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Hearing loss is common among older adults. Thus, it was of interest to explore differences in health care utilization and costs associated with hearing loss and hearing aid use. Hearing loss and hearing aid use were assessed through self-reports and included 5 categories: no hearing loss, aided mild, unaided mild, aided severe, and unaided severe hearing loss. Health care utilization and costs were obtained from medical claims. Those with aided mild or severe hearing loss were significantly more likely to have an emergency department visit. Conversely, those with aided severe hearing loss were about 15% less likely to be hospitalized. Individuals with unaided severe hearing loss had the highest annual medical costs ($14349) compared with those with no hearing loss ($12118, P < .001). In this study, those with unaided severe hearing loss had the highest medical costs. Further studies should attempt to better understand the relationship between hearing loss, hearing aid use, and medical costs.

Hot-carrier transistors are a class of devices that leverage the excess kinetic energy of carriers. Unlike regular transistors, which rely on steady-state carrier transport, hot-carrier transistors modulate carriers to high-energy states, resulting in enhanced device speed and functionality. These characteristics are essential for applications that demand rapid switching and high-frequency operations, such as advanced telecommunications and cutting-edge computing technologies 1-5 . However, the traditional mechanisms of hot-carrier generation are either carrier injection 6-11 or acceleration 12,13 , which limit device performance in terms of power consumption and negative differential resistance 14-17 . Mixed-dimensional devices, which combine bulk and low-dimensional materials, can offer different mechanisms for hot-carrier generation by leveraging the diverse potential barriers formed by energy-band combinations 18-21 . Here we report a hot-emitter transistor based on double mixed-dimensional graphene/germanium Schottky junctions that uses stimulated emission of heated carriers to achieve a subthreshold swing lower than 1 millivolt per decade beyond the Boltzmann limit and a negative differential resistance with a peak-to-valley current ratio greater than 100 at room temperature. Multi-valued logic with a high inverter gain and reconfigurable logic states are further demonstrated. This work reports a multifunctional hot-emitter transistor with significant potential for low-power and negative-differential-resistance applications, marking a promising advancement for the post-Moore era., (© 2024. The Author(s).)

Abstract: Quantification of gamma-H2AX foci can estimate exposure to ionizing radiation. Most nuclear and radiation accidents are partial-body irradiation, and the doses estimated using the total-body irradiation dose estimation formula are often lower than the actual dose. To evaluate the dose-response relation of gamma-H2AX foci in human peripheral blood lymphocytes after partial-body irradiation and establish a simple and high throughput model to estimate partial-body irradiation dose, we collected human peripheral blood and irradiated with 0-, 0.5-, 1-, 2-, 3-, 4-, 5-, 6-, and 8-Gy gamma rays to simulate total-body irradiation in vitro. Gamma-H2AX foci were quantitated by flow cytometry at 1 h after irradiation, and a dose-response curve was established for total-body irradiation dose estimation. Then, a partial-body irradiation dose-response calibration curve was established by adding calibration coefficients based on the Dolphin method. To reflect the data distribution of all doses more realistically, the partial-body irradiation dose-response calibration curve was divided into two sections. In addition, partial-body irradiation was simulated in vitro, and the PBI data were substituted into curves to verify the accuracy of the two partial-body irradiation calibration curves. Results showed that the dose estimation variations were all less than 30% except the 25% partial-body irradiation group at 1 Gy, and the partial-body irradiation calibration dose-response curves were YF 1 = - 3.444 x 2 + 18.532 x + 3.109, R 2 = 0.92 (YF ≤ 27.95); YF 2 = - 2.704 x 2 + 37.97 x - 56.45, R 2 = 0.86 (YF > 27.95). Results also suggested that the partial-body irradiation dose-response calibration curve based on the gamma-H2AX foci quantification in human peripheral blood lymphocytes is a simple and high throughput model to assess partial-body irradiation dose., Competing Interests: These authors contributed equally to this work. The authors declare no conflicts of interest., (Copyright © 2023 Health Physics Society.)

Childhood maltreatment is an established risk factor for psychopathology. However, it remains unclear how childhood traumatic events relate to mental health problems and how the brain is involved. This study examined the serial mediation effect of brain morphological alterations and emotion-/reward-related functions on linking the relationship from maltreatment to depression. We recruited 156 healthy adolescents and young adults and an additional sample of 31 adolescents with major depressive disorder for assessment of childhood maltreatment, depressive symptoms, cognitive reappraisal and anticipatory/consummatory pleasure. Structural MRI data were acquired to identify maltreatment-related cortical and subcortical morphological differences. The mediation models suggested that emotional maltreatment of abuse and neglect, was respectively associated with increased gray matter volume in the ventral striatum and greater thickness in the middle cingulate cortex. These structural alterations were further related to reduced anticipatory pleasure and disrupted cognitive reappraisal, which contributed to more severe depressive symptoms among healthy individuals. The above mediating effects were not replicated in our clinical group partly due to the small sample size. Preventative interventions can target emotional and reward systems to foster resilience and reduce the likelihood of future psychiatric disorders among individuals with a history of maltreatment.

Objective: This study aimed to investigate the effects of low-dose radiation on the abdominal aorta of mice and vascular endothelial cells., Methods: Wild-type and tumor-bearing mice were exposed to 15 sessions of low-dose irradiation, resulting in cumulative radiation doses of 187.5, 375, and 750 mGy. The effect on the cardiovascular system was assessed. Immunohistochemistry analyzed protein expressions of PAPP-A, CD62, P65, and COX-2 in the abdominal aorta. Microarray technology, Gene Ontology analysis, and pathway enrichment analysis evaluated gene expression changes in endothelial cells exposed to 375 mGy X-ray. Cell viability was assessed using the Cell Counting Kit 8 assay. Immunofluorescence staining measured γ-H2AX levels, and real-time polymerase chain reaction quantified mRNA levels of interleukin-6 (IL-6), ICAM-1, and Cx43., Results: Hematoxylin and eosin staining revealed thickening of the inner membranes and irregular arrangement of smooth muscle cells in the media membrane at 375 and 750 mGy. Inflammation was observed in the inner membranes at 750 mGy, with a clear inflammatory response in the hearts of tumor-bearing mice. Immunohistochemistry indicated increased levels of PAPP-A, P65, and COX-2 post-irradiation. Microarray analysis showed 425 up-regulated and 235 down-regulated genes, associated with processes like endothelial cell-cell adhesion, IL-6, and NF-κB signaling. Cell Counting Kit 8 assay results indicated inhibited viability at 750 mGy in EA.hy926 cells. Immunofluorescence staining demonstrated a dose-dependent increase in γ-H2AX foci. Reverse transcription quantitative PCR results showed increased expression of IL6, ICAM-1, and Cx43 in EA.hy926 cells post 750 mGy X-ray exposure., Conclusion: Repeated low-dose ionizing radiation exposures triggered the development of pro-atherosclerotic phenotypes in mice and damage to vascular endothelial cells., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Integrating a graphene transparent electrode (TE) matrix with driving circuits is essential for the practical use of graphene in optoelectronics such as active-matrix organic light-emitting diode (OLED) display, however it is disabled by the transport of carriers between graphene pixels after deposition of a semiconductor functional layer caused by the atomic thickness of graphene. Here, the carrier transport regulation of a graphene TE matrix by using an insulating polyethyleneimine (PEIE) layer is reported. The PEIE forms an ultrathin uniform film (≤10 nm) to fill the gap of the graphene matrix, blocking horizontal electron transport between graphene pixels. Meanwhile, it can reduce the work function of graphene, improving the vertical electron injection through electron tunneling. This enables the fabrication of inverted OLED pixels with record high current and power efficiencies of 90.7 cd A -1 and 89.1 lm W -1 , respectively. By integrating these inverted OLED pixels with a carbon nanotube-based thin-film transistor (CNT-TFT)-driven circuit, an inch-size flexible active-matrix OLED display is demonstrated, in which all OLED pixels are independently controlled by CNT-TFTs. This research paves a way for the application of graphene-like atomically thin TE pixels in flexible optoelectronics such as displays, smart wearables, and free-form surface lighting., (© 2023 Wiley-VCH GmbH.)

