Cardioprotection via mitochondrial transplantation supports fatty acid metabolism in ischemia-reperfusion injured rat heart.

In addition to cellular damage, ischemia-reperfusion (IR) injury induces substantial damage to the mitochondria and endoplasmic reticulum. In this study, we sought to determine whether impaired mitochondrial function owing to IR could be restored by transplanting mitochondria into the heart under ex vivo IR states. Additionally, we aimed to provide preliminary results to inform therapeutic options for ischemic heart disease (IHD). Healthy mitochondria isolated from autologous gluteus maximus muscle were transplanted into the hearts of Sprague-Dawley rats damaged by IR using the Langendorff system, and the heart rate and oxygen consumption capacity of the mitochondria were measured to confirm whether heart function was restored. In addition, relative expression levels were measured to identify the genes related to IR injury. Mitochondrial oxygen consumption capacity was found to be lower in the IR group than in the group that underwent mitochondrial transplantation after IR injury (p < 0.05), and the control group showed a tendency toward increased oxygen consumption capacity compared with the IR group. Among the genes related to fatty acid metabolism, Cpt1b (p < 0.05) and Fads1 (p < 0.01) showed significant expression in the following order: IR group, IR + transplantation group, and control group. These results suggest that mitochondrial transplantation protects the heart from IR damage and may be feasible as a therapeutic option for IHD.

Noninvasive hemoglobin monitoring for maintaining hemoglobin concentration within the target range during major noncardiac surgery: A randomized controlled trial.

STUDY OBJECTIVE: The effect of noninvasive CO-oximetry hemoglobin (SpHb) monitoring on the clinical outcomes of patients undergoing surgery remains unclear. This trial aimed to evaluate whether SpHb monitoring helps maintain hemoglobin levels within a predefined target range during major noncardiac surgeries with a potential risk of intraoperative hemorrhage. DESIGN: A single-center, prospective, randomized controlled trial. SETTING: University hospital. PATIENTS: One hundred and thirty patients undergoing elective noncardiac surgery with a potential risk of hemorrhage. INTERVENTIONS: Patients were randomly allocated to undergo either SpHb-guided management (SpHb group) or usual care (control group). MEASUREMENTS: The primary outcome was the rate of deviation of the total hemoglobin concentration (determined from laboratory testing) from a pre-specified target range (8-14 g/dL). This was defined as the number of laboratory tests revealing such deviations divided by the total number of laboratory tests performed during the surgery. MAIN RESULTS: The primary outcome occurred significantly less frequently in the SpHb group as compared to that in the control group (15/555 [2.7%]) vs. 68/598 [11.4%]; relative risk, 0.24; 95% confidence interval, 0.13-0.41; P < 0.001). Fewer point-of-care blood tests were performed in the SpHb group than in the control group (median [interquartile range], 2 [1-4] vs. 4 [2-5]; P < 0.001). There were no significant intergroup differences in the number of patients who received red blood cell transfusions during surgery (SpHb vs. control, 33.8% vs. 46.2%; P = 0.201). The incidence of unnecessary red blood cell preparation (>2 units) was lower in the SpHb group than in the control group (3.1% vs. 16.9%; P = 0.024). CONCLUSIONS: Compared with routine care, SpHb-guided management resulted in significantly lower rates of hemoglobin deviation outside the target range intraoperatively in patients undergoing major noncardiac surgeries with a potential risk of hemorrhage. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT03816514).

A Graphene-Based Polymer-Dispersed Liquid Crystal Device Enabled through a Water-Induced Interface Cleaning Process.

We report the use of four-layer graphene (4LG) as a highly reliable transparent conductive electrode (TCE) for polymer-dispersed liquid crystal (PDLC)-based smart window devices. The adhesion between 4LG and the substrate was successfully improved through a water-induced interface-cleaning (WIIC) process. We compared the performance of a device with a WIIC-processed 4LG electrode with that of devices with a conventional indium tin oxide (ITO) electrode and a 4LG electrode without a WIIC. With the application of the WIIC process, the PDLC smart window with a 4LG electrode exhibited reduced turn-on voltage and haze compared to 4LG without the WIIC process and characteristics comparable to those of the ITO electrode. The WIIC-processed 4LG electrode demonstrated enhanced electrical properties and better optical performance, leading to improved device efficiency and reliability. Furthermore, our study revealed that the WIIC process not only improved the adhesion between 4LG and the substrate but also enhanced the compatibility and interfacial interactions, resulting in the superior performance of the smart window device. These findings suggest that 4LG with WIIC holds great promise as a transparent conductive electrode for flexible smart windows, offering a cost-effective and efficient alternative to conventional ITO electrodes.

