Batteryless implantable device with built-in mechanical clock for automated and precisely timed drug administration.

Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.

Inactivation of VRK1 sensitizes ovarian cancer to PARP inhibition through regulating DNA-PK stability.

Ovarian cancer is the leading cause of gynecologic cancer death. Among the most innovative anti-cancer approaches, the genetic concept of synthetic lethality is that mutations in multiple genes work synergistically to effect cell death. Previous studies found that although vaccinia-related kinase-1 (VRK1) associates with DNA damage repair proteins, its underlying mechanisms remain unclear. Here, we found high VRK1 expression in ovarian tumors, and that VRK1 depletion can significantly promote apoptosis and cell cycle arrest. The effect of VRK1 knockdown on apoptosis was manifested by increased DNA damage, genomic instability, and apoptosis, and also blocked non-homologous end joining (NHEJ) by destabilizing DNA-PK. Further, we verified that VRK1 depletion enhanced sensitivity to a PARP inhibitor (PARPi), olaparib, promoting apoptosis through DNA damage, especially in ovarian cancer cell lines with high VRK1 expression. Proteins implicated in DNA damage responses are suitable targets for the development of new anti-cancer therapeutic strategies, and their combination could represent an alternative form of synthetic lethality. Therefore, normal protective DNA damage responses are impaired by combining olaparib with elimination of VRK1 and could be used to reduce drug dose and its associated toxicity. In summary, VRK1 represents both a potential biomarker for PARPi sensitivity, and a new DDR-associated therapeutic target, in ovarian cancer.

Degradation of AZGP1 suppresses apoptosis and facilitates cholangiocarcinoma tumorigenesis via TRIM25.

Alpha-2-Glycoprotein 1, Zinc-binding (AZGP1, ZAG) is a secreted protein that is synthesized by adipocytes and epithelial cells; it is downregulated in several malignancies such as breast, prostate, liver and lung cancers. However, its function remains unclear in cholangiocarcinoma (CCA). Here, we evaluated the impact AZGP1 in CCA using Gene Expression Omnibus (GEO) and GEPIA. In addition, we analysed AZGP1 expression using quantitative reverse transcription PCR and western blotting. Expression of AZGP1 was nearly deficient in CCA patients and cell lines and was associated with poor prognosis. AZGP1 overexpression upregulated apoptosis markers. Co-immunoprecipitation experiments showed that AZGP1 interacts with tripartite motif-containing protein 25 (TRIM25), and tissue microarray and bioinformatic analysis showed that AZGP1 is negatively correlated with TRIM25 expression in CCA. Thereafter, TRIM25 knockdown led to AZGP1 upregulation and induced cancer cell apoptosis. TRIM25 targets AZGP1 for degradation by catalysing its ubiquitination. AZGP1 overexpression significantly suppressed tumour growth in a xenograft mouse model. This study findings suggest that AZGP1 is a potential therapeutic target or a diagnostic biomarker for treating patients with CCA.

Secular Trends in Outcomes and Impact of Novel Oral Anticoagulants in Atrial Fibrillation-Related Acute Ischemic Stroke.

BACKGROUND: Novel oral anticoagulants (NOACs) are currently recommended for the secondary prevention of stroke in patients with acute ischemic stroke (AIS) accompanied by atrial fibrillation (AF). However, the impact of NOACs on clinical outcomes in real-world practice remains ambiguous. This study analyzes the trend of clinical events in patients with AF-related AIS and determines how much the introduction of NOACs has mediated this trend. METHODS: We identified patients with AIS and AF between January 2011 and December 2019 using a multicenter stroke registry. Annual rates of NOAC prescriptions and clinical events within 1 year were evaluated. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. To assess the mediation effect of NOACs on the relationship between the calendar year and these outcomes, we used natural effect models and conducted exposure-mediator, exposure-outcome, and mediator-outcome analyses using multivariable regression models or accelerated failure time models, adjusting for potential confounders. RESULTS: Among the 12 977 patients with AF-related AIS, 12 500 (average age: 74.4 years; 51.3% male) were analyzed after excluding cases of valvular AF. Between 2011 and 2019, there was a significant decrease in the 1-year incidence of the primary composite outcome from 28.3% to 21.7%, while the NOAC prescription rate increased from 0% to 75.6%. A 1-year increase in the calendar year was independently associated with delayed occurrence of the primary outcome (adjusted time ratio, 1.10 [95% CI, 1.07-1.14]) and increased NOAC prescription (adjusted odds ratio, 2.20 [95% CI, 2.14-2.27]). Increased NOAC prescription was associated with delayed occurrence of the primary outcome (adjusted time ratio, 3.82 [95% CI, 3.17 to 4.61]). Upon controlling for NOAC prescription (mediator), the calendar year no longer influenced the primary outcome (adjusted time ratio, 0.97 [95% CI, 0.94-1.00]). This suggests that NOAC prescription mediates the association between the calendar year and the primary outcome. CONCLUSIONS: Our study highlights a temporal reduction in major clinical events or death in Korean patients with AF-related AIS, mediated by increased NOAC prescription, emphasizing NOAC use in this population.

