Glucose metabolism and radiodensity of abdominal adipose tissue: A 5-year longitudinal study in a large PET cohort.

OBJECTIVE: 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) allows noninvasive assessment of glucose metabolism and radiodensity in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). We aimed to address the effects of ageing and metabolic factors on abdominal adipose tissue. DESIGN, PATIENTS AND MEASUREMENTS: We retrospectively analyzed data from 435 healthy men (mean 42.8 years) who underwent a health check-up programme twice, at baseline and the 5-year follow-up. The mean standardized uptake value (SUV) was measured using SAT and VAT and divided by the liver SUV. The mean Hounsfield units (HU) of the SAT and VAT were measured from the CT scans. The effects of clinical variable clusters on SUVR were investigated using Bayesian hierarchical modelling; metabolic cluster (BMI, waist-to-hip ratio, fat percentage, muscle percentage*-1, HOMA-IR), blood pressure (systolic, diastolic), glucose (fasting plasma glucose level, HbA1c) and C-reactive protein. RESULTS: All the clinical variables changed during the 5-year follow-up period. The SUVR and HU of the VAT increased during follow-up; however, those of the SAT did not change. SUVR and HU were positively correlated with both VAT and SAT. SAT and VAT SUVR were negatively associated with metabolic clusters. CONCLUSIONS: Ageing led to increased glucose metabolism and radiodensity in VAT, but not in SAT. VAT may reflect the ageing process more directly than SAT. Glucose metabolism was higher and radiodensity was lower in VAT than in SAT, probably owing to differences in gene expression and lipid density. Both glucose metabolism and radiodensity of VAT and SAT reflect metabolic status.

Demonstration of high-accuracy 3D imaging using a Si optical phased array with a tunable radiator.

Precise imaging in three-dimension (3D) is an essential technique for solid-state light detection and ranging (LiDAR). Among various solid-state LiDAR technologies, silicon (Si) optical phased array (OPA)-based LiDAR has the significant advantage of robust 3D imaging due to its high scanning speed, low power consumption, and compactness. Numerous techniques employing a Si OPA have utilized two-dimensional arrays or wavelength tuning for longitudinal scanning but the operation of those systems is restricted by additional requirements. Here, we demonstrate high-accuracy 3D imaging using a Si OPA with a tunable radiator. As we adapted a time-of-flight approach for distance measurement, we have developed an optical pulse modulator that allows a ranging accuracy of less than 2 cm. The implemented Si OPA is composed of an input grating coupler, multimode interferometers, electro-optic p-i-n phase shifters, and thermo-optic n-i-n tunable radiators. With this system, it is possible to attain a wide beam steering range of 45° in a transversal angle with a 0.7° divergence angle, and 10° in a longitudinal angle with a 0.6° divergence angle can be achieved using Si OPA. The character toy model was successfully imaged in three dimensions with a range resolution of 2 cm using the Si OPA. The further improvement of each component of the Si OPA will allow even more accurate 3D imaging over a longer distance.

Assessment of Escherichia coli-derived Recombinant Human Bone Morphogenic Protein-2 on Fertilization and Early Embryonic Development in Rats.

OBJECTIVE: Bone morphogenetic protein-2 (BMP-2) impacts fertility in women by affecting the menstrual cycle and embryonic development. We aimed to determine the reproductive toxicity of Escherichia coli (E. coli)-derived recombinant human BMP-2 (rhBMP-2) by measuring changes in the reproductive performance and organs in rhBMP-2-treated rats. METHODS: Overall, 88 male and female rats each were categorized into one control and three experimental groups. rhBMP-2 was intravenously administered to the experimental groups at 0.05, 0.15, and 0.50 mg/kg/day, respectively. The male rats were administered rhBMP-2 daily, starting from 28 days before mating until the day of necropsy (48 days), after which they were euthanized and necropsied. The female rats were administered rhBMP-2 daily, starting from 14 days before mating until 7 days after fertilization (22-36 days), after which they were necropsied 13 days after fertilization. RESULTS: No rhBMP-2-related death occurred throughout the study period. All rhBMP-2-treated groups showed swelling in the tail at the site of rhBMP-2 administration. In the high-dose rhBMP-2 group, the male rats showed a slight reduction in body weight and food consumption, whereas the female rats showed a reduction in the weights of the ovary and oviduct. Examining the fertilization status and necropsy showed no effect of rhBMP-2 on fertility and early embryonic development. The no-observed-adverse-effect level of rhBMP-2 was 0.50 mg/kg/day in all rats. CONCLUSION: rhBMP-2 had no reproductive toxicity on the reproductive performance and organs in female and male rats. Therefore, these results provide new toxicology information on E. coli-derived rhBMP-2 as a therapeutic protein.

Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1.

Mutations in the E3 ubiquitin ligase Parkin have been linked to familial Parkinson's disease. Parkin has also been implicated in mitosis through mechanisms that are unclear. Here we show that Parkin interacts with anaphase promoting complex/cyclosome (APC/C) coactivators Cdc20 and Cdh1 to mediate the degradation of several key mitotic regulators independent of APC/C. We demonstrate that ordered progression through mitosis is orchestrated by two distinct E3 ligases through the shared use of Cdc20 and Cdh1. Furthermore, Parkin is phosphorylated and activated by polo-like kinase 1 (Plk1) during mitosis. Parkin deficiency results in overexpression of its substrates, mitotic defects, genomic instability, and tumorigenesis. These results suggest that the Parkin-Cdc20/Cdh1 complex is an important regulator of mitosis.

Asivatrep, a TRPV1 antagonist, for the topical treatment of atopic dermatitis: Phase 3, randomized, vehicle-controlled study (CAPTAIN-AD).

BACKGROUND: Asivatrep is a potent and selective antagonist of transient receptor potential vanilloid subfamily V member 1 (TRPV1), which plays an important role in itch and inflammation in atopic dermatitis (AD). OBJECTIVE: This current study aimed to evaluate the efficacy and safety of asivatrep cream in patients with AD. METHODS: For this phase 3 double-blind, vehicle-controlled study, patients aged ≥12 years with mild to moderate AD were enrolled and randomly assigned 2:1 to the 1.0% asivatrep or vehicle group for 8 weeks of twice-daily application (n = 240). The primary end point was the proportion of patients with an Investigator's Global Assessment score (IGA) of 0 or 1 at week 8. Standard safety assessments were conducted. RESULTS: At week 8, significantly more patients in the asivatrep group (36.0%) than in the vehicle group (12.8%) had IGA scores of 0 or 1 (P < .001); significantly more had ≥2 points of improvement on the IGA from baseline score (20.3% vs 7.7%; P = .01). The mean percentage reduction in the Eczema Area and Severity Index (EASI) score was 44.3% for the asivatrep group and 21.4% for the vehicle group at week 8 (P < .001). Significantly more asivatrep-treated patients experienced an improvement of at least 50%, 75%, and 90% on the EASI than the vehicle group. The mean ± SD change in the pruritus visual analog scale score at week 8 was -2.3 ± 2.4 for the asivatrep group and -1.5 ± 2.4 for the vehicle group (P = .02). No significant safety issues were reported. CONCLUSION: Asivatrep improved clinical signs and symptoms of AD and was well tolerated.

Allogeneic Umbilical Cord-Blood-Derived Mesenchymal Stem Cells and Hyaluronate Composite Combined with High Tibial Osteotomy for Medial Knee Osteoarthritis with Full-Thickness Cartilage Defects.