The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence, while its molecular mechanism remains unclear. In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We performed AXL transcriptome analysis from TCGA datasets, and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis, epithelial-mesenchymal transition (EMT) and immune-tolerant tumor microenvironment (TME). Knockdown of AXL or treatment with two independent AXL antibodies (named anti-AXL and AXL02) all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines. In a mouse model of 4T1 TNBC, administration of anti-AXL antibody substantially inhibited lung metastases formation and growth, accompanied by reduced downstream signaling activation, EMT and proliferation index, as well as an increased apoptosis and activated anti-tumor immunity. We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages. A specific anti-AXL antibody blocked bone marrow-derived macrophage (BMDM) M2-polarization in vitro. Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME, leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages, mature dendritic cells, cytotoxic T cells and B cells. We generated a novel and humanized AXL-ADC (AXL02-MMAE) employing a site-specific conjugation platform. AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines (IC 50  < 0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors (a minimum efficacy dose<1 mg/kg). Compared to chemotherapy, AXL02-MMAE achieved a superior efficacy in regressing large sized tumors, eliminated AXL-H tumor cell-dependent M2-macrophage infiltration with a robust accumulation of inflammatory macrophages and mature dendritic cells. Our results support AXL-targeted therapy for treatment of advanced NSCLC and TNBC., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

UVB exposure accelerates skin aging and pigmentation. Melatonin effectively regulates tyrosinase (TYR) activity and aging. The purpose of this study was to determine the association between premature senescence and pigmentation, and the mechanism of melanin synthesis effected by melatonin. Primary melanocytes were extracted and identified from the male foreskin. To inhibit TYR expression, primary melanocytes were transduced with the lentivirus pLKD-CMV-EGFP-2A-Puro-U6-TYR. The wild-type TYR (+/+) and TYR (-/-) or TYR (+/-) knockout C57BL/6 J mice were used to determine the role of TYR on melanin synthesis in vivo. Results showed that UVB-induced melanin synthesis is dependent on TYR in primary melanocytes and mice. Furthermore, in primary melanocytes pretreated with Nutlin-3 or PFT-α to up or downregulate p53, results showed that premature senescence and melanin synthesis increased in primary melanocytes after UVB irradiation at 80 mJ/cm 2 , and further increased after being treated with Nutlin-3, while significantly decreased with PFT-α. In addition, melatonin inhibited UVB-induced premature senescence associated with inactivation of p53 and phosphorylation of p53 on Ser15 (ser-15), a decrease of melanin synthesis accompanied by reduced TYR expression. Moreover, skin erythema and pigmentation induced by UVB were reduced in the dorsal and ear skin of mice topically pretreated with 2.5% melatonin. These indicate that melatonin inhibits UVB-induced senescence-associated pigmentation via the p53-TYR pathway in primary melanocytes and prevents pigmentation obviously in the dorsal and ear skin of C57BL/6 J mice after UVB irradiation. KEY MESSAGES: P53 links UVB irradiation-induced senescence and senescence-associated pigmentation and regulates TYR in primary melanocytes after UVB irradiation. Melatonin inhibits senescence-associated pigmentation through the p53-TYR pathway in primary melanocytes. Melatonin prevents skin erythema and melanin pigmentation induced by UVB irradiation in the dorsal and ear skin of C57BL/6J mice., (© 2023. The Author(s).)

Highly conductive concrete/mortar has been long pursued to realize structural health monitoring in the development of smart-cement-based facilities. However, it remains challenging to significantly increase the electrical conductivity of concrete/mortar without lowering the compressive strength and flowability. Here, nanocrystalline-graphene-coated aggregates (termed Gr@AGs) are synthesized to break this conductivity-strength tradeoff. Admixing Gr@AGs with cement enables the construction of a conductive network of graphene that simultaneously strengthens the interfacial transition zone between aggregates and paste. As a result, high conductivity and improved mechanical properties have been simultaneously realized in Gr@AGs-based smart mortars. The significant positive effects of Gr@AGs are further enhanced by combining them with a low percentage of carbon fiber. Typically, the 28-day compressive/flexural strength of the optimized mortar increases by 12.2%/19.4%, with the electrical resistivity reduced by over 3 orders of magnitude from ∼4.6 × 10 5 to 182 Ω cm. On this basis, we demonstrate high-sensitivity cement-based piezoresistive sensors with a fractional change in resistivity as high as ∼25%, which is more than 1 order of magnitude higher than those reported in comparable systems. This study provides a solution to the critical issues in developing smart cementitious composites by taking full advantage of graphene's properties.

The intestinal compensatory proliferative potential is a key influencing factor for susceptibility to radiation-induced intestinal injury. Studies indicated that the carnitine palmitoyltransferase 1 (CPT1) mediated fatty acid β-oxidation (FAO) plays a crucial role in promoting the survival and proliferation of tumor cells. Here, we aimed to explore the effect of 60Co gamma rays on CPT1 mediated FAO in the radiation-induced intestinal injury models, and investigate the role of CPT1 mediated FAO in the survival and proliferation of intestinal cells after irradiation. We detected the changed of FAO in the plasma and small intestine of Sprague Dawley (SD) rats at 24 h after 60Co gamma irradiation (0, 5 and 10 Gy), using target metabolomics, qRT-PCR, immunohistochemistry (IHC), western blot (WB) and related enzymatic activity kits. We then analyzed the FAO changes in radiation-induced intestinal injury models regardless of ex vivo (mice enteroids), or in vitro (normal human intestinal epithelial cell lines, HIEC-6). HIEC-6 cells were transduced with lentivirus vector GV392 and treated with puromycin for obtaining CPT1 stable knockout cell lines, named CPT1 KO. CPT1 enzymatic activities of HIEC-6 cells and mice enteroids were also inhibited by pharmaceutical inhibitor ST1326 and Etomoxir (ETO), to study the function of CPT1 in the survival and proliferation of HIEC-6 cells after 60Co gamma irradiation. We found that CPT1 mediated FAO was altered in the small intestine of the SD rats after irradiation, especially, the expression level and enzymatic activity of CPT1 were significantly increased. Similarly, the expression levels of CPT1 were also remarkably enhanced in mice enteroids and HIEC-6 cells after irradiation. CPT1 inhibition decreased the proliferation of the HIEC-6 cells and mice enteroids after irradiation partially by reducing the extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways activation, CPT1 inhibition also reduced the proliferation of mice enteroids after irradiation partially by down-regulating the Wnt/β-catenin signaling activity. In conclusion, our study indicated that CPT1 plays a crucial role in promoting intestinal epithelial cell proliferation after irradiation., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)