Novel structure of secreted small molecular weight antigen Mtb12 from Mycobacterium tuberculosis.

Mtb12, a small protein secreted by Mycobacterium tuberculosis, is known to elicit immune responses in individuals infected with the pathogen. It serves as an antigen recognized by the host's immune system. Due to its immunogenic properties and pivotal role in tuberculosis (TB) pathogenesis, Mtb12 is considered a promising candidate for TB diagnosis and vaccine development. However, the structural and functional properties of Mtb12 are largely unexplored, representing a significant gap in our understanding of M. tuberculosis biology. In this study, we present the first structure of Mtb12, which features a unique tertiary configuration consisting of four beta strands and four alpha helices. Structural analysis reveals that Mtb12 has a surface adorned with a negatively charged pocket adjacent to a central cavity. The features of these structural elements and their potential effects on the function of Mtb12 warrant further exploration. These findings offer valuable insights for vaccine design and the development of diagnostic tools.

Novel structure of the anti-CRISPR protein AcrIE3 and its implication on the CRISPR-Cas inhibition.

As a response to viral infections, bacteria have evolved the CRISPR-Cas system as an adaptive immune mechanism, enabling them to target and eliminate viral genetic material introduced during infection. However, viruses have also evolved mechanisms to counteract this bacterial defense, including anti-CRISPR proteins, which can inactivate the CRISPR-Cas adaptive immune system, thus aiding the viruses in their survival and replication within bacterial hosts. In this study, we establish the high-resolution crystal structure of the Type IE anti-CRISPR protein, AcrIE3. Our structural examination showed that AcrIE3 adopts a helical bundle fold comprising four α-helices, with a notably extended loop at the N-terminus. Additionally, surface analysis of AcrIE3 revealed the presence of three acidic regions, which potentially play a crucial role in the inhibitory function of this protein. The structural information we have elucidated for AcrIE3 will provide crucial insights into fully understanding its inhibitory mechanism. Furthermore, this information is anticipated to be important for the application of the AcrIE family in genetic editing, paving the way for advancements in gene editing technologies.

Zika Virus Infection Induces Interleukin-1ß-Mediated Inflammatory Responses by Macrophages in the Brain of an Adult Mouse Model.

