A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding.

The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, results mainly from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lissencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion, that oRGs are necessary for neocortical folding, and that defects in oRG expansion may cause primary microcephaly.

SAN: Mitigating spatial covariance heterogeneity in cortical thickness data collected from multiple scanners or sites.

In neuroimaging studies, combining data collected from multiple study sites or scanners is becoming common to increase the reproducibility of scientific discoveries. At the same time, unwanted variations arise by using different scanners (inter-scanner biases), which need to be corrected before downstream analyses to facilitate replicable research and prevent spurious findings. While statistical harmonization methods such as ComBat have become popular in mitigating inter-scanner biases in neuroimaging, recent methodological advances have shown that harmonizing heterogeneous covariances results in higher data quality. In vertex-level cortical thickness data, heterogeneity in spatial autocorrelation is a critical factor that affects covariance heterogeneity. Our work proposes a new statistical harmonization method called spatial autocorrelation normalization (SAN) that preserves homogeneous covariance vertex-level cortical thickness data across different scanners. We use an explicit Gaussian process to characterize scanner-invariant and scanner-specific variations to reconstruct spatially homogeneous data across scanners. SAN is computationally feasible, and it easily allows the integration of existing harmonization methods. We demonstrate the utility of the proposed method using cortical thickness data from the Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) study. SAN is publicly available as an R package.

Preclinical evaluation of an 18F-labeled Tenascin-C aptamer for PET imaging of atherosclerotic plaque in mouse models of atherosclerosis.

Tenascin-C is an extracellular matrix glycoprotein strongly expressed in coronary atherosclerotic plaque. Aptamers are single-stranded oligonucleotides that bind to specific target molecules with high affinity. This study hypothesized that tenascin-C expression at atherosclerotic plaque in vivo could be detected by tenascin-C specific aptamers using positron emission tomography (PET). This paper reports the radiosynthesis of a fluorine-18 (18F)-labeled tenascin-C aptamer for the biodistribution and PET imaging of the tenascin-C expression in apolipoprotein E-deficient (ApoE-/-) mice. The aortas ApoE-/- mice showed significantly increased positive areas of Oil red O staining than control C57BL/6 mice, and tenascin-C expression was detected in foam cells accumulated in the subendothelial lesions of ApoE-/- mice. The ex vivo biodistribution of the 18F-labeled tenascin-C aptamer showed significantly increased uptake at the aorta of ApoE-/- mice, and ex vivo autoradiography of aorta revealed the high accumulation of the 18F-labeled tenascin-C aptamer in the atherosclerotic lesions of ApoE-/- mice, which was consistent with the location of the atherosclerotic plaques detected by Oil red O staining. PET imaging of the 18F-labeled tenascin-C aptamer revealed a significantly higher mean standardized uptake in the aorta of the ApoE-/- mice than the control C57BL/6 mice. These data highlight the potential use of tenascin-C aptamer to diagnose atherosclerotic lesions in vivo.

Machine learning-based quantification for disease uncertainty increases the statistical power of genetic association studies.

MOTIVATION: Allowance for increasingly large samples is a key to identify the association of genetic variants with Alzheimer's disease (AD) in genome-wide association studies (GWAS). Accordingly, we aimed to develop a method that incorporates patients with mild cognitive impairment and unknown cognitive status in GWAS using a machine learning-based AD prediction model. RESULTS: Simulation analyses showed that weighting imputed phenotypes method increased the statistical power compared to ordinary logistic regression using only AD cases and controls. Applied to real-world data, the penalized logistic method had the highest AUC (0.96) for AD prediction and weighting imputed phenotypes method performed well in terms of power. We identified an association (P<5.0×10-8) of AD with several variants in the APOE region and rs143625563 in LMX1A. Our method, which allows the inclusion of individuals with mild cognitive impairment, improves the statistical power of GWAS for AD. We discovered a novel association with LMX1A. AVAILABILITY AND IMPLEMENTATION: Simulation codes can be accessed at https://github.com/Junkkkk/wGEE_GWAS.

