Metformin is an anti-diabetic drug that exerts protective effects against neurodegenerative diseases. In this study, we investigated the protective effects of metformin against manganese (Mn)-induced ...cytotoxicity associated with Parkinson’s disease-like symptoms in N27-A dopaminergic (DA) cells. Metformin (0.1–1 mM) suppressed Mn (0.4 mM)-induced cell death in a concentration-dependent manner. Metformin pretreatment effectively suppressed the Mn-mediated increase in the levels of oxidative stress markers, such as reactive oxygen species (ROS) and thiobarbituric acid reactive substances. Moreover, metformin restored the levels of the antioxidants, superoxide dismutase, intracellular glutathione, and glutathione peroxidase, which were reduced by Mn. Metformin (0.5 mM) significantly attenuated the decrease in sirtuin-1 (SIRT1) and peroxisome proliferator activated receptor gamma coactivator-1 alpha levels, which were increased by Mn (0.4 mM). In addition, metformin inhibited the expression of microRNA-34a, which directly targeted SIRT1. Metformin also inhibited the loss of Mn-induced mitochondrial membrane potential (ΔΨm) and activation of the apoptosis marker, caspase-3. Furthermore, metformin-mediated inhibition of ROS generation and caspase-3 activation, recovery of ΔΨm, and restoration of cell viability were partially reversed by the SIRT1 inhibitor, Ex527. These results suggest that metformin may protects against Mn-induced DA neuronal cell death mediated by oxidative stress and mitochondrial dysfunction possibly via the regulation of SIRT1 pathway.
Abstract
Although prime editing is a promising genome editing method, the efficiency of prime editor 2 (PE2) is often insufficient. Here we generate a more efficient variant of PE2, named hyPE2, by ...adding the Rad51 DNA-binding domain. When tested at endogenous sites, hyPE2 shows a median of 1.5- or 1.4- fold (range, 0.99- to 2.6-fold) higher efficiencies than PE2; furthermore, at sites where PE2-induced prime editing is very inefficient (efficiency < 1%), hyPE2 enables prime editing with efficiencies ranging from 1.1% to 2.9% at up to 34% of target sequences, potentially facilitating prime editing applications.
The sensitivity of organic–inorganic perovskites to environmental factors remains a major barrier for these materials to become commercially viable for photovoltaic applications. In this work, the ...degradation of formamidinium lead iodide (FAPbI3) perovskite in a moist environment is systematically investigated. It is shown that the level of relative humidity (RH) is important for the onset of degradation processes. Below 30% RH, the black phase of the FAPbI3 perovskite shows excellent phase stability over 90 d. Once the RH reaches 50%, degradation of the FAPbI3 perovskite occurs rapidly. Results from a Kelvin probe force microscopy study reveal that the formation of nonperovskite phases initiates at the grain boundaries and the phase transition proceeds toward the grain interiors. Also, ion migration along the grain boundaries is greatly enhanced upon degradation. A post‐thermal treatment (PTT) that removes chemical residues at the grain boundaries which effectively slows the degradation process is developed. Finally, it is demonstrated that the PTT process improves the performance and stability of the final device.
Moisture‐induced degradation of FAPbI3 perovskite is systematically investigated. A Kelvin probe force microscopy study reveals that the formation of nonperovskite phases initiates at the grain boundaries and the phase transition proceeds toward the grain interiors. A post‐thermal treatment that removes chemical residues at the grain boundaries which effectively slows the degradation process is developed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary Background Compared with open resection, laparoscopic resection of rectal cancers is associated with improved short-term outcomes, but high-level evidence showing similar long-term outcomes ...is scarce. We aimed to compare survival outcomes of laparoscopic surgery with open surgery for patients with mid-rectal or low-rectal cancer. Methods The Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was an open-label, non-inferiority, randomised controlled trial done between April 4, 2006, and Aug 26, 2009, at three centres in Korea. Patients (aged 18–80 years) with cT3N0–2M0 mid-rectal or low-rectal cancer who had received preoperative chemoradiotherapy were randomly assigned (1:1) to receive either open or laparoscopic surgery. Randomisation was stratified by sex and preoperative chemotherapy regimen. Investigators were masked to the randomisation sequence; patients and clinicians were not masked to the treatment assignments. The primary endpoint was 3 year disease-free survival, with a non-inferiority margin of 15%. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00470951. Findings We randomly assigned 340 patients to receive either open surgery (n=170) or laparoscopic surgery (n=170). 3 year disease-free survival was 72·5% (95% CI 65·0–78·6) for the open surgery group and 79·2% (72·3–84·6) for the laparoscopic surgery group, with a difference that was lower than the prespecified non-inferiority margin (–6·7%, 95% CI −15·8 to 2·4; p<0·0001). 25 (15%) patients died in the open group and 20 (12%) died in the laparoscopic group. No deaths were treatment related. Interpretation Our results show that laparoscopic resection for locally advanced rectal cancer after preoperative chemoradiotherapy provides similar outcomes for disease-free survival as open resection, thus justifying its use. Funding National Cancer Center, South Korea.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Introduction
To devise appropriate preventive strategies after stroke, knowledge of the association between post-stroke cognitive impairment (PSCI) and prognosis of stroke patients is important. We ...investigated the association between PSCI and the vascular outcomes in patients with ischemic stroke with best medical care considering their risk factors and adherence to medications.
