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Rambutan (Nephelium lappaceum L.) peel contains bioactive compounds such as geraniin, corilagin, ellagic acid, and gallic acid, known for their antioxidant, anti-inflammatory, and anticancer properties. Traditional extraction methods involve toxic solvents like methanol and ethanol, posing environmental and safety concerns. This study optimized the extraction of ellagitannins from rambutan peel using Natural Deep Eutectic Solvents (NADES), which are sustainable, non-toxic, and cost-effective. The optimal conditions-water content (20 %), temperature (80 °C), and time (60 min)-were identified using Response Surface Methodology (RSM). The NADES system, composed of betaine (hydrogen bond acceptor) and 1,2-propanediol (donor) in a 1:2 M ratio, achieved the highest ellagitannin yield (54.29 μg/mg) and antioxidant activity (DPPH IC 50  = 35.86 μg/mL, ABTS IC 50  = 37.66 μg/mL). These findings demonstrate that NADES can be effectively tailored for bioactive compound extraction from rambutan peel, providing a greener alternative for the food, pharmaceutical, and cosmetic industries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Korean Red Ginseng and ginsenosides have been studied for their efficacy against various diseases, including those related to aging. However, most aging studies use D-galactose to induce aging, which often does not accurately represent natural aging. This study aimed to verify improvements in auditory, cognitive, and liver function through administering red ginseng to an 18-month-old naturally aging mouse model., Methods: Auditory function was assessed using Auditory Brainstem Response (ABR) and Auditory Middle Latency Response (AMLR). Cognitive function was evaluated electrophysiologically with P300 and mismatch negativity (MMN), and behaviorally using the Y-maze. Additionally, biochemical tests and histological analysis were conducted to assess liver function. The effects of red ginseng on gene expression regulation were also examined in the cochlea, auditory cortex, and liver, focusing on age-related disease processes., Results: Red ginseng significantly decreased hearing thresholds and improved central auditory function. It also enhanced cognitive behavior and function in response to external stimulation. Furthermore, red ginseng regulated alkaline phosphatase (ALP), albumin (Alb), and total protein (TP) levels, notably decreasing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Hematoxylin and eosin (H&E) staining of liver tissue showed significant improvement in fat droplets. These effects appear to be mediated by the regulation of aging-related genes Dec , c-Jun , Stat5b , and Lims2 ., Conclusion: These results suggest that red ginseng improves auditory, cognitive, and liver functions in a naturally aged mouse model., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Korean Society of Ginseng. Publishing services by Elsevier B.V.)

Background: Patients with respiratory disease often need oxygen supplements through a High-flow nasal cannula (HFNC), both hypoxia and hyperoxia can be harmful. Proper oxygen therapy requires careful monitoring of oxygen levels and adjustments to oxygen levels. A new automated system called Targeted SpO2 Feedback (TSF) improved the oxygen delivery system compared to manual adjustments. [Correction added on 25 October 2024, after first online publication: Background subsection in Abstract has been added on this version.] AIM: To test whether targeted SpO2 feedback (TSF), an automatic control system for fraction of inspired oxygen (FiO2), achieves more time in the optimal SpO2 range and/or reduces the frequency of manual adjustments to administered FiO2 compared with conventional manual titration in patients with hypoxia on high-flow nasal cannula (HFNC) therapy., Study Design: Twenty-two patients were recruited from two hospitals. For each, two sessions of manual mode and two sessions of TSF were applied in a random order, each session lasting 2 h. The target SpO2 on TSF was 95%. Oxygen monitoring levels were classified into four SpO2 ranges: hypoxia (≤ 89%), borderline (90%-93%), optimal (94%-96%) and hyperoxia (≥ 97%). The two modes were compared based on the proportion of time spent in each SpO2 range and the number of manual FiO2 adjustments., Results: The proportion of time in the optimal SpO2 range was 20.5% under manual titration mode and 65.4% under TSF (p < .01). The proportions of time in the hypoxia range were 1.1% and 0.4%, respectively (p = .31), in the borderline range 4.7% and 3.5%, respectively (p = .54), and in the hyperoxia range 73.7% and 30.7%, respectively (p < .01). There were statistical differences only in the optimal and hyperoxia SpO2 ranges. During the 8 h, the frequency of manual FiO2 adjustment was 0.7 times for the manual mode and 0.2 times for TSF, showing no statistically significant difference (p = 0.076)., Conclusion: Compared with manual titration, TSF achieved greater time of the optimal SpO2 and less time of hyperoxia during HFNC. The frequency of manual adjustments on TSF tended to be less than on manual titration mode., Relevance to Clinical Practice: Automatic closed-loop algorithm FiO2 monitoring systems can achieve better oxygen treatments than conventional monitoring and may reduce nurse workloads. In the era of pandemic respiratory diseases, this system can also facilitate contactless SpO2 monitoring during HFNC therapy., (© 2024 British Association of Critical Care Nurses.)

Sensorineural hearing loss (SNHL), characterized by damage to the inner ear or auditory nerve, is a prevalent auditory disorder. This study explores the potential of Castanopsis echinocarpa (CAE) as a therapeutic agent for SNHL. In vivo experiments were conducted using zebrafish and mouse models. Zebrafish with neomycin-induced ototoxicity were treated with CAE, resulting in otic hair cell protection with an EC 50 of 0.49 µg/mL and a therapeutic index of 1020. CAE treatment improved auditory function and protected cochlear sensory cells in a mouse model after noise-induced hearing loss (NIHL). RNA sequencing of NIHL mouse cochleae revealed that CAE up-regulates genes involved in neurotransmitter synthesis, secretion, transport, and neuronal survival. Real-time qPCR validation showed that NIHL decreased the mRNA expression of genes related to neuronal function, such as Gabra1 , Gad1 , Slc32a1 , CaMK2b , CaMKIV , and Slc17a7 , while the CAE treatment significantly elevated these levels. In conclusion, our findings provide strong evidence that CAE protects against hearing loss by promoting sensory cell protection and enhancing the expression of genes critical for neuronal function and survival.

