Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.

For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.

Determinants of Readmission in the Intensive Care Unit: A Prospective Observational Study.

Background The antecedents of readmission among survivors of intensive care units (ICUs) are complex and comprise an array of elements that impact the rehabilitation process after leaving the ICU. The aforementioned determinants may comprise socioeconomic factors, access to follow-up healthcare, the nature and severity of the initial illness or injury, the presence of comorbidities, the sufficiency of transitional care and rehabilitation services, and patient and family support systems. Added to this, the risk of readmission may be increased by complications that develop during the ICU stay, including but not limited to infections, organ dysfunction, and psychological distress. Comprehending these determinants is of the utmost importance for healthcare providers in order to execute focused interventions that seek to diminish readmission rates, enhance patient outcomes, and elevate the standard of care for survivors of ICUs. Objective The objective of the study is to determine the factors associated with readmission among ICU survivors and the cause of readmission. Methodology This prospective observational study was conducted in a tertiary-level ICU. The duration of the study was one year and we enrolled 108 ICU survivors in our study. We have recorded patient demographic data, comorbidity, primary diagnosis, previous treatment history (vasopressor, sedation), causes of readmission, duration of previous ICU stay, and outcome of readmitted patient (discharge, death, and transfer to lower facility). Result The incidence of readmission in our ICU is 10.4%; 50-70 age groups are more prone to readmission of which the male sex is predominant (64.81%). In our study, hypertension (cardiac, 18.52%) and diabetes mellitus (11.11%) were the most common comorbidities reported in readmitted patients. The majority of patients who get readmission suffered from blunt trauma abdomen. In the majority of readmitted patients, sedation was used in the previous admission for ventilation and patient comfort (66.67%). Most of the readmitted patients (68.51%) have a previous ICU stay of more than five days. Patients were readmitted mainly because of respiratory (30.56%) and neurological (25%) complications. In this study, readmitted patients have high mortality (59.26%). Conclusion In a tertiary care ICU, the incidence rate of readmitted patients was 10.4%. Respiratory and neurological problems were the main cause of readmission. In readmitted patients, mortality was high up to 59.26%. Old age, male sex, prolonged ICU stay, comorbidities like hypertension, blunt trauma abdomen, use of sedation, and prolonged mechanical ventilation in previous ICU admission are major risk factors for ICU readmission.

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting.

OBJECTIVE: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. RESULTS: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. CONCLUSIONS: Esrra regulation of Rplp1-mediated translation of lysosome / autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.

High-throughput tagging of endogenous loci for rapid characterization of protein function.

To facilitate the interrogation of protein function at scale, we have developed high-throughput insertion of tags across the genome (HITAG). HITAG enables users to rapidly produce libraries of cells, each with a different protein of interest C-terminally tagged. HITAG is based on a modified strategy for performing Cas9-based targeted insertions, coupled with an improved approach for selecting properly tagged lines. Analysis of the resulting clones generated by HITAG reveals high tagging specificity, with most successful tagging events being indel free. Using HITAG, we fuse mCherry to a set of 167 stress granule-associated proteins and elucidate the features that drive a subset of proteins to strongly accumulate within these transient RNA-protein granules.

Comparative evaluation of pre-emptive analgesic efficacy of Posterior Transversus Abdominis Plane block with Fascia Transversalis Plane Block in adult patients undergoing unilateral inguinal hernia repair: A prospective, randomized, single-blind, two-arm parallel study.