During the 2015-2016 Zika virus (ZIKV) epidemic, ZIKV-associated neurological diseases were reported in adults, including microcephaly, Guillain-Barre syndrome, myelitis, meningoencephalitis, and fatal encephalitis. However, the mechanisms underlying the neuropathogenesis of ZIKV infection are not yet fully understood. In this study, we used an adult ZIKV infection mouse model (Ifnar1-/-) to investigate the mechanisms underlying neuroinflammation and neuropathogenesis. ZIKV infection induced the expression of proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-6, gamma interferon, and tumor necrosis factor alpha, in the brains of Ifnar1-/- mice. RNA-seq analysis of the infected mouse brain also revealed that genes involved in innate immune responses and cytokine-mediated signaling pathways were significantly upregulated at 6 days postinfection. Furthermore, ZIKV infection induced macrophage infiltration and activation and augmented IL-1ß expression, whereas microgliosis was not observed in the brain. Using human monocyte THP-1 cells, we confirmed that ZIKV infection promotes inflammatory cell death and increases IL-1ß secretion. In addition, expression of the complement component C3, which is associated with neurodegenerative diseases and known to be upregulated by proinflammatory cytokines, was induced by ZIKV infection through the IL-1ß-mediated pathway. An increase in C5a produced by complement activation in the brains of ZIKV-infected mice was also verified. Taken together, our results suggest that ZIKV infection in the brain of this animal model augments IL-1ß expression in infiltrating macrophages and elicits IL-1ß-mediated inflammation, which can lead to the destructive consequences of neuroinflammation. IMPORTANCE Zika virus (ZIKV) associated neurological impairments are an important global health problem. Our results suggest that ZIKV infection in the mouse brain can induce IL-1ß-mediated inflammation and complement activation, thereby contributing to the development of neurological disorders. Thus, our findings reveal a mechanism by which ZIKV induces neuroinflammation in the mouse brain. Although we used adult type I interferon receptor IFNAR knockout (Ifnar1-/-) mice owing to the limited mouse models of ZIKV pathogenesis, our conclusions contributed to the understanding ZIKV-associated neurological diseases to develop treatment strategies for patients with ZIKV infection based on these findings.

Molecular characterization and identification of Stellaria aquatica virus C, a novel putative member of the genus Closterovirus infecting Stellaria aquatica in South Korea.

A novel virus infecting Stellaria aquatica plants, tentatively named "Stellaria aquatica virus C" (StAVC), was identified in Gangwon-do Province, South Korea. Its monopartite genome consists of a single-stranded RNA of 15,024 nucleotides, and it shares 38.24 to 56.2% nucleotide sequence identity with known closterovirus genome sequences. Its genome contains nine hypothetical open reading frames. These encode the multifunctional protein RNA-dependent RNA polymerase (RdRp), hydrophobic protein (P7), heat shock protein 70 homolog (HSP70h), coat protein homolog (CPh), minor coat protein (CPm), and major coat protein (CP), along with proteins involved in suppressing RNA silencing. Phylogenetic analysis reveals that, based on its HSP70h amino acid sequence, StAVC is closely related to members of the genus Closterovirus within the family Closteroviridae. This is the first record of the full genome sequence of StAVC in South Korea.

Assessing regional disparities and vulnerability in stroke care across Gyeonggi Province: A focus on hospital service areas.

BACKGROUND: This study aims to illuminate regional disparities and identify vulnerable areas in stroke care across Gyeonggi Province's hospital service areas. METHODS: Using data from the Korea National Cardio-cerebrovascular Disease Management Commission, we included 4,427 acute stroke patients admitted in 2018 to hospitals within Gyeonggi Province. Our evaluation focused on: 1) stroke care quality indicators, including rates of defect-free care, intravenous thrombolysis (IVT), endovascular thrombectomy (EVT), and acute reperfusion therapy (either IVT or EVT); 2) intra-regional treatment rates; and 3) one-year mortality across the province and its 12 hospital service areas. These were compared both with national averages and inter-regionally. Vulnerable areas were pinpointed by evaluating the number of quality indicators falling below the national average and through visual distribution mapping, categorizing each indicator into higher (ranks 1-4), middle (ranks 5-8), and lower (ranks 9-12) tiers. RESULTS: Despite fewer qualified stroke centers and specialists, Gyeonggi Province exhibited higher defect-free care rates (84.6 % vs. 80.7 %), intra-regional treatment rates (57.8 % vs. 51.0 %), and marginally lower one-year mortality (16.2 % vs. 17.3 %) compared to national averages. Notable regional disparities were observed; the highest-performing areas for defect-free care and acute reperfusion therapy exceeded the lowest by 1.4 and 3.3 times, respectively. Nine out of twelve areas fell below the national average for EVT rates, seven for IVT and reperfusion therapy rates, and five for intra-regional treatment rates. Pyeongtaek, with all stroke care quality indicators below the national average coupled with the highest one-year mortality, emerges as a critical area needing improvement in acute stroke care. CONCLUSION: This study not only exposes the regional disparities in stroke care within Gyeonggi Province's hospital service areas but also identifies areas most vulnerable. Consequently, a customized support strategy for these areas is imperative.