Human ST3Gal II and ST6GalNAc IV genes increase human serum-mediated cytotoxicity to xenogeneic cells.

Carbohydrate-antigens widely existed on glycoproteins and glycosphingolipids of all mammalian cells play a crucial role in self-defense and immunity. Xeno-reactive antibodies included in natural human sera play a protecting role in an acute phase-rejection of xenotransplantation. In this study, we investigated the effect of an alteration of glycosylation-pattern, caused by human sialyltransferases such as hST3Gal II or hST6GalNAc IV, on human serum mediated cytotoxicity in pig kidney PK15 cells. From LDH cytotoxicity assay, cytotoxicity to human serum was significantly increased in hST3Gal II and hST6GalNAc IV-transfected PK15 cells, as compared to the control. In the hST6Gal I-carrying cells, the cytotoxicity to human serum was rather decreased. Moreover, flow cytometry analysis revealed that an alteration of pig glycosylation-pattern by hST3Gal II or hST6GalNAc IV influences on a binding of human IgM or IgG, respectively, in pig kidney cells, regardless of Gal antigen alteration. Finally, we found that hST6GalNAc IV contributed to increase of terminal disialylated tetrasaccharide structure, disialyl T antigen, as evidenced by increase of the MAL II lectin binding capacity in the hST6GalNAc IV-transfected PK15 cells, compared with control. Therefore, our results suggest that carbohydrate antigens, such as disialyl T antigen, newly synthesized by the ST3Gal II- and ST6GalNAc IV are potentially believed to be new xeno-reactive elements.

Single voxel autocorrelation uncovers gradients of temporal dynamics in the hippocampus and entorhinal cortex during rest and navigation.

During navigation, information at multiple scales needs to be integrated. Single-unit recordings in rodents suggest that gradients of temporal dynamics in the hippocampus and entorhinal cortex support this integration. In humans, gradients of representation are observed, such that granularity of information represented increases along the long axis of the hippocampus. The neural underpinnings of this gradient in humans, however, are still unknown. Current research is limited by coarse fMRI analysis techniques that obscure the activity of individual voxels, preventing investigation of how moment-to-moment changes in brain signal are organized and how they are related to behavior. Here, we measured the signal stability of single voxels over time to uncover previously unappreciated gradients of temporal dynamics in the hippocampus and entorhinal cortex. Using our novel, single voxel autocorrelation technique, we show a medial-lateral hippocampal gradient, as well as a continuous autocorrelation gradient along the anterolateral-posteromedial entorhinal extent. Importantly, we show that autocorrelation in the anterior-medial hippocampus was modulated by navigational difficulty, providing the first evidence that changes in signal stability in single voxels are relevant for behavior. This work opens the door for future research on how temporal gradients within these structures support the integration of information for goal-directed behavior.

Predicting mild cognitive impairments from cognitively normal brains using a novel brain age estimation model based on structural magnetic resonance imaging.

Brain age prediction is a practical method used to quantify brain aging and detect neurodegenerative diseases such as Alzheimer's disease (AD). However, very few studies have considered brain age prediction as a biomarker for the conversion of cognitively normal (CN) to mild cognitive impairment (MCI). In this study, we developed a novel brain age prediction model using brain volume and cortical thickness features. We calculated an acceleration of brain age (ABA) derived from the suggested model to estimate different diagnostic groups (CN, MCI, and AD) and to classify CN to MCI and MCI to AD conversion groups. We observed a strong association between ABA and the 3 diagnostic groups. Additionally, the classification models for CN to MCI conversion and MCI to AD conversion exhibited acceptable and robust performances, with area under the curve values of 0.66 and 0.76, respectively. We believe that our proposed model provides a reliable estimate of brain age for elderly individuals and can identify those at risk of progressing from CN to MCI. This model has great potential to reveal a diagnosis associated with a change in cognitive decline.

Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians.

This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer's and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.

Comparison emergence of sedation, using dexmedetomidine and remimazolam, in spinal anaesthesia - double blinded randomized controlled trial.