Objective: To investigate the feasibility and correlation of sacroiliac joint (SIJ) fat fraction (FF) and R2 ∗ as markers of bone metabolism in patients with ankylosing spondylitis (AS)., Methods: 75 AS patients were classified into an early active group (EA), late active group (LA), and inactive group (IA). Additionally, 54 matched healthy individuals were selected to be part of the normal control group (NC). All participants underwent chemical shift encoded based MRI (IDEAL-IQ) and routine clinical SIJ MRI at 3.0 T. FF and R2 ∗ were measured in subchondral bone, bone marrow edema (BME), and fat metaplasia (FM). Out of the participants, 39 with BME lesions (15 from EA, 16 from LA, 8 from IA) and 39 with FM lesions (9 from EA, 17 from LA, 13 from IA) were included. Differences in FF, R2 ∗ value for subchondral bone of all participants and for BME, FM lesions were evaluated. Subsequently, different stages of BME and FM in patient groups were compared, and the relationship between FF and R2 ∗ was analyzed., Results: A significant difference in FF was demonstrated among the BME, FM and the normal bone marrow ( p < 0.001), meanwhile, the difference of R2 ∗ value in FM was significantly lower (p = 0.034, 0.012) than that of BME and that of normal bone marrow. At lever of different lesions, only the FF for BME was significantly different among 3 patient groups ( p = 0.001), while there was no significantly different FF for FM among 3 patient groups. Unlike in BME lesions, the FF in FM lesions had a negative correlation with R2 ∗ ( p < 0.001, r = -0.488)., Conclusion: FF and R2 ∗ measurements help to quantitatively analyze the bone marrow fat composition and bony trabecular microstructure changes in AS, providing a noninvasive and accurate assessment basis for AS bone metabolism abnormalities., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Li-ping Ma et al.)

Ambient solution-processed conductive materials with a sufficient low work function are essential to facilitate electron injection in electronic and optoelectronic devices but are challenging. Here, we design an electrically conducting and ambient-stable polymer electrolyte with an ultralow work function down to 2.2 eV, which arises from heavy n-doping of dissolved salts to polymer matrix. Such materials can be solution processed into uniform and smooth films on various conductors including graphene, conductive metal oxides, conducting polymers and metals to substantially improve their electron injection, enabling high-performance blue light-emitting diodes and transparent light-emitting diodes. This work provides a universal strategy to design a wide range of stable charge injection materials with tunable work function. As an example, we also synthesize a high-work-function polymer electrolyte material for high-performance solar cells., (© 2022. The Author(s).)

Objective: To evaluate the clinical efficacy and safety of baricitinib, a Janus kinase (JAK) inhibitor, in treating patient with progressing vitiligo, and to further explore the regulation of baricitinib on melanocytes (MCs) in vitro., Methods: Four patients with progressing vitiligo were treated with oral baricitinib for a total of 12 weeks. MCs were cultured in vitro and irradiated by high-dose ultraviolet B (UVB, 150mJ/cm 2 ) to make an MC damaged model (MC-Ds). Baricitinib was added at a final concentration of 25 μM. Dopamine staining and NaOH method were used to measure the tyrosinase activity and melanin level, respectively, real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure the mRNA levels of tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1)., Results: Significant re-pigmentation was observed in the week 12 without obvious side effects. Depigmentation occurred in 2 patients at the 3-month follow-up. Laboratory research found that higher doses of UVB irradiation (150mJ/cm 2 ) could decrease melanin content of MCs, baricitinib (25 μM) could significantly promote tyrosinase activity, melanin content, and TYR, TRP-1 gene expression of MC-Ds., Conclusion: Our preliminary study showed that baricitinib was effective and safe in treating progressing vitiligo. Baricitinib could promote tyrosinase activity, melanin content and TYR, TRP1 gene expression of MC-Ds in vitro., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2022.)

Attending cram school has long been a trend in ethnic Chinese culture areas, including Taiwan. Despite the fact that school reform policies have been implemented in Taiwan, cram schools have continued to prosper. Therefore, in this educational culture, how to achieve a good educational effect is also a topic worthy of discussion. However, whether students really engage in those tutoring programs provided by cram schools has seldom been studied. To address this gap, this study explored how parents' hovering attitude toward life and coursework influences their children's engagement in cram schools. This study targeted those students who attend English cram schools to test the correlates between two types of helicopter parenting, tutoring engagement and continued attendance at cram schools. A total of 320 questionnaires were sent out, and 300 were returned, giving an overall response rate of 93.75%. Excluding seven incomplete or invalid questionnaires, 293 valid questionnaires were received. The results of this study show that hovering behavior awareness is negatively related to cram school engagement, whereas cram school engagement is positively related to the intention to continue attending cram school. Moreover, the results imply that parents should alleviate their helicoptering behavior to enhance their children's engagement in cram school tutoring programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ho, Hong, Ye, Chen, Ma and Chang Lee.)

Objective: This study aims to explore the incidence and clinical features of acute pancreatitis (AP) in patients with type 2 diabetes diabetic ketoacidosis (DKA) in the emergency department and discuss the predictive value of some pathological indicators for AP in DKA., Methods: Inpatient medical data of DKA patients hospitalized to our hospital's emergency department between January 2017 and January 2021 were evaluated retrospectively. These DKA patients were split into two groups based on whether they had AP or not. We examined the two groups' epidemiologic features, baseline laboratory results, and clinical outcomes. The Bedside Index for Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II), and Logistic Organ Failure System (LODS) scores were computed and compared across groups., Results: The prevalence of AP in DKA patients was 15.53%. The difference in Abdominal pain between the two groups of patients was statistically significant ( p < 0.001), and there was no statistical difference in age, gender, and BMI. The DKA and AP group LOS ( P < 0.001), ICU admission rate ( P = 0.046), anion gap ( P < 0.001), red blood cell ( P = 0.002), hemoglobin ( P < 0.001), hematocrit ( P = 0.002), serum triglyceride ( P < 0.001), serum cholesterol ( P < 0.001), serum amylase ( P = 0.004), random glucose ( P = 0.028), plasma fibrinogen ( P < 0.001), glycosylated hemoglobin [HbA1c (%); P = 0.008] higher than the DKA group, pH ( P < 0.001), carbon dioxide combining power (CO2CP; P < 0.001), ionized calcium (Ca2+; P = 0.022), ionized sodium (Na+; P = 0.001), and correction Na ( P = 0.034) lower than the DKA group. Multivariate analysis showed that low pH ( P < 0.05), hypertriglyceridemia ( P = 0.001), and hypercholesterolemia ( P = 0.01) were risk factors for DKA combined with AP. ROC curve analysis showed that the three cut-off value: serum triglycerides of 10.52 mmol/L, serum cholesterol of 9.03 mmol/L, and pH of 7.214. Serum triglyceride has the largest area under the curve (0.93). Under this cut-off value, the sensitivity (80%) and specificity of serum triglyceride, the degree (93.7%) is the highest, while the positive predictive value (62.0%) and negative predictive value (94.7%) of serum cholesterol are the highest., Conclusions: A severe episode of DKA with significant acidosis and hyperlipidemia is more likely to be linked with AP. The frequently used critical illness score is ineffective in determining the severity of the condition. When the serum triglyceride cut-off value is 10.52mmol/L, it has a higher predicted value for AP in DKA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ma, Liu, Cui, Liu, Wang and Zhao.)