The role of O-GlcNAcylation mediated by OGT during tooth development.

To understand the mechanisms underlying tooth morphogenesis, we examined the developmental roles of important posttranslational modification, O-GlcNAcylation, which regulates protein stability and activity by the addition and removal of a single sugar (O-GlcNAc) to the serine or threonine residue of the intracellular proteins. Tissue and developmental stage-specific immunostaining results against O-GlcNAc and O-GlcNAc transferase (OGT) in developing tooth germs would suggest that O-GlcNAcylation is involved in tooth morphogenesis, particularly in the cap and secretory stage. To evaluate the developmental function of OGT-mediated O-GlcNAcylation, we employed an in vitro tooth germ culture method at E14.5, cap stage before secretory stage, for 1 and 2 days, with or without OSMI-1, a small molecule OGT inhibitor. To examine the mineralization levels and morphological changes, we performed renal capsule transplantation for one and three weeks after 2 days of in vitro culture at E14.5 with OSMI-1 treatment. After OGT inhibition, morphological and molecular alterations were examined using histology, immunohistochemistry, real-time quantitative polymerase chain reaction, in situ hybridization, scanning electron microscopy, and ground sectioning. Overall, inhibition of OGT resulted in altered cellular physiology, including proliferation, apoptosis, and epithelial rearrangements, with significant changes in the expression patterns of ß-catenin, fibroblast growth factor 4 (fgf4), and sonic hedgehog (Shh). Moreover, renal capsule transplantation and immunolocalizations of Amelogenin and Nestin results revealed that OGT-inhibited tooth germs at cap stage exhibited with structural changes in cuspal morphogenesis, amelogenesis, and dentinogenesis of the mineralized tooth. Overall, we suggest that OGT-mediated O-GlcNAcylation regulates cell signaling and physiology in primary enamel knot during tooth development, thus playing an important role in mouse molar morphogenesis.

Covert Brain Infarction as a Risk Factor for Stroke Recurrence in Patients With Atrial Fibrillation.

BACKGROUND: We aimed to evaluate covert brain infarction (CBI), frequently encountered during the diagnostic work-up of acute ischemic stroke, as a risk factor for stroke recurrence in patients with atrial fibrillation (AF). METHODS: For this prospective cohort study, from patients with acute ischemic stroke hospitalized at 14 centers between 2017 and 2019, we enrolled AF patients without history of stroke or transient ischemic attack and divided them into the CBI (+) and CBI (-) groups. The 2 groups were compared regarding the 1-year cumulative incidence of recurrent ischemic stroke and all-cause mortality using the Fine and Gray subdistribution hazard model with nonstroke death as a competing risk and the Cox frailty model, respectively. Each CBI lesion was also categorized into either embolic-appearing (EA) or non-EA pattern CBI. Adjusted hazard ratios and 95% CIs of any CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were estimated. RESULTS: Among 1383 first-ever stroke patients with AF, 578 patients (41.8%) had CBI. Of these 578 with CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were 61.8% (n=357), 21.8% (n=126), and 16.4% (n=95), respectively. The estimated 1-year cumulative incidence of recurrent ischemic stroke was 5.2% and 1.9% in the CBI (+) and CBI (-) groups, respectively (P=0.001 by Gray test). CBI increased the risk of recurrent ischemic stroke (adjusted hazard ratio [95% CI], 2.91 [1.44-5.88]) but did not the risk of all-cause mortality (1.32 [0.97-1.80]). The EA pattern CBI only and both CBIs elevated the risk of recurrent ischemic stroke (2.76 [1.32-5.77] and 5.39 [2.25-12.91], respectively), while the non-EA pattern only did not (1.44 [0.40-5.16]). CONCLUSIONS: Our study suggests that AF patients with CBI might have increased risk of recurrent stroke. CBI could be considered when estimating the stroke risk in patients with AF.