Background and Objectives: Although the effects of cartilage repair in patients who are undergoing high tibial osteotomy (HTO) remains controversial, cartilage repair may be required for the full-thickness cartilage defect because of a concern of lower clinical outcome. The purpose of this study was to investigate clinical outcome and cartilage repair following implantation of allogeneic umbilical cord-blood-derived MSCs (UCB-MSCs)-hyaluronate composite in patients who received HTO for medial knee osteoarthritis (OA) with full-thickness cartilage defect. Materials and Methods: Inclusion criteria were patients with a medial knee OA, a full-thickness cartilage defect (International Cartilage Repair Society (ICRS) grade IV) ≥ 3 cm2 of the medial femoral condyle, and a varus deformity ≥ 5°. The full-thickness cartilage defect was treated with implantation of an allogeneic UCB-MSCs-hyaluronate composite following medial open-wedge HTO. Visual analogue scale for pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score were assessed at each follow-up. Cartilage repair was assessed by the ICRS cartilage repair assessment system at second-look arthroscopy when the plate was removed. Results: Twelve patients (mean age 56.1 years; mean defect size: 4.5 cm2) were included, and 10 patients underwent second-look arthroscopy during plate removal after a minimum of 1 year after the HTO. At the final follow-up of mean 2.9 years (range; 1-6 years), all clinical outcomes had improved. At second-look arthroscopy, repaired tissue was observed in all cases. One case (10%) showed grade I, seven (70%) cases showed grade II, and two (20%) cases showed grade III according to ICRS cartilage repair assessment system, which meant that 80% showed an overall repair assessment of "normal" or "nearly normal". Conclusion: Allogeneic UCB-MSCs-HA composite implantation combined with HTO resulted in favorable clinical outcome and cartilage repair in all cases. These findings suggest that UCB-MSCs-HA composite implantation combined with HTO would be a good therapeutic option for patients with knee OA and full-thickness cartilage defects.

Demonstration of beam steering using a passive silica optical phased array with wavelength tuning.

We demonstrate beam steering using a passive silica optical phased array (OPA) with wavelength tuning. In this OPA, a constant path difference is built up to assign sequential phase delays with a wavelength variation in arrayed waveguide channels for the beam steering. From as-fabricated 1 × 101 passive silica OPA chips, we successfully achieved beam forming with a transversal divergence angle of 0.57° at a 1548.3-nm wavelength and also beam steering of 15.4° by wavelength tuning of 30.7 nm. Combining a cylindrical lens in front of the end-fire radiators, the longitudinal divergence angle could be reduced from 13.0° to 0.42°. The side-mode suppression ratio of the beam was 10.3 dB at the center position. Through simulation, we analyzed the effects of the phase errors on the beam quality, due to the effective index fluctuation of the waveguide channels, and provided an allowable error range to attain beam forming from the passive OPA.

Brain Metabolic Correlates of Dopaminergic Denervation in Prodromal and Early Parkinson's Disease.

BACKGROUND: It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD). OBJECTIVE: To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD. METHODS: This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder (denovo PD), and 28 healthy controls (HCs) who underwent two positron emission tomography scans with 18 F-fluorodeoxyglucose (all participants) and 18 F-N-3-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)-nortropane (except for one denovo PD patient and 15 HCs). We analyzed striatal and voxel-wise whole-brain glucose metabolism in relation to nigrostriatal dopaminergic integrity and comparatively investigated the whole-brain metabolic connectivity among the groups. We also assessed longitudinal metabolic changes against progressive dopaminergic denervation over 4 years in the iRBD group. RESULTS: From HCs to iRBD and finally to the denovo PD, dopaminergic integrity positively correlated with metabolic activity in the caudate, whereas a negative correlation was observed in the posterior putamen. In the iRBD group, there was a metabolic increase in the inferior orbitofrontal cortex against putaminal dopaminergic denervation at baseline, but negative correlations were newly observed in the superior orbitofrontal cortex and superior frontal gyrus at the 4-year follow-up. The denovo PD group showed negative correlations in the cerebellum and fusiform gyrus. Intra- and inter-regional metabolic connectivities in the parieto-occipital cortices were enhanced in the iRBD group compared with the denovo PD and HC groups. In the iRBD group, overall metabolic connectivity was strengthened along with enhanced basal ganglia-frontal connection by advancing dopaminergic denervation. CONCLUSIONS: Our findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.

Whole-exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract.

