Embryonically active piriform cortex neurons promote intracortical recurrent connectivity during development.

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used targeted recombination in active populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.

Embryonically Active Piriform Cortex Neurons Promote Intracortical Recurrent Connectivity during Development.

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used Targeted Recombination in Active Populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing of these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.

An inversion problem for optical spectrum data via physics-guided machine learning.

We propose the regularized recurrent inference machine (rRIM), a novel machine-learning approach to solve the challenging problem of deriving the pairing glue function from measured optical spectra. The rRIM incorporates physical principles into both training and inference and affords noise robustness, flexibility with out-of-distribution data, and reduced data requirements. It effectively obtains reliable pairing glue functions from experimental optical spectra and yields promising solutions for similar inverse problems of the Fredholm integral equation of the first kind.

Planckian behavior of cuprates at the pseudogap critical point simulated via flat electron-boson spectral density.

Planckian behavior has been recently observed in La1·76Sr0·24CuO4 at the pseudogap critical point. The Planckian behavior takes place in an intriguing quantum metallic state at a quantum critical point. Here, the Planckian behavior was simulated with an energy-independent (or flat) and weakly temperature-dependent electron-boson spectral density (EBSD) function by using a generalized Allen's (Shulga's) formula. We obtained various optical quantities from the flat EBSD function, such as the optical scattering rate, the optical effective mass, and the optical conductivity. These quantities are well fitted with the recently observed Planckian behavior. Fermi-liquid behavior was also simulated with an energy-linear and temperature-independent EBSD function. The EBSD functions agree well with the overall doping- and temperature-dependent trends of the EBSD function obtained from the optically measured spectra of cuprate systems, which can be crucial for understanding the microscopic electron-pairing mechanism for high-Tc superconductivity in cuprates.

Computational, optical and feasibility studies of organic luminescence TMB-PPT blend for photovoltaic application.

For enhanced applications of solar cells, organic luminescence materials like long persistent luminescence (LPL) present one of the promising avenues for light enhancement. Currently, most existing luminescent materials are based on an inorganic system that requires rare elements such as europium and dysprosium, with a very high processing temperature. Adopting organic luminescence materials that are free from rare elements is necessary, considering the low-temperature fabrication and low material cost. In this work, we investigate the optical properties of an organic luminescence blend consisting of 2,8-bis(diphenylphosphoryl)dibenzo [b,d]thiophene (PPT) and N,N,N',N'-tetramethylbenzidine (TMB) through computational studies and experimental validations. Optical characteristics of the luminescence materials like optical absorption, photoluminescence, and time-resolved photoluminescence spectroscopy are characterized. To validate the functionality of the organic luminescence blend, the material is incorporated into the perovskite solar cell structure. Unfortunately, the blend is unable to emit sufficient illumination over extended periods due to its low intersystem crossing efficiency and weak spin-orbit coupling. Although the power conversion efficiency of the Luminescence/FTO/TiO2/Perovskite/Carbon structure is observed to be small under dark conditions, the application of organic luminescence materials can be further enhanced and explored.

Health Economic Considerations in the Deployment of an Alzheimer's Prevention Therapy.

INTRODUCTION: As treatments for secondary prevention of Alzheimer's disease (AD) are being studied, concerns about their value for money have appeared. We estimate cost-effectiveness of a hypothetical screening and prevention program. METHODS: We use a Markov model to project cost-effectiveness of a treatment that reduces progression to symptomatic AD by 50% with either chronic treatment until progression to mild cognitive impairment or treatment for one year followed by monitoring with AD blood tests and retreatment with one dose in case of amyloid re-accumulation. Diagnoses would be made with an AD blood test with sensitivity and specificity of 80%, and inconclusive results in 20%. Individuals testing negative would be re-tested in five years and those with inconclusive results in one. RESULTS: The program would generate per-person value of $53,721 from a payer (reduction of direct cost and patient QALY gains) and $69,861 from a societal perspective (adding valuation of reduced caregiver burden). With chronic treatment, it would be cost-effective up to annual drug prices of $7,000 and $10,300, respectively. Time-limited treatment would be cost-effective at annual drug prices of $54,257 and $78,458 from a payer and societal perspective, respectively. Higher specificity of the blood test would decrease cost per person with similar value generation DISCUSSION: A hypothetical prevention treatment for AD could be economically viable from a payer and societal perspective.