DGG-300273, a novel WNT/ß-catenin inhibitor, induces apoptotic cell death by activating ROS-BIM signaling in a Wnt-dependent manner in colon cancer cells.

Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/ß-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/ß-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/ß-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study.

Small (≤5 cm) soft tissue tumors of the extremity and superficial trunk: MRI features and demographic characteristics associated with malignancy.

BACKGROUND: Although a substantial proportion of small soft tissue tumors are malignant, magnetic resonance imaging (MRI) features and demographic characteristics associated with these tumors have not been well described. PURPOSE: To investigate the MRI features and demographic characteristics associated with small (≤5 cm) malignant soft tissue tumors, and to identify independent predictors that allow differentiation of small benign and malignant soft tissue tumors. MATERIAL AND METHODS: This retrospective study evaluated patients who underwent surgical excision of small soft tissue tumors of the extremities and superficial trunk, and preoperative contrast-enhanced MRI. Seven MRI findings (tumor depth, tumor-fascia relationship, heterogeneity of signal intensity, necrosis, peritumoral edema, peritumoral enhancement, and margin) and two demographic parameters (age and sex) were included in univariate and multivariate logistic regression analyses to identify independent predictors of small malignant soft tissue tumors. RESULTS: A total of 221 patients (102 men; mean age=45.6 ± 17.6 years) with 72 malignant and 149 benign tumors were included. In the univariate analysis, peritumoral edema (odds ratio [OR] = 3.854; P < 0.001) and peritumoral enhancement (OR = 3.966; P < 0.001) and patient age (≥46 years) (OR = 2.154; P = 0.009) were significantly associated with malignancy. Multivariate analysis showed that peritumoral enhancement on MRI (OR = 3.728; P < 0.001) and patient age (≥46 years) (OR = 1.907; P = 0.036) were independent predictors of malignancy. The combination of these two parameters showed accuracy of 75.1%, sensitivity of 55.6%, and specificity of 84.6% to predict malignancy. CONCLUSION: Among several MRI and demographic features, the presence of peritumoral enhancement on MRI and patient age (≥46 years) were independent predictors of malignancy in small soft tissue tumors.

Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.

Nocardioides palaemonis sp. nov. and Tessaracoccus palaemonis sp. nov., isolated from the gastrointestinal tract of lake prawn.

Two novel Gram-stain-positive, non-motile and non-spore-forming bacterial strains, designated J2M5T and J1M15T, were isolated from the gastrointestinal tract of a lake prawn Palaemon paucidens. Strain J2M5T was an obligately aerobic bacterium that formed milky-coloured colonies and showed a rod-coccus cell cycle, while strain J1M15T was a facultatively aerobic bacterium that formed orangish-yellow-coloured colonies and showed rod-shaped cells. Strains J2M5T and J1M15T showed the highest 16S rRNA gene sequence similarity to Nocardioides ganghwensis JC2055T (98.63 %) and Tessaracoccus flavescens SST-39T (98.08 %), respectively. The whole-genome sequence of strain J2M5T was 4.52 Mbp in size and the genomic G+C content directly calculated from the genome sequence of strain J2M5T was 72.5 mol%. The whole-genome sequence of strain J1M15T was 3.20 Mbp in size and the genomic G+C content directly calculated from the genome sequence of strain J1M15T was 69.6mol %. Strains J2M5T and J1M15T showed high OrthoANI similarity to N. ganghwensis JC2055T (83.6 %) and T. flavescens (77.2 %), respectively. We analysed the genome sequences of strains J2M5T and J1M15T in terms of carbohydrate-active enzymes, antibiotic resistance genes and virulence factor genes. Strains J2M5T and J1M15T contained MK-8 (H4) and MK-9 (H4) as the predominant respiratory quinones, respectively. The major polar lipids of both strains were phosphatidylglycerol and diphosphatidylglycerol. Additionally, strain J2M5T possessed phosphatidylcholine, phosphatidylserine and phosphatidylethanolamine. The cellular sugar components of strain J2M5T were ribose, mannose, glucose and galactose, and its cellular amino acid components were l-alanine and l-lysine. The cellular sugar components of strain J1M15T were rhamnose, ribose, mannose and glucose, and its cellular amino acid component was l-alanine. The major cellular fatty acids of strains J2M5T and J1M15T were iso-C16 : 0 and anteiso-C15 : 0, respectively. The multiple taxonomic analyses indicated that strains J2M5T and J1M15T represent novel species of the genus Nocardioides and Tessaracoccus, respectively. We propose the names Nocardioides palaemonis sp. nov. and Tessaracoccus palaemonis sp. nov. for strain J2M5T (=KCTC 49461T=CCUG 74767T) and strain J1M15T (=KCTC 49462T=CCUG 74766T), respectively.