BACKGROUND: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidneys, may also represent monogenic causes of CAKUT. METHODS: We here performed whole-exome sequencing (WES) in 541 families with CAKUT and generated four lists of CAKUT candidate genes: (A) 36 FOX genes showing high expression during renal development, (B) 4 FOX genes known to cause CAKUT to validate list A, (C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families and (D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. RESULTS: To prioritize potential novel CAKUT candidates in the FOX gene family, we overlapped 36 FOX genes (list A) with lists C and D of WES-derived CAKUT candidates. Intersection with list C identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. CONCLUSIONS: We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

Significant Therapeutic Effects of Adult Human Neural Stem Cells for Spinal Cord Injury Are Mediated by Monocyte Chemoattractant Protein-1 (MCP-1).

The limited capability of regeneration in the human central nervous system leads to severe and permanent disabilities following spinal cord injury (SCI) while patients suffer from no viable treatment option. Adult human neural stem cells (ahNSCs) are unique cells derived from the adult human brain, which have the essential characteristics of NSCs. The objective of this study was to characterize the therapeutic effects of ahNSCs isolated from the temporal lobes of focal cortical dysplasia type IIIa for SCI and to elucidate their treatment mechanisms. Results showed that the recovery of motor functions was significantly improved in groups transplanted with ahNSCs, where, in damaged regions of spinal cords, the numbers of both spread and regenerated nerve fibers were observed to be higher than the vehicle group. In addition, the distance between neuronal nuclei in damaged spinal cord tissue was significantly closer in treatment groups than the vehicle group. Based on an immunohistochemistry analysis, those neuroprotective effects of ahNSCs in SCI were found to be mediated by inhibiting apoptosis of spinal cord neurons. Moreover, the analysis of the conditioned medium (CM) of ahNSCs revealed that such neuroprotective effects were mediated by paracrine effects with various types of cytokines released from ahNSCs, where monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) was identified as a key paracrine mediator. These results of ahNSCs could be utilized further in the preclinical and clinical development of effective and safe cell therapeutics for SCI, with no available therapeutic options at present.

Introduction of Non-Native Ticks Collected from Fresh Migratory Bird Carcasses on a Stopover Island in the Republic of Korea.

When free-ranging birds are accidentally killed or die, there may be greater potential for their associated ticks to detach, seek alternate hosts, and become established. We examined 711 carcasses of 95 avian species for ticks at a stopover island of migratory birds in the Republic of Korea where only Ixodes nipponensis and I. persulcatus were previously reported from local mammals and vegetation. A total of 16 ticks, I. turdus and Haemaphysalis flava, were collected from 8 fresh carcasses belonging to 5 avian species. Despite their known abundance on migratory birds and mainland Korea, these species had not colonized the isolated insular ecosystem possibly due to the low abundance and diversity of local hosts. The results imply that increasing human impact, such as the anthropogenic mortality of migratory birds and the introduction of non-native mammalian hosts, will increase the potential invasion and colonization risk of ticks. This finding also suggests that tick surveillance consisting of fresh carcasses of dead migratory birds may provide additional information, often ignored in surveillance of ticks on live birds, for the potential introduction of non-native ticks and associated pathogens affecting animal and human health.

Process of Obtaining Social Consensus and 3-Year Functional Outcomes of the First Hand Allotransplantation in Korea.

BACKGROUND: On February 2, 2017, the surgical team of ten board-certified hand specialists of W Hospital in Korea successfully performed the nation's first hand transplantation at Yeungnam University Medical Center (YUMC). This paper reports on the legal, financial, and cultural hurdles that were overcome to open the way for hand transplantation and its functional outcomes at 36 months after the operation. METHODS: W Hospital formed a memorandum of understanding with Daegu city and YUMC to comply with government regulations regarding hand transplantation. Campaigns were initiated in the media to increase public awareness and understanding. With the city's financial and legal support and the university's medical cooperation, a surgical team performed a left distal forearm hand transplantation from a brain-dead 48-year-old man to a 35-year-old left-handed man. RESULTS: With this successful allotransplantation, the Korean Act on Organ Transplantation has now been amended to include hand transplantation. Korean national health insurance has also begun covering hand transplantation. Functional outcome at 36 months after the operation showed satisfactory progress in both motor and sensory functions. The disabilities of the arm, shoulder, and hand score were 23. The final Hand Transplantation Score was 90 points. Functional brain magnetic resonance imaging shows significant cortical reorganization of the corticospinal tract, and reinnervation of intrinsic muscle is observed. CONCLUSIONS: Hand transplantation at the distal forearm shows very satisfactory outcomes in functional, aesthetical, and psychological aspects. Legal and financial barriers against hand transplantation have long been the most burdensome issues. Despite this momentous success, there have been no other clinical applications of vascularized composite allotransplantation due to the limited acceptance by Korean doctors and people. Further public education campaigns for vascularized composite allotransplantation are needed to increase awareness and acceptance.