Functional variants identify sex-specific genes and pathways in Alzheimer's Disease.

The incidence of Alzheimer's Disease in females is almost double that of males. To search for sex-specific gene associations, we build a machine learning approach focused on functionally impactful coding variants. This method can detect differences between sequenced cases and controls in small cohorts. In the Alzheimer's Disease Sequencing Project with mixed sexes, this approach identified genes enriched for immune response pathways. After sex-separation, genes become specifically enriched for stress-response pathways in male and cell-cycle pathways in female. These genes improve disease risk prediction in silico and modulate Drosophila neurodegeneration in vivo. Thus, a general approach for machine learning on functionally impactful variants can uncover sex-specific candidates towards diagnostic biomarkers and therapeutic targets.

Stretchable and Skin-Mountable Temperature Sensor Array Using Reduction-Controlled Graphene Oxide for Dermatological Thermography.

Since thermometry of human skin is critical information that provides important aspects of human health and physiology, accurate and continuous temperature measurement is required for the observation of physical abnormalities. However, conventional thermometers are uncomfortable because of their bulky and heavy features. In this work, we fabricated a thin, stretchable array-type temperature sensor using graphene-based materials. Furthermore, we controlled the degree of graphene oxide reduction and enhanced the temperature sensitivity. The sensor exhibited an excellent sensitivity of 2.085% °C-1. The overall device was designed in a wavy meander shape to provide stretchability for the device so that precise detection of skin temperature could be performed. Furthermore, polyimide film was coated to secure the chemical and mechanical stabilities of the device. The array-type sensor enabled spatial heat mapping with high resolution. Finally, we introduced some practical applications of skin temperature sensing, suggesting the possibility of skin thermography and healthcare monitoring.

Relationships between common carotid artery blood flow and anesthesia, pneumoperitoneum, and head-down tilt position: a linear mixed-effect analysis.

This study investigated the effects of pneumoperitoneum and the head-down tilt position on common carotid artery (CCA) blood flow in surgical patients. METHODS: This prospective observational study included 20 patients who underwent gynecological surgery. CCA blood flow was measured using Doppler ultrasound at four-time points: awake in the supine position [T1], 3 min after anesthesia induction in the supine position [T2], 3 min after pneumoperitoneum in the supine position [T3], and 3 min after pneumoperitoneum in the head-down tilt position [T4]. Hemodynamic and respiratory parameters were also recorded at each time point. Linear mixed-effect analyses were performed to compare CCA blood flow across the time points and assess its relationship with hemodynamic parameters. RESULTS: Compared with T1, CCA blood flow decreased significantly at T2 (345.4 [288.0-392.9] vs. 293.1 [253.0-342.6], P = 0.048). CCA blood flow were also significantly lower at T3 and T4 compared with T1 (345.4 [288.0-392.9] vs. 283.6 [258.8-307.6] and 287.1 [242.1-321.4], P = 0.005 and 0.016, respectively). CCA blood flow at T3 and T4 did not significantly differ from that at T2. Changes in CCA blood flow were significantly associated with changes in cardiac index and stroke volume index (P = 0.011 and 0.024, respectively). CONCLUSION: CCA blood flow was significantly decreased by anesthesia induction. Inducing pneumoperitoneum, with or without the head-down tilt position, did not further decrease CCA blood flow if the cardiac index remained unchanged. The cardiac index and stroke volume index were significantly associated with CCA blood flow. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (NCT04233177, January 18, 2020).

Defect-selective-etched porous GaN as a buffer layer for high efficiency InGaN/GaN light-emitting diodes.

