Let-7 underlies metformin-induced inhibition of hepatic glucose production.

SignificanceA clear mechanistic understanding of metformin's antidiabetic effects is lacking. This is because suprapharmacological concentrations of metformin have been used in most studies. Using mouse models and human primary hepatocytes, we show that metformin, at clinically relevant doses, suppresses hepatic glucose production by activating a conserved regulatory pathway encompassing let-7, TET3, and a fetal isoform of hepatocyte nuclear factor 4 alpha (HNF4α). We demonstrate that metformin no longer has potent antidiabetic actions in a liver-specific let-7 loss-of-function mouse model and that hepatic delivery of let-7 ameliorates hyperglycemia and improves glucose homeostasis. Our results thus reveal an important role of the hepatic let-7/TET3/HNF4α axis in mediating the therapeutic effects of metformin and suggest that targeting this axis may be a potential therapeutic for diabetes.

An MMIC LNA for Millimeter-Wave Radar and 5G Applications with GaN-on-SiC Technology.

This paper presents a monolithic microwave integrated circuit (MMIC) low noise amplifier (LNA) that is compatible with n257 (26.5-29.5 GHz) and n258 (24.25-27.5 GHz) frequency bands for fifth-generation mobile communications system (5G) and millimeter-wave radar. The total circuit size of the LNA is 2.5 × 1.5 mm2. To guarantee a trade-off between noise figure (NF) and small signal gain, the transmission lines are connected to the source of gallium nitride (GaN)-on-SiC high electron mobility transistors (HEMT) by analyzing the nonlinear small signal equivalent circuit. A series of stability enhancement measures including source degeneration, an RC series network, and RF choke are put forward to enhance the stability of designed LNA. The designed GaN-based MMIC LNA adopts hybrid-matching networks (MNs) with co-design strategy to realize low NF and broadband characteristics across 5G n257 and n258 frequency band. Due to the different priorities of these hybrid-MNs, distinguished design strategies are employed to benefit small signal gain, input-output return loss, and NF performance. In order to meet the testing conditions of MMIC, an impeccable system for measuring small has been built to ensure the accuracy of the measured results. According to the measured results for small signal, the three-stage MMIC LNA has a linear gain of 18.2-20.3 dB and an NF of 2.5-3.1 dB with an input-output return loss better than 10 dB in the whole n257 and n258 frequency bands.

Frontotemporal Dementia P301L Mutation Potentiates but Is Not Sufficient to Cause the Formation of Cytotoxic Fibrils of Tau.

The P301L mutation in tau protein is a prevalent pathogenic mutation associated with neurodegenerative frontotemporal dementia, FTD. The mechanism by which P301L triggers or facilitates neurodegeneration at the molecular level remains unclear. In this work, we examined the effect of the P301L mutation on the biochemical and biological characteristics of pathologically relevant hyperphosphorylated tau. Hyperphosphorylated P301L tau forms cytotoxic aggregates more efficiently than hyperphosphorylated wildtype tau or unphosphorylated P301L tau in vitro. Mechanistic studies establish that hyperphosphorylated P301L tau exacerbates endoplasmic reticulum (ER) stress-associated gene upregulation in a neuroblastoma cell line when compared to wildtype hyperphosphorylated tau treatment. Furthermore, the microtubule cytoskeleton is severely disrupted following hyperphosphorylated P301L tau treatment. A hyperphosphorylated tau aggregation inhibitor, apomorphine, also inhibits the harmful effects caused by P301L hyperphosphorylated tau. In short, the P301L single mutation within the core repeat domain of tau renders the underlying hyperphosphorylated tau more potent in eliciting ER stress and cytoskeleton damage. However, the P301L mutation alone, without hyperphosphorylation, is not sufficient to cause these phenotypes. Understanding the conditions and mechanisms whereby selective mutations aggravate the pathogenic activities of tau can provide pivotal clues on novel strategies for drug development for frontotemporal dementia and other related neurodegenerative tauopathies, including Alzheimer's disease.

Hemostatic efficacy of two topical adjunctive hemostats in a porcine spleen biopsy punch model of moderate bleeding.