The effect of listening to SMT music made using musical expectancy violations on brain concentration and activation.

This study investigated the effect of listening to self-music therapy training (SMT) music, which was specially developed using musical expectancy violations, on improving brain concentration and activation. It was performed with a sample of 12 adults. Electroencephalograms (EEG) were obtained and analyzed after allowing the participants to listen to SMT music. An EEG device with eight channels was used to measure the brain waves. The changes in the EEGs were recorded when listening to SMT music in three states (stable, basic, and stimulated) after attaching the electrodes to the prefrontal cortex (Fp1 and Fp2), and the frontal (F3 and F4), temporal (T3 and T4), and parietal lobes (P3 and P4) according to the International 10/20 system. The EEG data were analyzed to determine the m-ß wave appearance rate and absolute total power (ATP) for the three conditions, and a t-test was performed. The results showed that the rate of m-ß wave appearance was higher in the stimulated and basic states than in the stable state (Fp1, Fp2, F4, T3, T4, P3, and P4) and higher in the stimulated state than in the basic state (Fp1, Fp2, T3, T4, and P4). The ATP was lower in the basic state than in the stable state (Fp2, F3, F4, and T3), but the ATP in the stimulated state was higher than in the basic or stable state in all areas excluding the left and right parietal lobes (Fp1, Fp2, F3, F4, T3, and T4). These results demonstrated that listening to SMT music by normal adults could increase brain concentration and activation.

Optimal Preclinical Conditions for Using Adult Human Multipotent Neural Cells in the Treatment of Spinal Cord Injury.

Stem cell-based therapeutics are amongst the most promising next-generation therapeutic approaches for the treatment of spinal cord injury (SCI), as they may promote the repair or regeneration of damaged spinal cord tissues. However, preclinical optimization should be performed before clinical application to guarantee safety and therapeutic effect. Here, we investigated the optimal injection route and dose for adult human multipotent neural cells (ahMNCs) from patients with hemorrhagic stroke using an SCI animal model. ahMNCs demonstrate several characteristics associated with neural stem cells (NSCs), including the expression of NSC-specific markers, self-renewal, and multi neural cell lineage differentiation potential. When ahMNCs were transplanted into the lateral ventricle of the SCI animal model, they specifically migrated within 24 h of injection to the damaged spinal cord, where they survived for at least 5 weeks after injection. Although ahMNC transplantation promoted significant locomotor recovery, the injection dose was shown to influence treatment outcomes, with a 1 × 106 (medium) dose of ahMNCs producing significantly better functional recovery than a 3 × 105 (low) dose. There was no significant gain in effect with the 3 × 106 ahMNCs dose. Histological analysis suggested that ahMNCs exert their effects by modulating glial scar formation, neuroprotection, and/or angiogenesis. These data indicate that ahMNCs from patients with hemorrhagic stroke could be used to develop stem cell therapies for SCI and that the indirect injection route could be clinically relevant. Moreover, the optimal transplantation dose of ahMNCs defined in this preclinical study might be helpful in calculating its optimal injection dose for patients with SCI in the future.

Relationship between 18F-FDG uptake and heat shock protein 90α expression in colorectal cancer.