Background: Continuous intravenous infusion of remimazolam may be suitable for sedation in patients undergoing regional anaesthesia. However, there have been no studies comparing remimazolam and dexmedetomidine for this purpose. This study compared emergence from sedation between dexmedetomidine and remimazolam following continuous intravenous infusion in patients undergoing spinal anaesthesia. Methods: This double-blinded, randomised controlled trial assessed the sedative effects of dexmedetomidine and remimazolam. Following spinal anaesthesia, patients were sedated using continuous intravenous infusion of either dexmedetomidine (D group) or remimazolam (R group).The D group received dexmedetomidine administered at 6 mL/kg/h (6 µg/kg/h) for 10 minutes, followed by 1 mL/kg/h (1 µg/kg/h). The R group received remimazolam administered at 6 mL/kg/h (6 mg/kg/h) for 10 minutes, followed by 1 mL/kg/h (1 mg/kg/h). Sedation levels were evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The time to reach MOAA/S ≤ 3 from the start of drug infusion and the time to reach MOAA/S = 5 from the end of infusion were recorded. Hemodynamic parameters and respiratory rate were also monitored. Results: The R group reached MOAA/S ≤ 3 significantly faster than the D group during induction of sedation (4 ± 1 minutes and 11 ± 3 minutes, respectively, p < 0.001). The R group also reached MOAA/S = 5 significantly faster than the D group during emergence from sedation (11 ± 3 minutes and 16 ± 5 minutes, respectively, p < 0.001). Both groups maintained stable hemodynamic parameters and respiratory rate without any significant differences, although the mean heart rate was significantly lower in the D group than in the R group after the start of infusion. Conclusion: Remimazolam demonstrated significantly faster induction of and emergence from sedation compared to dexmedetomidine, with no significant differences in haemodynamics or respiratory depression.

Evaluating Pain Management from Peripheral Nerve Block for Geriatric Patients following Bipolar Hemiarthroplasty for Displaced Femoral-Neck Fracture.

INTRODUCTION: The purpose of this study was to evaluate peripheral nerve block (PNB) effectiveness in postoperative pain management and surgical outcomes for displaced femoral-neck fracture in geriatric patients (>70 years) who underwent bipolar hemiarthroplasty (BHA). METHODS: From January 2017 to December 2021, 231 geriatric patients with displaced femoral-neck fracture who consecutively underwent BHA were retrospectively reviewed. Patients were divided into two groups: the patient-controlled analgesia (PCA) group (n = 132) who received only intravenous (IV) PCA for postoperative pain management, and all others who received PNB with IV PCA (PNB+PCA) such as femoral nerve block or fascia iliaca compartment block after surgery (n = 99). Primary outcomes were postoperative visual analog scale (VAS) at rest and during activity at 6, 24, and 48 h postoperatively. Secondary outcomes were postoperative complications, changes in hemoglobin, length of hospital stay, and total morphine usage after surgery. RESULTS: Postoperative resting VAS at 6 h and 48 h was significantly lower in the PNB+PCA group compared with the PCA group (p = 0.075, p = 0.0318, respectively). However, there was no significant difference in either resting VAS at 24 h or active VAS. Complications of pneumonia and delirium until 1 month postoperative were significantly lower in the PNB + PCA group than the PCA group (p = 0.0022, p = 0.0055, respectively). CONCLUSION: PNB with IV PCA seems to have a beneficial effect on geriatric femoral-neck patients who underwent BHA with postoperative analgesia for reducing postoperative resting pain and complications, especially pneumonia and delirium.

Chemical Hypoxia Induces Pyroptosis in Neuronal Cells by Caspase-Dependent Gasdermin Activation.