Objective: To explore the effect and mechanism of ultraviolet B (UVB) on melanin synthesis and premature senescence in human immortalized keratinocytes (HaCaT) cells., Methods: HaCaT cells were irradiated with 0, 20, 50, 80, 100, 150, and 200 mJ/cm 2 of UVB. NaOH method was used for melanin content assay, cellular tyrosinase (TYR) activity was determined by 3,4-Dihydroxy-L-phenylalanine (L-DOPA) oxidation to dopachrome, premature senescence was analyzed by senescence-associated beta-galactosidase (SA-β-gal) staining kit, and the levels of p21, p16, p62, and GATA4 proteins were detected by Western blotting. Premature senescence was inhibited by the inhibitors of ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related (ATR), and the p53 signaling pathway was activated by Nutlin-3. The mRNA levels of senescence-associated secretory phenotype (SASP) factors including tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor A (VEGF-A), and interleukin-8 (IL-8) were measured by real-time quantitative polymerase chain reaction in HaCaT cells after 80 mJ/cm 2 of UVB irradiation., Results: The melanin level increased significantly with the elevation of irradiation dose ( F = 28.19, 43.82, 143.60, P < .05), reaching the peak at the dose of 80 mJ/cm 2 . The tyrosinase activity increased significantly ( F = 84.50, P < .05), the percentage of premature senescence increased ( F = 16.31, P < .05), the levels of p62 decreased, and the level of GATA4 increased obviously with the increase of UVB dose after irradiation. The UVB-induced promotion of GATA4 level was significantly inhibited by being treated with ATM or ATR inhibitor. However, this did not occur in the Nutlin-3-treated group. The mRNA and protein expression of TNF-α increased significantly at 72 h at 80 mJ/cm 2 of UVB irradiation., Conclusions: Melanin contents increased first and decreased afterward with the increasing of UVB irradiation. The decrease of p62-mediated selective autophagy was accompanied by the accumulation of GATA4 after different doses of UVB irradiation. Activation of this p62/GATA4 pathway depends on the ATM and ATR but is independent of p53, and the SASP factor was activated in HaCaT cells at 80 mJ/cm 2 of UVB irradiation., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Purpose: Ionizing radiation (IR) can induce autophagy and premature senescence; however, the link between them has not been clarified. Our research has shown that X-ray irradiation induces premature senescence in lung adenocarcinoma cells, and its occurrence partially depends on the signal transducer and activator of transcription 3 (STAT3). STAT3 can bind to the promoter region of Beclin1 and regulate its expression. Therefore, it is speculated that there may be a close link between premature senescence and autophagy induced by ionizing radiation in lung adenocarcinoma cells. p62 plays a regulatory role in both autophagy and premature senescence, and it is also an irreplaceable molecule that causes the senescence -associated secretory phenotype (SASP) and a substrate for selective autophagy. This study focused on STAT3, Beclin1 and p62 to clarify the regulatory relationship between IR-induced autophagy and premature senescence., Materials and Methods: After exposure to 4 Gy X-rays, a β-galactosidase staining kit was used to detect the positive rate of premature senescence. STAT3 was overexpressed by pcDNA3.0-STAT3 transfection, and was inhibited by AG490 and rapamycin. Lung adenocarcinoma cells were transduced with the adenovirus vector GV119-Beclin1 to knockdown the expression of Beclin1, or treated with ATM and ATR inhibitors to inhibit premature senescence. Western blotting was used to examine alterations in the radiation response proteins STAT3 and p-STAT3, senescence-related proteins p62 and GATA4, autophagy-related proteins Beclin1, and LC3-II/LC3-I. The mRNA expression levels of SASP factors, including IL-6 and IL-8, were examined by real-time polymerase chain reaction., Results: The activity of SA-β-gal increased significantly ( p  < .05), and the expression of p62 decreased significantly at 72 h after 4 Gy X-ray irradiation, accompanied by the increased expression of STAT3, p-STAT3, Beclin1, and the LC3-II/LC3-I ratio. Up- or down-regulation of STAT3 expression was followed by an increase or decrease in Beclin1 expression. After treatment with ATM and ATR inhibitors, there were no significant changes in Beclin1 expression or LC3-II/LC3-I ratio in A549 cells after 4 Gy X-ray irradiation. The p62 expression, the percentage of the SA-β-gal-positive staining cells, and the expression of IL-6 and IL-8 mRNA in cells transduced with GV119-Beclin1 were also decreased significantly after 4 Gy X-ray irradiation compared with that of the 0 Gy group., Conclusion: Radiation induces premature senescence and autophagy in lung adenocarcinoma cells. Autophagy regulates X-ray radiation-induced premature senescence through the STAT3-Beclin1-p62 pathway in lung adenocarcinoma cells.

Background: The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic vasculopathy. However, the role of profilin-1 as a multifunctional actin-binding protein in AGEs-induced atherosclerosis (AS) is largely unknown., Aim: To explore the potential role of profilin-1 in the pathogenesis of AS induced by AGEs, particularly in relation to the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) signaling pathway., Methods: Eighty-nine individuals undergoing coronary angiography were enrolled in the study. Plasma cytokine levels were detected using ELISA kits. Rat aortic vascular smooth muscle cells (RASMCs) were incubated with different compounds for different times. Cell proliferation was determined by performing the MTT assay and EdU staining. An AGEs-induced vascular remodeling model was established in rats and histological and immunohistochemical analyses were performed. The mRNA and protein levels were detected using real-time PCR and Western blot analysis, respectively. In vivo , shRNA transfection was performed to verify the role of profilin-1 in AGEs-induced proatherogenic mediator release and aortic remodeling. Statistical analyses were performed using SPSS 22.0 software., Results: Compared with the control group, plasma levels of profilin-1 and receptor for AGEs (RAGE) were significantly increased in patients with coronary artery disease, especially in those complicated with diabetes mellitus ( P < 0.01). The levels of profilin-1 were positively correlated with the levels of RAGE ( P < 0.01); additionally, the levels of both molecules were positively associated with the degree of coronary artery stenosis ( P < 0.01). In vivo , tail vein injections of AGEs induced the release of proatherogenic mediators, such as asymmetric dimethylarginine, intercellular adhesion molecule-1, and the N-terminus of procollagen III peptide, concomitant with apparent aortic morphological changes and significantly upregulated expression of the profilin-1 mRNA and protein in the thoracic aorta ( P < 0.05 or P < 0.01). Downregulation of profilin-1 expression with an shRNA significantly attenuated AGEs-induced proatherogenic mediator release ( P < 0.05) and aortic remodeling. In vitro , incubation of vascular smooth muscle cells (VSMCs) with AGEs significantly promoted cell proliferation and upregulated the expression of the profilin-1 mRNA and protein ( P < 0.05). AGEs (200 μg/mL, 24 h) significantly upregulated the expression of the STAT3 mRNA and protein and JAK2 protein, which was blocked by a JAK2 inhibitor (T3042-1) and/or STAT3 inhibitor (T6308-1) ( P < 0.05). In addition, pretreatment with T3042-1 or T6308-1 significantly inhibited AGEs-induced RASMC proliferation ( P < 0.05)., Conclusion: AGEs induce proatherogenic events such as VSMC proliferation, proatherogenic mediator release, and vascular remodeling, changes that can be attenuated by silencing profilin-1 expression. These results suggest a crucial role for profilin-1 in AGEs-induced vasculopathy., Competing Interests: Conflict-of-interest statement: 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., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: This study intends to investigate the prognostic risk factors of bloodstream infection in Beijing., Methods: This study is a clinical retrospective study. Four hundred forty-six patients with community-onset bloodstream infections (COBSI), admitted to the emergency department and inpatient department of Beijing Jishuitan Hospital from January 1, 2015, to December 31, 2019, were selected as the main research objects. According to whether the patient survives for 100 days or not, 363 cases were in the survival group, and 83 cases were in the death group. By analyzing the clinical data of the two groups of patients, the epidemiology, clinical characteristics, bacterial resistance, and risk factors affecting the prognosis of the patients were analyzed., Results: A total of 446 pathogenic bacteria were isolated in this study, including 324 Gram-negative (G-) bacteria (72.6%), 121 Gram-positive (G+) bacteria (27.1%). The results of the study showed that there were significant differences in MDR, initial antibiotic use, solid tumor, CKD, septic shock, acute liver injury, AKI, central venous catheter, urinary catheter, blood replacement therapy, invasive operation, and use of three or more antibiotics between the two groups (p<0.05). The multiple logistic regression analysis showed that solid tumors (OR=3.339, 95% CI: (1.441, 7.734), p=0.005), combined septic shock (OR=20.729, 95% CI: (10.235, 41.982), p<0.001), indwelling catheters (OR=3.556, 95% CI: (1.538, 8.222), p=0.003) and continuous venovenous hemofiltration (CVVH, OR=19.548, 95% CI: (8.724, 35.641), p=0.003) are independent risk factors affecting the prognosis of COBSI patients. Appropriate initial antibiotic therapy is a protective factor affecting the prognosis of COBSI patients., Conclusion: Solid tumors, combined septic shock, indwelling catheters, CVVH are independent risk factors affecting the prognosis of COBSI patients., Competing Interests: Competing interests: The authors declare no conflict of Interest.

