed to identify hDCs in liver biopsies from 128 patients with MAFLD associated with obesity. MATERIAL AND METHODS In this cross-sectional study, 128 liver biopsies from 128 patients with MAFLD (diagnosed as presence of hepatic steatosis, plus T2DM, metabolic dysregulation or overweight/obesity) were collected and assessed for CD11c⁺ immunoreactivity degree (CD11c as dendritic cell biomarker), through antigen retrieval, reaction with CD11c antibodies (primary), and marking with diaminobenzidine chromogen. RESULTS Among the 128 patients with MAFLD, 64 (50%) had MAFLD and fibrosis and 72 (56.2%) positively expressed hDCs (CD11c⁺). Among morbidly obese patients, 49 (64.5%) positively expressed hDCs (CD11c⁺) in liver tissue; from patients with obesity grade I- grade II (GI-II), 18 (54.5%) positively expressed hDCs (CD11c⁺) in liver tissue; and from non-obese patients with MAFLD, 5 (26.3%) positively expressed hDCs (CD11c⁺) in liver tissue. CONCLUSIONS hDC expression increases significantly in morbidly obese patients with MAFLD compared with non-obese patients, independent of the degree of fibrosis, suggesting the role of adaptive changes within hDCs in the perpetuation of inflammatory insults in chronic liver diseases.

Evaluation of off-targets predicted by sgRNA design tools.

The ease of programming CRISPR/Cas9 system for targeting a specific location within the genome has paved way for many clinical and industrial applications. However, its widespread use is still limited owing to its off-target effects. Though this off-target activity has been reported to be dependent on both sgRNA sequence and experimental conditions, a clear understanding of the factors imparting specificity to CRISPR/Cas9 system is important. A machine learning-based computational model has been developed for prediction of off-targets with more likelihood to be cleaved in vivo with an accuracy of 91.49%. The sequence features important for the prediction of positive off-targets were found to be accessibility, mismatches, GC-content and position-specific conservation of nucleotides. The instructions and code to generate the dataset and reproduce the analysis has been made available at http://web.iitd.ac.in/crispcut/off-targets/.

The neural bases of cognitive emotion regulation: The roles of strategy and intensity.

When confronted with unwanted negative emotions, individuals use a variety of cognitive strategies for regulating these emotions. The brain mechanisms underlying these emotion regulation strategies have not been fully characterized, and it is not yet clear whether these mechanisms vary as a function of emotion intensity. To address these issues, 30 community participants (17 females, 13 males, Mage = 24.3 years) completed a picture-viewing emotion regulation task with neutral viewing, reacting to negative stimuli, cognitive reappraisal, attentional deployment, and self-distancing conditions. Brain and behavioral data were simultaneously collected in a 3T GE MRI scanner. Findings indicated that prefrontal regions were engaged by all three regulation strategies, but reappraisal showed the least amount of increase in activity as a function of intensity. Overall, these results suggest that there are both brain and behavioral effects of intensity and that intensity is useful for probing strategy-specific effects and the relationships between the strategies. Furthermore, while these three strategies showed significant overlap, there also were specific strategy-intensity interactions, such as frontoparietal control regions being preferentially activated by reappraisal and self-distancing. Conversely, self-referential and attentional regions were preferentially recruited by self-distancing and distraction as intensity increased. Overall, these findings are consistent with the notion that there is a continuum of cognitive emotion regulation along which all three of these strategies lie.

Chemical Crosslinking-Mass Spectrometry (CXL-MS) for Proteomics, Antibody-Drug Conjugates (ADCs) and Cryo-Electron Microscopy (cryo-EM).

Chemical crosslinking-mass spectrometry (CXL-MS) has emerged as a powerful tool in structural biology to elucidate protein-protein interactions. This review throws light on the advent of these technologies incorporating chemical crosslinking in proteomics, structural biology and extended to studies and applications of antibody-drug conjugates (ADCs). Monoclonal ASCs are known to target their specific receptors, where the drug could be released for vastly improved therapeutic effect. Cryo-electron microscopy (cryo-EM) is being referred to as the "revolution of the century" as it can help attain almost atomic resolution, while preserving the biological samples at near-native state and has been recognized by the Nobel award 2017. CXL-MS and appropriate bioinformatics tools in combination with cryo-EM reveal better 3D information about dynamic interactions in proteins, interactive domains and motifs, among others in ADCs and in viruses like Zika virus, Rota virus, Dengue virus and also spliceosomes at resolutions, especially below 3 Å. © 2018 IUBMB Life, 70(10):947-960, 2018.