Substrate-induced biaxial compressive stress and threading dislocations (TDs) have been recognized to severely impair the performance, stability, and reliability of InGaN/GaN light-emitting diodes (LEDs) for quite some time. In this study, a defect-selective-etched (DSE) porous GaN layer is fabricated employing electro-chemical etching and applied as a buffer layer for the development of InGaN/GaN LEDs with high quantum efficiency. Based on the analysis of photoluminescence and micro-Raman spectra, it has been revealed that the overgrown GaN epilayer on the DSE porous GaN has a relatively low TDs and relaxation of compressive stress in comparison to the conventional GaN epilayer. The remarkable improvement in the internal quantum efficiency of the InGaN/GaN LEDs is directly attributable to the strong radiative recombination in InGaN/GaN multi-quantum-wells caused by stress relaxation and TDs annihilation. Our findings indicate that the use of DSE porous GaN as a buffer layer may be a viable approach for producing crystalline GaN epilayers and high-performance LEDs.

Enhanced Performance of Triboelectric Nanogenerators and Sensors via Cold Spray Particle Deposition.

In this study, a high-performance triboelectric nanogenerator (TENG) is developed based on cold spray (CS) deposition of composite material layers. Composite layers were fabricated by cold spraying of micron-scale tin (Sn) particles on aluminum (Al) and polytetrafluoroethylene (PTFE) films, which led to improved TENG performance owing to functionalized composite layers as friction layers and electrodes, respectively. As-sprayed tin composite layers not only enhanced the flow of charges by strong adhesion to the target layer but also formed a nano-microstructure on the surface of the layers, thereby increasing the surface area during friction. More importantly, the electricity generation performance was improved more than 6 times as compared to the TENG without CS deposition on it. From parametric studies, the TENG using the cold-sprayed composite layer produced an electrical potential of 1140 V for a simple structure with a 25.4 × 25.4 mm2 contact area. We also optimize the geometry and fabrication process of the TENG to increase the manufacturing efficiency while reducing the processing cost. The resultant sprayed layers and structures exhibited sustainable robustness by showing consistent electrical performance after the mechanical adhesion test. The proposed manufacturing approach is also applicable for processing three-dimensional (3D) complex layers owing to the technological convergence of a cold spray gun attached to a robotic arm, which makes possible to fabricate the 3D TENG. To elaborate, a composite layer having the shape of a 3D ball is produced, and the exercise status of the ball is monitored in real-time. The fabricated 3D ball using the TENG transmitted a distinguishable signal in real-time according to the state of the ball. The proposed TENG sensing system can be utilized as a self-powered sensor without the need of a battery, amplifier, and rectifier. The results of this study can potentially provide insights for the practical material design and fabrication of self-powered TENG systems.

Comparison of Indoor Air Quality in Summer and Winter According to Four-Way Cassette Fan Coil Unit Operation in a Four-Bed Ward.

This study targeted a four-bed ward with a ventilation system and a four-way cassette fan coil unit (4-way FCU) installed on the ceiling. The indoor air quality under summer and winter conditions was comparatively analyzed. The age of air was calculated by conducting tests and simulations under diverse conditions, assuming that the ventilation system and 4-way FCU were continuously operating. The use of an air cleaner and ward curtain was investigated for its impact on the air quality in the breathing zone of a patient lying on the bed, and effects of the airflow and discharge angle of the 4-way FCU were considered. Because the 4-way FCU was installed in the central part of the ceiling, where indoor air is sucked in and subsequently discharged in four directions, the age of air at each bed was found to vary depending on the airflow and discharge angle of the 4-way FCU. When the airflow and discharge angle of the 4-way FCU was fixed, the age of air at each bed appeared to be lower during winter heating than in summer cooling mode. The age of air was significantly lowered at each bed, depending on the use of the curtain and the air cleaner along with the ventilation system and 4-way FCU, and appropriate seasonal operating conditions were identified to maintain a lower age of air at each bed.

Investigation of the Optimal Operating Position of an Air Cleaner in Terms of Indoor Air Quality in a Four-Bed Hospital Ward.

The use of air cleaners indoors has increased with the increase in indoor activities driven by the COVID-19 outbreak. In this study, the indoor air quality was determined at the location of each patient's respirator in a four-bed hospital ward equipped with a ventilation system and curtains, by varying the position of one air cleaner. By operating the air cleaner alone without the ventilation system, it was confirmed that it is better to place the air cleaner close to the center of the ward, regardless of whether curtains are used. It was further identified that the farther away the air cleaner is from the center, the worse the age of air could be, compared to the case of operating it in the center. Moreover, the situation where the ventilation system and air cleaner were operated simultaneously in the hospital ward was considered. It was discovered that operating the air cleaner close to the ventilation inlets in the absence of curtains helps to improve the indoor air quality. Furthermore, it was found that the age of the air is generally low near the location where the air cleaner is operated in the presence of curtains. Selecting an optimal position for the air cleaner can improve the air quality at the location of each bed in a four-bed hospital ward.