G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite the effectiveness of hepatitis B virus (HBV) vaccination in reducing the prevalence of chronic HBV infection as well as the incidence of acute hepatitis B, fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC), there was still a large crowd of chronically infected populations at risk of developing cirrhosis or HCC. In this study, we established a comprehensive prognostic system covering multiple signatures to elevate the predictive accuracy for overall survival (OS) of hepatitis B virus carriers with HCC development. Weighted Gene Co-Expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine Recursive Feature Elimination (SVM-RFE), and multivariate COX analysis, along with a suite of other online analyses were successfully applied to filtrate a three-gene signature model ( TP53 , CFL1 , and UBA1 ). Afterward, the gene-based risk score was calculated based on the Cox coefficient of the individual gene, and the prognostic power was assessed by time-dependent receiver operating characteristic (tROC) and Kaplan-Meier (KM) survival analysis. Furthermore, the predictive power of the nomogram, integrated with the risk score and clinical parameters (age at diagnosis and TNM stage), was revealed by the calibration plot and tROC curves, which was verified in the validation set. Taken together, our study may be more effective in guiding the clinical decision-making of personalized treatment for HBV carriers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Tu, Yao, Cai and Ma.)

Background: China has successfully reduced tuberculosis (TB) incidence rate over the past three decades, however, challenges remain in improving the quality of TB diagnosis and treatment. In this paper, we assess the effects of the implementation of "China National Health Commission (NHC) and Gates Foundation TB Prevention and Control Project" on the quality of TB care in the three provinces., Methods: We conducted the baseline study in 2016 and the final evaluations in 2019 in the 12 selected project counties. We obtained TB patients' information from the TB Information Management System and reviewed medical records of TB cases in the TB designated hospitals. We compared TB diagnosis and treatment services with the national practice guideline and used Student's t-test and Pearson χ 2 tests or Fisher's exact tests to compare the difference before and after the project implementation., Results: The percentage of sputum smear-negative (SS-) patients taking culture or rapid molecular test (RMT) doubled between 2015 and 2018 (from 35% to 87%), and the percentage of bacteriologically confirmed pulmonary TB cases increased from 36% to 52%. RMT has been widely used and contributed an additional 20% of bacteriologically confirmed TB cases in 2018. The percentage of TB patients taking drug susceptibility tests (DST) also doubled (from 40% in 2015 to 82% in 2018), and the proportion of TB patients receiving adequate diagnosis services increased from 85% to 96%. Among all SS- TB patients, over 86% received the recommended diagnostic services at the end of the study period, an improvement from 75% prior to the project implementation. However, the proportion of TB patients treated irrationally using second-line anti-TB drugs (SLDs) increased from 12.6% in 2015 to 19.9% in 2018. The regional disparities remained within the project provinces, albeit the gaps between them narrowed down for almost all indicators., Conclusions: The quality of TB diagnosis services has been improved substantially, which is attributable to the coverage of new diagnosis technology. However, irrational use of SLDs remains a concern after the project implementation.

Background: Flexible ureteroscopic holmium laser lithotripsy is used to treat urinary tract calculi, but postoperative complications include shivering, fever and infection. To investigate the effects of irrigation fluid temperature on postoperative complications., Methods: This randomized controlled trial included 120 consecutive patients undergoing flexible ureteroscopic holmium laser lithotripsy at the Urology Department, Suining Central Hospital, Sichuan, China between January 2017 and July 2019. Patients were randomized 1:1:1 into three groups (17 °C, 27 °C or 37 °C). Primary outcome was fever incidence (body temperature > 37.5 °C) within 48 h after surgery. Secondary outcomes included shivering incidence during recovery from anesthesia, white blood cell count (WBC), serum procalcitonin (PCT) and incidence of suspected infection (temperature > 38.5 °C and PCT > 0.5 µg/L)., Results: There were 108 patients, (17 °C group, n = 36; 27 °C group, n = 35; 37 °C group, n = 37), received flexible ureteroscopic holmium laser lithotripsy and analyzed. Age, gender distribution, body mass index, ASA grade, stone burden, preoperative creatinine, preoperative core temperature and irrigation fluid volume did not differ significantly between groups. 17 °C, 27 °C and 37 °C groups exhibited significant differences in the incidences of postoperative fever (38.9% vs. 17.1% vs. 13.5%) and shivering (22.2% vs. 5.7% vs. 2.7%) (p < 0.05 for all pairwise comparisons). There was no significant difference of WBC, PCT and incidence of suspected infection in 37 °C or 27 °C group compared with 17 °C group. One case each of flash pulmonary edema and bleeding occurred in 37 °C group., Conclusion: Warming the irrigation fluid can reduce the incidence of postoperative fever and shivering, but further studies are needed to determine the optimal temperature. Trial registration The trial was registered at the Chinese Clinical Trials Registry and allocated as ChiCTR2000031683. The trial was registered on 07/04/2020 and this was a retrospective registration.

Objective: To evaluate whether the efficacy of Getong Tongluo Capsule (, GTC, consisted of total flavone of Radix Puerariae) on improving patients' quality of life and lowering blood pressure are superior to the extract of Ginkgo biloba (EGB) for patients with convalescent-phase ischemic stroke and primary hypertension., Methods: This randomized, positive-drug- and placebo-controlled, double-blind trial was conducted from September 2015 to October 2017. Totally 477 eligible patients from 18 hospitals in China were randomly assigned in a 2:1:1 ratio to the following interventions, twice a day for 12 weeks: (1) GTC 250 mg plus EGB-matching placebo 40 mg (237 cases, GTC group), (2) EGB 40 mg plus GTC-matching placebo 250 mg (120 cases, EGB group) or (3) GTC-matching placebo 250 mg plus EGB-matching placebo 40 mg (120 cases, placebo group). Moreover, all patients were orally administered aspirin enteric-coated tablets 100 mg, once a day for 12 weeks. The primary outcome was the Barthel Index (BI). The secondary outcomes included the control rate of blood pressure and National Institutes of Health Stroke Scale (NIHSS) scores. The incidence and severity of adverse events (AEs) were calculated and assessed., Results: The BI relative independence rates, the clinical recovery rates of NIHSS, and the total effective rates of NIHSS in the GTC and EGB groups were significantly higher than the placebo group at 12 weeks after treatment (P<0.05), and no statistical significance was found between the GTC and EGB groups (P>0.05). The control rate of blood pressure in the GTC group was significantly higher than the EGB and placebo groups at 12, 18 and 24 weeks after treatment (P<0.01). There were no statistically significant differences in the incidences of AEs, adverse drug reactions, or serious AEs among the 3 groups (P>0.05)., Conclusion: GTC exhibited significant efficacy in improving patients' quality of life as well as neurological function and controlling hypertension. (Registration No. ChiCTR1800016667).