Projected Savings to Canadian Provincial Budgets from Reduced Long-Term Care Home Utilization Due to a Disease-Modifying Alzheimer's Treatment.

BACKGROUND: A disease-modifying Alzheimer's treatment could provide budgetary savings to Canadian provinces from a reduction in long-term care home use, yet we do not know the magnitude of those potential savings. OBJECTIVE: We project savings to each Canadian province's budget from 2023 to 2043. DESIGN: Annual savings are projected using a Markov model. We account for reduction in long-term care home use and in use of Alternative Level of Care (ALC) beds, which are hospital beds occupied by care home-eligible patients on the wait list for admission. RESULTS: A treatment that delays disease progression by 40% is projected to avoid 142,507 long-term care home and ALC years, resulting in $17.2 billion cumulative savings across all Canadian provinces, a 21% relative reduction among treatment eligible patients. Average per capita savings were $1,132, ranging from $734 (Alberta) to $2,895 (Prince Edward Island). Cumulative savings could increase to $22.7 billion with enhanced triage of patients in primary care stages and to $25.6 billion if all capacity constraints for diagnosis and treatment were removed. CONCLUSION: A disease-modifying treatment could create budgetary savings from lower long-term care home use, offsetting part of the treatment cost. With the increasing demand for long-term care home beds and the high rates of patients being held in hospitals while wait-listed, such a treatment could additionally provide relief to the overburdened long-term care system in Canada.

Detection Rates of Mild Cognitive Impairment in Primary Care for the United States Medicare Population.

BACKGROUND: Existing evidence points to substantial gaps in detecting mild cognitive impairment in primary care but is based on limited or self-reported data. The recent emergence of disease-modifying treatments for the Alzheimer's disease, the most common etiology of mild cognitive impairment, calls for a systematic assessment of detection rates in primary care. OBJECTIVES: The current study aims to examine detection rates for mild cognitive impairment among primary care clinicians and practices in the United States using Medicare claims and encounter data. DESIGN: Observational study. SETTING: Medicare administrative data. PARTICIPANTS: The study sample includes a total of 226,756 primary care clinicians and 54,597 practices that had at least 25 patients aged 65 or older, who were enrolled in Medicare fee-for-service or a Medicare Advantage plan between 2017 and 2019. MEASUREMENTS: The detection rate for mild cognitive impairment is assessed as the ratio between the observed diagnosis rate of a clinician or practice as documented in the data, and the expected rate based on a predictive model. RESULTS: The average detection rates for mild cognitive impairment is 0.08 (interquartile range=0.00-0.02) for both clinicians and practices, suggesting that only about 8% of expected cases were diagnosed on average. Only 0.1% of clinicians and practices had diagnosis rates within the expected range. CONCLUSIONS: Mild cognitive impairment is vastly underdiagnosed, pointing to an urgent need to improve early detection in primary care.

Global Cardio Oncology Registry (G-COR): Registry Design, Primary Objectives, and Future Perspectives of a Multicenter Global Initiative.