Introduction: The changes in soft tissue profile following alveolar ridge preservation (ARP) with/without primary flap closure (PC) in periodontally damaged sockets have yet to be discovered., Methods: For periodontally damaged non-molar extraction sockets, ARP with PC (group PC)/without PC (group SC) was performed using granule-type xenogeneic bone substitute material and a collagen barrier. Intraoral scans were performed at the time of ARP and 4 months thereafter. Superimposition of STL files was performed to examine tissue change on the soft tissue level. The level of mucogingival junction (MGJ) was also evaluated., Results: A total of 28 patient (13 in group PC, 15 in group SC) completed the study. Soft tissue profile change was evaluated only when the measurement level was located on the non-mobile tissue. Group PC tended to shrink less on the long axis of the extraction socket than group SC (-4.3 ± 3.1 mm vs. -5.9 ± 4.4 mm at the 1 mm below the pre-extraction gingival margin, p > 0.05). Profilometric analysis (on the region of interest) also have a tendency of less tissue profile change in group PC than group SC (-1.0 ± 0.8 mm vs. -1.3 ± 0.5 mm, p > 0.05). The MGJ level change was not statistically significantly different between the groups (p > 0.05) even though the MGJ level was located more apically at 4 months in group SC compared with group PC., Conclusions: Alveolar ridge preservation with PC tended to yield less soft tissue shrinkage than ARP without PC., (© 2023 Wiley Periodicals LLC.)

In a conventional two-dimensional (2D) culture method, cells are attached to the bottom of the culture dish and grow into a monolayer. These 2D culture methods are easy to handle, cost-effective, reproducible, and adaptable to growing many different types of cells. However, monolayer 2D cell culture conditions are far from those of natural tissue, indicating the need for a three-dimensional (3D) culture system. Various methods, such as hanging drop, scaffolds, hydrogels, microfluid systems, and bioreactor systems, have been utilized for 3D cell culture. Recently, external physical stimulation-based 3D cell culture platforms, such as acoustic and magnetic forces, were introduced. Acoustic waves can establish acoustic radiation force, which can induce suspended objects to gather in the pressure node region and aggregate to form clusters. Magnetic targeting consists of two components, a magnetically responsive carrier and a magnetic field gradient source. In a magnetic-based 3D cell culture platform, cells are aggregated by changing the magnetic force. Magnetic fields can manipulate cells through two different methods: positive magnetophoresis and negative magnetophoresis. Positive magnetophoresis is a way of imparting magnetic properties to cells by labeling them with magnetic nanoparticles. Negative magnetophoresis is a label-free principle-based method. 3D cell structures, such as spheroids, 3D network structures, and cell sheets, have been successfully fabricated using this acoustic and magnetic stimuli-based 3D cell culture platform. Additionally, fabricated 3D cell structures showed enhanced cell behavior, such as differentiation potential and tissue regeneration. Therefore, physical stimuli-based 3D cell culture platforms could be promising tools for tissue engineering., (© 2023. Korean Tissue Engineering and Regenerative Medicine Society.)

Lung mast cells are important in host defense, and excessive proliferation or activation of these cells can cause chronic inflammatory disorders like asthma. Two parallel pathways induced by KIT-stem cell factor (SCF) and FcεRI-immunoglobulin E interactions are critical for the proliferation and activation of mast cells, respectively. Here, we report that mast cell-expressed membrane protein1 (MCEMP1), a lung-specific surface protein, functions as an adaptor for KIT, which promotes SCF-mediated mast cell proliferation. MCEMP1 elicits intracellular signaling through its cytoplasmic immunoreceptor tyrosine-based activation motif and forms a complex with KIT to enhance its autophosphorylation and activation. Consequently, MCEMP1 deficiency impairs SCF-induced peritoneal mast cell proliferation in vitro and lung mast cell expansion in vivo. Mcemp1-deficient mice exhibit reduced airway inflammation and lung impairment in chronic asthma mouse models. This study shows lung-specific MCEMP1 as an adaptor for KIT to facilitate SCF-mediated mast cell proliferation., (© 2023. The Author(s).)

Introduction: The effect of primary wound closure (PC) on alveolar ridge preservation (ARP) in periodontally damaged sockets has yet to be fully discovered., Methods: Periodontally damaged sockets were allocated to one of the following groups: (1) ARP with PC (group PC), and (2) ARP without PC (group secondary wound closure [SC]). Following tooth extraction and flap elevation, granule-type xenogeneic bone substitute material and a collagen barrier were applied. Ridge change was evaluated using cone-beam computed tomographic (CBCT) scans immediately after ARP and at 4 months. Core biopsy specimens were examined histomorphometrically., Results: A total of 28 patients were included in the analysis (13 in group PC, 15 in group SC). Histomorphometrically, the percentage of newly formed bone was 26.2 ± 17.7% and 24.6 ± 18.4% in groups PC and SC, respectively (independent t-test, degree of freedom [df] = 25, p > 0.05). Horizontal ridge changes on CBCT were -4.9 ± 3.1 mm and - 4.2 ± 2.5 mm in groups PC and SC at the 1 mm level below the ridge crest, respectively (independent t-test, df = 26, p > 0.05). Approximately half of the sites required additional bone augmentation at implant placement., Conclusions: ARP with/without PC yielded similar new bone formation and radiographic ridge change. This clinical trial was not registered prior to participant recruitment and randomization (https://cris.nih.go.kr/cris/search/detailSearch.do/19718)., (© 2022 Wiley Periodicals LLC.)