Parasphingorhabdus cellanae sp. nov., isolated from the gut of a Korean limpet, Cellana toreuma.

A novel bacterium, designated strain JHSY0214T, was isolated from the gut of a Korean limpet, Cellana toreuma. Cells of strain JHSY0214T were Gram-stain-negative, strictly aerobic, yellow-pigmented, non-spore-forming, non-motile and showed a rod-coccus growth cycle. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain belonged to the genus Parasphingorhabdus, and was most closely related to Parasphingorhabdus litoris KCTC 12764T (98.71 %). Strain JHSY0214T had two fluoroquinolone-resistance genes and seven multidrug-resistance efflux pump genes, but did not have beta-lactamase genes and zinc resistance genes compared with P. litoris KCTC 12764T. Strain JHSY0214T grew optimally at 30 °C, pH 7.0 and in the presence of 2 % (w/v) NaCl. The predominant cellular fatty acids of strain JHSY0214T were summed feature 8 (C18 : 1 ω6c and/or C18 : 1 ω7c; 41.2 %), summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c; 21 %) and C16 : 0 (18.9 %). The major isoprenoid quinone was ubiquinone-10. The major polar lipids were sphingoglycolipid and phosphatidylethanolamine. The genomic DNA G+C content was 52.8 mol%. Based on phylogenetic, genotypic and phenotypic data, strain JHSY0214T represents a novel species of the genus Parasphingorhabdus, for which the name Parasphingorhabdus cellanae is proposed. The type strain is JHSY0214T (=KCTC 82387T=DSM 112279T).

Association of Depression With Susceptibility and Adaptation to Seasickness in the Military Seafarers.

BACKGROUND: Although depression and motion sickness are prevalent in military personnel and seafarers, the association between depression and seasickness has been not yet elucidated. We aimed to evaluate the relationship of depression with initial susceptibility and adaptation to seasickness amongst military seafarers. METHODS: This retrospective cohort enrolled Navy seafarers who started seafaring between 2017 and 2019. Three groups were established according to the Beck Depression Inventory (BDI) score: no depression (BDI score of 0), minimal depression (BDI score 1-9), and mild-to-moderate depression (BDI score 10-29). The occurrence of seasickness requiring treatment was observed as the prescription of medication for the first 30 distant seafaring days. Considering adjustment period, the two different outcomes were defined. The susceptibility to seasickness was evaluated via at least one day suffered from seasickness requiring treatment during the early period (the first 5 seafaring days), and adaptation ability to seasickness was defined by more than 10% of the ratio, calculated days suffered from seasickness requiring treatment/days of seafaring during the late period (the 6-30th seafaring days). Binary logistic regression was further evaluated to estimate the odds of BDI groups and BDI score adjusted for age and workplace whether outside visual perception was possible. RESULTS: Among the 185 recruits, 179 participants (97%) sailed for more than 5 days were included in the study. Of the participants, 36% was susceptible to seasickness in the early and 17% was poorly adapted to seasickness in the late period. Multivariable model revealed that mild-to-moderate depression had elevated risk of poor adaptation (odds ratio [OR], 4.63; 95% confidence interval [CI], 1.31-16.98) whereas the results were not statistically significant for susceptibility to seasickness in the early period BDI score was independently associated with increased odds of poor adaptation (OR, 1.10; 95% CI, 1.04-1.18). CONCLUSION: The present study suggests that depression is associated with poor adaptation to seasickness in Navy seafarers. Depression screening tool might be helpful for providing preventable strategies for population at risk.