Hypoxia-induced neuronal death is a major cause of neurodegenerative diseases. Pyroptosis is a type of inflammatory programmed cell death mediated by elevated intracellular levels of reactive oxygen species (ROS). Therefore, we hypothesized that hypoxia-induced ROS may trigger pyroptosis via caspase-dependent gasdermin (GSDM) activation in neuronal cells. To test this, we exposed SH-SY5Y neuronal cells to cobalt chloride (CoCl2) to trigger hypoxia and then evaluated the cellular and molecular responses to hypoxic conditions. Our data revealed that CoCl2 induced cell growth inhibition and the expression of hypoxia-inducible factor-1α in SH-SY5Y cells. Exposure to CoCl2 elicits excessive accumulation of cytosolic and mitochondrial ROS in SH-SY5Y cells. CoCl2-induced hypoxia not only activated the intrinsic (caspases-3, -7, and -9) apoptotic pathway but also induced caspase-3/GSDME-dependent and NLRP3/caspase-1/GSDMD-mediated pyroptosis in SH-SY5Y cells. Importantly, inhibition of caspase-3 and -1 using selective inhibitors ameliorated pyroptotic cell death and downregulated GSDM protein expression. Additionally, treatment with a ROS scavenger significantly suppressed caspase- and pyroptosis-related proteins in CoCl2-treated SH-SY5Y cells. Our findings indicate that hypoxia-mediated ROS production plays an important role in the activation of both apoptosis and pyroptosis in SH-SY5Y neuronal cells, thus providing a potential therapeutic strategy for hypoxia-related neurological diseases.

Risk factors for early septic failure after two-stage exchange total knee arthroplasty for treatment of periprosthetic joint infection.

BACKGROUND: The cause of early septic failure after two-stage exchange revision total knee arthroplasty (TKA) for chronic periprosthetic joint infection (PJI) and the factors affecting it are not well known. The purpose of this study was to determine the surgical outcomes and the risk factors for early septic failure after two-stage revision TKA for chronic PJI. METHODS: We identified a total of 246 adult patients who met the Musculoskeletal Infection Society (MSIS) diagnostic criteria for chronic PJI at two academic tertiary hospitals from March 2012 to December 2018. Finally, 151 patients who consecutively received two-stage exchange revision TKA for chronic PJI and who had a minimum 3-year follow-up were enrolled and retrospectively reviewed. Successful surgical treatment was evaluated for two-stage revision TKA and risk factors for early septic failure were identified. RESULTS: Early septic failures occurred within 3 years after reimplantation in 48 patients (31.8%). After accounting for potentially confounding variables, we found that male patient [odds ratio (OR): 2.753, 95% confidence interval (CI) 1.099-6.893, p = 0.031], fungus or mycobacterial infection (OR: 5.224, 95% CI 1.481-18.433, p = 0.01), and positive culture at reimplantation (OR: 4.407, 95% CI 1.255-15.480, p = 0.021) were independently associated with early septic failure after two-stage exchange revision TKA. CONCLUSION: Male patients, fungus or mycobacterial infection, and positive culture at reimplantation were independently associated with an increased risk of early septic failure after two-stage exchange revision TKA despite normal C-reactive protein values prior to reimplantation. Further prospective and high-quality studies are needed to determine the risk factors of two-stage exchange revision TKA for chronic PJI. LEVEL OF EVIDENCE: level IV; retrospective comparison; treatment study.

Virus-induced gene silencing for in planta validation of gene function in cucurbits.

Virus-induced gene silencing (VIGS) is a powerful tool for high-throughput analysis of gene function. Here, we developed the VIGS vector pCF93, from which expression of the cucumber fruit mottle mosaic virus genome is driven by the cauliflower mosaic virus 35S promoter to produce viral transcripts in inoculated plants. To test the utility of the pCF93 vector, we identified candidate genes related to male sterility (MS) in watermelon (Citrullus lanatus), which is recalcitrant to genetic transformation. Specifically, we exploited previously reported reference-based and de novo transcriptome data to define 38 differentially expressed genes between a male-sterile line and its fertile near-isogenic line in the watermelon cultivar DAH. We amplified 200- to 300-bp fragments of these genes, cloned them into pCF93, and inoculated DAH with the resulting VIGS clones. The small watermelon cultivar DAH enabled high-throughput screening using a small cultivation area. We simultaneously characterized the phenotypes associated with each of the 38 candidate genes in plants grown in a greenhouse. Silencing of 8 of the 38 candidate genes produced male-sterile flowers with abnormal stamens and no pollen. We confirmed the extent of gene silencing in inoculated flowers using reverse transcription-qPCR. Histological analysis of stamens from male-fertile and male-sterile floral buds and mature flowers revealed developmental defects and shrunken pollen sacs. Based on these findings, we propose that the pCF93 vector and our VIGS system will facilitate high-throughput analysis for the study of gene function in watermelons.