Background: Although the proportion of patients with chronic respiratory failure requiring home mechanical ventilation (HMV) is increasing, hospital readmissions in these patients are also increasing., Objective: We investigated the factors for early readmission in patients receiving HMV., Methods: We retrospectively analyzed the data of adult patients readmitted to the hospital within a year who first received HMV and were discharged from the Asan Medical Center between March 2014 and February 2019. We compared the clinical characteristics at discharge before readmission between the early (readmission within 30 days) and late readmission groups (readmission between day 31 and 1 year) and investigated the clinical characteristics and outcomes at readmission., Results: Of the 116 patients identified, 36.2% had been readmitted early. The patients who received invasive HMV had a higher rate of early readmission than those who received non-invasive HMV. Pneumonia was the most common reason of readmission in the two groups. The rate of aspiration was significantly higher in the early readmission group (28.6% vs. 8.1%; P = .003). In multivariate logistic regression analysis, nasogastric tube feeding, sequelae of pneumonia or acute respiratory distress syndrome, and central nervous system disorders as causes for HMV were significantly associated with early readmission., Conclusion: Feeding methods and causes for HMV were associated with early readmission. Educating caregivers on respiratory care (suction and feeding methods) is important for preventing early readmission., Competing Interests: Conflict of interest No potential conflict of interest relevant to this article was reported., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

In recent years, manufacturing industries (e.g., medical, aerospace, and automobile) have been changing their manufacturing process to small-quantity batch production to flexibly cope with fluctuations in demand. Therefore, many companies are trying to produce products by introducing 3D printing technology into the manufacturing process. The 3D printing process is based on additive manufacturing (AM), which can fabricate complex shapes and reduce material waste and production time. Although AM has many advantages, its product quality is poor compared to conventional manufacturing systems. This study proposes a methodology to improve the quality of AM products based on data analysis. The targeted quality of AM is the surface roughness of the stacked wall. Surface roughness is one of the important quality indicators and can cause short product life and poor structure performance. To control the surface roughness, the resultant surface roughness needs to be predicted in advance depending on the process parameters. Various analysis methods such as data pre-processing and deep neural networks (DNN) combined with sensor data are used to predict surface roughness in the proposed methodology. The proposed methodology is applied to field data from operated wire + arc additive manufacturing (WAAM), and the analysis result shows its effectiveness, with a mean absolute percentage error (MAPE) of 1.93%.

Background: Evidence for using high-flow nasal cannula (HFNC) in hypercapnia is still limited. Most of the clinical studies had been conducted retrospectively, and there had been conflicting reports for the effects of HFNC on hypercapnia correction in prospective studies. Therefore, more evidence is needed to understand the effect of the HFNC in hypercapnia., Methods: We conducted a multicenter prospective observational study after applying HFNC to 45 hospitalized subjects who had moderate hypercapnia (arterial partial pressure of carbon dioxide [PaCO2], 43-70 mm Hg) without severe respiratory acidosis (pH <7.30). The primary outcome was a change in PaCO2 level in the first 24 hours of HFNC use. The secondary outcomes were changes in other parameters of arterial blood gas analysis, changes in respiration rates, and clinical outcomes., Results: There was a significant decrease in PaCO2 in the first hour of HFNC application (-3.80 mm Hg; 95% confidence interval, -6.35 to -1.24; P<0.001). Reduction of PaCO2 was more prominent in subjects who did not have underlying obstructive lung disease. There was a correction in pH, but no significant changes in respiratory rate, bicarbonate, and arterial partial pressure of oxygen/fraction of inspired oxygen ratio. Mechanical ventilation was not required for 93.3% (42/45) of our study population., Conclusions: We suggest that HFNC could be a safe alternative for oxygen delivery in hypercapnia patients who do not need immediate mechanical ventilation. With HFNC oxygenation, correction of hypercapnia could be expected, especially in patients who do not have obstructive lung diseases.

Small-bowel tumors, both benign and malignant, are rare lesions that clinicians often do not encounter, accounting for less than 2% of gastrointestinal malignancies. Usually, benign small-bowel tumors, including polyps, are asymptomatic. The diagnosis of small-bowel tumors is difficult because of an often-delayed presentation and nonspecific signs and symptoms. We report an incidentally detected case of a long, pedunculated, large polyp of the terminal ileum, which protruded through the ileocecal valve into the cecum that was removed by colonoscopy in a 41-year-old male with intermittent right-sided lower-abdominal pain. The polyp was resected through snare polypectomy without complications. The histopathology of the resected polyp was confirmed as an ileal hyperplastic polyp. Two years later, there was no recurrence observed via postpolypectomy surveillance colonoscopy.

Anal gland/duct cyst (AGC) is rare and observed in only 0.05% of patients undergoing anal surgery. AGC is thought to be a retention cyst in the anal gland and arises when an obstruction of the anal duct causes fluid collection in the anal gland. We report a case of AGC in a 66-year-old woman without anal symptoms. Found by colonoscopy, the AGC was excised transanally. The histopathology of the specimen confirmed AGC. Colonoscopists should include AGC in the differential diagnosis of anal canal mass and rule out of malignancy. Excision is recommended for definitive diagnosis and treatment.

Hidradenoma papilliferum is a rare benign cystic tumor that originates from apocrine glands or anogenital mammary glands. Here, we describe 2 cases of hidradenoma papilliferum of the anus. Two female patients aged 39 and 35 presented with perianal masses with hemorrhoids. The patients underwent hemorrhoidectomy and excision of the lesion. Histopathology confirmed the masses as hidradenoma papilliferum. The postoperative course was uneventful for both patients, and there were no recurrences after 18 and 12 months of follow-up, respectively. Proctologists should consider hidradenoma papilliferum in their differential diagnosis of benign anal tumors. Surgical excision is necessary for diagnosis and treatment of hidradenoma papilliferum.