Does energy transition reduce carbon inequality? A global analysis.

Energy transition from fossil fuels to renewables is instrumental in mitigating climate change. Low-income countries have a higher share of renewable energy in their total energy consumption than rich countries (WDI, 2023). Thus, it is imperative to examine the role of energy transition in affecting relative CO2 emissions between rich and poor sections of the societies across income groups of the countries. In this context, our study contributes by constructing the carbon inequality models with renewable and non-renewable energy consumption as prime explanatory variables separately for 114 countries over a data period 1990-2019. The models are estimated individually for high-middle-low-income countries by controlling for foreign direct investment (FDI), economic growth, and innovations. Starting with preliminary econometric operations, we employ the dynamic simulated panel autoregressive distributed lag approach and Driscoll-Kraay standard error regression for empirical investigation. We find that energy transition reduces carbon inequality globally. Innovation has a negative impact, economic growth has a positive impact on carbon inequality, and FDI has an asymmetric impact based on the income level of the countries. The crucial global policy implications are discussed.

Does environmental policy stringency improve nature's health in BRICS economies? Implications for sustainable development.

In our groundbreaking exploration, we meticulously delve into the relationship between environmental policy stringency, international trade dynamics, and financial openness within the BRICS group (Brazil, Russia, India, China, and South Africa) spanning from 1996 to 2021. With a focus on critical variables such as economic growth and technological innovation, our empirical findings challenge conventional wisdom. Surprisingly, we found that those stringent environmental policies, when standing alone, do not invariably lead to reduce CO2 emissions. Equally interesting is our startling discovery that the anticipated moderating influence of environmental policy stringency, catalyzed by trade and foreign direct investment, on the well-being of our environment does not materialize; contrarily, both trade and foreign direct investment moderating channels exhibit unanticipated positive correlations with CO2 emissions. These revelations provoke us with the presence of a "pollution haven" phenomenon within the BRICS economies. Furthermore, our investigation reveals that, when examined individually, trade and foreign direct investment also appear to contribute to elevated emission levels. These findings provide a resolute solution to our research quandary, underlining the indispensable requirement for cutting-edge and robust environmental policies. These policies must possess the prowess to effectively counteract the adverse environmental consequences stemming from the amalgamation of global trade and financial integration. In doing so, they shall propel BRICS nations toward a future firmly grounded in principles of sustainability and ecological integrity.

Insulin resistance and adipose tissue interactions as the cornerstone of metabolic (dysfunction)-associated fatty liver disease pathogenesis.

The relationship between metabolic derangements and fatty liver development are undeniable, since more than 75% of patients with type 2 diabetes mellitus present with fatty liver. There is also significant epidemiological association between insulin resistance (IR) and metabolic (dysfunction)-associated fatty liver disease (MAFLD). For little more than 2 years, the nomenclature of fatty liver of non-alcoholic origin has been intended to change to MAFLD by multiple groups. While a myriad of reasons for which MAFLD is thought to be of metabolic origin could be exposed, the bottom line relies on the role of IR as an initiator and perpetuator of this disease. There is a reciprocal role in MAFLD development and IR as well as serum glucose concentrations, where increased circulating glucose and insulin result in increased de novo lipogenesis by sterol regulatory element-binding protein-1c induced lipogenic enzyme stimulation; therefore, increased endogenous production of triglycerides. The same effect is achieved through impaired suppression of adipose tissue (AT) lipolysis in insulin-resistant states, increasing fatty acid influx into the liver. The complementary reciprocal situation occurs when liver steatosis alters hepatokine secretion, modifying fatty acid metabolism as well as IR in a variety of tissues, including skeletal muscle, AT, and the liver. The aim of this review is to discuss the importance of IR and AT interactions in metabolic altered states as perhaps the most important factor in MAFLD pathogenesis.