Introduction: Abdominal wall blocks, in conjunction with multimodal analgesia, have demonstrated efficacy in providing post-operative analgesia, reducing opioid requirements in patients undergoing inguinal hernia repair. The inguinal region is primarily innervated by the ilioinguinal nerve (IIN) and iliohypogastric nerve (IIH). Posterior transverse abdominis plane block (pTAP) and fascia transversalis plane block (TFP) have been observed to reliably block IIN and IIH. We hypothesized that posterior TAP block (pTAP) owing to its potential paravertebral spread will provide better post-operative analgesia than TFP block in patients undergoing unilateral open inguinal hernia repair. Methods: This prospective, randomized, single-blind, two-arm parallel study was conducted over a duration of one year for which sixty patients undergoing unilateral open inguinal hernia repair under spinal anesthesia were enrolled. They were equally and randomly assigned to receive either preoperative pTAP block or TFP block. The primary aim of the study was to compare median static and dynamic NRS scores during a 24-hour period, with the secondary aim to compare the number of patients who required rescue analgesics in each group. Results: All enrolled patients completed the study. Results showed no statistically significant difference in median static NRS scores between Group pTAP and Group TFP at the designated time of observation during the 24-hour period [1.2 (0.4-1.60 vs. 1 (0.6-1)]. Group pTAP reported a higher median dynamic NRS scores during the 24-hour period [2.6 (1.2-3) v/s 2 (1.6-2.4); P < 0.035], although this difference was clinically insignificant. The mean time to request for the first rescue analgesia was comparable (11.7 h v/s 12 h; P = 0.99). In all the patients of both groups, loss of pinprick and cold touch sensation was observed at T10, T12, and L1 dermatomal levels. However, sensory assessment at T6 and T8 levels showed variability between the two groups (P > 0.05). Conclusion: In conjunction with background analgesia and the use of dexamethasone as an adjuvant, both blocks (pTAP and TFP) were observed to be equally effective for post-operative pain relief with similar patient satisfaction scores.

The emerging role of liquid biopsy in oral squamous cell carcinoma detection: advantages and challenges.

INTRODUCTION: Oral Squamous Cell Carcinoma (OSCC), the sixth most widespread malignancy in the world, accounts for 90% of all cases of oral cancer. The primary risk factors are tobacco chewing, alcohol consumption, viral infection, and genetic modifications. OSCC has a high morbidity rate due to the lack of early diagnostic methods. Nowadays, liquid biopsy plays a vital role in the initial diagnosis of oral cancer. ctNAs extracted from saliva and serum/plasma offer meaningful insights into tumor genetics and dynamics. The interplay of these elements in saliva and serum/plasma showcases their significance in advancing noninvasive, effective OSCC detection and monitoring. AREAS COVERED: This review mainly focused on the role of liquid biopsy as an emerging point in the diagnosis and prognosis of OSCC and the current advancements and challenges associated with liquid biopsy. EXPERT OPINION: Liquid biopsy is regarded as a new, minimally invasive, real-time monitoring tool for cancer diagnosis and prognosis. Many biomolecules found in bodily fluids, including ctDNA, ctRNA, CTCs, and EVs, are significant biomarkers to identify cancer in its early stages. Despite these groundbreaking strides, challenges persist. Standardization of sample collection, isolation, processing, and detection methods is imperative for ensuring result reproducibility across diverse studies.

Controlled experimental generation of perturbed high-order Ince-Gaussian laser modes.

We present an experimental approach for generating perturbed high-order Ince-Gaussian laser modes by transforming the low and moderate-intensity lobes of high-order Ince-Gaussian (IG) modes into high-intensity lobes and vice versa. This perturbation reshuffles optical energy among the different lobes and generates new, to the best of our knowledge, modulated Ince-Gaussian (MIG) modes. Computer-generated holograms displayed over spatial light modulators were used to modulate the IGMs. Compared to IG modes, MIG modes are generated precisely in a sense that enhances the IG modes and provides a maximum number of highly intense lobes in a particular mode. That enables the newly generated MIG modes to be utilized more efficiently than IG modes in applications such as particle manipulation and optical trapping of microparticles, which exploit highly intense lobes.

Estrogen receptor-related receptor (Esrra) induces ribosomal protein Rplp1-mediated adaptive hepatic translation during prolonged starvation.

Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods in vitro and in vivo to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, estrogen-related receptor alpha (Esrra) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating 60S acidic ribosomal protein P1 (Rplp1) gene expression. Overexpression or siRNA knockdown of Esrra expression in vitro or in vivo led to parallel changes in Rplp1 gene expression, lysosome/autophagy protein translation, and autophagy. Remarkably, we have found that Esrra had dual functions by not only regulating transcription but also controling adaptive translation via the Esrra/Rplp1/lysosome/autophagy pathway during prolonged starvation.

Inhibition of Ephrin B2 Reverse Signaling Abolishes Multiple Myeloma Pathogenesis.

Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes. SIGNIFICANCE: Ephrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.

Super-oscillatory spots with different inhomogeneous linear polarized states.