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca 2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.

Herpes simplex virus 1 (HSV-1) establishes infections in humans and mice, but some non-human primates exhibit resistance via unknown mechanisms. Innate immune recognition pathways are highly conserved but are pivotal in determining susceptibility to DNA virus infections. We report that variation of a single amino acid residue in the innate immune sensor cGAS determines species-specific inactivation by HSV-1. The HSV-1 UL37 tegument protein deamidates human and mouse cGAS. Deamidation impairs the ability of cGAS to catalyze cGAMP synthesis, which activates innate immunity. HSV-1 with deamidase-deficient UL37 promotes robust antiviral responses and is attenuated in mice in a cGAS- and STING-dependent manner. Mutational analyses identified a single asparagine in human and mouse cGAS that is not conserved in many non-human primates. This residue underpins UL37-mediated cGAS deamidation and species permissiveness of HSV-1. Thus, HSV-1 mediates cGAS deamidation for immune evasion and exploits species sequence variation to disarm host defenses., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Intracellular nucleic acid sensors often undergo sophisticated modifications that are critical for the regulation of antimicrobial responses. Upon recognition of DNA, the cytosolic sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the second messenger cGAMP, which subsequently initiates downstream signaling to induce interferon-αβ (IFNαβ) production. Here we report that TRIM56 E3 ligase-induced monoubiquitination of cGAS is important for cytosolic DNA sensing and IFNαβ production to induce anti-DNA viral immunity. TRIM56 induces the Lys335 monoubiquitination of cGAS, resulting in a marked increase of its dimerization, DNA-binding activity, and cGAMP production. Consequently, TRIM56-deficient cells are defective in cGAS-mediated IFNαβ production upon herpes simplex virus-1 (HSV-1) infection. Furthermore, TRIM56-deficient mice show impaired IFNαβ production and high susceptibility to lethal HSV-1 infection but not to influenza A virus infection. This adds TRIM56 as a crucial component of the cytosolic DNA sensing pathway that induces anti-DNA viral innate immunity.

Background: High flow nasal cannula (HFNC) is known to increase global ventilation volume in healthy subjects. We sought to investigate the effect of HFNC on global and regional ventilation patterns in patients with hypoxia., Methods: Patients were randomized to receive one of two oxygen therapies in sequence: nasal cannula (NC) followed by HFNC or HFNC followed by NC. Global and regional ventilation was assessed using electric impedance tomography., Results: Twenty-four patients participated. Global tidal variation (TV) in the lung was higher during HFNC (NC, 2,241 ± 1,381 arbitrary units (AU); HFNC, 2,543 ± 1,534 AU; P < 0.001). Regional TVs for four iso-gravitational quadrants of the lung were also all higher during HFNC than NC. The coefficient of variation for the four quadrants of the lung was 0.90 ± 0.61 during NC and 0.77 ± 0.48 during HFNC (P = 0.035). Within the four gravitational layers of the lung, regional TVs were higher in the two middle layers during HFNC when compared to NC. Regional TV values in the most ventral and dorsal layers of the lung were not higher during HFNC compared with NC. The coefficient of variation for the four gravitational layers of the lung were 1.00 ± 0.57 during NC and 0.97 ± 0.42 during HFNC (P = 0.574)., Conclusions: In patients with hypoxia, ventilation of iso-gravitational regions of the lung during HFNC was higher and more homogenized compared with NC. However, ventilation of gravitational layers increased only in the middle layers. (Clinical trials registration number: NCT02943863)., Competing Interests: Dräger Korea (Seoul, Korea) provided electric impedance tomography monitor (PulmoVista 500) with data analysis software. The funder had no role in the design, collection, analysis or interpretation of this study. No other potential conflict of interest relevant to this article was reported., (Copyright © 2018 The Korean Society of Critical Care Medicine.)

Purpose: Opioid analgesics are potent respiratory depressants. The purpose of this study was to describe the effects of opioids administered within 24hours before cardiac arrest on clinical outcomes., Materials and Methods: We retrospectively collected the cardiac arrest data of noncancer patients who were admitted to the general ward of Asan Medical Center from January 2008 to August 2012. We investigated the proportion of these patients who received opioids within 24hours of a cardiac arrest event, as well as the cardiac arrest characteristics, survival rates, and opioid administration patterns., Results: Of the 193 patients identified, 58 (30%) had been administered opioids within the previous 24hours (the opioid group), whereas the remaining 135 (70%) had not been administered opioids (the nonopioid group). The survival rate did not differ significantly between these 2 groups. In the opioid group, as-needed opioid administration was associated with a lower 24-hour survival rate than regular opioid administration (9 [33.3%] of 27 patients vs 20 [64.5%] of 31 patients; P=.030). In multivariate logistic regression analysis, as-needed opioid administration was negatively associated with 24-hour survival., Conclusions: Opioid administration within 24hours before cardiac arrest per se was not associated with adverse outcomes. However, administration of opioid analgesics on an as-needed basis was associated with poorer survival outcomes than regular dosing. Greater attention should be paid to patients who receive as-needed opioid administration in the general ward., (Copyright © 2016 Elsevier Inc. All rights reserved.)

STING is a crucial component of the mammalian innate immune response to microbial infection. In this issue of Cell Host & Microbe, Wang et al. (2016) report that TRIF, an adaptor of Toll-like receptors (TLRs), is essential for STING-mediated innate antiviral immunity as well as pro-protozoal responses., (Copyright © 2016. Published by Elsevier Inc.)

Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts' immune responses to DNA stimulation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Intubation in patients with respiratory failure can be avoided by high-flow nasal cannula (HFNC) use. However, it is unclear whether waiting until HFNC fails, which would delay intubation, has adverse effects. The present retrospective observational study assessed overall ICU mortality and other hospital outcomes of patients who received HFNC therapy that failed., Methods: All consecutive patients in one tertiary hospital who received HFNC therapy that failed and who then required intubation between January 2013 and March 2014 were enrolled and classified according to whether intubation started early (within 48 h) or late (at least 48 h) after commencing HFNC., Results: Of the 175 enrolled patients, 130 (74.3 %) and 45 (25.7 %) were intubated before and after 48 h of HFNC, respectively. The groups were similar in terms of most baseline characteristics. The early intubated patients had better overall ICU mortality (39.2 vs. 66.7 %; P = 0.001) than late intubated patients. A similar pattern was seen with extubation success (37.7 vs. 15.6 %; P = 0.006), ventilator weaning (55.4 vs. 28.9 %; P = 0.002), and ventilator-free days (8.6 ± 10.1 vs. 3.6 ± 7.5; P = 0.011). In propensity-adjusted and -matched analysis, early intubation was also associated with better overall ICU mortality [adjusted odds ratio (OR) = 0.317, P = 0.005; matched OR = 0.369, P = 0.046]., Conclusions: Failure of HFNC might cause delayed intubation and worse clinical outcomes in patients with respiratory failure. Large prospective and randomized controlled studies on HFNC failure are needed to draw a definitive conclusion.

We demonstrate a new solution-processed electron transport layer (ETL), zinc oxide doped with cesium carbonate (ZnO:Cs2CO3), for achieving organic photovoltaics (OPVs) with good operational stability at ambient air. An OPV employing the ZnO:Cs2CO3 ETL exhibits a fill factor of 62%, an open circuit voltage of 0.90 V, and a short circuit current density of -6.14 mA/cm(2) along with 3.43% power conversion efficiency. The device demonstrated air stability for a period over 4 weeks. In addition, we also studied the device structure dependence on the performance of organic photovoltaics. Thus, we conclude that ZnO:Cs2CO3 ETL could be employed in a suitable architecture to achieve high-performance OPV.

The MB21D1/cGAS (Mab-21 domain-containing 1/cyclic GMP-AMP [cGAMP] synthetase), acts as an intracellular pattern recognition receptor (PPR) to sense cytosolic pathogen DNAs and subsequently generates the second messenger cGAMP to initiate the TMEM173/STING pathway for interferon (IFN) production. Intriguingly, we have recently demonstrated crosstalk between the intracellular DNA sensing pathway and autophagy machinery by demonstrating a direct interaction between the MB21D1 DNA sensor and the BECN1/Beclin 1 autophagy protein. This interaction not only suppresses MB21D1 enzymatic activity to halt cGAMP production, but also enhances the autophagy-mediated degradation of cytosolic microbial DNAs. This demonstrates that MB21D1 is the molecular link between the intracellular DNA sensing pathway and the autophagy pathway, ultimately developing well-balanced immune responses against pathogens.

We demonstrate that there is a new solution-processed electron transport layer, lithium-doped zinc oxide (LZO), with high-performance inverted organic photovoltaic device. The device exhibits a fill factor of 68.58%, an open circuit voltage of 0.86 V, a short-circuit current density of -9.35 cm/mA2 along with 5.49% power conversion efficiency. In addition, we studied the performance of blend ratio dependence on inverted organic photovoltaics. Our device also demonstrates a long stability shelf life over 4 weeks in air.

Robust immune responses are essential for eliminating pathogens but must be metered to avoid prolonged immune activation and potential host damage. Upon recognition of microbial DNA, the cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) produces the second messenger cGAMP to initiate the stimulator of interferon genes (STING) pathway and subsequent interferon (IFN) production. We report that the direct interaction between cGAS and the Beclin-1 autophagy protein not only suppresses cGAMP synthesis to halt IFN production upon double-stranded DNA (dsDNA) stimulation or herpes simplex virus-1 infection, but also enhances autophagy-mediated degradation of cytosolic pathogen DNA to prevent excessive cGAS activation and persistent immune stimulation. Specifically, this interaction releases Rubicon, a negative autophagy regulator, from the Beclin-1 complex, activating phosphatidylinositol 3-kinase class III activity and thereby inducing autophagy to remove cytosolic pathogen DNA. Thus, the cGAS-Beclin-1 interaction shapes innate immune responses by regulating both cGAMP production and autophagy, resulting in well-balanced antimicrobial immune responses., (Copyright © 2014 Elsevier Inc. All rights reserved.)

RNA interference (RNAi) is an established antiviral defense mechanism in plants and invertebrates. Whether RNAi serves a similar function in mammalian cells remains unresolved. We find that in some cell types, mammalian RNAi activity is reduced shortly after viral infection via poly-ADP-ribosylation of the RNA-induced silencing complex (RISC), a core component of RNAi. Well-established antiviral signaling pathways, including RIG-I/MAVS and RNaseL, contribute to inhibition of RISC. In the absence of virus infection, microRNAs repress interferon-stimulated genes (ISGs) associated with cell death and proliferation, thus maintaining homeostasis. Upon detection of intracellular pathogen-associated molecular patterns, RISC activity decreases, contributing to increased expression of ISGs. Our results suggest that, unlike in lower eukaryotes, mammalian RISC is not antiviral in some contexts, but rather RISC has been co-opted to negatively regulate toxic host antiviral effectors via microRNAs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The nucleotide cofactor specificity of the DNA ligase from the hyperthermophilic crenarchaeon Hyperthermus butylicus (Hbu) was studied to investigate the evolutionary relationship of DNA ligases. The Hbu DNA ligase gene was expressed under control of the T7lac promoter of pTARG in Escherichia coli BL21-CodonPlus(DE3)-RIL. The expressed enzyme was purified using the IMPACT™-CN system (intein-mediated purification with an affinity chitin-binding tag) and cation-ion (Arg-tag) chromatography. The optimal temperature for Hbu DNA ligase activity was 75 °C, and the optimal pH was 8.0 in Tris-HCl. The activity was highly dependent on MgCl2 or MnCl2 with maximal activity above 5 mM MgCl2 and 2 mM MnCl2. Notably, Hbu DNA ligase can use ADP and GTP in addition to ATP. The broad nucleotide cofactor specificity of Hbu DNA ligase might exemplify an undifferentiated ancestral stage in the evolution of DNA ligases. This study provides new evidence for possible evolutionary relationships among DNA ligases.

