Implantable phakic contact lens: vault evaluation 5 years postoperatively.

PURPOSE: To evaluate the stability of the postoperative vault of the implantable phakic contact lens (IPCL) 5 years after implantation. SETTING: Clínica de Ojos Dr. Nano, Olivos, Buenos Aires, Argentina. DESIGN: Retrospective case-series study. METHODS: Myopic patients operated with the IPCL for spherical correction in which preoperative data were compared with different scenarios of postoperative vault at 1, 3, and 5 years postoperatively. The main parameter to be evaluated was the vault obtained 5 years postoperatively. RESULTS: 140 eyes of 72 patients, aged 31.9 ± 2.8 years (21 to 50), were included. Most of the eyes (78.6%) obtained a vault between 250 µm and 750 µm, while in 15% of the eyes, it was less than 250 µm, and 6.4% were greater than 750 µm. The vault evaluated 1, 3, and 5 years postoperatively remained stable. Subcapsular cataracts were detected in 2 eyes, with vault <250 µm. A total of 50 eyes (35.7%) had cysts in the sulcus (5 cases in the group of eyes with vault >750 µm). No changes were detected in relation to intraocular pressure or endothelial cell count. CONCLUSIONS: In eyes implanted with the IPCL over 5 years, it was observed that the vault remained stable over time. The proportion of eyes with cysts was higher in eyes with vaults larger than 750 µm.

The Impact of Varying Nipple Properties on Infant Feeding Physiology and Performance Throughout Ontogeny in a Validated Animal Model.

Infant feeding requires successful interactions between infant physiology and the maternal (or bottle) nipple. Within artificial nipples, there is variation in both nipple stiffness and flow rates, as well as variation in infant physiology as they grow and mature. However, we have little understanding into how infants interact with variable nipple properties to generate suction and successfully feed. We designed nipples with two different stiffnesses and hole sizes and measured infant feeding performance through ontogeny using a pig model. We evaluated their response to nipple properties using high-speed X-Ray videofluoroscopy. Nipple properties substantially impacted sucking physiology and performance. Hole size had the most profound impact on the number of sucks infants took per swallow. Pressure generation generally increased with age, especially in nipples where milk acquisition was more difficult. However, most strikingly, in nipples with lower flow rates the relationship between suction generation and milk acquisition was disrupted. In order to design effective interventions for infants with feeding difficulties, we must consider how variation in nipple properties impacts infant physiology in a targeted manner. While reducing flow rate may reduce the frequency an infant aspirates, it may impair systems involved in sensorimotor integration.

Emergency laparoscopic intervention for fibrous band-induced intestinal obstruction and ischemia associated with Meckel's diverticulum: A case report.

INTRODUCTION AND IMPORTANCE: Meckel's diverticulum (MD) is a common congenital malformation of the digestive tract, often asymptomatic but occasionally leading to complications such as bowel obstruction and ischemia. Timely recognition and treatment of these complications are crucial. PRESENTATION OF CASE: We report the case of a 27-year-old male patient presenting with complete intestinal obstruction and ischemia of the ileum due to a fibrous band associated with MD. The patient presented with severe abdominal pain lasting for 10 h. Physical examination revealed a distended abdomen, antalgic position, and positive decompression. Laboratory tests showed leukocytosis and elevated lactic acid levels. Computed tomography revealed dilated small bowel loops with signs of intestinal ischemia. Emergency exploratory laparoscopy confirmed a complete ileum with ischemia and identified a fibrous band originating from the mesentery, strangulating the affected loop. The fibrous band was dissected and sectioned, confirming its association with the MD, which was resected with subsequent recovery of peristalsis and vascularization of the compromised segment. The patient had a favorable postoperative recovery without complications. DISCUSSION: MD is a rare cause of bowel obstruction, requiring a high index of suspicion for diagnosis. Despite the challenges in preoperative identification, early surgical intervention is crucial to prevent adverse outcomes. This case emphasizes the importance of promptly recognizing and managing MD-related complications to optimize patient outcomes. CONCLUSION: MD should be considered in cases of acute occlusive abdomen, despite its infrequent occurrence. Early diagnosis and timely surgical intervention are essential to minimize morbidity and mortality associated with MD-related complications.