We present the formation of super-oscillatory (SO) spots by tightly focusing the inhomogeneous linear polarized beam of different polarization states. At the entrance pupil of the focusing lens, a suitable phase manipulation in the incident beam results in a small super-oscillatory spot. Our numerical study based on the vectorial diffraction theory shows that SO spots of controllable size and various polarization combinations are possible. We also discuss the effect of the different polarization patterns of the incident beam on the size and energy distribution of the generated SO spots, which are potentially valuable for the orientation determination of single molecules and polarization-resolved imaging. This study reveals more influence of polarization states on the different components of the focused beam under the utilization of the proposed method rather than the usual tight focusing conditions.

Effect of Carbohydrate Loading in Diabetic Patients Undergoing Laparoscopic Cholecystectomy: A Randomized Controlled Trial.

INTRODUCTION: Investigations of preoperative oral carbohydrate (CHO) loading have primarily examined benefits among patients without diabetes. Preoperative CHO-rich beverages in general populations have resulted in reductions in insulin resistance after surgery, protein loss, metabolic derangements, and immune dysfunction. The aim of this study was to assess the effect of CHO loading in diabetic patients undergoing laparoscopic cholecystectomy. METHODS: Diabetic patients controlled on oral hypoglycemic agent were randomly divided into two groups: (1) Group T - this group will be given 50 g of maltodextrin before two hours of surgery; (2) Group C - this group will be kept nil per oral as per standard protocol. Blood sugar, serum insulin, serum cortisol, and insulin requirement were compared in both groups. RESULTS: Blood sugar levels of Group C were found to be significantly higher than that of Group T at six hours and 24 hours. In Group T, a rise in baseline serum insulin (8.94 ± 3.43 mIU/l) was observed at 24 hours (13.23 ± 5.71 mIU/l). A change of 4.29 ± 3.00 mIU/l in serum insulin level was observed. The change in baseline serum insulin levels was 47.99%. In Group C too, a rise in baseline serum insulin (6.27 ± 1.74 mIU/l) was observed at 24 hours (18.00 ± 5.34 mIU/l). A change of 11.73 ± 4.97 mIU/l in serum insulin level was observed. The change in baseline HOMA-IR (homeostatic model assessment for insulin resistance) levels in Group T was 53.66%. A rise (4.39 ± 1.63) in baseline HOMA-IR of Group C (1.65 ± 0.45) was observed at 24 hours (6.04 ± 1.76). The change in baseline HOMA-IR levels in Group C was 266.06%. CONCLUSIONS: CHO loading is observed to be beneficial in diabetic patients undergoing laparoscopic cholecystectomy. No adverse effects or an increased risk of aspiration were observed in the intervention group during the study period.

Controllable experimental modulation of high-order Laguerre-Gaussian laser modes.

High-order helical and sinusoidal Laguerre-Gaussian (LG) laser modes have uneven energy distribution among their multiple concentric vortex core rings and lobes, respectively. Here, we explore an experimental method to reshuffle the optical energy among their multiple concentric vortex core rings and lobes of high-order LG modes in a controllable manner. We numerically designed a diffractive optical element displayed over a spatial light modulator to rearrange optical energy among multiple concentric vortex core rings. This changes outer low-intensity concentric vortex core rings into high-intensity vortex core rings of high-order helical LG modes at the Fourier plane. The precise generation of a high-order modulated helical LG laser mode has a maximum number of highly intense concentric vortex core rings compared to known standard helical LG modes. Further, this method is extended to high-order sinusoidal LG modes consisting of both low- and high-intensity lobes to realize modulated sinusoidal LG modes with a maximum number of highly intense lobes in a controllable manner. We envisage that the modulated helical and sinusoidal high-order LG modes may surpass standard LG modes in many applications where highly intense rings and lobes are crucial, as in particle manipulation of micro- and nanoparticles, and optical lithography.

LINC00116-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane.

LINC00116 encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by reports with differing findings about its molecular functions and submitochondrial localization. To clarify the apparent discrepancies, we constructed multiple orthogonal methods of determining the localization of MTLN, including split GFP-based reporters that enable efficient and reliable topology analyses for microproteins. These methods unequivocally demonstrate MTLN primarily localizes to the outer membrane of mitochondria, where it interacts with enzymes of fatty acid metabolism including CPT1B and CYB5B. Loss of MTLN causes the accumulation of very long-chain fatty acids (VLCFAs), especially docosahexaenoic acid (DHA). Intriguingly, loss of MTLN protects mice against western diet/fructose-induced insulin-resistance, suggests a protective effect of VLCFAs in this context. MTLN thus serves as an attractive target to control the catabolism of VLCFAs.