Objective: To evaluate the effect of adding butylscopolammonium bromide (BB) to morphine and ketorolac in the treatment of acute renal colic in the ED., Methods: A prospective, double-blind, randomized controlled trial of i.v. triple therapy (morphine, ketorolac and BB) versus double therapy (morphine and ketorolac) in adult ED patients with a clinical diagnosis of acute renal colic and a pain rating greater than five on a 10 cm visual analogue scale (VAS). VAS was recorded at time 0, 20 and 40 min. Patients received rescue morphine at 20 or 40 min according to the protocol if needed. We compared pain reduction and the need for rescue analgesia at 4 min between two groups., Results: Eighty-nine patients were randomized over a 13 month period. A total of 46 (51.7%) patients received BB in addition to morphine and ketorolac. The mean difference in change in pain score in the triple therapy group and double therapy group was 7.1 cm (95% CI 6.4-7.8) and 5.9 cm (95% CI 5.1-6.7), respectively (P= 0.024). Rescue morphine was required by 7/46 (15.2% [95% CI 4.4-20.6]) patients in the triple therapy group and 14/43 (32.6% [95% CI 18.0-47.1]) in the double therapy group (OR 0.37 [95% CI 0.133-1.038])., Conclusions: Although the addition of BB to morphine and ketorolac appeared to show a statistically significant reduction in pain compared with morphine and ketorolac alone, a reduction of 1.2 cm on VAS is unlikely to be clinically significant., (© 2011 The Authors. EMA © 2011 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.)

Several different members of the Polyomaviridae, including some human pathogens, encode microRNAs (miRNAs) that lie antisense with respect to the early gene products, the tumor (T) antigens. These miRNAs negatively regulate T antigen expression by directing small interfering RNA (siRNA)-like cleavage of the early transcripts. miRNA mutant viruses of some members of the Polyomaviridae express increased levels of early proteins during lytic infection. However, the importance of miRNA-mediated negative regulation of the T antigens remains uncertain. Bandicoot papillomatosis carcinomatosis virus type 1 (BPCV1) is associated with papillomas and carcinomas in the endangered marsupial the western barred bandicoot (Perameles bougainville). BPCV1 is the founding member of a new group of viruses that remarkably share distinct properties in common with both the polyomavirus and papillomavirus families. Here, we show that BPCV1 encodes, in the same orientation as the papillomavirus-like transcripts, a miRNA located within a long noncoding region (NCR) of the genome. Furthermore, this NCR serves the function of both promoter and template for the primary transcript that gives rise to the miRNA. Unlike the polyomavirus miRNAs, the BPCV1 miRNA is not encoded antisense to the T antigen transcripts but rather lies in a separate, proximal region of the genome. We have mapped the 3' untranslated region (UTR) of the BPCV1 large T antigen early transcript and identified a functional miRNA target site that is imperfectly complementary to the BPCV1 miRNA. Chimeric reporters containing the entire BPCV1 T antigen 3' UTR undergo negative regulation when coexpressed with the BPCV1 miRNA. Notably, the degree of negative regulation observed is equivalent to that of an identical reporter that is engineered to bind to the BPCV1 miRNA with perfect complementarity. We also show that this miRNA and this novel mode of early gene regulation are conserved with the related BPCV2. Finally, papillomatous lesions from a western barred bandicoot express readily detectable levels of this miRNA, stressing its likely importance in vivo. Combined, the alternative mechanisms of negative regulation of T antigen expression between the BPCVs and the polyomaviruses support the importance of miRNA-mediated autoregulation in the life cycles of some divergent polyomaviruses and polyomavirus-like viruses.

Castleman's disease is a benign lymphoid proliferative disorder, which most commonly presents as a solitary mass in the mediastinum, although extrathoracic sites have been reported in the neck, axilla, pelvis, mesentery, pancreas, and retroperitoneum. We report a case of asymptomatic, isolated Castleman's disease in the mesorectum, which is extremely rare. The patient was a 34-year-old woman who underwent investigations for vaginal spotting. A presacral mass was located on the left side of the rectum, 10 cm from the anal verge. Contrast-enhanced computed tomography showed a large, well-demarcated, strongly enhancing mass with internal radiating septa in the mesorectum. The mass was well circumscribed and isointense to muscle on T1-weighted magnetic resonance imaging, appearing as a slightly hyperintense mass on T2-weighted imaging. We performed laparoscopic mesorectal mass excision, and histological examination revealed features typical of the hyaline-vascular type of Castleman's disease. Thus, when a mesorectal mass is being investigated, Castleman's disease should be considered in the differential diagnosis.