BACKGROUND: Global collaboration in cardio-oncology is needed to understand the prevalence of cancer therapy-related cardiovascular toxicity in different risk groups, practice settings, and geographic locations. There are limited data on the socioeconomic and racial/ethnic disparities that may impact access to care and outcomes. To address these gaps, we established the Global Cardio-Oncology Registry, a multinational, multicenter prospective registry. METHODS: We assembled cardiologists and oncologists from academic and community settings to collaborate in the first Global Cardio-Oncology Registry. Subsequently, a survey for site resources, demographics, and intention to participate was conducted. We designed an online data platform to facilitate this global initiative. RESULTS: A total of 119 sites responded to an online questionnaire on their practices and main goals of the registry: 49 US sites from 23 states and 70 international sites from 5 continents indicated a willingness to participate in the Global Cardio-Oncology Registry. Sites were more commonly led by cardiologists (85/119; 72%) and were more often university/teaching (81/119; 68%) than community based (38/119; 32%). The average number of cardio-oncology patients treated per month was 80 per site. The top 3 Global Cardio-Oncology Registry priorities in cardio-oncology care were breast cancer, hematologic malignancies, and patients treated with immune checkpoint inhibitors. Executive and scientific committees and specific committees were established. A pilot phase for breast cancer using Research Electronic Data Capture Cloud platform recently started patient enrollment. CONCLUSIONS: We present the structure for a global collaboration. Information derived from the Global Cardio-Oncology Registry will help understand the risk factors impacting cancer therapy-related cardiovascular toxicity in different geographic locations and therefore contribute to reduce access gaps in cardio-oncology care. Risk calculators will be prospectively derived and validated.

Acute Myeloid Leukemia Treatment in the Elderly: A Comprehensive Review of the Present and Future.

BACKGROUND: Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology in the past decade. It is also an affliction of the elderly that predominantly affects patients over 60 years of age. Standard therapy involves intensive chemotherapy that is often difficult to tolerate in older populations. Fortunately, recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies that are easier to tolerate. SUMMARY: Venetoclax, a BCL-2 inhibitor, when combined with a hypomethylating agent, has proven to be a highly effective and well-tolerated drug and established itself as a new standard for treating AML in patients who are unfit for standard intensive therapy. Other targeted therapies include clinically proven and FDA-approved agents, such as IDH1/2 inhibitors, FLT3 inhibitors, and Gemtuzumab, as well as newer and more experimental drugs such as magrolimab, PI-kinase inhibitors, and T-cell engaging therapy. Some of the novel agents such as magrolimab and menin inhibitors are particularly promising, providing therapeutic options to a wider population of patients than ever before. Determining who will benefit from intense or novel low-intense therapy remains a challenge, and it requires careful assessment of individual patient's fitness and disease characteristics. KEY MESSAGES: This article reviews past and current treatment strategies that harness various mechanisms of leukemia-targeting agents and introduces novel therapies on the horizon aimed at exploring therapeutic options for the elderly and unfit patient population. It also provides a strategy to select the best available therapy for elderly patients with both newly diagnosed and relapsed/refractory AML.

Dynamic contrast enhanced (DCE) MRI estimation of vascular parameters using knowledge-based adaptive models.

We introduce and validate four adaptive models (AMs) to perform a physiologically based Nested-Model-Selection (NMS) estimation of such microvascular parameters as forward volumetric transfer constant, Ktrans, plasma volume fraction, vp, and extravascular, extracellular space, ve, directly from Dynamic Contrast-Enhanced (DCE) MRI raw information without the need for an Arterial-Input Function (AIF). In sixty-six immune-compromised-RNU rats implanted with human U-251 cancer cells, DCE-MRI studies estimated pharmacokinetic (PK) parameters using a group-averaged radiological AIF and an extended Patlak-based NMS paradigm. One-hundred-ninety features extracted from raw DCE-MRI information were used to construct and validate (nested-cross-validation, NCV) four AMs for estimation of model-based regions and their three PK parameters. An NMS-based a priori knowledge was used to fine-tune the AMs to improve their performance. Compared to the conventional analysis, AMs produced stable maps of vascular parameters and nested-model regions less impacted by AIF-dispersion. The performance (Correlation coefficient and Adjusted R-squared for NCV test cohorts) of the AMs were: 0.914/0.834, 0.825/0.720, 0.938/0.880, and 0.890/0.792 for predictions of nested model regions, vp, Ktrans, and ve, respectively. This study demonstrates an application of AMs that quickens and improves DCE-MRI based quantification of microvasculature properties of tumors and normal tissues relative to conventional approaches.