Topical hemostatic agents have become essential tools to aid in preventing excessive bleeding in surgical or emergency settings and to mitigate the associated risks of serious complications. In the present study, we compared the hemostatic efficacy of SURGIFLO® Hemostatic Matrix Kit with Thrombin (Surgiflo-flowable gelatin matrix plus human thrombin) to HEMOBLAST™ Bellows Hemostatic Agent (Hemoblast-a combination product consisting of collagen, chondroitin sulfate, and human thrombin). Surgiflo and Hemoblast were randomly tested in experimentally induced bleeding lesions on the spleens of four pigs. Primary endpoints included hemostatic efficacy measured by absolute time to hemostasis (TTH) within 5 min. Secondary endpoints included the number of product applications and the percent of product needed from each device to achieve hemostasis. Surgiflo demonstrated significantly higher hemostatic efficacy and lower TTH (p < 0.01) than Hemoblast. Surgiflo-treated lesion sites achieved hemostasis in 77.4% of cases following a single product application vs. 3.3% of Hemoblast-treated sites. On average, Surgiflo-treated sites required 63% less product applications than Hemoblast-treated sites (1.26 ± 0.0.51 vs. 3.37 ± 1.16). Surgiflo provided more effective and faster hemostasis than Hemoblast. Since both products contain thrombin to activate endogenous fibrinogen and accelerate clot formation, the superior hemostatic efficacy of Surgiflo in the porcine spleen punch biopsy model seems to be due to Surgiflo's property as a malleable barrier able to adjust to defect topography and to provide an environment for platelets to adhere and aggregate. Surgiflo combines a flowable gelatin matrix and a delivery system well-suited for precise application to bleeding sites where other methods of hemostasis may be impractical or ineffective.

A Patch/Dipole Hybrid-Mode Antenna for Sub-6GHz Communication.

A low-profile antenna with a high gain and broad bandwidth is proposed for Sub-6GHz communication in this paper. A narrow-band patch mode and a narrow-band dipole mode are shared in one radiator and simultaneously excited to broaden the bandwidth. A compact prototype with a projection size of 0.90 λ0 × 0.78 λ0 and a profile of 0.13 λ0 (λ0 is the wavelength in the free space at the center of the operating frequency) is fabricated and measured. The measurement demonstrates an impedance bandwidth of 67.50%, covering the frequency range from 2.75 GHz to 5.45 GHz and an average gain of 8.4 dBi in the operating band of 3.0⁻5.0 GHz.

Qualitative research: An overview of emerging approaches for data collection.

OBJECTIVE: The aim of this study was to introduce new approaches to conduct qualitative research that may provide valuable insight into issues related to education, training and patient care in psychiatry. CONCLUSIONS: A variety of data-collection tools is available for researchers and practitioners in psychiatry. These can be used independently or in conjunction with other quantitative and qualitative methods.

Wireless Passive Ultra High Frequency RFID Antenna Sensor for Surface Crack Monitoring and Quantitative Analysis.

An exponential increase in large-scale infrastructure facilitates the development of wireless passive sensors for permanent installation and in-service health monitoring. Due to their wireless, passive and cost-effective characteristics, ultra-high frequency (UHF) radio frequency identification (RFID) tag antenna based sensors are receiving increasing attention for structural health monitoring (SHM). This paper uses a circular patch antenna sensor with an open rectangular window for crack monitoring. The sensing mechanism is quantitatively studied in conjunction with a mode analysis, which can uncover the intrinsic principle for turning an antenna into a crack sensor. The robustness of the feature is examined when the variation of crack position associated with an aluminum sample and the antenna sensor is considered. The experimental results demonstrate a reasonable sensitivity and resolution for crack characterization.

An In Vivo Comparison of Hemostatic Gelatin Matrix Products in a Porcine Spleen Biopsy-punch Model.

Flowable gelatin matrix products have established themselves as effective, easy-to-use hemostatic agents useful in a variety of surgical situations. A recently reformulated gelatin matrix, Surgiflo® (Ethicon Inc., Somerville, NJ), can be prepared quickly and provides consistent flow over an 8-hr. period. No in vivo studies have yet been reported comparing hemostasis with the new Surgiflo to other currently marketed flowable gelatin matrix products. This study was conducted to determine whether Surgiflo in actual use has hemostatic qualities different from another commercial gelatin matrix. An in vivo model based on porcine spleen biopsy punch-induced bleeding was used to compare Surgiflo and Floseal™ (Baxter Healthcare Corporation, Hayward, CA), both with thrombin. Time required to achieve hemostasis and proportion of sites achieving hemostasis within 30 s were determined for both hemostatic agents and a control of saline-soaked gauze. Results were stratified by the degree of initial bleeding (mild, moderate, severe). Hemostasis was achieved within 3 minutes at all sites for both test products regardless of level of initial bleeding, and control sites continued bleeding past 10 minutes. There were no statistically significant differences between Surgiflo and Floseal for either mean time to hemostasis or proportion of sites hemostatic within 30 s. In this realistic in vivo model both gelatin matrix products were effective, and there were no significant differences observed in hemostatic efficacy between Surgiflo and Floseal. Other factors, such as ease of preparation and application, in-use stability, and economic considerations may affect a surgeon's decision in selection of a desirable hemostatic product.