Effect of Agave Fructans on Changes in Chemistry, Morphology and Composition in the Biomass Growth of Milk Kefir Grains.

Prebiotic effects have been attributed to agave fructans through bacterial and yeast fermentations, but there are few reports on their use as raw materials of a carbon source. Kefir milk is a fermented drink with lactic acid bacteria and yeast that coexist in a symbiotic association. During fermentation, these microorganisms mainly consume lactose and produce a polymeric matrix called kefiran, which is an exopolysaccharide composed mainly of water-soluble glucogalactan, suitable for the development of bio-degradable films. Using the biomass of microorganisms and proteins together can be a sustainable and innovative source of biopolymers. In this investigation, the effects of lactose-free milk as a culture medium and the addition of other carbon sources (dextrose, fructose, galactose, lactose, inulin and fructans) in concentrations of 2, 4 and 6% w/w, coupled with initial parameters such as temperature (20, 25 and 30 °C), % of starter inoculum (2, 5 and 10% w/w) was evaluated. The method of response surface analysis was performed to determine the optimum biomass production conditions at the start of the experiment. The response surface method showed that a 2% inoculum and a temperature of 25 °C were the best parameters for fermentation. The addition of 6% w/w agave fructans in the culture medium favored the growth of biomass (75.94%) with respect to the lactose-free culture medium. An increase in fat (3.76%), ash (5.57%) and protein (7.12%) content was observed when adding agave fructans. There was an important change in the diversity of microorganisms with an absence of lactose. These compounds have the potential to be used as a carbon source in a medium culture to increase kefir granule biomass. There was an important change in the diversity of microorganisms with an absence of lactose, where the applied image digital analysis led to the identification of the morphological changes in the kefir granules through modification of the profile of such microorganisms.

An updated examination of the perception of barriers for pharmacogenomics implementation and the usefulness of drug/gene pairs in Latin America and the Caribbean.

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region's continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the "need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics". Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%-99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC.

The Function of the Mammal Extrinsic Tongue Musculature in the Transition from Suckling to Drinking.

The transition from suckling to drinking is a developmental pathway that all mammals take. In both behaviors, the tongue is the primary structure involved in acquiring, transporting, and swallowing the liquid. However, the two processes are fundamentally different: during suckling, the tongue must function as a pump to generate suction to move milk, whereas during drinking, the tongue moves backwards and forwards through the mouth to acquire and move water. Despite these fundamental differences, we have little understanding of how tongues role varies between these behaviors. We used an infant pig model to investigate the relationships between anatomy, physiology, and function of the tongue to examine how lingual function is modulated in the transition from infancy to adulthood. We found that while some muscles were proportionally largest at birth, others were proportionally larger at the time of weaning. Furthermore, we found variation in tongue movements between suckling and drinking along both the mediolateral and anteroposterior axes, resulting in differences in tongue deformation between the two behaviors. The extrinsic tongue muscles also changed in function differently between drinking and suckling. Genioglossus increased its activity and turned on and off earlier in the cycle during drinking, whereas hyoglossus fired at lower amplitudes during drinking, and turned on and off later in the cycle. Together, the data highlight the significant need for high neuroplasticity in the control of the tongue at a young age in mammals and suggest that the ability to do so is key in the ontogeny and evolution of feeding in these animals.

Integration of longitudinal deep-radiomics and clinical data improves the prediction of durable benefits to anti-PD-1/PD-L1 immunotherapy in advanced NSCLC patients.