Screening for MAFLD: who, when and how?

Metabolic-associated fatty liver disease (MAFLD) is a highly prevalent disease with increasing prevalence worldwide. Currently, no universal screening methods have been standardized, even when this disease poses a major health burden. MAFLD as a spectrum of diseases can range from simple steatosis, and steatohepatitis to fibrosis and hepatocellular carcinoma. Its extra-hepatic manifestations are vast and include cardiovascular diseases, extra-hepatic malignancies, cognitive and respiratory alterations. Given its extensive damage targets as well as its high prevalence, timely identification of the high-risk population presenting metabolic dysfunction should undergo universal non-invasive screening methods, which can be carried out through blood tests, easy and effective imaging techniques, such as ultrasound, score calculation and general clinical information brought together from primary patient-physician contact.

How far are we from an approved drug for nonalcoholic steatohepatitis?

INTRODUCTION: Metabolic-associated fatty liver disease (MAFLD) previously known but still debatable, as nonalcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease and subsequent cirrhosis worldwide, accounting for around 30% of liver diseases. The change in its nomenclature has been brought about by the novel discoveries regarding its pathogenesis, in which metabolic dysfunction plays the most important role. It is widely known that for every disease, the treatment should always be targeted toward the underlying etiology and pathogenesis. AREAS COVERED: MAFLD/NAFLD pathogenesis is heterogeneous, and includes multiple gene polymorphisms, presence of insulin resistance, as well as concomitant diseases that contribute to the disease onset and progression. As a result of this, even though lifestyle modification (owing to metabolic abnormalities) is the first line of treatment, multiple drugs have been tested to target each of the known pathways leading to MAFLD/NAFLD and progression of steatohepatitis. We aim to review the most relevant information regarding previous and ongoing research and recommendations regarding treatment of MAFLD/NAFLD. EXPERT OPINION: Combination therapies associated to weight loss and exercise will be the optimal approach for these patients. It is important to evaluate each patient to select the specific combination according to patient characteristics.

The role of environmental degradation in macroeconomic instability: panel evidence from emerging economies.

This study examines the role of environmental degradation in macroeconomic instability for a balanced panel sample of 22 emerging market economies from 1996 to 2019. Governance is included in the macroeconomic instability function as a moderating factor. Besides, bank credit and government spending are also included in the estimated function as control variables. The long-run results from using the PMG-ARDL method show that environmental degradation and bank credit induce macroeconomic instability, whereas governance and government spending reduce it. Interestingly, environmental degradation creates greater macroeconomic instability than the bank credit. We also find that governance being a moderating factor weakens the adverse impact of environmental degradation on macroeconomic instability. These findings are robust to the FGLS technique, suggesting that governments in emerging economies should prioritize environmental degradation and governance in mitigating climate change and ensuring macroeconomic stability in the long run.

Nonalcoholic Fatty Liver Disease in Latin America and Australia.

The epidemiologic and demographical features of nonalcoholic fatty liver disease (NAFLD) vary significantly across countries and continents. In this review, we analyze current data regarding prevalence of NAFLD in Latin America and Caribbean and Australia and review some peculiarities found in these regions. We stress the need of greater awareness of NAFLD and the development of cost-effective risk stratification strategies and clinical care pathways of the disease. Finally, we highlight the need of effective public health policies to control the main risk factors for NAFLD.

Molecular Mechanisms Involved in MAFLD in Cholecystectomized Patients: A Cohort Study.