Annual Case Volume and One-Year Mortality for Endovascular Treatment in Acute Ischemic Stroke.

BACKGROUND: The association between endovascular treatment (EVT) case volume per hospital and clinical outcomes has been reported, but the exact volume threshold has not been determined. This study aimed to examine the case volume threshold in this context. METHODS: National audit data on the quality of acute stroke care in patients admitted via emergency department, within 7 days of onset, in hospitals that treated ≥ 10 stroke cases during the audit period were analyzed. Ischemic stroke cases treated with EVT during the last three audits (2013, 2014, and 2016) were selected for the analysis. Annual EVT case volume per hospital was estimated and analyzed as a continuous and a categorical variable (in quartiles). The primary outcome measure was 1-year mortality as a surrogate of 3-month functional outcome. As post-hoc sensitivity analysis, replication of the study results was examined using the 2018 audit data. RESULTS: We analyzed 1,746 ischemic stroke cases treated with EVT in 120 acute care hospitals. The median annual EVT case volume was 12.0 cases per hospital, and mortality rates at 1 month, 3 months, and 1 year were 12.7%, 16.6%, and 23.3%, respectively. Q3 and Q4 had 33% lower odds of 1-year mortality than Q1. Adjustments were made for predetermined confounders. Annual EVT case volume cut-off value for 1-year mortality was 15 cases per year (P < 0.02). The same cut-off value was replicated in the sensitivity analysis. CONCLUSION: Annual EVT case volume was associated with 1-year mortality. The volume threshold per hospital was 15 cases per year.

Anti-Inflammatory and Neuroprotective Mechanisms of GTS-21, an α7 Nicotinic Acetylcholine Receptor Agonist, in Neuroinflammation and Parkinson's Disease Mouse Models.

Neuroinflammation is crucial in the progression of neurodegenerative diseases. Thus, controlling neuroinflammation has been proposed as an important therapeutic strategy for neurodegenerative disease. In the present study, we examined the anti-inflammatory and neuroprotective effects of GTS-21, a selective α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, in neuroinflammation and Parkinson's disease (PD) mouse models. GTS-21 inhibited the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and primary microglia. Further research revealed that GTS-21 has anti-inflammatory properties by inhibiting PI3K/Akt, NF-κB, and upregulating AMPK, Nrf2, CREB, and PPARγ signals. The effects of GTS-21 on these pro-/anti-inflammatory signaling molecules were reversed by treatment with an α7 nAChR antagonist, suggesting that the anti-inflammatory effects of GTS-21 are mediated through α7 nAChR activation. The anti-inflammatory and neuroprotective properties of GTS-21 were then confirmed in LPS-induced systemic inflammation and MPTP-induced PD model mice. In LPS-injected mouse brains, GTS-21 reduced microglial activation and production of proinflammatory markers. Furthermore, in the brains of MPTP-injected mice, GTS-21 restored locomotor activity and dopaminergic neuronal cell death while inhibiting microglial activation and pro-inflammatory gene expression. These findings suggest that GTS-21 has therapeutic potential in neuroinflammatory and neurodegenerative diseases such as PD.

Cultivation of human skin cells under physiological oxygen concentration modulates expression of skin significant genes and response to hydroxy acids.

Physiological oxygen concentration (physioxia) ranges from 1 to 8% in human tissues while many researchers cultivate mammalian cells under an atmospheric concentration of 21% (hyperoxia). Oxygen is one of the significant gases which functions in human cells including energy production in mitochondria, metabolism in peroxidase, and transcription of various genes in company with HIF (Hypoxia-inducible factors) in the nucleus. Thus, mammalian cell culture should be deliberated on the oxygen concentration to mimic in vivo physiology. Here, we studied if the cultivation of human skin cells under physiological conditions could affect skin significant genes in barrier functions and dermal matrix formation. We further examined that some representative active ingredients in dermatology such as glycolic acid, gluconolactone, and salicylic acid work in different ways depending on the oxygen concentration. Taken together, we present the importance of oxygen concentration in skin cell culture for proper screening of novel ingredients as well as the mechanistic study of skin cell regulation.