Anesthetic Management of a Patient with Renal Cell Carcinoma-Associated Venous Thrombosis and Massive Transfusion.

A 53-year-old male with a history of multiple deep venous thromboses (DVTs) underwent a right open radical nephrectomy with inferior vena cava (IVC) thrombectomy in the context of renal cell carcinoma (RCC)-associated venous thrombosis. Imaging and renal biopsy revealed a diagnosis of RCC with non-occlusive thrombosis of the left renal vein and occlusive thrombosis of the infrarenal IVC. The major risks of concern for the procedure included thrombus embolization from surgical manipulation and massive bleeding. Intraoperatively, the patient experienced significant hemorrhage requiring massive transfusion protocol. The purpose of this case report is to emphasize the importance of multidisciplinary involvement, intraoperative thrombus monitoring, and principles of massive transfusion in the management of similar cases.

Emergency Department SpO2/FiO2 Ratios Correlate with Mechanical Ventilation and Intensive Care Unit Requirements in COVID-19 Patients.

Background: Patients with coronavirus 2019 (COVID-19) are at high risk for respiratory dysfunction. The pulse oximetry/fraction of inspired oxygen (SpO2/FiO2) ratio is a non-invasive assessment of respiratory dysfunction substituted for the PaO2:FiO2 ratio in Sequential Organ Failure Assessment scoring. We hypothesized that emergency department (ED) SpO2/FiO2 ratios correlate with requirement for mechanical ventilation in COVID-19 patients. Our objective was to identify COVID-19 patients at greatest risk of requiring mechanical ventilation, using SpO2/FiO2 ratios. Methods: We performed a retrospective review of patients admitted with COVID-19 at two hospitals. Highest and lowest SpO2/FiO2 ratios (percent saturation/fraction of inspired O2) were calculated on admission. We performed chi-square, univariate, and multiple regression analysis to evaluate the relationship of admission SpO2/FiO2 ratios with requirement for mechanical ventilation and intensive care unit (ICU) care. Results: A total of 539 patients (46% female; 84% White), with a mean age 67.6 ± 18.6 years, met inclusion criteria. Patients who required mechanical ventilation during their hospital stay were statistically younger in age (P = 0.001), had a higher body mass index (P < .001), and there was a higher percentage of patients who were obese (P = 0.03) and morbidly obese (P < .001). Shortness of breath, cough, and fever were the most common presenting symptoms with a median temperature of 99°F. Average white blood count was higher in patients who required ventilation (P = <0.001). A highest obtained ED SpO2/FiO2 ratio of ≤300 was associated with a requirement for mechanical ventilation. A lowest obtained ED SpO2/FiO2 ratio of ≤300 was associated with a requirement for intensive care unit care. There was no statistically significant correlation between ED SpO2/FiO2 ratios >300 and mechanical ventilation or intensive care unit (ICU) requirement. Conclusion: The ED SpO2/FiO2 ratios correlated with mechanical ventilation and ICU requirements during hospitalization for COVID-19. These results support ED SpO2/FiO2 as a possible triage tool and predictor of hospital resource requirements for patients admitted with COVID-19. Further investigation is warranted.

Suppression of hepatic ChREBP⍺-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH.

OBJECTIVES: Compromised hepatic fatty acid oxidation (FAO) has been observed in human MASH patients and animal models of MASLD/MASH. It remains poorly understood how and when the hepatic FAO pathway is suppressed during the progression of MASLD towards MASH. Hepatic ChREBP⍺ is a classical lipogenic transcription factor that responds to the intake of dietary sugars. METHODS: We examined its role in regulating hepatocyte fatty acid oxidation (FAO) and the impact of hepatic Chrebpa deficiency on sensitivity to diet-induced MASLD/MASH in mice. RESULTS: We discovered that hepatocyte ChREBP⍺ is both necessary and sufficient to maintain FAO in a cell-autonomous manner independently of its DNA-binding activity. Supplementation of synthetic PPAR⍺/δ agonist is sufficient to restore FAO in Chrebp-/- primary mouse hepatocytes. Hepatic ChREBP⍺ was decreased in mouse models of diet-induced MAFSLD/MASH and in patients with MASH. Hepatocyte-specific Chrebp⍺ knockout impaired FAO, aggravated liver steatosis and inflammation, leading to early-onset fibrosis in response to diet-induced MASH. Conversely, liver overexpression of ChREBP⍺-WT or its non-lipogenic mutant enhanced FAO, reduced lipid deposition, and alleviated liver injury, inflammation, and fibrosis. RNA-seq analysis identified the CYP450 epoxygenase (CYP2C50) pathway of arachidonic acid metabolism as a novel target of ChREBP⍺. Over-expression of CYP2C50 partially restores hepatic FAO in primary hepatocytes with Chrebp⍺ deficiency and attenuates preexisting MASH in the livers of hepatocyte-specific Chrebp⍺-deleted mice. CONCLUSIONS: Our findings support the protective role of hepatocyte ChREBPa against diet-induced MASLD/MASH in mouse models in part via promoting CYP2C50-driven FAO.