Investigation of the Ligand Exchange Process on Gold Nanorods by Using Laser Desorption/Ionization Time-of-Flight Mass Spectrometry.

The ligand exchange process on gold nanorods (Au NRs) was explored by using laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF-MS). Cetyltrimethylammonium bromide (CTAB) adsorbed on Au NRs was replaced with alkanethiol derivatives presenting different functional groups. The ligand exchange process was investigated under various conditions, such as in the presence of different functional groups in the ligands and with different concentrations of CTAB. The ligand-exchanged Au NRs were characterized by using a combination of UV-Vis spectroscopy and LDI-TOF-MS. Based on the results, it was revealed that LDI-TOF-MS analysis can provide crucial and distinct information about the degree of ligand exchange on Au NRs.

Ultrasound-assisted spinal anesthesia: A randomized comparison between midline and paramedian approaches.

STUDY OBJECTIVE: Neuraxial ultrasonography can improve the technical performance of spinal anesthesia. However, there are no data regarding the optimal approach for ultrasound-assisted spinal anesthesia. This study aimed to compare the midline and paramedian approaches for ultrasound-assisted spinal anesthesia in adult orthopedic patients. DESIGN: A single-center, prospective, randomized controlled trial. SETTING: Operating room. PATIENTS: One hundred and twelve patients undergoing orthopedic surgery were included. INTERVENTIONS: Patients were randomized to undergo either the midline or paramedian approach for preprocedural ultrasound-assisted spinal anesthesia. MEASUREMENTS: The primary outcome was the number of needle passes required for successful dural puncture. Secondary outcomes were the number of needle insertions, first pass/attempt success rate, procedural time, and the incidence of periprocedural complications. MAIN RESULTS: The median number of needle passes was significantly lower in the paramedian group (1 [IQR, 1-2]) than in the midline group (3 [2-6]; P < 0.001). The paramedian approach showed higher first pass/attempt success rates compared with the midline group (58.9% vs. 21.4%; 91.1% vs. 53.6%; both, P < 0.001). Total procedure times were significantly shorter in the paramedian group than in the midline group (113 [72.5-146.5] vs. 196 [138-298.5] seconds; P < 0.001). The quality of sonographic images was graded as good in 94.6% of paramedian sagittal oblique views and 54.5% of transverse median views. No significant intergroup differences were found in the incidence of periprocedural complications. CONCLUSIONS: Compared with the midline approach, the ultrasound-assisted paramedian approach showed improved efficacy in terms of the number of needle manipulations, first pass success rates, and procedural time. These results suggest that the paramedian approach may be more efficient for preprocedural ultrasound-assisted spinal anesthesia. TRIAL REGISTRATION NUMBER: NCT03491943.

Three-dimensionally printed recombinant human parathyroid hormone-soaked nanofiber sheet accelerates tendon-to-bone healing in a rabbit model of chronic rotator cuff tear.

BACKGROUND: Recombinant human parathyroid hormone (rhPTH) promotes tendon-to-bone healing in humans and animals with rotator cuff tear (RCT). However, problems regarding repeated systemic rhPTH injections in humans exist. This study was conducted to evaluate the effect of topical rhPTH administration using 3-dimensionally (3D) printed nanofiber sheets on tendon-to-bone healing in a rabbit RCT model compared to that of direct topical rhPTH administration. METHODS: Eighty rabbits were randomly assigned to 5 groups (n = 16 each). To create the chronic RCT model, we induced complete supraspinatus tendon tears in both shoulders and left them untreated for 6 weeks. All transected tendons were repaired in a transosseous manner with saline injection in group A, hyaluronic acid (HA) injection in group B, 3D-printed nanofiber sheet fixation in group C, rhPTH and HA injection in group D, and 3D-printed rhPTH- and HA-soaked nanofiber sheet fixation in group E. Genetic (messenger RNA expression evaluation) and histologic evaluations (hematoxylin and eosin and Masson trichrome staining) were performed in half of the rabbits at 4 weeks postrepair. Genetic, histologic, and biomechanical evaluations (mode of tear and load to failure) were performed in the remaining rabbits at 12 weeks. RESULTS: For genetic evaluation, group E showed a higher collagen type I alpha 1 expression level than did the other groups (P = .008) at 4 weeks. However, its expression level was downregulated, and there was no difference at 12 weeks. For histologic evaluation, group E showed greater collagen fiber continuity, denser collagen fibers, and more mature tendon-to-bone junction than did the other groups (P = .001, P = .001, and P = .003, respectively) at 12 weeks. For biomechanical evaluation, group E showed a higher load-to-failure rate than did the other groups (P < .001) at 12 weeks. CONCLUSION: Three-dimensionally printed rhPTH-soaked nanofiber sheet fixation can promote tendon-to-bone healing of chronic RCT.