Impact of Chart-Derived Frailty Index on 1-Year Mortality After Radical Cystectomy in 1004 Patients with Bladder Cancer.

BACKGROUND: Radical cystectomy is a major urological procedure with high morbidity and mortality. The chart-derived frailty index (CFI), a measure of preoperative frailty, can be calculated by using demographic and routine laboratory variables. We assessed the impact of CFI on 1-year mortality after radical cystectomy. METHODS: This retrospective study included patients with bladder cancer who underwent radical cystectomy between 2007 and 2021. The CFI was calculated as the sum of the presence of the following parameters: age > 70 years, body mass index < 18.5 kg/m2, hematocrit < 35%, albumin < 3.4 g/dL, and creatinine > 2.0 mg/dL. Patients were divided into those with low (0-2) and high (3-5) CFI. The 1-year, all-cause and cancer-specific mortalities after radical cystectomy were evaluated. RESULTS: Of the 1004 patients, 914 (91.0%) had a low CFI and 90 (9.0%) had a high CFI. The 1-year, all-cause mortality in the low and high CFI groups was 12.0% and 27.8%, respectively (P < 0.001). Multivariate Cox regression analysis revealed that high CFI (P < 0.001), tumor stage (P = 0.003), and red blood cell transfusion amount (P < 0.001) were significantly associated with 1-year, all-cause mortality after radical cystectomy. Kaplan-Meier survival analysis demonstrated significantly different 1-year, all-cause and cancer-specific mortalities after radical cystectomy between patients with a high CFI and those with a low CFI (log-rank test, both P < 0.001). CONCLUSIONS: High CFI is associated with higher 1-year mortality after radical cystectomy, suggesting that the CFI can effectively predict mortality after radical cystectomy.

Efficacy of bougie dilation for normal diet in benign esophageal stricture.

OBJECTIVES: Bougination is one of the first-line treatments in benign esophageal stricture (BES). The aim of the study was to identify clinical and endoscopic factors affecting the achievement of a normal diet with only bougie dilation in patients with BES. PATIENTS AND METHODS: Patients treated with only bougination for BES at three hospitals were retrospectively investigated. Data including patient demographics, stricture and procedural characteristics were collected. Clinical success was defined as normal diet without additional procedures for two months after bougination. Clinical success rate and associated factors were assessed. RESULTS: A total of 121 patients with BES were included. The most common cause of BES was post-operative stricture (n = 55). Finally, 43 (36%) patients were able to eat a normal diet with only bougination. Of these patients, 42 (97.7%) achieved clinical success in the first three sessions or less. Among causes of stenosis, corrosive injury had the lowest success rate (9/40, 22.5%). Clinical success rate was significantly higher for those with the length of stricture of less than 2 cm (47.2%), those with pre-procedural dysphagia of semi-solid or soft diet (51.3%) and those with dilation of 13 mm or more (46.1%). However, the duration of symptom, the number of previous endoscopic treatments and the location of stenosis were not related to clinical success. CONCLUSIONS: Normal diet is possible in one-third of BES after bougination alone. Predictable factors for achieving a normal diet were less than four sessions of dilation, short length of stricture, pre-procedural dysphagia status and diameter of dilator.

Overcoming multidrug-resistant lung cancer by mitochondrial-associated ATP inhibition using nanodrugs.