Gallstone disease and metabolic dysfunction-associated fatty liver disease (MAFLD) share numerous common risk factors and progression determinants in that they both manifest as organ-specific consequences of metabolic dysfunction. Nevertheless, the precise molecular mechanisms underlying fibrosis development in cholecystectomized MAFLD patients remain inadequately defined. This study aimed to investigate the involvement of farnesoid X receptor 1 (FXR1) and fibroblast growth factor receptor 4 (FGFR4) in the progression of fibrosis in cholecystectomized MAFLD patients. A meticulously characterized cohort of 12 patients diagnosed with MAFLD, who had undergone liver biopsies during programmed cholecystectomies, participated in this study. All enrolled patients underwent a follow-up regimen at 1, 3, and 6 months post-cholecystectomy, during which metabolic biochemical markers were assessed, along with elastography, which served as indirect indicators of fibrosis. Additionally, the hepatic expression levels of FGFR4 and FXR1 were quantified using quantitative polymerase chain reaction (qPCR). Our findings revealed a robust correlation between hepatic FGFR4 expression and various histological features, including the steatosis degree (r = 0.779, p = 0.023), ballooning degeneration (r = 0.764, p = 0.027), interphase inflammation (r = 0.756, p = 0.030), and steatosis activity score (SAS) (r = 0.779, p = 0.023). Conversely, hepatic FXR1 expression did not exhibit any significant correlations with these histological features. In conclusion, our study highlights a substantial correlation between FGFR4 expression and histological liver damage, emphasizing its potential role in lipid and glucose metabolism. These findings suggest that FGFR4 may play a crucial role in the progression of fibrosis in cholecystectomized MAFLD patients. Further research is warranted to elucidate the exact mechanisms through which FGFR4 influences metabolic dysfunction and fibrosis in this patient population.

Detangling the interrelations between MAFLD, insulin resistance, and key hormones.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has increasingly become a significant and highly prevalent cause of chronic liver disease, displaying a wide array of risk factors and pathophysiologic mechanisms of which only a few have so far been clearly elucidated. A bidirectional interaction between hormonal discrepancies and metabolic-related disorders, including obesity, type 2 diabetes mellitus (T2DM), and polycystic ovarian syndrome (PCOS) has been described. Since the change in nomenclature from non-alcoholic fatty liver disease (NAFLD) to MAFLD is based on the clear impact of metabolic elements on the disease, the reciprocal interactions of hormones such as insulin, adipokines (leptin and adiponectin), and estrogens have strongly pointed to the intrinsic links that lead to the heterogeneous epidemiology, clinical presentations, and risk factors involved in MAFLD in different populations. The objective of this work is twofold. Firstly, there is a brief discussion regarding the change in nomenclature as well as epidemiology, risk factors, and pathophysiologic mechanisms other than hormonal effects, which include nutrition and the gut microbiome, as well as genetic and epigenetic influences. Secondly, we review the basis of the most important hormonal factors involved in the development and progression of MAFLD that act both independently and in an interrelated manner.

Novel Bent Conformation of CD4 Induced by HIV-1 Inhibitor Indirectly Prevents Productive Viral Attachment.

GSK3732394 is a multi-specific biologic inhibitor of HIV entry currently under clinical evaluation. A key component of this molecule is an adnectin (6940_B01) that binds to CD4 and inhibits downstream actions of gp160. Studies were performed to determine the binding site of the adnectin on CD4 and to understand the mechanism of inhibition. Using hydrogen-deuterium exchange with mass spectrometry (HDX), CD4 peptides showed differential rates of deuteration (either enhanced or slowed) in the presence of the adnectin that mapped predominantly to the interface of domains 2 and 3 (D2-D3). In addition, an X-ray crystal structure of an ibalizumab Fab/CD4(D1-D4)/adnectin complex revealed an extensive interface between the adnectin and residues on CD4 domains D2-D4 that stabilize a novel T-shaped CD4 conformation. A cryo-EM map of the gp140/CD4/GSK3732394 complex clearly shows the bent conformation for CD4 while bound to gp140. Mutagenic analyses on CD4 confirmed that amino acid F202 forms a key interaction with the adnectin. In addition, amino acid L151 was shown to be a critical indirect determinant of the specificity for binding to the human CD4 protein over related primate CD4 molecules, as it appears to modulate CD4's flexibility to adopt the adnectin-bound conformation. The significant conformational change of CD4 upon adnectin binding brings the D1 domain of CD4 in proximity to the host cell membrane surface, thereby re-orienting the gp120 binding site in a direction that is inaccessible to incoming virus due to a steric clash between gp160 trimers on the virus surface and the target cell membrane.