Safety and efficacy of trastuzumab biosimilar plus irinotecan or gemcitabine in patients with previously treated HER2 (ERBB2)-positive non-breast/non-gastric solid tumors: a phase II basket trial with circulating tumor DNA analysis.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) (ERBB2)-directed agents are standard treatments for patients with HER2-positive breast and gastric cancer. Herein, we report the results of an open-label, single-center, phase II basket trial to investigate the efficacy and safety of trastuzumab biosimilar (Samfenet®) plus treatment of physician's choice for patients with previously treated HER2-positive advanced solid tumors, along with biomarker analysis employing circulating tumor DNA (ctDNA) sequencing. METHODS: Patients with HER2-positive unresectable or metastatic non-breast, non-gastric solid tumors who failed at least one prior treatment were included in this study conducted at Asan Medical Center, Seoul, Korea. Patients received trastuzumab combined with irinotecan or gemcitabine at the treating physicians' discretion. The primary endpoint was the objective response rate as per RECIST version 1.1. Plasma samples were collected at baseline and at the time of disease progression for ctDNA analysis. RESULTS: Twenty-three patients were screened from 31 December 2019 to 17 September 2021, and 20 were enrolled in this study. Their median age was 64 years (30-84 years), and 13 patients (65.0%) were male. The most common primary tumor was hepatobiliary cancer (seven patients, 35.0%), followed by colorectal cancer (six patients, 30.0%). Among 18 patients with an available response evaluation, the objective response rate was 11.1% (95% confidence interval 3.1% to 32.8%). ERBB2 amplification was detected from ctDNA analysis of baseline plasma samples in 85% of patients (n = 17), and the ERBB2 copy number from ctDNA analysis showed a significant correlation with the results from tissue sequencing. Among 16 patients with post-progression ctDNA analysis, 7 (43.8%) developed new alterations. None of the patients discontinued the study due to adverse events. CONCLUSIONS: Trastuzumab plus irinotecan or gemcitabine was safe and feasible for patients with previously treated HER2-positive advanced solid tumors with modest efficacy outcomes, and ctDNA analysis was useful for detecting HER2 amplification.

Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (ß = 0.21; 95% CI 0.04-0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (ß = -0.28; 95% CI -0.41 to -0.15, p < 0.001) and across multiple domains of function (ß = -0.14; 95% CI -0.22 to -0.06, p < 0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI 3%-58%, p = 0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (odds ratio 1.04, 95% CI 1.01-1.08, p = 0.004). DISCUSSION: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets.

Exogenous protease supplementation to the diet enhances growth performance, improves nitrogen utilization, and reduces stress in finishing pigs.

We have conducted this experiment to evaluate a new exogenous protease in finishing pigs' growth performance, nutrient digestibility, gas emission, blood profiles, and meat quality. A total of 200 pigs of 52.15 ± 2.31 kg average body weight (BW) were divided into four dietary treatments named as: CON, basal diet; TRT1, basal diet + 0.05% protease; TRT2, basal diet + 0.1% protease; TRT3, basal diet + 1.5% protease. Each treatment consisted of 10 pens, where five pigs were allotted to each pen according to their body weight and sex. The dietary treatments were allotted to the pens in a randomized block design. During this 10-week-long experiment, BW, average daily gain (ADG), average daily feed intake (ADFI), and gain to feed ratio (G:F) were calculated for Week 0-5, Week 6-10, and the overall period. During Week 6-10, ADG was higher in TRT2 and TRT3 than in the CON and TRT1 groups. At the same time, a linear increase was observed in ADG and G:F of the pigs. In addition, the final BW of pigs' was linearly increased by protease supplementation. On Week 10, there was a linear trend of increase (p = 0.0575) in crude protein digestibility and a trend of linear reduction (p = 0.0651) in NH3 gas emission. In blood profile, cortisol presented a linear decrease in both Week 5 (p = 0.251) and Week 10 (p = 0.0585). In addition, increasing doses of protease showed a trend of linear increase (p = 0.0592) in creatinine, whereas linear reduction was observed in the concentration of epinephrine (p = 0.0636) and norepinephrine (p = 0.0167) during Week 10. In conclusion, protease supplementation helped in improving daily gain in finishing pigs through protein digestibility with associated reduction of ammonia emission and blood stress hormones.