BACKGROUND: Identifying predictive non-invasive biomarkers of immunotherapy response is crucial to avoid premature treatment interruptions or ineffective prolongation. Our aim was to develop a non-invasive biomarker for predicting immunotherapy clinical durable benefit, based on the integration of radiomics and clinical data monitored through early anti-PD-1/PD-L1 monoclonal antibodies treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: In this study, 264 patients with pathologically confirmed stage IV NSCLC treated with immunotherapy were retrospectively collected from two institutions. The cohort was randomly divided into a training (n = 221) and an independent test set (n = 43), ensuring the balanced availability of baseline and follow-up data for each patient. Clinical data corresponding to the start of treatment was retrieved from electronic patient records, and blood test variables after the first and third cycles of immunotherapy were also collected. Additionally, traditional radiomics and deep-radiomics features were extracted from the primary tumors of the computed tomography (CT) scans before treatment and during patient follow-up. Random Forest was used to implementing baseline and longitudinal models using clinical and radiomics data separately, and then an ensemble model was built integrating both sources of information. RESULTS: The integration of longitudinal clinical and deep-radiomics data significantly improved clinical durable benefit prediction at 6 and 9 months after treatment in the independent test set, achieving an area under the receiver operating characteristic curve of 0.824 (95% CI: [0.658,0.953]) and 0.753 (95% CI: [0.549,0.931]). The Kaplan-Meier survival analysis showed that, for both endpoints, the signatures significantly stratified high- and low-risk patients (p-value< 0.05) and were significantly correlated with progression-free survival (PFS6 model: C-index 0.723, p-value = 0.004; PFS9 model: C-index 0.685, p-value = 0.030) and overall survival (PFS6 models: C-index 0.768, p-value = 0.002; PFS9 model: C-index 0.736, p-value = 0.023). CONCLUSIONS: Integrating multidimensional and longitudinal data improved clinical durable benefit prediction to immunotherapy treatment of advanced non-small cell lung cancer patients. The selection of effective treatment and the appropriate evaluation of clinical benefit are important for better managing cancer patients with prolonged survival and preserving quality of life.

Laparoscopic right adrenalectomy in a patient with Carney syndrome: A case report.

INTRODUCTION AND IMPORTANCE: Carney complex (CNC) is an extremely infrequent multiple endocrine neoplasia syndrome characterized by distinctive pigmented skin and mucosal lesions, cardiac and noncardiac myxomatous tumors, and multiple endocrine tumors. We herein report a case of CNC and surgical and history of laparoscopic left adrenalectomy complicated with a primary pigmented nodular adrenocortical disease (PPNAD). PRESENTATION OF CASE: We present the case of a 38-year-old woman with a previous diagnosis of CNC and history of laparoscopic left adrenalectomy who consulted for severe depression refractory to medical treatment. In the laboratory tests performed, altered ACTH, prolactin, Somatomedin C-IGF-1 and estradiol. An abdomen and pelvis C/T scan was requested, where an 8 mm lesion was found at the level of the right adrenal gland. Laparoscopic right adrenalectomy was performed. Histopathology of the surgical resection specimen revealed PPNAD. DISCUSSION: CNC is an infrequent syndrome with autosomal dominant inheritance and genetically heterogeneous. PPNAD is a consistent feature in CNC patients, however, reports of Cushing's syndrome in the literature indicate that only 25-45 % of CNC patients have PPNAD. CONCLUSION: PPNAD can be present in patients with Carney complex, with surgical adrenalectomy history. With an adequate selection of patients, laparoscopic adrenalectomy with subsequent hormone replacement therapy should be performed.

Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma.

BACKGROUND: The impact of exposure to air pollutants, such as fine particulate matter (PM), on the immune system and its consequences on pediatric asthma, are not well understood. We investigated whether ambient levels of fine PM with aerodynamic diameter ≤2.5 microns (PM2.5 ) are associated with alterations in circulating monocytes in children with or without asthma. METHODS: Monocyte phenotyping was performed by cytometry time-of-flight (CyTOF). Cytokines were measured using cytometric bead array and Luminex assay. ChIP-Seq was utilized to address histone modifications in monocytes. RESULTS: Increased exposure to ambient PM2.5 was linked to specific monocyte subtypes, particularly in children with asthma. Mechanistically, we hypothesized that innate trained immunity is evoked by a primary exposure to fine PM and accounts for an enhanced inflammatory response after secondary stimulation in vitro. We determined that the trained immunity was induced in circulating monocytes by fine particulate pollutants, and it was characterized by the upregulation of proinflammatory mediators, such as TNF, IL-6, and IL-8, upon stimulation with house dust mite or lipopolysaccharide. This phenotype was epigenetically controlled by enhanced H3K27ac marks in circulating monocytes. CONCLUSION: The specific alterations of monocytes after ambient pollution exposure suggest a possible prognostic immune signature for pediatric asthma, and pollution-induced trained immunity may provide a potential therapeutic target for asthmatic children living in areas with increased air pollution.

