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OBJECTIVE:: To further investigate the mortality risk of employees who worked in the petroleum refinery industry, we updated an earlier investigation by extending the mortality follow-up by an additional 14 years through 2003. METHODS:: The cohort consisted of 10,621 employees with an average follow-up of 34 years. We used the standardized mortality ratio (SMR) adjusted for age, race, and calendar years as a measure of risk. RESULTS:: Overall mortality (SMR = 0.77, 95% confidence interval [CI], 0.74-0.79), all cancer mortality (SMR = 0.87, 95% CI = 0.82-0.93), and most cause-specific mortalities for the total study population were lower than or similar to that of the population of Harris County, Texas. This study did not show a significant increase in leukemia in the total population or in any of the subgroups. The only statistically significant excess of mortality found in this study was an increase in mesothelioma among maintenance employees; the SMR was 4.78 (95% CI = 2.54-8.17) among employees who worked for a minimum of one year and was 7.51 (95% CI = 3.75-13.45) among those with 10 or more years of employment and 20 or more years of latency. CONCLUSIONS:: After more than half a century of follow-up, employees at this facility continue to show more favorable mortality outcomes than the general local population. Overall, no statistically significant increase of leukemia or of any of the specific cell types was found. The increased mesothelioma is likely related to past exposure to asbestos. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although obesity is an established risk factor for coronary heart disease and stroke mortality, its role as a risk factor for other causes of death has not been extensively investigated, particularly in an industrial population. METHODS: This prospective mortality study included 20 years of follow up of middle-aged industrial workers (n = 7139) at Shell Oil Company's manufacturing and research facilities. Baseline health risk factor data as of December 31, 1983, and mortality data as of December 31, 2003, were extracted from the company's Health Surveillance System. Relative risks (RRs) for selected causes of death by body mass index (BMI) category were calculated using the Cox proportional hazards model adjusted for age, sex, and smoking status as well as other potential risk factors, ie, cholesterol, hypertension, and fasting blood glucose. RESULTS: Compared with employees with BMI between 18.5 and 24.9 kg/m, those with BMI of 30 kg/m or greater had a statistically increased RR (adjusted for age, sex, and smoking status) for all causes (RR, 1.25; 95% confidence interval [CI] = 1.03-1.51), coronary heart diseases (RR, 2.29; 95% CI = 1.50-3.50), cardiovascular diseases (RR, 2.22; 95% CI = 1.51-3.27), diabetes (RR, 16.97; 95% CI = 2.11-136.44), and accidental deaths (RR, 2.64; 95% CI = 1.23-5.66). After adjusting for additional covariates, coronary heart diseases and cardiovascular diseases remained statistically significant. CONCLUSIONS: Obesity was associated with increased death rates for all causes, cardiovascular diseases, diabetes, and all accidents. Overweight individuals had a statistically lower cancer rate. Death rates for lung cancer and respiratory disease were lower among overweight/obese employees but did not reach statistical significance. Reductions of employee obesity can be an effective means of reducing these causes of death. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study is to determine the incidence of cancer among employees at two petrochemical facilities in south Louisiana, and to compare their cancer rates to those of the general population of south Louisiana. METHODS: Records on 4639 active and former employees and retirees from the two plants were linked to the Louisiana Tumor Registry (LTR) database by LTR staff to ascertain incident cases of cancer. Standardized incidence ratios (SIRs) were then calculated using the south Louisiana population as the comparison and adjusted for age, race, and time period. RESULTS: There was a significant 16% deficit of overall cancer cases for males in this cohort (SIR=0.84; 95% CI, 0.74-0.95). The only significantly elevated SIR in males was for cancer of the bone and joint (SIR=6.89; 95% CI, 1.42-20.1). This result was based on three non-fatal cases of bone cancer with different histologies, occurring in different parts of the body. These cases worked in different units of one plant. Significant deficits were seen for lung cancer, non-Hodgkin's lymphoma, and cancer of the oral cavity and pharynx. Cancer incidence among 719 female employees was non-significantly increased (SIR=1.24; 95% CI, 0.81-1.82). Breast cancer accounts for the excess (SIR=1.46; 95% CI, 0.73-2.61). Seventy percent of the breast cancer cases worked in an office setting. CONCLUSIONS: This study found little evidence of any association between cancer incidence and employment at these two petrochemical facilities. The increased incidence of bone cancer is unlikely to be due to occupational exposures. The non-significant excess of breast cancer may be due to early detection or other important unmeasured confounders, such as certain reproductive factors. [ABSTRACT FROM AUTHOR]