An Efficient 24-30 GHz GaN-on-Si Driver Amplifier Using Synthesized Matching Networks.

This paper presents a broadband GaN microwave monolithic integrated circuit driver amplifier (MMIC DA) with compact dimensions of 1.65 mm × 0.78 mm for 5G millimeter-wave communication. The optimal impedance domain satisfying the preset goals was first acquired using the simplified load-pull procedure and small-signal simulations, followed by a weighted average method to determine the reference center matching point from which the optimal intrinsic load can be deduced. By means of de-embedding load-pull contours, modeling based on theoretical analysis, and simulation fitting for parameter identification, the nonlinear output capacitance and a series RLC model circuit approximating the input impedance response of the stabilized transistor were extracted. Under the design principle of fully absorbing the parasitic parameters of the device, explicit formulas and tabulated methods related to the Chebyshev impedance transformer were applied to construct filter-based synthesized matching networks at each stage and finally convert them into an implementable mixed-element form via the single-frequency equivalence technique. Measured on-wafer pulsed results for the proposed two-stage DA across 24-30 GHz demonstrated up to 31.1 dBm of saturated output power (Psat) with less than 1 dB total fluctuation, 19.3 ± 1 dB of small-signal gain, and 39.8% of peak power-added efficiency (PAE) at the mid-frequency.

An efficient non-iterative smoothed particle hydrodynamics fluid simulation method with variable smoothing length.

In classical smoothed particle hydrodynamics (SPH) fluid simulation approaches, the smoothing length of Lagrangian particles is typically constant. One major disadvantage is the lack of adaptiveness, which may compromise accuracy in fluid regions such as splashes and surfaces. Attempts to address this problem used variable smoothing lengths. Yet the existing methods are computationally complex and non-efficient, because the smoothing length is typically calculated using iterative optimization. Here, we propose an efficient non-iterative SPH fluid simulation method with variable smoothing length (VSLSPH). VSLSPH correlates the smoothing length to the density change, and adaptively adjusts the smoothing length of particles with high accuracy and low computational cost, enabling large time steps. Our experimental results demonstrate the advantages of the VSLSPH approach in terms of its simulation accuracy and efficiency.

Fructose as a novel nutraceutical for acetaminophen (APAP)-induced hepatotoxicity.

Acetaminophen (APAP) is the most widely used analgesic in the world. APAP overdose can cause severe hepatotoxicity and therefore is the most common cause of drug-induced liver injury. The only approved treatment for APAP overdose is N-acetyl-cysteine (NAC) supplementation. However, the narrow efficacy window of the drug severely limits its clinical use, prompting the search for other therapeutic options to counteract APAP toxicity. Recent research has pointed to fructose as a novel nutraceutical for APAP-induced liver injury. This review summarizes the current understanding of the molecular mechanisms underlying APAP-induced liver injury, introduces how fructose supplementation could prevent and treat APAP liver toxicity with a focus on the ChREBPα-FGF21 pathway, and proposes possible future directions of study.

Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis.

Obesity is increasing worldwide and leads to a multitude of metabolic diseases, including cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis (NASH). Cysteine-rich angiogenic inducer 61 (CYR61) is associated with the progression of NASH, but it has been described to have anti- and proinflammatory properties. We sought to examine the role of liver CYR61 in NASH progression. CYR61 liver-specific knockout mice on a NASH diet showed improved glucose tolerance, decreased liver inflammation, and reduced fibrosis. CYR61 polarized infiltrating monocytes promoting a proinflammatory/profibrotic phenotype through an IRAK4/SYK/NF-κB signaling cascade. In vitro, CYR61 activated a profibrotic program, including PDGFa/PDGFb expression in macrophages, in an IRAK4/SYK/NF-κB-dependent manner. Furthermore, targeted-antibody blockade reduced CYR61-driven signaling in macrophages in vitro and in vivo, reducing fibrotic development. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis in NASH.

Thoracoscopic-assisted rib plating (TARP): initial single-center case series, including TARP in the super elderly, technical lessons learned, and proposed expanded indications.