The Pathway from Anatomy and Physiology to Diagnosis: A Developmental Perspective on Swallowing and Dysphagia.

Dysphagia results from diverse and distinct etiologies. The pathway from anatomy and physiology to clinical diagnosis is complex and hierarchical. Our approach in this paper is to show the linkages from the underlying anatomy and physiology to the clinical presentation. In particular, the terms performance, function, behavior, and physiology are often used interchangeably, which we argue is an obstacle to clear discussion of mechanism of pathophysiology. We use examples from pediatric populations to highlight the importance of understanding anatomy and physiology to inform clinical practice. We first discuss the importance of understanding anatomy in the context of physiology and performance. We then use preterm infants and swallow-breathe coordination as examples to explicate the hierarchical nature of physiology and its impact on performance. We also highlight where the holes in our knowledge lie, with the ultimate endpoint of providing a framework that could enhance our ability to design interventions to help patients. Clarifying these terms, and the roles they play in the biology of dysphagia will help both the researchers studying the problems as well as the clinicians applying the results of those studies.

Regional Variation in Contractile Patterns and Muscle Activity in Infant Pig Feeding.

At the level of the whole muscle, contractile patterns during activity are a critical and necessary source of variation in function. Understanding if a muscle is actively lengthening, shorting, or remaining isometric has implications for how it is working to power a given behavior. When feeding, the muscles associated with the tongue, jaws, pharynx, and hyoid act together to transport food through the oral cavity and into the esophagus. These muscles have highly coordinated firing patterns, yet also exhibit high levels of regional heterogeneity in both their timing of activity and their contractile characteristics when active. These high levels of variation make investigations into function challenging, especially in systems where muscles power multiple behaviors. We used infant pigs as a model system to systematically evaluate variation in muscle firing patterns in two muscles (mylohyoid and genioglossus) during two activities (sucking and swallowing). We also evaluated the contractile characteristics of mylohyoid during activity in the anterior and posterior regions of the muscle. We found that the posterior regions of both muscles had different patterns of activity during sucking versus swallowing, whereas the anterior regions of the muscles did not. Furthermore, the anterior portion of mylohyoid exhibited concentric contractions when active during sucking, whereas the posterior portion was isometric during sucking and swallowing. This difference suggests that the anterior portion of mylohyoid in infant pigs is functioning in concert with the tongue and jaws to generate suction, whereas the posterior portion is likely acting as a hyoid stabilizer during sucking and swallowing. Our results demonstrate the need to evaluate both the contractile characteristics and activity patterns of a muscle in order to understand its function, especially in cases where there is potential for variation in either factor within a single muscle.

Preclinical Efficacy and Toxicology Evaluation of RAC1 Inhibitor 1A-116 in Human Glioblastoma Models.

Malignant gliomas are the most common primary central nervous system tumor in adults. Despite current therapeutics, these tumors are associated with poor prognosis and a median survival of 16 to 19 months. This highlights the need for innovative treatments for this incurable disease. Rac1 has long been associated with tumor progression and plays a key role in glioma's infiltrative and invasive nature. The aim of this study is to evaluate the 1A-116 molecule, a Rac1 inhibitor, as targeted therapy for this aggressive disease. We found that targeting Rac1 inhibits cell proliferation and cell cycle progression using different in vitro human glioblastoma models. Additionally, we evaluated 1A-116 in vivo, showing a favorable toxicological profile. Using in silico tools, 1A-116 is also predicted to penetrate the blood-brain barrier and present a favorable metabolic fate. In line with these results, 1A-116 i.p daily treatment resulted in a dose-dependent antitumor effect in an orthotopic IDH-wt glioma model. Altogether, our study provides a strong potential for clinical translation of 1A-116 as a signal transduction-based precision therapy for glioma and also increases the evidence of Rac1 as a key molecular target.