OBJECTIVE: We investigated whether heat shock protein 90α (HSP90α) expression is associated with fluorine-18-labeled fluoro-2-deoxy-D-glucose (18F-FDG) uptake and whether 18F-FDG positron emission tomography/computed tomography (PET/CT) can be used to predict the status of HSP90α expression in colorectal cancer (CRC). SUBJECTS AND METHODS: The medical records and preoperative 18F-FDG PET/CT studies of 51 patients with newly diagnosed CRC who underwent surgical treatment were retrospectively reviewed. The maximum standardized uptake value (SUVmax) of the primary tumor was calculated from the level of 18F-FDG uptake. HSP90α expression was determined by immunohistochemistry. The relationship between SUVmax and HSP90α expression was analyzed. RESULTS: Colorectal cancer with high HSP90α expression had significantly higher SUVmax than CRC with low HSP90α expression (18.88±10.06 vs. 12.38±5.04, P=0.003). There was a significant correlation between HSP90α expression and 18F-FDG uptake (r=0.354, P=0.011). The highest accuracy for determining HSP90α status (68.6%) was obtained with a SUVmax cut-off of 15.4. Maximum SUV was the only predictor of HSP90α expression on multivariate logistic regression analysis (Odds Ratio=5.384, P=0.016). CONCLUSION: The expression status of HSP90α was significantly related to 18F-FDG uptake in CRC.

Effect of Group-Task-Oriented Training on Gross and Fine Motor Function, and Activities of Daily Living in Children with Spastic Cerebral Palsy.

Aims: To determine the effects of group-task-oriented training (group-TOT) on gross and fine motor function, activities of daily living (ADL) and social function of children with spastic cerebral palsy (CP).Methods: Eighteen children with spastic CP (4-7.5 years, gross motor function classification system level I-III) were randomly assigned to the Group-TOT (9 children received group-TOT for 1 hour, twice a week for 8 weeks) or the comparison group (9 children received individualized traditional physical and occupational therapy). The Gross Motor Function Measure (GMFM)-88, the Bruininks-Oseretsky Test of Motor Proficiency 2nd edition (BOT-2), and the Pediatric Evaluation of Disability Inventory (PEDI) were administered before and after the intervention, and in the Group-TOT, 16 weeks after the intervention.Results: Children in the Group-TOT showed significant improvements in the GMFM-88 standing and walking/running/jumping subscales, the BOT-2 manual dexterity subscale, and the PEDI social function subscale (p < 0.05); changes were maintained 16 weeks after the intervention ended. In contrast, the comparison group improved in only the BOT-2 fine motor integration subscale (p < 0.05).Conclusions: The findings provide evidence of effectiveness of group-TOT in improving gross and fine motor function, and social function in children with CP.

Effect of health consciousness behavior and health-promoting behavior on the quality of life in elders in South Korea.

[Purpose] This study aimed to examine the correlation between health consciousness behavior and health-promoting behavior and quality of life, and to examine the factors affecting the quality of life for elders in South Korea. [Participants and Methods] This study is a cross-sectional study. A total of 191 respondents were selected through convenient sampling. Data were collected with a self-reported questionnaire from August 20 to September 20, 2019. [Results] Differences in health consciousness behavior and health-promoting behavior according to general characteristics and health behavior were as follows. Health consciousness behavior was significantly different according to gender, age, education, religion, occupation, exercise, smoking, drinking, health checkup. Health health-promoting behavior was significantly different according to gender, age, education, stress, health status, drinking. Quality of life was significantly different according to education, stress, health status, exercise, drinking. There was a positive correlation between health-promoting behavior and quality of life. Fifty three point zero percent of the variance in quality of life was explained by health-promoting behavior, health status and exercise. [Conclusion] The findings of this study may be useful in understanding the quality of life for elders and developing more specific programs about health-promoting behavior programs and health status and exercise management strategy is required.

Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling.