The extent of interaction between smoking and diabetes has been under-appreciated. Smokers had more diabetes, and when diabetes patients smoke, the combined mortality effect was greater than either the addition or multiplication of these two medical problems. Patients seen in the office are usually more interested in reducing blood glucose than in quitting smoking, and yet, smoking caused mortality risks, at a magnitude similar to or more than diabetes. The concept of 'glucose equivalent of smoking' was developed to direct more attention to smoking in clinical management. Based on the follow-up observations from a large Asian cohort, the risk of an individual who smokes, from all-cause mortality, was found to be equivalent to an elevation of blood glucose by an average of 41mg/dl for the cohort in general and 68mg/dl for the diabetes in particular. By relating the message of smoking hazards in terms of 'glucose equivalent', clinicians will be more alerted to counsel and patients will be more likely to quit. Appreciating this concept has a potential to change the paradigm of diabetes management, to bridge the clinical disconnect between the two, and to provide new ammunition for the diabetes epidemic in Taiwan. [ABSTRACT FROM AUTHOR]

BACKGROUND: Both end-stage renal disease and chronic kidney disease are increasing worldwide; however, the full effect of chronic kidney disease is unknown because mortality risks for all five stages are unavailable. We assessed prevalence and mortality risks for all stages of chronic kidney disease and quantified its attributable mortality in Taiwan. METHODS: The cohort consisted of 462 293 individuals aged older than 20 years who participated in a standard medical screening programme since 1994. As of Dec 31, 2006, we identified 14 436 deaths. Chronic kidney disease was determined by glomerular filtration rate and urinary protein. We estimated national prevalence in Taiwan from the cohort by adjusting age and educational levels. Hazard ratios (HRs) were calculated with Cox proportionate hazards model. We calculated mortality attributable to chronic kidney disease for national population and for low socioeconomic status. FINDINGS: The national prevalence of chronic kidney disease was 11.93% (95% CI 11.66-12.28), but only 3.54% (3.37-3.68) of participants in the cohort were aware of their disorder. Prevalence was substantially higher in the group with low socioeconomic status than in the high status group (19.87% [19.84-19.91] vs 7.33% [7.31-7.35]). 56 977 (12%) of cohort participants had chronic kidney disease; those with disease had 83% higher mortality for all cause (HR 1.83 [1.73-1.93]) and 100% higher for cardiovascular diseases (2.00 [1.78-2.25]), in a cohort that was observed for 13 years with median follow-up of 7.5 years (IQR 4.0-10.1). 10.3% (95% CI 9.57-11.03) of deaths in the entire population were attributable to chronic kidney disease, but 17.5% (16.27-18.67) of deaths in the low socioeconomic status population. 2350 (39%) deaths occurred before 65 years of age in those with chronic kidney disease. Regular users of Chinese herbal medicines had a 20% (odds ratio 1.20 [1.16-1.24]) increased risk of developing chronic kidney disease. INTERPRETATION: The high prevalence of chronic kidney disease and its associated all-cause mortality, especially in people with low socioeconomic status, make reduction of this disorder a public-health priority. Promotion of its recognition through the general public knowing their glomerular filtration rate and testing their urine is crucial to reduce premature deaths from all causes and to attenuate this global epidemic. [ABSTRACT FROM AUTHOR]

Leisure-time physical activity (LTPA) has been closely related to health improvement. The under-appreciation for energy output by nutritionists stems in part from limited data expressed in caloric equivalent. We converted the frequency, duration, and intensity of LTPA, reported from 15,390 adults in the Taiwan National Health Interview Survey 2001, into kilocalories (kcal). Half of Taiwanese adults admit to no LTPA. Women, lower education or income, younger age, smokers and chewers of betel quid; exercised significantly less than their counterparts. Less than 1/5 (18.9%) of the population in Taiwan was physically active at >or=750 kcal/week, and only 1/7 (13.9%) reached a more desirable goal of >or=1,000 kcal/week, compared with 1/3 in the U.S. The most disconcerting finding was the Taiwan unique U-shaped prevalence for males, with the 25-44 age group being the least active, >or=65 age group being the most active; and S-shaped for females, lowest at age 18-24 years and highest at the two older groups (45-64 and >or=65 years). LTPA was under-appreciated, particularly among the most productive work force (25-44-year group), who exercised with a prevalence only 1/4 of their U.S. counterparts. Expressing LTPA in kcal makes direct comparison easier. Invoking a goal of >or=750 kcal/week for Asians, attainable by exercising 4 hours/week, can facilitate nutritionists in assessing LTPA adequacy. Currently, 4/5 of adults in Taiwan failed to reach this goal. Recognizing the concept of cumulative energy expenditure, in contrast to disciplined daily work for 5 or more days, will encourage the infrequent exercisers such as 'weekend warriors' to continue with their activities. [ABSTRACT FROM AUTHOR]