A prospective study of a new presbyopia pseudophakic intraocular lens: Safety, efficacy and satisfaction.

Purpose: To evaluate the safety, visual performance, and patient satisfaction of a new presbyopic pseudophakic intraocular lens (IOL). Methods: A prospective non-randomized case-series study was performed in Buenos Aires, Argentina. Patients included in the study underwent a programmed Femtosecond laser assisted cataract surgery (FLACS), performed between October and December 2020, with a 6-month follow-up period. The Intensity (Hanita Lenses) IOL was bilaterally implanted. Spherical equivalent (SE) refraction, uncorrected distance and near visual acuity (UDVA/UNVA), defocus curve, endothelial cell density (ECD), central corneal thickness (CCT), and a satisfaction questionnaire were evaluated. Results: A total of 56 patients (112 eyes), aged 65 ± 6.12 years were included. The mean ± SD of preoperative SE was 1.85 ± 2.24 D (range; -4.50 to 4.75), which had decreased 6 months after surgery to -0.08 ±0.32 D (range; -0.75 to 0.63). No eyes experienced a loss of lines of vision, and 94% obtained SE values between ± 0.50 D. Defocus curve for different additions was 0.03 LogMAR (logarithm of the minimum angle of resolution) for -3.0 D, -0.005 LogMAR for -1.5 D, and -0.07 LogMAR for 0 D. The ECD, CCT remained stable (P: 0.09 and 0.58, respectively) and all patients achieved their preoperative expectations, with a 6-month follow-up period. Conclusion: Patients who underwent a safe bilateral implantation with Intensity IOL achieved a high degree of spectacle independence and satisfaction, 6 months after surgery.

Eficacia clínica de los umbrales de intervención híbridos y dependientes de la edad basados en FRAX en la población ecuatoriana / Clinical efficacy of FRAX-based age-dependent and hybrid intervention thresholds in the Ecuadorian population

Objetivo: Evaluar el impacto clínico de los umbrales de intervención basados en FRAX en mujeres ecuatorianas. Probar una combinación de umbrales de intervención fijo y específico de la edad para optimizar la selección de mujeres elegibles para intervención.Pacientes y métodos: Estudio transversal. Se seleccionaron 2.283 mujeres de 60 a 94 años. Calculamos el riesgo de fracturas osteoporóticas principales y de cuello de fémur con el modelo FRAX ecuatoriano (versión 4.1), y calculamos la proporción de individuos elegibles para tratamiento y evaluación de la densidad mineral ósea aplicando los umbrales específicos de edad de 60 a 94 años y un umbral fijo a partir de 75 años.Resultados: Aplicando los umbrales específicos de la edad, 2% de las mujeres calificaron para tratamiento y 73,7% para evaluación de la densidad mineral ósea. Según la edad, las mujeres elegibles para tratamiento fluctuaron entre 0,7 a 3,8% y las elegibles para evaluación de la densidad mineral ósea entre 58,3 al 80,5%.Con el umbral fijo, 31% de las mujeres calificaron para tratamiento y 76,3% para evaluación de la densidad mineral ósea. Dependiendo de la edad, las mujeres potencialmente elegibles para tratamiento fluctuaron de 3,8 a 76,5%, y las elegibles para evaluación de la densidad mineral ósea entre 65,2 al 85,4%.Conclusiones: La proporción de mujeres potencialmente elegible para el tratamiento, es baja comparada con países con riesgo alto de fracturas. Utilizar un umbral fijo a partir de los 75 años, optimiza la proporción de mujeres elegibles para tratamiento. En los países con riesgo de fractura bajo a moderado, con recursos limitados, un modelo híbrido puede ser más adecuado. (AU)

Multiple molecular mechanisms are involved in the activation of the kidney sodium-chloride cotransporter by hypokalemia.