The conventional strategy of fabricating resistive random access memory (RRAM) based on graphene oxide is limited to a resistive layer with homogeneous oxidation, and the switching behavior relies on its redox reaction with an active metal electrode, so the obtained RRAMs are typically plagued by inferior performance and reliability. Here, we report a strategy to develop high-performance flexible RRAMs by using graphene oxidized with a perpendicular oxidation gradient as the resistive layer. In contrast to a homogeneous oxide, this graphene together with its distinctive inter-layer oxygen diffusion path enables excellent oxygen ion/vacancy diffusion. Without an interfacial redox reaction, oxygen ions can diffuse to form conductive filaments with two inert metal electrodes by applying a bias voltage. Compared with state-of-the-art graphene oxide RRAMs, these graphene RRAMs have shown superior performance including a high on-off current ratio of ∼105, long-term retention of ∼106 s, reproducibility over 104 cycles and long-term flexibility at a bending strain of 0.6%, indicating that the material has great potential in wearable smart data-storage devices.

Graphene has emerged as an attractive candidate for flexible transparent electrode (FTE) for a new generation of flexible optoelectronics. Despite tremendous potential and broad earlier interest, the promise of graphene FTE has been plagued by the intrinsic trade-off between electrical conductance and transparency with a figure of merit (σ DC /σ Op ) considerably lower than that of the state-of-the-art ITO electrodes (σ DC /σ Op <123 for graphene vs. ∼240 for ITO). Here we report a synergistic electrical/optical modulation strategy to simultaneously boost the conductance and transparency. We show that a tetrakis(pentafluorophenyl)boric acid (HTB) coating can function as highly effective hole doping layer to increase the conductance of monolayer graphene by sevenfold and at the same time as an anti-reflective layer to boost the visible transmittance to 98.8%. Such simultaneous improvement in conductance and transparency breaks previous limit in graphene FTEs and yields an unprecedented figure of merit (σ DC /σ Op ∼323) that rivals the best commercial ITO electrode. Using the tailored monolayer graphene as the flexible anode, we further demonstrate high-performance green organic light-emitting diodes (OLEDs) with the maximum current, power and external quantum efficiencies (111.4 cd A -1 , 124.9 lm W -1 and 29.7%) outperforming all comparable flexible OLEDs and surpassing that with standard rigid ITO by 43%. This study defines a straightforward pathway to tailor optoelectronic properties of monolayer graphene and to fully capture their potential as a generational FTE for flexible optoelectronics., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Objective: To evaluate the effect of individualized antiplatelet therapy based on CYP2C19 genotype and platelet function on the prognosis of patients after percutaneous coronary intervention (PCI) compared with conventional antiplatelet therapy., Patients and Methods: Patients diagnosed with acute coronary syndromes (ACS) in Shandong Provincial Qianfoshan Hospital from December 2014 to December 2017 were included in this prospective study and randomly divided into conventional (CA) and individualized antiplatelet therapy group (IA) at 1:1 ratio. Patients in the CA group received clopidogrel 75 mg once a day (QD). Group IA was divided into extensive, intermediate, and poor metabolizers according to the results of the CYP2C19 gene test. Three genotypes were given clopidogrel 75 mg QD, 75 mg twice daily (BID) and ticagrelor 90 mg BID respectively. After taking these medicines for a period of time, platelet function was monitored by thromboelastography (TEG) and MAADP values were recorded. MAADP indicates the adenosine diphosphate (ADP) induced platelet function that not inhibited by medicine. High platelet reactivity (HPR) was defined as MAADP > 47mm, indicating a high risk of thrombus, and MAADP ≤ 31 mm indicates a high risk of hemorrhage. For extensive metabolizers (EMs) and intermediate metabolizers (IMs) patients with HPR, the antiplatelet therapy would be changed by the clinician according to the patient's conditions. Major adverse cardiovascular events (MACE) and hemorrhage events were monitored during 1-year follow-up., Results: The patients with MAADP > 47 mm were 89 (28.6%) in the IA group. There were 50 EMs patients with MAADP > 47 mm (33.3%). Of which, there were 2 cases which changed the dosage of clopidogrel to 75 mg BID, 14 cases who changed clopidogrel to ticagrelor. There were 36 IMs patients with MAADP > 47 mm (30.8%). Of which, there were 19 cases who changed clopidogrel to ticagrelor. There was no significant difference in the value of MAADP between EMs and IMs patients. Within 1 year after PCI, the occurrence of MACE in the IA group was significantly lower than that in the CA group (p=0.010)., Conclusions: (1) Patients with a CYP2C19 loss-of-function (LOF) gene who take double doses of clopidogrel overcome the decreased efficacy of clopidogrel which partly due to CYP2C19 LOF gene, without increasing the risk of hemorrhage. (2) Individualized antiplatelet therapy based on CYP2C19 genotype and platelet function can significantly reduce the occurrence of MACE (mainly acute non-fatal myocardial infarction) after PCI without increasing the risk of moderate or severe hemorrhage.

Objective: To assess the diagnostic value of the Xpert® MTB/RIF (GeneXpert) assay for tracheobronchial tuberculosis (TBTB) using bronchial washing fluid (BWF)., Methods: This retrospective study enrolled patients suspected of having TBTB and patients with non-TB pulmonary disease as controls. BWF were used to undertake acid-fast bacillus (AFB) smears, the GeneXpert assay and the Lӧwenstein-Jensen (LJ) culture method. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were compared among BWF AFB smears, BWF GeneXpert and the BWF LJ culture method., Results: A total of 130 patients with TBTB and 102 patients with non-TB pulmonary disease were enrolled in the study. Sputum AFB smears were positive in 62 of 130 patients (47.7%) with TBTB. Using the clinical diagnosis of TBTB as the gold standard, the sensitivity, specificity, PPV and NPV of the three methods using BWF were as follows: 93.1%, 99.0%, 99.2% and 91.8% for BWF GeneXpert; 73.1%, 100.0%, 100.0% and 74.5% for BWF LJ cultures; 53.8%, 99.0%, 98.6% and 62.7% for BWF AFB smears. The diagnostic yield of BWF GeneXpert was significantly higher compared with BWF cultures for type III and IV TBTB., Conclusion: The Xpert® MTB/RIF assay using BWF exhibited higher sensitivity than bacteriological diagnostic methods and was particularly useful for the early diagnosis of smear-negative TBTB.

Objective: Occipitalization of the atlas (OA) often is associated with atlantoaxial dislocation and basilar invagination. The purpose of this study is to determine the biomechanical difference between normal and OA conditions in the craniovertebral junction and to further explore the rationale for development of atlantoaxial dislocation and basilar invagination using the finite element model (FEM)., Methods: A ligamentous, nonlinear, sliding-contact, 3-dimensional FEM of the occipitoatlantoaxial complex was generated. Validation of the model was accomplished by comparing kinematic predictions with experimental data. We defined the atlantooccipital joint as a tie contact to simulate the OA deformity. The range of motion and the value of the maximum Von Mises stress were compared between the intact and OA models., Results: We found all of the predicted data in the intact FEM fell within 1 standard deviation of the cadaver data for all 6 loadings. The OA simulation significantly reduced the overall range of motion of the occipitoatlantoaxial complex at all loadings. The maximum Von Mises stress was predicted to increase at the transverse ligament and the superior articular facet of the axis for all the flexion, extension, lateral bending, and axial rotation loadings., Conclusions: The OA could result in hypermobility of the atlantoaxial segment and cause overstress in the transverse ligament and the lateral atlantoaxial joints. These changes explain the pathogenesis of atlantoaxial dislocation and basilar invagination associated with OA. Follow-up should be scheduled regularly due to the nature of the dynamic development of atlantoaxial dislocation and basilar invagination., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Clean transfer of two-dimensional (2D) materials grown by chemical vapor deposition is critical for their application in electronics and optoelectronics. Although rosin can be used as a support layer for the clean transfer of graphene grown on Cu, it has not been usable for the transfer of 2D materials grown on noble metals or for large-area transfer. Here, we report a poly(methyl methacrylate) (PMMA)/rosin double support layer that enables facile ultraclean transfer of large-area 2D materials grown on different metals. The bottom rosin layer ensures clean transfer, whereas the top PMMA layer not only screens the rosin from the transfer conditions but also improves the strength of the transfer layer to make the transfer easier and more robust. We demonstrate the transfer of monolayer WSe 2 and WS 2 single crystals grown on Au as well as large-area graphene films grown on Cu. As a result of the clean surface, the transferred WSe 2 retains the intrinsic optical properties of the as-grown sample. Moreover, it does not require annealing to form good ohmic contacts with metal electrodes, enabling high-performance field effect transistors with mobility and ON/OFF ratio ∼10 times higher than those made by PMMA-transferred WSe 2 . The ultraclean graphene film is found to be a good anode for flexible organic photovoltaic cells with a high power conversion efficiency of ∼6.4% achieved.