BACKGROUND: The FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML). However, the effects of dasatinib on microglial and/or astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail. METHODS: BV2 microglial cells, primary astrocytes, or primary microglial cells were treated with dasatinib (100 or 250 nM) or vehicle (1% DMSO) for 30 min or 2 h followed by lipopolysaccharide (LPS; 200 ng/ml or 1 µg/ml) or PBS for 5.5 h. RT-PCR, real-time PCR; immunocytochemistry; subcellular fractionation; and immunohistochemistry were subsequently conducted to determine the effects of dasatinib on LPS-induced neuroinflammation. In addition, wild-type mice were injected with dasatinib (20 mg/kg, intraperitoneally (i.p.) daily for 4 days or 20 mg/kg, orally administered (p.o.) daily for 4 days or 2 weeks) or vehicle (4% DMSO + 30% polyethylene glycol (PEG) + 5% Tween 80), followed by injection with LPS (10 mg/kg, i.p.) or PBS. Then, immunohistochemistry was performed, and plasma IL-6, IL-1ß, and TNF-α levels were analyzed by ELISA. RESULTS: Dasatinib regulates LPS-induced proinflammatory cytokine and anti-inflammatory cytokine levels in BV2 microglial cells, primary microglial cells, and primary astrocytes. In BV2 microglial cells, dasatinib regulates LPS-induced proinflammatory cytokine levels by regulating TLR4/AKT and/or TLR4/ERK signaling. In addition, intraperitoneal injection and oral administration of dasatinib suppress LPS-induced microglial/astrocyte activation, proinflammatory cytokine levels (including brain and plasma levels), and neutrophil rolling in the brains of wild-type mice. CONCLUSIONS: Our results suggest that dasatinib modulates LPS-induced microglial and astrocytic activation, proinflammatory cytokine levels, and neutrophil rolling in the brain.

Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis.

Germline mutations in SPRTN cause Ruijs-Aalfs syndrome (RJALS), a disorder characterized by genome instability, progeria and early onset hepatocellular carcinoma. Spartan, the protein encoded by SPRTN, is a nuclear metalloprotease that is involved in the repair of DNA-protein crosslinks (DPCs). Although Sprtn hypomorphic mice recapitulate key progeroid phenotypes of RJALS, whether this model expressing low amounts of Spartan is prone to DPC repair defects and spontaneous tumors is unknown. Here, we showed that the livers of Sprtn hypomorphic mice accumulate DPCs containing Topoisomerase 1 covalently linked to DNA. Furthermore, these mice exhibited DNA damage, aneuploidy and spontaneous tumorigenesis in the liver. Collectively, these findings provide evidence that partial loss of Spartan impairs DPC repair and tumor suppression.

Constitutive activation of T cells by γ2-herpesviral GPCR through the interaction with cellular CXCR4.

Members of the herpesviral family use multiple strategies to hijack infected host cells and exploit cellular signaling for their pathogenesis and latent infection. Among the most intriguing weapons in the arsenal of pathogenic herpesviruses are the constitutively active virally-encoded G protein-coupled receptors (vGPCRs). Even though vGPCRs contribute to viral pathogenesis such as immune evasion and proliferative disorders, the molecular details of how vGPCRs continuously activate cellular signaling are largely unknown. Here, we report that the vGPCR of Herpesvirus saimiri (HVS), an oncogenic γ2-herpesvirus, constitutively activates T cells via a heteromeric interaction with cellular CXCR4. Constitutive T cell activation also occurs with expression of the vGPCR of Kaposi's sarcoma-associated herpesvirus (KSHV), but not the vGPCR of Epstein-Barr virus. Expression of HVS vGPCR down-regulated the surface expression of CXCR4 but did not induce the degradation of the chemokine receptor, suggesting that vGPCR/CXCR4 signaling continues in cytosolic compartments. The physical association of vGPCR with CXCR4 was demonstrated by proximity ligation assay as well as immunoprecipitation. Interestingly, the constitutive activation of T cells by HVS vGPCR is independent of proximal T cell receptor (TCR) signaling molecules, such as TCRß, Lck, and ZAP70, whereas CXCR4 silencing by shRNA abolished T cell activation by vGPCRs of HVS and KSHV. Furthermore, previously identified inactive vGPCR mutants failed to interact with CXCR4. These findings on the positive cooperativity of vGPCR with cellular CXCR4 in T cell activation extend our current understanding of the molecular mechanisms of vGPCR function and highlight the importance of heteromerization for GPCR activity.