Objectives: The application of surgical stabilization of rib fractures (SSRF) remains inconsistent due to evolving indications and perceived associated morbidity. By implementing thoracoscopic-assisted rib plating (TARP), a minimally invasive SSRF approach, we expanded our SSRF application to patients who otherwise might not be offered fixation. This report presents our initial experience, including fixation in super elderly (aged ≥85 years), and technical lessons learned. Methods: This was a retrospective cohort study at a level 1 trauma center of admitted patients who underwent TARP between August 2019 and October 2020. Patient demographics, injury characteristics, surgical indications and outcomes are represented as mean±SD, median or percentage. Results: A total of 2134 patients with rib fractures were admitted. In this group, 39 SSRF procedures were performed, of which 54% (n=21) were TARP. Average age was 68.5±16 years. Patients had a median of 5 fractured ribs, with an average of 1 rib that was bicortically displaced, and 19% presented with 'clicking' on inspiration. Patient outcomes were a mean hospital length of stay (LOS) of 11±3.7 days, mean postoperative LOS of 8 days, and mean intensive care unit LOS of 6.6±2.9 days. Five patients were ≥85 years old with a mean age of 90.8±4.7 years. They presented with an average of 4 rib fractures, of which an average of 2.4 ribs were plated. The procedure was well tolerated in this age group with a hospital LOS of 9.4±2 days, and all five patients were discharged to a rehab facility with no in-hospital mortalities. Conclusion: Our experience incorporating TARP at our institution demonstrated feasibility of the technique and application across a broad range of patients. This approach and its application warrants further evaluation and potentially expands the application of SSRF..

Maternal-fetal immune responses in pregnant women infected with SARS-CoV-2.

Pregnant women represent a high-risk population for severe/critical COVID-19 and mortality. However, the maternal-fetal immune responses initiated by SARS-CoV-2 infection, and whether this virus is detectable in the placenta, are still under investigation. Here we show that SARS-CoV-2 infection during pregnancy primarily induces unique inflammatory responses at the maternal-fetal interface, which are largely governed by maternal T cells and fetal stromal cells. SARS-CoV-2 infection during pregnancy is also associated with humoral and cellular immune responses in the maternal blood, as well as with a mild cytokine response in the neonatal circulation (i.e., umbilical cord blood), without compromising the T-cell repertoire or initiating IgM responses. Importantly, SARS-CoV-2 is not detected in the placental tissues, nor is the sterility of the placenta compromised by maternal viral infection. This study provides insight into the maternal-fetal immune responses triggered by SARS-CoV-2 and emphasizes the rarity of placental infection.

Evaluation of the Hemostatic Efficacy of Two Powdered Topical Absorbable Hemostats Using a Porcine Liver Abrasion Model of Mild to Moderate Bleeding.

INTRODUCTION: Topical hemostatic agents, used alone or in combination, have become common adjuncts to manage tissue and organ bleeding resulting from trauma and surgical procedures. Oxidized regenerated cellulose (ORC) is one of the most commonly used adjunctive hemostatic agents. The aim of the present study was to compare the hemostatic efficacy of a novel ORC-based product, SURGICEL® Powder Absorbable Hemostat (Surgicel-P) to that of HEMOBLAST™ Bellows (Hemoblast-B), a collagen-based combination powder. METHODS: Using an established porcine liver abrasion model, we randomly tested Surgicel-P and Hemoblast-B in 60 experimental lesion sites (30 per product tested). Primary endpoints included hemostatic efficacy measured by absolute time to hemostasis (TTH) within 5 minutes. We also examined number of applications required to achieve hemostasis, and sustained hemostasis following saline irrigation of test sites that achieved hemostasis. RESULTS: Surgicel-P demonstrated significantly higher hemostatic efficacy and lower TTH (p < 0.01) than Hemoblast-B. Surgicel-P-treated lesion sites achieved hemostasis in 73.3% of cases following one product application vs. 3.3% of Hemoblast-B-treated sites. Of all sites that were assessed, hemostasis was achieved and sustained following irrigation at 93.3% of Surgicel-P-treated sites vs. 50.0% of Hemoblast-B-treated sites. The average number of Surgicel-P applications per site was 51% lower than the average number of applications used for Hemoblast-B. CONCLUSION: Surgicel-P provided more effective and sustained hemostasis and faster TTH than Hemoblast-B. Surgicel-P represents a novel clinical alternative to provide adjunctive control of diffuse mild and moderate bleeding. Surgicel-P combines an ORC powder formulation and a delivery system in a device that is particularly useful for application on large surfaces and difficult-to-access anatomical locations where application of other forms of topical hemostats may be impractical.