Preoperative Cannabis Use Associated With an Increased Rate of Reoperation and Postoperative Opioid Use Following Anterior Cervical Decompression and Fusion.

Objectives The objective of this retrospective cohort study was to evaluate the associations among preoperative cannabis use, postoperative opioid use, and postoperative outcomes following elective anterior cervical decompression and fusion (ACDF). Methods Patients who underwent one- or two-level ACDF were characterized preoperatively as active cannabis users, former users, or nonusers. Patients were also classified based on history of preoperative opioid use as chronic users, acute users, or nonusers. Groups were compared based on outcomes including the rate of emergency department visits six months postoperatively, rate of readmissions one year postoperatively, rate of reoperation two years postoperatively, and daily postoperative opioid use measured in milligram morphine equivalents (MMEs) at 0-6 months and 6-12 months postoperatively.  Results Of the 198 patients included in this study, 13 (6.6%) were active cannabis users, 11 (5.6%) were former users, and 174 (87.8%) were nonusers. The rate of reoperation within two years was 23.1% for active cannabis users, 0% for former users, and 4.0% for nonusers (p=0.0075). The average daily opioid use in MMEs 6-12 months postoperatively was 49.4 for active cannabis users, 4.1 for former users, and 13.3 for nonusers (p=0.0014). For chronic opioid users, acute users, and nonusers, the average daily opioid use in MMEs 6-12 months postoperatively was 39.9, 18.4, and 5.7, respectively (p<.0001). Conclusions History of cannabis use is associated with increased postoperative opioid use and increased rate of reoperation following elective ACDF.

Discovery of a CSF-1R inhibitor and PET tracer for imaging of microglia and macrophages in the brain.

Colony stimulating factor 1 receptor (CSF-1R) is a kinase expressed on macrophages and microglia in the brain. It has been recognized as a potential drug and imaging target in treatment of neuroinflammatory diseases and glioblastoma. Despite several attempts, no validated CSF-1R PET tracer is currently available. The aim of this work was to develop a brain permeable CSF-1R PET tracer for non-invasive imaging of CSF-1R in vivo. Based on fragments of two potent and selective CSF-1R inhibitors, novel hybrid molecules were designed and synthesized. Affinity for human recombinant CSF-1R and selectivity over c-KIT and PDGFR-ß was determined using a FRET based in vitro assay. Radiosynthesis was performed by fully automated [11C]CH3I methylation of the corresponding des-methyl precursor. PET imaging was performed at baseline, efflux transporter blocking and CSF-1R blocking conditions. Moreover, tracer distribution and blood and plasma radiometabolites were determined following injection in healthy mice. The most promising CSF-1R inhibitor, compound 4, showed high selectivity and high affinity for CSF-1R (IC50: 12 ± 3 nM) and no affinity for kinase family members c-KIT and PDGFR-beta. [11C]4 was obtained in good yield (15 ± 0.2 % decay corrected yield, (2.0 ± 0.26 GBq at end of synthesis) and excellent purity. The compound demonstrated high brain penetration and good metabolic stability (>2 %ID/g at 60 min post injection and 79 ± 8 % intact [11C]4 in brain at 60 min post injection) and no strong efflux transporter substrate behavior. Blocking CSF-1R prior to imaging with [11C]4 resulted in significant decrease in brain uptake. In conclusion, [11C]4 shows good potential as a novel PET tracer for imaging of CSF-1R in the CNS and future experiments in relevant animal models are warranted.

Curcumae Radix Decreases Neurodegenerative Markers through Glycolysis Decrease and TCA Cycle Activation.