RNA interference (RNAi) is a process whereby small RNAs serve as effectors to direct posttranscriptional regulation of gene expression. The effector small RNAs can arise from various sources including plasmids that express short-hairpin RNAs (shRNAs) or microRNA (miRNAs), or alternatively, from synthetic small-interfering RNAs (siRNAs). These small RNAs enter a protein complex that binds directly to mRNA targets and this results in transcript-specific inhibition of protein expression. Though the key core components of the mammalian RNAi processing and effector complexes have been identified, accessory and regulatory factors are less well-defined. Reporter assays that can quantitatively assess RNAi activity can be used to identify modulators of RNAi. We present two methods to quantitatively analyze RNAi activity that have overlapping and distinct utility. The first method uses an eGFP reporter in transiently transfected cells to identify RNAi modulators. The second method uses cells that express luciferase-based reporters in a stable fashion. This assay can easily be conducted in 96-well plate format. Both methods can be used to identify novel proteins or small molecules that modulate RNAi activity.

Background: Laparoscopic colorectal resection is widely used because of its safety and effectiveness compared with conventional surgery; however, surgical assistants find it difficult to perform this surgery in mirror image. This study aimed to evaluate assistants' learning curves in laparoscopic colorectal surgery., Methods: The subjects were three fellows who began their surgical fellowship training at the Center for Colorectal Cancer of the National Cancer Center, Korea, during 2008. We analyzed the data from 145 laparoscopic colorectal surgeries in which these assistants participated. A learning curve was generated for each assistant using the moving average method to assess the execution time and the error rate for grasping tissue., Results: Assistants A, B, and C participated in 50, 45, and 50 laparoscopic colorectal surgeries, respectively. Learning curves indicated that the execution time reached a steady state after 38 cases for Assistant A, 29 cases for Assistant B, and 24 cases for Assistant C. Based on a decline in the error rate, the steady state was reached after approximately 44 cases for Assistant A, 32 cases for Assistant B, and 41 cases for Assistant C., Conclusion: Analysis of the assistants' learning curves suggests that under reverse alignment conditions, assistants require participation in 30-40 cases before gaining surgical competence. These results have implications for training assistants for laparoscopic colorectal surgery.

Background: The initial surgical management of asymptomatic patients with unresectable stage IV colorectal cancer (CRC) is still controversy. The aim of this study was to compare the incidence of major intestinal complications in asymptomatic patients who received palliative treatment for unresectable stage IV CRC, according to the type of treatment., Methods: Between March 2001 and January 2008, we retrospectively analyzed 227 asymptomatic patients who underwent first-line resection of the primary tumor followed by chemotherapy (144 patients, resection group) or those who underwent first-line chemotherapy (83 patients, chemotherapy group)., Results: In the resection group, the incidences of intestinal obstruction, peritonitis, fistula, and intestinal hemorrhage were 14.6%, 0%, 0.7%, and 4.8%, respectively. In the chemotherapy group, these incidences were 15.2%, 1.2%, 0%, and 3.5%, respectively. There were no significant differences between the two groups in terms of intestinal complications. In multivariate analysis of overall survival, treatment type (resection group vs. chemotherapy group) was not a significant prognostic factor (P = 0.076)., Conclusions: In asymptomatic patients with unresectable stage IV CRC, first-line chemotherapy may be considered safe, with no increased risk of major intestinal complications compared with primary tumor resection plus chemotherapy., ((c) 2010 Wiley-Liss, Inc.)

Aim: To evaluate the safety and outcomes of endoscopic piecemeal mucosal resection (EPMR) for large sessile colorectal polyps., Methods: The patients enrolled in this study were 47 patients with 50 large sessile polyps (diameter, 2 cm or greater) who underwent EPMR using a submucosal saline injection technique between December 2002 and October 2005. All medical records, including characteristics of the patients and polyps, complications, and recurrences, were retrospectively reviewed. The first follow-up endoscopic examination was performed at 3-6 mo after initial endoscopic resection, and the second at 12 mo post-EPMR. Subsequent surveillance colonoscopic examinations were individualized, taking risk factors into account., Results: The patients were 23 men and 24 women, with a mean age of 60 years. Mean polyp size was 30.1 mm. Of 50 polyps identified, 34 (68%) were benign and 16 (32%) were malignant. There were 6 (12%) cases with EPMR-related bleeding: 5 intra-procedural and 1 early post-procedural bleeding. All bleeding episodes were managed by endoscopic clipping or argon beam coagulation. There were no perforations. Recurrence was identified in 5 cases (12.2%): 4 local recurrences detected at 3 mo post-EPMR and 1 local recurrence detected at 14 mo post-EPMR. The recurrence rate after EPMR was 3.1% for benign polyps and 33.3% for malignant polyps (P < 0.05). Median follow-up time was 37 mo., Conclusion: EPMR is safe, but should be applied carefully in malignant polyps. Close follow-up endoscopic examinations are necessary for early detection of recurrence.

microRNAs (miRNAs) are post-transcriptional regulators of gene expression that play a role in viral infection. We have developed a method to identify viral-encoded miRNAs from viruses in which abundant amounts of infected material is limiting. We show that Merkel Cell Polyomavirus (MCV), a recently identified human virus associated with cancer, encodes a miRNA. This miRNA is expressed from the late strand, lies antisense to the early transcripts and negatively regulates expression of chimeric reporters containing a portion of the early transcripts. Interestingly, different viral isolates have sequence polymorphisms in the pre-miRNA region that result in amino acids substitutions but fully preserve the processing and activity of the miRNAs.