Methods
Of the 1534 ischemic stroke patients who randomly assigned to aspirin or cilostazol treatment with best medical therapy by the PICASSO (PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage) trial, 1240 with baseline mini-mental state examination (MMSE) scores were analysed retrospectively. The patients were classified into three groups based on MMSE scores. Recurrence of ischemic stroke, stroke of any type and composite of major vascular events were compared among them.
Results
Of the 1240 patients, 376 had MMSE scores of 28–30 (highest tertile), 419 had scores of 24–27 (middle tertile) and 445 had scores of 0–23 (lowest tertile). The average time from stroke onset to MMSE examination was 31.8 days. By trend analysis, lower tertile of MMSE score was significantly associated with recurrent ischemic stroke (
p
= 0.0017), stroke of any type (
p
= 0.0053) and composite vascular outcome (
p
= 0.0122). After adjustment for covariates, PSCI was independently associated with risk of recurrent ischemic stroke (HR 2.40, 95% confidence interval 1.12–5.14).
Conclusions
Cognitive impairment was associated with recurrence of ischemic stroke in high risk patients during adequate medical therapy including antiplatelet therapy. However, the other vascular events were not.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ordered mesoporous carbons (OMCs) have attracted considerable interest owing to their broad utility. OMCs reported to date comprise amorphous rod‐like or tubular or graphitic rod‐like frameworks, ...which exhibit tradeoffs between conductivity and surface area. Here we report ordered mesoporous carbons constructed with graphitic tubular frameworks (OMGCs) with tunable pore sizes and mesostructures via dual templating, using mesoporous silica and molybdenum carbide as exo‐ and endo‐templates, respectively. OMGCs simultaneously realize high electrical conductivity and large surface area and pore volume. Benefitting from these features, Ru nanoparticles (NPs) supported on OMGC exhibit superior catalytic activity for alkaline hydrogen evolution reaction and single‐cell performance for anion exchange membrane water electrolysis compared to Ru NPs on other OMCs and commercial catalysts. Further, the OMGC‐based full‐carbon symmetric cell demonstrates excellent performances for Li‐ion capacitors.