Low potassium intake activates the kidney sodium-chloride cotransporter (NCC) whose phosphorylation and activity depend on the With-No-Lysine kinase 4 (WNK4) that is inhibited by chloride binding to its kinase domain. Low extracellular potassium activates NCC by decreasing intracellular chloride thereby promoting chloride dissociation from WNK4 where residue L319 of WNK4 participates in chloride coordination. Since the WNK4-L319F mutant is constitutively active and chloride-insensitive in vitro, we generated mice harboring this mutation that displayed slightly increased phosphorylated NCC and mild hyperkalemia when on a 129/sv genetic background. On a low potassium diet, upregulation of phosphorylated NCC was observed, suggesting that in addition to chloride sensing by WNK4, other mechanisms participate which may include modulation of WNK4 activity and degradation by phosphorylation of the RRxS motif in regulatory domains present in WNK4 and KLHL3, respectively. Increased levels of WNK4 and kidney-specific WNK1 and phospho-WNK4-RRxS were observed in wild-type and WNK4L319F/L319F mice on a low potassium diet. Decreased extracellular potassium promoted WNK4-RRxS phosphorylation in vitro and ex vivo as well. These effects might be secondary to intracellular chloride depletion, as reduction of intracellular chloride in HEK293 cells increased phospho-WNK4-RRxS. Phospho-WNK4-RRxS levels were increased in mice lacking the Kir5.1 potassium channel, which presumably have decreased distal convoluted tubule intracellular chloride. Similarly, phospho-KLHL3 was modulated by changes in intracellular chloride in HEK293 cells. Thus, our data suggest that multiple chloride-regulated mechanisms are responsible for NCC upregulation by low extracellular potassium.

Fermi surface chirality induced in a TaSe2 monosheet formed by a Ta/Bi2Se3 interface reaction.

Spin-momentum locking in topological insulators and materials with Rashba-type interactions is an extremely attractive feature for novel spintronic devices and is therefore under intense investigation. Significant efforts are underway to identify new material systems with spin-momentum locking, but also to create heterostructures with new spintronic functionalities. In the present study we address both subjects and investigate a van der Waals-type heterostructure consisting of the topological insulator Bi2Se3 and a single Se-Ta-Se triple-layer (TL) of H-type TaSe2 grown by a method which exploits an interface reaction between the adsorbed metal and selenium. We then show, using surface x-ray diffraction, that the symmetry of the TaSe2-like TL is reduced from D3h to C3v resulting from a vertical atomic shift of the tantalum atom. Spin- and momentum-resolved photoemission indicates that, owing to the symmetry lowering, the states at the Fermi surface acquire an in-plane spin component forming a surface contour with a helical Rashba-like spin texture, which is coupled to the Dirac cone of the substrate. Our approach provides a route to realize chiral two-dimensional electron systems via interface engineering in van der Waals epitaxy that do not exist in the corresponding bulk materials.

Autophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23.

There has been a global increase in rates of obesity with a parallel epidemic of non-alcoholic fatty liver disease (NAFLD). Autophagy is an essential mechanism involved in the degradation of cellular material and has an important function in the maintenance of liver homeostasis. Here, we explore the effect of Autophagy-related 5 (Atg5) deficiency in liver CD11c+ cells in mice fed HFD. When compared to control mice, Atg5-deficient CD11c+ mice exhibit increased glucose intolerance and decreased insulin sensitivity when fed HFD. This phenotype is associated with the development of NAFLD. We observe that IL-23 secretion is induced in hepatic CD11c+ myeloid cells following HFD feeding. We demonstrate that both therapeutic and preventative IL-23 blockade alleviates glucose intolerance, insulin resistance and protects against NAFLD development. This study provides insights into the function of autophagy and IL-23 production by hepatic CD11c+ cells in NAFLD pathogenesis and suggests potential therapeutic targets.

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation.

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.