MicroRNAs (miRNAs) are potent RNA regulators of gene expression. Some viruses encode miRNAs, most of unknown function. The majority of viral miRNAs are not conserved, and whether any have conserved functions remains unclear. Here, we report that two human polyomaviruses associated with serious disease in immunocompromised individuals, JC virus and BK virus, encode miRNAs with the same function as that of the monkey polyomavirus simian virus 40 miRNAs. These miRNAs are expressed late during infection to autoregulate early gene expression. We show that the miRNAs generated from both arms of the pre-miRNA hairpin are active at directing the cleavage of the early mRNAs. This finding suggests that despite multiple differences in the miRNA seed regions, the primary target (the early mRNAs) and function (the downregulation of early gene expression) are evolutionarily conserved among the primate polyomavirus-encoded miRNAs. Furthermore, we show that these miRNAs are expressed in individuals diagnosed with polyomavirus-associated disease, suggesting their potential as targets for therapeutic intervention.

Background: The extent of regional lymph node (LN) metastasis is the most important factor in the evaluation of resectability and prognosis of non-small cell lung cancer (NSCLC) to increase the chance of complete cure. The authors attempted to deduce a group of genes from the analysis of mRNA expression profiles of the tumor tissues of NSCLC patients with or without LN metastasis, and make a classification model for better prediction of LN metastasis., Methods: The authors analyzed mRNA expression profiles of 79 NSCLC patients with or without LN metastasis, and deduced the gene signature for the predictive model of LN metastasis in lung cancer. The authors evaluated the predictive accuracy of each of four algorithms by applying them to another set of 33 NSCLC patients. Each algorithm's accuracy was calculated by 10-fold cross-validation, and a combined model showed a level of accuracy that was higher than any one of the better three component algorithms (i.e., ANN, DT, or NB). Avadis, SAS, ArrayXPath, and R-package were the statistical analysis software packages used., Results: The authors selected 949 genes using a classical permutation t test (p < 0.01) and finally obtained a gene signature consisting of 31 genes by adjustment of multiple-hypothesis testing. The LN metastasis prediction model derived from the signature (31 genes) and their characteristic interactions provided a predictive accuracy of 84.85% when applied to a test set of 33 patients., Conclusions: The authors have demonstrated that their gene signature developed by the expression profiling of mRNAs from the primary tissue could predict the LN metastasis status of NSCLC.

Since Fas-induced apoptosis is major pathway to eliminate unwanted or uncontrolled cells, many types of human cancer cells develop tactful mechanisms to get resistance against the apoptosis. One of the resistant mechanisms in human cancer is overexpression of FLICE-inhibitory protein (c-FLIP), human homolog of viral protein v-FLIP. c-FLIP has multiple splice variants at transcriptional level or two isoforms at protein level, a long (c-FLIP(L)) and a short form of c-FLIP (c-FLIP(S)). However, functional differences between these variants are not fully understood. In this study, we show that c-FLIP(L) but not c-FLIP(S) physically binds to Daxx through interaction between C-terminal domain of c-FLIP(L) and Fas-binding domain of Daxx, an alternative Fas signaling adaptor. Fas-induced cell death and JNK activation are sensitive to Fas stimulation in cell lines carrying undetectable level of c-FLIP(L). To support this, overexpression of c-FLIP(L) but not of c-FLIP(S) renders the cells resistant to Fas-induced cell death and to JNK activation. In signaling context, the interaction of c-FLIP(L) with Daxx is likely to inhibit JNK activation by preventing the normal interaction of Daxx and Fas, which is known to lead to apoptosis via JNK activation. This study implies that through this new mechanism, c-FLIP(L), acting at both FADD- and Daxx-mediated signaling pathways, may be involved in complete inhibition of Fas-induced cell death and may provide an answer to why c-FLIP(L) is more abundant and effective than c-FLIP(S).

Chk2/hCds1, the human homolog of Saccharomyces cerevisiae Rad53p and Schizosaccharomyces pombe Cds1p, plays a critical role in the DNA damage checkpoint pathway. While several in vivo targets of Chk2 have been identified, the other target proteins of Chk2 responsible for multiple functions, such as cell cycle arrest, DNA repair, and apoptosis, remain to be elucidated. We utilized the GST-peptide approach to identify physiological substrates for Chk2. Mutational analyses using GST-linked Cdc25A containing serine 123 revealed that residues at positions -5 and -3 are critical determinants for the recognition of the Chk2 substrate. We determined the general phosphorylation consensus sequence and identified in vitro targets of Chk2 using GST peptides as substrates. The newly identified in vitro target proteins include Abl1, Bub1R, Bub1, Bub3, Psk-H1, Smc3, Plk1, Cdc25B, Dcamkl1, Mre11, Pms1, and Xrcc9.

Ras, a well-known oncogene, induces cell cycle stimulation through the Raf/Erk pathway and leads to cellular transformation, accompanied by other oncogenes such as c-myc and viral oncogenic protein. Here we suggest the interfering role of Ras in tumor necrosis factor (TNF)-alpha-induced cell cycle regulation. In TSU-Pr1 and T24 (oncogenic Ras cell lines), TNF-alpha suppresses cell cycle progression without induction of apoptosis, whereas AGS (wild-type Ras) is stimulated in its cell cycle by TNF-alpha coupled with activation of Erk. However, in TSU-Pr1 and T24, TNF-alpha leads to dephosphorylation of Erk1/2. Inhibition or activation of Ras can restore or convert TNF-alpha-induced cell cycle regulation in the cell lines containing the oncogenic Ras (TSU-Pr1 and T24) or AGS, respectively. Regulation of Erk also shows the coincidental pattern. We suggest the competition between the Ras pathway and TNF signaling for the binding to Raf, a common downstream target, as the cause of such reciprocal response, based on co-immunoprecipitation (co-IP) with antibodies against Raf and Ras or cellular Flice-inhibitory protein (c-FLIP), which have been recently identified upstream of Raf in death-ligand-induced cell cycle stimulation. Overexpression of Raf in TSU-Pr1, to reduce the competition, overcomes TNF-induced cell cycle arrest, also supporting our hypotheses., (Copyright 2001 Academic Press.)