Excellent castability, significantly refined microstructure, and good mechanical properties make eutectic high-entropy alloys (EHEAs) a natural fit for rapid solidification processes, e.g., additive manufacturing. Previous investigations have focused on developing EHEAs through trial and error and mixing known binary eutectic materials. However, eutectic compositions obtained from near-equilibrium conditions do not guarantee a fully eutectic microstructure under rapid solidifications. In this work, a thermodynamically guided high-throughput framework is proposed to design EHEAs for rapid solidification. Empirical formulas derived from past experimental observations and thermodynamic computations are applied and considered phase growth kinetics under rapid solidification (skewed phase diagram). The designed alloy candidate, Co 25.6 Fe 17.9 Ni 22.4 Cr 19.1 Ta 8.9 Al 6.1 (wt.%), contains nanostructured eutectic lamellar and shows a high Vickers hardness of 675 Hv. In addition to this specific composition, the alloy design toolbox enables the development of new EHEAs for rapid solidification without the limitation of previous knowledge., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus-bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes., (© 2024. The Author(s).)

Pulmonary vascular remodeling is a key pathological process of pulmonary arterial hypertension (PAH), characterized by uncontrolled proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Bortezomib (BTZ) is the first Food and Drug Administration (FDA)-approved proteasome inhibitor for multiple myeloma treatment. Recently, there is emerging evidence showing its effect on reversing PAH, although its mechanisms are not well understood. In this study, anti-proliferative and anti-migratory effects of BTZ on PASMCs were first examined by different inducers such as fetal bovine serum (FBS), angiotensin II (Ang II) and platelet-derived growth factor (PDGF)-BB, while potential mechanisms including cellular reactive oxygen species (ROS) and mitochondrial ROS were then investigated; finally, signal transduction of ERK and Akt was examined. Our results showed that BTZ attenuated FBS-, Ang II- and PDGF-BB-induced proliferation and migration, with associated decreased cellular ROS production and mitochondrial ROS production. In addition, the phosphorylation of ERK and Akt induced by Ang II and PDGF-BB was also inhibited by BTZ treatment. This study indicates that BTZ can prevent proliferation and migration of PASMCs, which are possibly mediated by decreased ROS production and down-regulation of ERK and Akt. Thus, proteasome inhibition can be a novel pharmacological target in the management of PAH., (© 2024 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Recent years have seen the development of a variety of mammalian library approaches for display and secretion mode. Advantages include library approaches for engineering, preservation of precious immune repertoires and their repeated interrogation, as well as screening in final therapeutic format and host. Mammalian display approaches for antibody optimization exploit these advantages, necessitating the generation of large libraries but in turn enabling early screening for both manufacturability and target specificity. For suitable libraries, high antibody integration rates and resulting monoclonality need to be balanced - we present a solution for sufficient transmutability and acceptable monoclonality by applying an optimized ratio of coding to non-coding lentivirus. The recent advent of microfluidic-assisted hit discovery represents a perfect match to mammalian libraries in secretion mode, as the lower throughput fits well with the facile generation of libraries comprising a few million functional clones. In the presented work, Chinese Hamster Ovary cells were engineered to both express the target of interest and secrete antibodies in relevant formats, and specific clones were strongly enriched by high throughput screening for autocrine cellular binding. The powerful combination of mammalian secretion libraries and microfluidics-assisted hit discovery could reduce attrition rates and increase the probability to identify the best possible therapeutic antibody hits faster.