A general calculus of fitness landscapes finds genes under selection in cancers.

Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits. Over cancer cohorts, integration identified 460 likely tumor-driving genes. Many have literature and experimental support but had eluded prior genomic searches for positive selection in tumors. Beyond providing cancer insights, these results introduce a general calculus of evolution to quantify the genotype-phenotype relationship and discover genes associated with complex traits and diseases.

Transplantation of patient-specific bile duct bioengineered with chemically reprogrammed and microtopographically differentiated cells.

Cholangiopathy is a diverse spectrum of chronic progressive bile duct disorders with limited treatment options and dismal outcomes. Scaffold- and stem cell-based tissue engineering technologies hold great promise for reconstructive surgery and tissue repair. Here, we report a combined application of 3D scaffold fabrication and reprogramming of patient-specific human hepatocytes to produce implantable artificial tissues that imitate the mechanical and biological properties of native bile ducts. The human chemically derived hepatic progenitor cells (hCdHs) were generated using two small molecules A83-01 and CHIR99021 and seeded inside the tubular scaffold engineered as a synergistic combination of two layers. The inner electrospun fibrous layer was made of nanoscale-macroscale polycaprolactone fibers acting to promote the hCdHs attachment and differentiation, while the outer microporous foam layer served to increase mechanical stability. The two layers of fiber and foam were fused robustly together thus creating coordinated mechanical flexibility to exclude any possible breaking during surgery. The gene expression profiling and histochemical assessment confirmed that hCdHs acquired the biliary epithelial phenotype and filled the entire surface of the fibrous matrix after 2 weeks of growth in the cholangiocyte differentiation medium in vitro. The fabricated construct replaced the macroscopic part of the common bile duct (CBD) and re-stored the bile flow in a rabbit model of acute CBD injury. Animals that received the acellular scaffolds did not survive after the replacement surgery. Thus, the artificial bile duct constructs populated with patient-specific hepatic progenitor cells could provide a scalable and compatible platform for treating bile duct diseases.

Hepatic patch by stacking patient-specific liver progenitor cell sheets formed on multiscale electrospun fibers promotes regenerative therapy for liver injury.

Recently, use of cell sheets with bio-applicable fabrication materials for transplantation has been an attractive approach for the treatment of patients with liver failure. However, renewable and scalable cell sources for engineered tissue patches remain limited. We previously reported a new type of proliferating bipotent human chemically derived hepatic progenitor cells (hCdHs) developed by small molecule-mediated reprogramming. Here, we developed a patient-specific hepatic cell sheet constructed from liver biopsy-derived hCdHs on a multiscale fibrous scaffold by combining electrospinning and three-dimensional printing. Analysis of biomaterial composition revealed that the high-density electrospun sheet was superior in increasing the functional properties of hCdHs. Furthermore, the hepatic patch assembled by multilayer stacking with alternate cell sheets of hCdHs and human umbilical vein endothelial cells (HUVECs) recapitulated a liver tissue-like structure, with histological and morphological shape and size similar to those of primary human hepatocytes, and exhibited a significant increase in hepatic functions such as albumin secretion and activity of cytochrome P450 during in vitro hepatic differentiation compared with that in hCdH cells cultured in a two-dimensional monolayer. Interestingly, in the hepatic patch, the induction of functional hepatocytes was associated with both the electrospun fibrous-facilitated oncostatin M signaling and selective activation of AKT signaling by HUVECs. Notably, upon transplantation into a mouse model of therapeutic liver repopulation, the hepatic patch effectively repopulated the damaged parenchyma and induced the restoration of liver function with healthy morphology in the lobe and an improved survival rate (>70%) in mice. Overall, these results suggested that liver biopsy-derived hCdHs can be an efficient alternative source for developing hepatic cell sheets and patches with potential clinical applications in tissue engineering to advance liver regeneration.