Neurodegenerative diseases (ND) are being increasingly studied owing to the increasing proportion of the aging population. Several potential compounds are examined to prevent neurodegenerative diseases, including Curcumae radix, which is known to be beneficial for inflammatory conditions, metabolic syndrome, and various types of pain. However, it is not well studied, and its influence on energy metabolism in ND is unclear. We focused on the relationship between ND and energy metabolism using Curcumae radix extract (CRE) in cells and animal models. We monitored neurodegenerative markers and metabolic indicators using Western blotting and qRT-PCR and then assessed cellular glycolysis and metabolic flux assays. The levels of Alzheimer's disease-related markers in mouse brains were reduced after treatment with the CRE. We confirmed that neurodegenerative markers decreased in the cerebrum and brain tumor cells following low endoplasmic reticulum (ER) stress markers. Furthermore, glycolysis related genes and the extracellular acidification rate decreased after treatment with the CRE. Interestingly, we found that the CRE exposed mouse brain and cells had increased mitochondrial Tricarboxylic acid (TCA) cycle and Oxidative phosphorylation (OXPHOS) related genes in the CRE group. Curcumae radix may act as a metabolic modulator of brain health and help treat and prevent ND involving mitochondrial dysfunction.

The aqueous fraction of Castanea crenata inner shell extract reduces obesity and intramuscular lipid accumulation via induction of mitochondrial respiration and fatty acid oxidation in muscle.

BACKGROUND: Skeletal muscle is responsible for free fatty acid (FFA) disposal via mitochondrial respiration and fatty acid oxidation (FAO). Obesity triggers high levels of circulating FFAs, which can cause intramuscular lipid (IMCL) deposition. Diverse phytochemicals, including crude Castanea crenata inner shell extract (CCE), have been shown to possess an anti-obesity effect. PURPOSE: We aimed to demonstrate whether the aqueous fraction of CCE (ACCE) provides an anti-obesity effect with a decrease in plasma FFAs and reduces IMCL. METHODS: High-fat-fed C57BL/6 mice received ACCE via water intake. A204 cells incubated with fatty acids were treated with ACCE. Lipid accumulation and mitochondrial metabolism were assessed using histological and molecular techniques. RESULTS: ACCE possessed a notably higher gallic acid content than CCE among the constituents. ACCE-administered mice exhibited reduced plasma FFA levels, adiposity, and IMCL. Muscle lipotoxicity was suppressed, including apoptosis, ER stress, and inflammation. The anti-lipid effect of ACCE was observed with the induction of mitochondrial respiration and fatty acid oxidation in muscle. CONCLUSIONS: ACCE increases mitochondrial respiration and FAO in skeletal muscle and protects muscle from IMCL and lipotoxicity, reducing plasma FFA and adiposity.

Artificial Intelligence-Controlled Microfluidic Device for Fluid Automation and Bubble Removal of Immunoassay Operated by a Smartphone.

There have been tremendous innovations in microfluidic clinical diagnostics to facilitate novel point-of-care testing (POCT) over the past decades. However, the automatic operation of microfluidic devices that minimize user intervention still lacks reliability and repeatability because microfluidic errors such as bubbles and incomplete filling pose a major bottleneck in commercializing the microfluidic devices for clinical testing. In this work, for the first time, various states of microfluid were recognized to control immunodiagnostics by artificial intelligence (AI) technology. The developed AI-controlled microfluidic platform was operated via an Android smartphone, along with a low-cost polymer device to effectuate enzyme-linked immunosorbent assay (ELISA). To overcome the limited machine-learning capability of smartphones, the region-of-interest (ROI) cascading and conditional activation algorithms were utilized herein. The developed microfluidic chip was incorporated with a bubble trap to remove any bubbles detected by AI, which helps in preventing false signals during immunoassay, as well as controlling the reagents' movement with an on-chip micropump and valve. Subsequently, the developed immunosensing platform was tested for conducting real ELISA using a single microplate from the 96-well to detect the Human Cardiac Troponin I (cTnI) biomarker, with a detection limit as low as 0.98 pg/mL. As a result, the developed platform can be envisaged as an AI-based revolution in microfluidics for point-of-care clinical diagnosis.

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced ß-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from ß-oxidation to glycolysis, may induce cardiac structural remodeling.