Flexible graphene transparent conductive films (TCFs) prepared by chemical vapor deposition hold great promise for next-generation wearable optoelectronic devices, but the lack of low-cost scalable intact transfer and highly efficient doping greatly limits their commercialization. Here, we report a UV-epoxy adhesive as a robust multifunctional layer for the low-cost scalable production of high-performance flexible graphene TCF. Its high solvent stability, sufficient adhesion force, and conformal contact with graphene enable the intact bubbling transfer of graphene. More importantly, a highly strong and stable p-dopant, superacid HSbF 6 , is in situ generated from UV-epoxy. HSbF 6 substantially increases the hole concentration of pristine graphene by more than 10 times and consequently reduces its sheet resistance by up to 95% with high stability. Furthermore, it can be readily integrated with the roll-to-roll transfer process. These features enable continuous production of graphene TCFs with overall performances superior to those produced by common transfer methods and typical dopants. As an example, we demonstrate the use of this film in the capacitive multitouch panel of tablet computers.

Bacterial community in activated sludge (AS) is diverse and highly dynamic. Little is known about the mechanism shaping bacterial community composition and dynamics of AS and no study had quantitatively compared the contribution of abiotic environmental factors and biotic associations to the temporal dynamics of AS microbial communities with significantly different diversity. In this study, two full-scale sewage treatment plants (STPs) with distinct operational parameters and influent composition were sampled biweekly over 1 year to reveal the correlating factors to whole and sub-groups of AS bacterial community diversity and dynamics. The results show that the bacterial communities of the two STPs were entirely different and correlated with the influent composition and operating configurations. Bacterial associations represented by cohesion metrics and the environmental factor temperature were the primary correlated factors to the temporal bacterial community dynamics within each STP. The STP with high diversity and evenness could treat influent with higher suspended solid and a shorter sludge retention time, and was less correlated with environmental factors, implying the importance of diversity for AS system.

Previous studies have suggested that microsomal prostaglandin E synthase-1 (mPGES-1) is highly expressed and closely associated with mitogen-activated protein kinase (MAPK) signaling pathways in various types of malignant cells. However, their expression patterns and function with respect to T-cell acute lymphoblastic leukemia (T-ALL) remain largely unknown. The present study investigated whether mPGES-1 served a crucial role in T-ALL and aimed to identify interactions between mPGES-1 and the MAPK signaling pathway in T-ALL. The results indicated that mPGES-1 overexpression in T-ALL jurkat cells was significantly decreased by RNA silencing. Decreasing mPGES-1 on a consistent basis may inhibit cell proliferation, induce apoptosis and arrest the cell cycle in T-ALL jurkat cells. Microarray and western blot analyses revealed that c-Jun N-terminal kinase served a role in the mPGES-1/prostaglandin E2/EP4/MAPK positive feedback loops. In addition, P38 and extracellular signal-regulated kinase 1/2 exhibited negative feedback effects on mPGES-1. In conclusion, the results suggested that cross-talk between mPGES-1 and the MAPK signaling pathway was very complex. Therefore, the combined regulation of mPGES-1 and the MAPK signaling pathway may be developed into a new candidate therapy for T-ALL in the future.

Caffeine is contained within many drinks and food that are consumed daily. Prenatal caffeine ingestion (PCI) is a risk factor for intrauterine growth retardation (IUGR). We previously observed that PCI inhibits scavenger receptor class B type I (SR-BI)-mediated cholesterol uptake in fetal adrenals, subsequently decreasing glucocorticoid synthesis and inducing IUGR. In the present study, we aimed to investigate the long-term effects of PCI on adrenal glucocorticoid synthesis in adult male offspring rats. After establishing the PCI-induced IUGR, adult male offspring was injected intraperitoneally with 5 mg/kg·d lipopolysaccharide (LPS) for 2 days to induce acute stress. We observed persistent inhibition of SR-BI expression in PCI adrenals before and after stress. Compared with the controls, the PCI offspring had higher corticosterone concentrations after stress. The serum cholesterol concentration was stable without intergroup differences before and after stress. The cholesterol concentration in PCI adrenals showed a higher decrease rate than that of the control after stress. In summary, PCI induced long-term alterations in SR-BI expression and glucocorticoid synthesis in adult male offspring rat adrenals. Cholesterol has to be over-consumed in PCI adrenals against acute stress. This study provides an experimental basis to explain the susceptibility of IUGR offspring to metabolic diseases in adults., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The microtubulin inhibitor MT189 possesses anticancer activity and has been shown to overcome multidrug resistance. Here, we report that MT189 also inhibits angiogenesis. MT189 inhibited the proliferation, migration and differentiation of endothelial cells, with or without VEGF stimulation, and suppressed microvessel formation ex vivo and in vivo. MT189 reduced VEGF expression and secretion in both tumor and endothelial cells, under either hypoxic or normoxic conditions. The activation of VEGFR2 and downstream Src was thus abrogated in the MT189-treated endothelial cells. MT189 subsequently stabilized endothelial cell-cell junctions consist of VE-cadherin, β-catenin, vinculin, and actin. MT189 also disrupted endothelial cell-matrix junctions by inhibiting the turnover of focal adhesions containing FAK, paxillin, vinculin, and actin. Inhibition of JNK reversed MT189-mediated inhibition of endothelial migration and differentiation, JNK activation, the reduction of VEGF expression and secretion, and the decrease of Src and FAK phosphorylation. These results indicate that MT189 suppresses angiogenesis by reducing endothelial proliferation, migration, and differentiation via the JNK-VEGF/VEGFR2 signaling axis. Together with our previous report showing that MT189 exhibited anticancer activity via the JNK-MCL-1 pathway, these new findings further support MT189-based drug development for cancer therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Patients facing a high-stakes clinical decision are often confronted with an overwhelming array of options. High-quality decisions about treatment should reflect patients' preferences as well as their clinical characteristics. Preference-assessment instruments typically focus on pre-selected clinical outcomes and attributes chosen by the investigator., Objective: We sought to develop a patient-centered approach to elicit and compare the treatment goals of patients with multiple sclerosis (MS) and healthcare providers (HCPs)., Methods: We conducted five nominal group technique (NGT) meetings to elicit and prioritize treatment goals from patients and HCPs. Five to nine participants in each group responded silently to one question about their treatment goals. Responses were shared, consolidated, and ranked to develop a prioritized list for each group. The ranked lists were combined. Goals were rated and sorted into categories. Multidimensional scaling and hierarchical cluster analysis were used to derive a visual representation, or cognitive map, of the data and to identify conceptual clusters, reflecting how frequently items were sorted into the same category., Results: Five NGT groups yielded 34 unique patient-generated treatment goals and 31 unique HCP-generated goals. There were differences between patients and HCPs in the goals generated and how they were clustered. Patients' goals tended to focus on the impact of specific symptoms on their day-to-day lives, whereas providers' goals focused on slowing down the course of disease progression., Conclusions: Differences between the treatment goals of patients and HCPs underscore the limitations of using HCP- or investigator-identified goals. This new adaptation of cognitive mapping is a patient-centered approach that can be used to generate and organize the outcomes and attributes for values clarification exercises while minimizing investigator bias and maximizing relevance to patients.