Despite the development of therapeutic modalities to treat cancer, multidrug resistance (MDR) and incomplete destruction of deeply embedded lung tumors remain long-standing problems responsible for tumor recurrence and low survival rates. Therefore, developing therapeutic approaches to treat MDR tumors is necessary. In this study, nanodrugs with enhanced intracellular drug internalization were identified by the covalent bonding of carbon nanotubes of a specific nano size and doxorubicin (DOX). In addition, carbon nanotube conjugated DOX (CNT-DOX) sustained in the intracellular environment in multidrug-resistant tumor cells for a long time causes mitochondrial damage, suppresses ATP production, and results in the effective therapeutic effect of drug-resistant tumors. This study identified that H69AR lung cancer cells, an adriamycin (DOX) drug-resistant tumor cell line, did not activate drug resistance function on designed nano-anticancer drugs with a specific nano size. In summary, this study identified that the specific size of the nanodrug in combination with DOX overcame multidrug-resistant tumors by inducing selective accumulation in tumor cells and inhibiting ATP by mitochondrial damage.

Long-term end-stage renal disease risks after living kidney donation: a systematic review and meta-analysis.

BACKGROUND: Recent studies have shown that donor nephrectomy can induce renal function impairment. However, few meta-analysis studies about this have proceeded. Therefore, the objective of this systematic review and meta-analysis including all data of recent research studies was to determine whether living donor nephrectomy (LDN) could induce renal function impairment. METHODS: By November 2020, comprehensive literature searches were performed on PubMed, Embase, and Cochrane databases. Inclusion criteria were: (1) observational studies with data about overall end-stage renal disease (ESRD) or chronic kidney disease (CKD) of living kidney donors, (2) control group consisted of people without donor nephrectomy, and (3) outcomes of studies included long-term end-stage renal disease risks after living kidney donation. Risk of Bias in Non-randomized Studies of interventions (ROBINS-I) assessment tool was used to evaluate our methodological quality. RESULTS: The qualitative review included 11 studies and the meta-analysis included 5 studies. In the meta-analysis, the integrated overall ESRD risk was 5.57 (95% CI: 2.03-15.30). Regarding the overall risk of bias using ROBINS-I assessment tool, 0 studies was rated as "Low", 7 studies were rated as "moderate", 2 studies were rated as "Serious", and two studies were rated as "Critical". CONCLUSIONS: Our study showed that LDN increased ESRD risk in LDN patients. However, in our meta-analysis, variables in included studies were not uniform and the number of included studies was small. To have a definite conclusion, meta-analyses of well-planned and detailed studies need to be conducted in the future.

Influence of Surgical Experience and Risk Factors for Surgical Failure in Primary Retinal Detachment Surgery.

INTRODUCTION: The aim of this study was to report surgical outcomes and risk factors for primary surgical failure following rhegmatogenous retinal detachment (RRD) repair. METHODS: In this retrospective cohort study, RRD patients who underwent primary surgery at a tertiary center between January 1, 2006, and December 31, 2020, were enrolled. Surgical failure was defined as reoperation within 60 days postoperatively due to retinal re-detachment and putative risk factors for surgical failure were analyzed. RESULTS: Of 2,383 eyes (2,335 patients), 1,342 (56.3%) underwent vitrectomy and 1,041 (43.7%) underwent scleral buckling. The surgical failure rate was 9.1% overall, and 6.0% and 13.1% for the vitrectomy and scleral buckling groups, respectively. In the multivariate logistic regression analysis, surgical failure was associated with surgical experience (first-year fellow vs. senior professor) (odds ratio [OR]: 1.66; p = 0.018), scleral buckling (OR: 2.33; p < 0.001), and longer axial length (AL; ≥26.5 mm) (OR: 1.49; p = 0.017). In each surgical approach, age <40 years (OR: 2.11; p = 0.029) in the vitrectomy group and age >40 years (OR, 1.84; p = 0.004), male sex (OR: 1.65; p = 0.015), and first-year fellows compared to senior professors (OR: 1.95; p = 0.013) in the scleral buckling group were associated with surgical failure. Lens status were not associated with the surgical failure rate. CONCLUSION: In this large retrospective study using data from Korea, vitrectomy was superior to scleral buckling in terms of primary anatomical outcomes in the management of RRD. First-year fellows were a risk factor for surgical failure, especially for scleral buckling. Longer AL was a significant parameter for predicting the success rates.