Recurrent Desmoid Fibromatosis of the Thyroid Gland: A Diagnostic Challenge.

A 31-year-old Indian female with a history of near-total thyroidectomy 2.5 years prior presented with recurrent neck swelling. Magnetic resonance imaging (MRI) of the neck revealed an infiltrating mass involving the thyroid bed. Biopsy from the mass and review of slides from the previous thyroidectomy revealed a spindle cell tumour with interspersed areas of fibrosis and infiltrative edges entrapping thyroid follicles. Beta-catenin immunopositivity and CTNNB1 mutation confirmed the diagnosis of fibromatosis. The case is being reported for its rarity and the discussion of its differential diagnoses.

Creation of pure longitudinal super-oscillatory spot.

We present a method that creates a super-oscillatory focal spot of a tightly focused radially polarized beam using the concept of a phase mask. Using vector diffraction theory, we report a super-oscillatory focal spot that is much smaller than the diffraction limit and the super-oscillation criterion. The proposed mask works as a special polarization filter that enhances the longitudinal component and filters out the transverse component of radial polarization at focus, permitting the creation of a pure longitudinal super-oscillatory focal spot.

Nicotinamide riboside rescues dysregulated glycolysis and fatty acid ß-oxidation in a human hepatic cell model of citrin deficiency.

Citrin deficiency (CD) is an inborn error of metabolism caused by loss-of-function of the mitochondrial aspartate/glutamate transporter, CITRIN, which is involved in both the urea cycle and malate-aspartate shuttle. Patients with CD develop hepatosteatosis and hyperammonemia but there is no effective therapy for CD. Currently, there are no animal models that faithfully recapitulate the human CD phenotype. Accordingly, we generated a CITRIN knockout HepG2 cell line using Clustered Regularly Interspaced Short Palindromic Repeats/Cas 9 genome editing technology to study metabolic and cell signaling defects in CD. CITRIN KO cells showed increased ammonia accumulation, higher cytosolic ratio of reduced versus oxidized form of nicotinamide adenine dinucleotide (NAD) and reduced glycolysis. Surprisingly, these cells showed impaired fatty acid metabolism and mitochondrial activity. CITRIN KO cells also displayed increased cholesterol and bile acid metabolism resembling those observed in CD patients. Remarkably, normalizing cytosolic NADH:NAD+ ratio by nicotinamide riboside increased glycolysis and fatty acid oxidation but had no effect on the hyperammonemia suggesting the urea cycle defect was independent of the aspartate/malate shuttle defect of CD. The correction of glycolysis and fatty acid metabolism defects in CITRIN KO cells by reducing cytoplasmic NADH:NAD+ levels suggests this may be a novel strategy to treat some of the metabolic defects of CD and other mitochondrial diseases.

Metabolic switching of estrogen-related receptor alpha in breast cancer aggression.

Orphan nuclear receptor estrogen-related receptor alpha (ERRα) is an important regulator of energy metabolism, whereas its hyperactivation in breast cancer has been shown to regulate cell migration, proliferation, and tumour development. These findings suggest a fine balance in the status of ERRα in regulating metabolic homeostasis or promoting cancer progression. In this issue, Brindisi et al. have shown that ERRα is endogenously activated by cholesterol and caused breast cancer aggressiveness. This study also supports the anti-tumour mechanisms of cholesterol-lowering drugs such as statins.

Pharmacological inhibition of CFTR attenuates nonalcoholic steatohepatitis (NASH) progression in mice.

Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NASH is multifactorial and identifying reliable molecular players has proven difficult. Presently, there are no approved drugs for NASH treatment, which has become a leading cause of liver transplants worldwide. Here, using public human transcriptomic NAFLD dataset, we uncover Cystic fibrosis transmembrane conductance receptor (CFTR) as a differentially expressed gene in the livers of human NASH patients. Similarly, murine Cftr expression was also found to be upregulated in two mouse models of diet-induced NASH. Furthermore, the pharmacological inhibition of CFTR significantly reduced NASH progression in mice and its overexpression aggravated lipotoxicity in human hepatic cells. These results, thus, underscore the involvement of murine Cftr in the pathogenesis of NASH and raise the intriguing possibility of its pharmacological inhibition in human NASH.