Background: Although biological aging has been proposed as a more accurate measure of aging, few biological aging measures have been developed for Asians, especially for young adults., Methods: A total of 521 656 participants were enrolled in the MJ cohort (1996-2011) and were followed until death, loss-to-follow-up, or December 31, 2011, whichever came first. We selected 14 clinical biomarkers, including chronological age, using a random forest algorithm, and developed a multidimensional aging measure (MDAge). Model performance was assessed by area under the curve (AUC) and internal calibration. We evaluated the associations of MDAge and residuals from regressing MDAge on chronological age (MDAgeAccel) with mortality and morbidity, and assessed the robustness of our findings., Results: MDAge achieved an excellent AUC of 0.892 in predicting all-cause mortality (95% confidence interval [CI]: 0.889-0.894). Participants with higher MDAge at baseline were at a higher risk of death (per 5 years, hazard ration [HR] = 1.671, 95% CI: 1.662-1.680), and the association remained after controlling for other variables and in different subgroups. Furthermore, participants with higher MDAgeAccel were associated with shortened life expectancy. For instance, compared to men who were biologically younger (MDAgeAccel ≤ 0) at baseline, men in the highest tertiles of MDAgeAccel had shortened life expectancy by 17.23 years. In addition, higher MDAgeAccel was associated with having chronic disease either cross-sectionally (per 1-standard deviation [SD], odds ratio [OR] = 1.564, 95% CI: 1.552-1.575) or longitudinally (per 1-SD, OR = 1.218, 95% CI: 1.199-1.238)., Conclusion: MDAge accurately predicted mortality and morbidity, which has great potential in the early identification of individuals at higher risk and therefore promoting early intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study evaluated the risks of childhood acute bronchitis and bronchiolitis (CABs) for children with asthma or allergic rhinitis (AR). Using insurance claims data of Taiwan, we identified, from children of ≤12 years old in 2000-2016, cohorts with and without asthma (N = 192,126, each) and cohorts with and without AR (N = 1,062,903, each) matched by sex and age. By the end of 2016, the asthma cohort had the highest bronchitis incidence, AR and non-asthma cohorts followed, and the lowest in the non-AR cohort (525.1, 322.4, 236.0 and 169.9 per 1000 person-years, respectively). The Cox method estimated adjusted hazard ratios (aHRs) of bronchitis were 1.82 (95% confidence interval (CI), 1.80-1.83) for the asthma cohort and 1.68 (95% CI, 1.68-1.69) for the AR cohort, relative to the respective comparisons. The bronchiolitis incidence rates for these cohorts were 42.7, 29.5, 28.5 and 20.1 per 1000 person-years, respectively. The aHRs of bronchiolitis were 1.50 (95% CI, 1.48-1.52) for the asthma cohort and 1.46 (95% CI, 1.45-1.47) for the AR cohort relative to their comparisons. The CABs incidence rates decreased substantially with increasing age, but were relatively similar for boys and girls. In conclusion, children with asthma are more likely to develop CABs than are children with AR.

Recently, there has been a co-evolution of mammalian libraries and diverse microfluidic approaches for therapeutic antibody hit discovery. Mammalian libraries enable the preservation of full immune repertoires, produce hit candidates in final format and facilitate broad combinatorial bispecific antibody screening, while several available microfluidic methodologies offer opportunities for rapid high-content screens. Here, we report proof-of-concept studies exploring the potential of combining microfluidic technologies with mammalian libraries for antibody discovery. First, antibody secretion, target co-expression and integration of appropriate reporter cell lines enabled the selection of in-trans acting agonistic bispecific antibodies. Second, a functional screen for internalization was established and comparison of autocrine versus co-encapsulation setups highlighted the advantages of an autocrine one cell approach. Third, synchronization of antibody-secreting cells prior to microfluidic screens reduced assay variability. Furthermore, a display to secretion switchable system was developed and applied for pre-enrichment of antibody clones with high manufacturability in conjunction with subsequent screening for functional properties. These case studies demonstrate the system's feasibility and may serve as basis for further development of integrated workflows combining manufacturability sorting and functional screens for the identification of optimal therapeutic antibody candidates.

We report the development of a fully automatic large-volume 3D electron backscatter diffraction (EBSD) system (ELAVO 3D), consisting of a scanning electron microscope (ZEISS crossbeam XB 1540) with a dedicated sample holder, an adapted polishing automaton (Saphir X-change, QATM), a collaborative robotic arm (Universal Robots UR5), and several in-house built devices. The whole system is orchestrated by an in-house designed software, which is also able to track the process and report errors. Except for the case of error, the system runs without any user interference. For the measurement of removal thickness, the samples are featured with markers put on the perpendicular lateral surface, cut by plasma focused ion beam (PFIB) milling. The individual effects of both 1 μm diamond suspension and oxide polishing suspension polishing were studied in detail. Coherent twin grain boundaries (GBs) were used as an internal standard to check the removal rates measured by the side markers. The two methods for Z-spacing measurements disagreed by about 10%, and the inaccurate calibration of the PFIB system was found to be the most probable reason for this discrepancy. The angular accuracy of the system was determined to be ∼2.5°, which can be significantly improved with more accurate Z-spacing measurements. When reconstructed grain boundary meshes are sufficiently smoothed, an angular resolution of ±4° is achieved. In a 3D EBSD dataset of a size of 587 × 476 × 72 μm 3 , we focused on the investigation of coincidence site lattice ∑9 GBs. While bearing predominantly a pure tilt character, ∑9 GBs can be categorized into three groups based on correlative 3D morphologies and crystallography.