Primary breast tuberculosis is rare. We report a case of bilateral primary breast tuberculosis. The patient received incisional drainage and debridement of both breasts. Histopathology of the breast tissues revealed chronic granulomatous inflammation and positive acid-fast stain. The patient received antitubercular therapy for 18 months, and she achieved complete resolution.

This study was designed to observe the effects of maternal food restriction (MFR) on the development of fetal thymus in different gestation periods. Timed pregnant rats were randomized into 3 groups: CN (free access to standard chow throughout gestation), MFR 0-21 (50% MFR throughout gestation), MFR 0-14 (50% MFR from gestational day (GD) 0 to GD14, early-mid gestation). Results showed that MFR during early-mid period had few impact on the fetal thymus and T cell subpopulations. However, MFR throughout gestation resulted in thymic atrophy, deceased frequency of both CD4 + and CD8 + single positive (SP) T cells and enhanced thymocyte apoptosis in fetus. Our results suggest the fetal thymus is more vulnerable to the adverse intrauterine environments in the late gestation period, and the decreased number of SP T cells could result from the enhanced thymocyte apoptosis., (Copyright © 2017. Published by Elsevier B.V.)

Intrauterine growth retardation (IUGR) is a common obstetric complication lacking an optimal method for prenatal screening. DNA methylation profile in maternal blood holds significant promise for prenatal screening. Here, we aimed to screen out potential IUGR biomarkers in maternal blood from the perspective of DNA methylation. The IUGR rat model was established by prenatal maternal undernutrition. High-throughput bisulfite sequencing of genomic DNA methylation followed by functional clustering analysis for differentially methylated region (DMR)-associated genes demonstrated that genes regulating transcription had the most significantly changed DNA methylation status in maternal blood with IUGR. Genes about apoptosis and placental development were also changed. Besides increased placental apoptosis, IUGR rats demonstrated the same hypermethylated CpG sites of steroidogenic factor-1 (SF-1, a DMR-associated transcription factor about placenta) promoter in maternal blood and placentae. Further, ff1b, the SF-1 ortholog, was knocked out in zebrafish by CRISPR/Cas9 technology. The knock-out zebrafish demonstrated developmental inhibition and increased IUGR rates, which confirmed the role of SF-1 in IUGR development. Finally, hypermethylated SF-1 was observed in human maternal blood of IUGR. This study firstly presented distinct DNA methylation profile in maternal blood of IUGR and showed hypermethylated SF-1 could be a potential IUGR biomarker in maternal rat blood., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed.

Autophagy is a ubiquitous intracellular process for cellular homeostasis maintenance by recycling damaged protein and organelles. Dysregulation of cardiomyocytes autophagic activity is implicated in various heart diseases. Recent studies had demonstrated that long non-coding RNAs (lncRNAs) played crucial roles on modulation of autophagic activity. In this study, we first established an angiotensin II-induced autophagy model on neonatal rat cardiomyocytes. Western blot assay confirmed that the expression of Beclin 1 and the conversion of soluble LC3-I to lipid bound LC3-II were significantly increased at 12 h after angiotensin II stimulation, but the cardiomyocytes surface area and hypertrophic markers expression had no significant change. Then microarray analysis and real-time PCR were applied to detect differentially expressed lncRNAs during cardiomyocytes autophagy. A total of 1,249 lncRNAs were determined as differentially expressed, including 700 upregulated lncRNAs and 549 downregulated lncRNAs. LncRNAs subgroup analysis showed there were 43 transcribed ultra-conserved noncoding RNAs (T-UCRs) differentially expressed in cardiomyocytes autophagy, of which 26 T-UCRs were upregulated and 17 T-UCRs were downregulated. Bioinformatics analysis further showed that 94 differentially expressed lncRNAs contained potential binding sites of miR-22, a pro-hypertrophic and pro-autophagic microRNA. Therefore, these differentially expressed lncRNAs might play critical roles in cardiomyocytes autophagy. This finding would provide an experimental basis for future investigation on ischemic heart disease., (© 2017 International Federation for Cell Biology.)

BackgroundEmerging evidence suggests that DNA methylation in maternal blood is a promising target for intrauterine growth retardation (IUGR) screening, a common developmental toxicity. Here, we aimed to screen out IUGR-related DNA methylation status in maternal blood via high-throughput profiling.MethodsPregnant Wistar rats were subcutaneously administered nicotine (1 mg/kg) twice per day from gestational day (GD) 11 to GD20 to establish the IUGR model. MeDIP array assays and the following GO analysis were used to evaluate DNA methylation status in maternal blood. One placental development-associated gene was selected for further confirmation.ResultsGenes regulating the development of multiple organs and major body systems had changed DNA methylation frequencies in the maternal blood of IUGR rats. Placental development, which can affect the development of multiple fetal organs and induce IUGR, is a hypermethylated cluster consisting of four significantly changed genes, including syncytin b (Synb), Lrrc15, Met, and Tex19.1. With the most significant change, Synb hypermethylation in maternal blood was confirmed by bisulfite-sequencing PCR (BSP). Moreover, decreased Synb expression and histological changes were observed in IUGR placentae.ConclusionThe IUGR-associated DNA methylation profile in maternal blood, such as placenta-related Synb hypermethylation, provides evidence for further studies on possible IUGR biomarkers.

We assessed the role of diabetes mellitus (DM) on treatment effects in drug-susceptible initial pulmonary tuberculosis (PTB) patients. A prospective study was conducted in eight provinces of China from October 2008 to December 2010. We enrolled 1,313 confirmed drug-susceptible initial PTB patients, and all subjects received the treatment regimen (2H3R3E3Z3/4H3R3) as recommended by the national guidelines. Of the 1,313 PTB patients, 157 (11.9%) had DM; these patients had more sputum smear-positive rates at the end of the second month [adjusted odds ratios (aOR) 2.829, 95% confidence intervals (CI) 1.783-4.490], and higher treatment failure (aOR 2.120, 95% CI 1.565-3.477) and death rates (aOR 1.536, 95% CI 1.011-2.628). DM was a contributing factor for culture-positive rates at the end of the second month and treatment failure and death of PTB patients, thus playing an unfavorable role in treatment effects of PTB., (Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

The aim of this study was to evaluate the diagnostic value of the cerebrospinal fluid (CSF) T-SPOT.TB test for the diagnosis of TB meningitis (TBM). A retrospective analysis of 96 patients with manifested meningitis was conducted; T-SPOT.TB test was performed for diagnosing TBM to determine the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). A receiver operating characteristic (ROC) curve was also drawn to assess the diagnostic accuracy. The sensitivity, specificity, PPV, and NPV of CSF T-SPOT.TB test were 97.8%, 78.0%, 80.3%, and 97.5%, respectively, for 52 patients (54.2%) of the 96 enrolled patients. The area under the curve (AUC) was 0.910, and the sensitivities of CSF T-SPOT.TB for patients with stages I, II, and III of TBM were 96.7%, 97.2%, and 98.9%, respectively. CSF T-SPOT.TB test is a rapid and accurate diagnostic method with higher sensitivity and specificity for diagnosing TBM., (Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)