A method to delineate de novo missense variants across pathways prioritizes genes linked to autism.

Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method to de novo missense variants in whole-exome sequences of individuals with autism spectrum disorder (ASD) to unravel genes and pathways connected to ASD. Evolutionary action predicts the impact of missense variants on protein function by measuring the fitness effect based on phylogenetic distances and substitution odds in homologous gene sequences. By examining de novo missense variants in 2384 individuals with ASD (probands) compared to matched siblings without ASD, we found missense variants in 398 genes representing 23 pathways that were biased toward higher evolutionary action scores than expected by random chance; these pathways were involved in axonogenesis, synaptic transmission, and neurodevelopment. The predicted fitness impact of de novo and inherited missense variants in candidate genes correlated with the IQ of individuals with ASD, even for new gene candidates. Taking an evolutionary action method, we detected those missense variants most likely to contribute to ASD pathogenesis and elucidated their phenotypic impact. This approach could be applied to integrate missense variants across a patient cohort to identify genes contributing to a shared phenotype in other complex diseases.

Transcriptomic insight into the translational value of two murine models in human atopic dermatitis.

This study sought to develop a novel diagnostic tool for atopic dermatitis (AD). Mouse transcriptome data were obtained via RNA-sequencing of dorsal skin tissues of CBA/J mice affected with contact hypersensitivity (induced by treatment with 1-chloro-2,4-dinitrobenzene) or brush stimulation-induced AD-like skin condition. Human transcriptome data were collected from German, Swedish, and American cohorts of AD patients from the Gene Expression Omnibus database. edgeR and SAM algorithms were used to analyze differentially expressed murine and human genes, respectively. The FAIME algorithm was then employed to assign pathway scores based on KEGG pathway database annotations. Numerous genes and pathways demonstrated similar dysregulation patterns in both the murine models and human AD. Upon integrating transcriptome information from both murine and human data, we identified 36 commonly dysregulated differentially expressed genes, which were designated as a 36-gene signature. A severity score (AD index) was applied to each human sample to assess the predictive power of the 36-gene AD signature. The diagnostic power and predictive accuracy of this signature were demonstrated for both AD severity and treatment outcomes in patients with AD. This genetic signature is expected to improve both AD diagnosis and targeted preclinical research.

Far-infrared rays enhance mitochondrial biogenesis and GLUT3 expression under low glucose conditions in rat skeletal muscle cells.

Far-infrared rays (FIR) are known to have various effects on atoms and molecular structures within cells owing to their radiation and vibration frequencies. The present study examined the effects of FIR on gene expression related to glucose transport through microarray analysis in rat skeletal muscle cells, as well as on mitochondrial biogenesis, at high and low glucose conditions. FIR were emitted from a bio-active material coated fabric (BMCF). L6 cells were treated with 30% BMCF for 24 h in medium containing 25 or 5.5 mM glucose, and changes in the expression of glucose transporter genes were determined. The expression of GLUT3 (Slc2a3) increased 2.0-fold (p < 0.05) under 5.5 mM glucose and 30% BMCF. In addition, mitochondrial oxygen consumption and membrane potential (ΔΨm) increased 1.5- and 3.4-fold (p < 0.05 and p < 0.001), respectively, but no significant change in expression of Pgc-1a, a regulator of mitochondrial biogenesis, was observed in 24 h. To analyze the relationship between GLUT3 expression and mitochondrial biogenesis under FIR, GLUT3 was down-modulated by siRNA for 72 h. As a result, the ΔΨm of the GLUT3 siRNA-treated cells increased 3.0-fold (p < 0.001), whereas that of the control group increased 4.6-fold (p < 0.001). Moreover, Pgc-1a expression increased upon 30% BMCF treatment for 72 h; an effect that was more pronounced in the presence of GLUT3. These results suggest that FIR may hold therapeutic potential for improving glucose metabolism and mitochondrial function in metabolic diseases associated with insufficient glucose supply, such as type 2 diabetes.

Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease.

The strongest genetic risk factor for idiopathic late-onset Alzheimer's disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease-free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau- or ß42-induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type-specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available.