Ordered mesoporous carbons constructed with graphitic tubular frameworks (OMGCs) were synthesized by a dual templating route. The OMGCs simultaneously realize high electrical conductivity and large surface area, which enable high performance in alkaline hydrogen evolution reaction, anion exchange membrane water electrolysis single‐cell, and Li‐ion capacitor.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Blood pressure variability (BPV) is associated with higher cardiovascular morbidity risks; however, its association with cognitive decline remains unclear. We investigated whether higher BPV is ...associated with faster declines in cognitive function in ischemic stroke (IS) patients. Cognitive function was evaluated between April 2010 and August 2015 using the Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment in 1,240 Korean PICASSO participants. Patients for whom baseline and follow-up cognitive test results and at least five valid BP readings were available were included. A restricted maximum likelihood-based Mixed Model for Repeated Measures was used to compare changes in cognitive function over time. Among a total of 746 participants (64.6 ± 10.8 years; 35.9% female). Baseline mean-MMSE score was 24.9 ± 4.7. The median number of BP readings was 11. During a mean follow-up of 2.6 years, mean baseline and last follow-up MMSE scores were 25.4 ± 4.8 vs. 27.8 ± 4.4 (the lowest BPV group) and 23.9 ± 5.2 vs. 23.2 ± 5.9 (the highest BPV group). After adjusting for multiple variables, higher BPV was independently associated with faster cognitive decline over time. However, no significant intergroup difference in cognitive changes associated with mean systolic BP was observed. Further research is needed to elucidate how BPV might affect cognitive function.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study aimed to explore the risk of dementia in a middle- and older-aged population with severe or profound hearing impairments. Data were collected for the Korean National Health Insurance ...Service-National Sample Cohort from 2002 to 2013. Participants aged 40 or older were selected. The 4,432 severely hearing-impaired participants were matched 1:4 with 17,728 controls, and the 958 profoundly hearing-impaired participants were matched 1:4 with 3,832 controls who had not reported any hearing impairment. Age, sex, income, region of residence, hypertension, diabetes mellitus, and dyslipidemia histories were matched between hearing-impaired and control groups. The crude (simple) and adjusted (age, sex, income, region of residence, dementia, hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease, cerebrovascular disease, and depression) hazard ratios (HRs) of hearing impairment on dementia were analyzed using Cox-proportional hazard models. The severe hearing impairment group showed an increased risk of dementia (adjusted HR = 1.17, 95% confidence interval CI = 1.04-1.31, P = 0.010). The profound hearing impairment group also showed an increased risk of dementia (adjusted HR = 1.51, 95% CI = 1.14-2.00, P = 0.004). Both severe and profound hearing impairments were associated with elevated the risk of dementia in middle- and older-aged individuals.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The molecular mechanisms of the degeneration of the aortic wall in abdominal aortic aneurysm (AAA) are poorly understood. The monomeric form of C-reactive protein (mCRP) is deposited in damaged ...cardiovascular organs and aggravates the prognosis; however, it is unknown whether mCRP is deposited in the degenerated aorta of abdominal aortic aneurysm (AAA). We investigated whether mCRP is deposited in AAA and examined the associated pathogenic signaling pathways.
Twenty-four cases of AAA were analyzed and their histological features were compared according to the level of serum CRP and the degree of mCRP deposition. Proteomic analysis was performed in AAA cases with strong and diffuse CRP immunopositivity (n = 7) and those with weak, focal, and junctional CRP immunopositivity (n = 3).
mCRP was deposited in the aortic specimens of AAA in a characteristic pattern that coincided with the lesion of the diminished elastic layer of the aortic wall. High serum CRP level was associated with stronger mCRP immunopositivity and a larger maximal diameter of aortic aneurysm. Proteomic analysis in AAA showed that multiple proteins were differentially expressed according to mCRP immunopositivity. Also, ingenuity pathway analysis showed that pathways associated with atherosclerosis, acute phase response, complement system, immune system, and coagulation were enriched in AAA cases with high mCRP immunopositivity.
AAA showed a characteristic deposition of mCRP, and multiple potentially pathologic signaling pathways were upregulated in AAA cases with strong CRP immunopositivity. mCRP and the aforementioned pathological pathways may serve as targets for managing the progression of AAA.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The number of brain MRI with contrast media performed in patients with cognitive impairment has increased without universal agreement. We aimed to evaluate the detection rate of contrast-enhanced ...brain MRI in patients with cognitive impairment.
This single-institution, retrospective study included 4,838 patients who attended outpatient clinics for cognitive impairment evaluation and underwent brain MRI with or without contrast enhancement from December 2015 to February 2020. Patients who tested positive for cognitive impairment were followed-up to confirm whether the result was true-positive and provide follow-up management. Detection rate was defined as the proportion of patients with true-positive results and was compared between groups with and without contrast enhancement. Individual matching in a 1:2 ratio according to age, sex, and year of test was performed.
The overall detection rates of brain MRI with and without contrast media were 4.7% (57/1,203; 95% CI: 3.6%-6.1%) and 1.8% (65/3,635; 95% CI: 1.4%-2.3%), respectively (P<0.001); individual matching demonstrated similar results (4.7% and 1.9%). Among 1,203 patients with contrast media, 3.6% was only detectable with the aid of contrast media. The proportion of patients who underwent follow-up imaging or treatment for the detected lesions were significantly higher in the group with contrast media (2.0% and 0.6%, P < .001).
Detection rate of brain MRI for lesions only detectable with contrast media in patients with cognitive impairment was not high enough and further study is needed to identify whom would truly benefit with contrast media.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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