Mitochondrial Reactive Oxygen Species in TRIF-Dependent Toll-like Receptor 3 Signaling in Bronchial Epithelial Cells against Viral Infection.

Toll-like receptor 3 (TLR3) plays an important role in double-stranded RNA recognition and triggers the innate immune response by acting as a key receptor against viral infections. Intracellular reactive oxygen species (ROS) are involved in TLR3-induced inflammatory responses during viral infections; however, their relationship with mitochondrial ROS (mtROS) remains largely unknown. In this study, we show that polyinosinic-polycytidylic acid (poly(I:C)), a mimic of viral RNA, induced TLR3-mediated nuclear factor-kappa B (NF-κB) signaling pathway activation and enhanced mtROS generation, leading to inflammatory cytokine production. TLR3-targeted small interfering RNA (siRNA) and Mito-TEMPO inhibited inflammatory cytokine production in poly(I:C)-treated BEAS-2B cells. Poly(I:C) recruited the TLR3 adaptor molecule Toll/IL-1R domain-containing adaptor, inducing IFN (TRIF) and activated NF-κB signaling. Additionally, TLR3-induced mtROS generation suppression and siRNA-mediated TRIF downregulation attenuated mitochondrial antiviral signaling protein (MAVS) degradation. Our findings provide insights into the TLR3-TRIF signaling pathway and MAVS in viral infections, and suggest TLR3-mtROS as a therapeutic target for the treatment of airway inflammatory and viral infectious diseases.

Naturally-Occurring Tyrosinase Inhibitors Classified by Enzyme Kinetics and Copper Chelation.

Currently, there are three major assaying methods used to validate in vitro whitening activity from natural products: methods using mushroom tyrosinase, human tyrosinase, and dopachrome tautomerase (or tyrosinase-related protein-2, TRP-2). Whitening agent development consists of two ways, melanin synthesis inhibition in melanocytes and downregulation of melanocyte stimulation. For melanin levels, the melanocyte cell line has been used to examine melanin synthesis with the expression levels of TRP-1 and TRP-2. The proliferation of epidermal surfaced cells and melanocytes is stimulated by cellular signaling receptors, factors, or mediators including endothelin-1, α-melanocyte-stimulating hormone, nitric oxide, histamine, paired box 3, microphthalmia-associated transcription factor, pyrimidine dimer, ceramide, stem cell factors, melanocortin-1 receptor, and cAMP. In addition, the promoter region of melanin synthetic genes including tyrosinase is upregulated by melanocyte-specific transcription factors. Thus, the inhibition of growth and melanin synthesis in gene expression levels represents a whitening research method that serves as an alternative to tyrosinase inhibition. Many researchers have recently presented the bioactivity-guided fractionation, discovery, purification, and identification of whitening agents. Melanogenesis inhibition can be obtained using three different methods: tyrosinase inhibition, copper chelation, and melanin-related protein downregulation. There are currently four different types of inhibitors characterized based on their enzyme inhibition mechanisms: competitive, uncompetitive, competitive/uncompetitive mixed-type, and noncompetitive inhibitors. Reversible inhibitor types act as suicide substrates, where traditional inhibitors are classified as inactivators and reversible inhibitors based on the molecule-recognizing properties of the enzyme. In a minor role, transcription factors can also be downregulated by inhibitors. Currently, the active site copper iron-binding inhibitors such as kojic acid and chalcone exhibit tyrosinase inhibitory activity. Because the tyrosinase catalysis site structure is important for the mechanism determination of tyrosinase inhibitors, understanding the enzyme recognition and inhibitory mechanism of inhibitors is essential for the new development of tyrosinase inhibitors. The present review intends to classify current natural products identified by means of enzyme kinetics and copper chelation to exhibit tyrosinase enzyme inhibition.