Studies have associated the human respiratory syncytial virus which causes seasonal childhood acute bronchitis and bronchiolitis (CABs) with climate change and air pollution. We investigated this association using the insurance claims data of 3,965,560 children aged ≤ 12 years from Taiwan from 2006−2016. The monthly average incident CABs increased with increasing PM2.5 levels and exhibited an inverse association with temperature. The incidence was 1.6-fold greater in January than in July (13.7/100 versus 8.81/100), declined during winter breaks (February) and summer breaks (June−August). The highest incidence was 698 cases/day at <20 °C with PM2.5 > 37.0 μg/m3, with an adjusted relative risk (aRR) of 1.01 (95% confidence interval [CI] = 0.97−1.04) compared to 568 cases/day at <20 °C with PM2.5 < 15.0 μg/m3 (reference). The incidence at ≥30 °C decreased to 536 cases/day (aRR = 0.95, 95% CI = 0.85−1.06) with PM2.5 > 37.0 μg/m3 and decreased further to 392 cases/day (aRR = 0.61, 95% CI = 0.58−0.65) when PM2.5 was <15.0 μg/m3. In conclusion, CABs infections in children were associated with lowered ambient temperatures and elevated PM2.5 concentrations, and the high PM2.5 levels coincided with low temperature levels. The role of temperature should be considered in the studies of association between PM2.5 and CABs.

Background: Evidences have shown that the stroke risk associated with long-term exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM 2.5 ) varies among people in North America, Europe and Asia, but studies in Asia rarely evaluated the association by stroke type. We examined whether long-term exposure to PM 2.5 is associated with developing all strokes, ischemic stroke and hemorrhagic stroke., Methods: The retrospective cohort study consisted of 1,362,284 adults identified from beneficiaries of a universal health insurance program in 2011. We obtained data on air pollutants and meteorological measurements from air quality monitoring stations across Taiwan in 2010-2015. Annual mean levels of all environmental measurements in residing areas were calculated and assigned to cohort members. We used Cox proportional hazards models to estimate hazard ratio (HR) and 95% confidence interval (CI) of developing stroke associated with 1-year mean levels of PM 2.5 at baseline in 2010, and yearly mean levels from 2010 to 2015 as the time-varying exposure, adjusting for age, sex, income and urbanization level., Results: During a median follow-up time of 6.0 years, 12,942 persons developed strokes, 9919 (76.6%) were ischemic. The adjusted HRs (95% CIs) per interquartile range increase in baseline 1-year mean PM 2.5 were 1.03 (1.00-1.06) for all stroke, 1.06 (1.02-1.09) for ischemic stroke, and 0.95 (0.89-1.10) for hemorrhagic stroke. The concentration-response curves estimated in the models with and without additional adjustments for other environmental measurements showed a positively linear association between baseline 1-year mean PM 2.5 and ischemic stroke at concentrations greater than 30 μg/m 3 , under which no evidence of association was observed. There was an indication of an inverse association between PM 2.5 and hemorrhagic stroke, but the association no longer existed after controlling for nitrogen dioxide or ozone. We found similar shape of the concentration-response association in the Cox regression models with time-varying PM 2.5 exposures., Conclusion: Long-term exposure to PM 2.5 might be associated with increased risk of developing ischemic stroke. The association with high PM 2.5 concentrations remained significant after adjustment for other environmental factors., (© 2022. The Author(s).)

Background: Capsaicin is used in several areas of non-human primate research including allodynia and dermal blood flow (DBF). The capsaicin-induced DBF increase was measured using laser Doppler imaging (LDI), but this response is known to diminish upon repeated topical applications. Refinement of the experimental procedures could improve the rigor and reproducibility of the DBF migraine model., Methods: Optimal anatomical site in cynomolgus was determined, and conditions and experimental settings for DBF measurement using LDI were established. Then, two study design trial structures were compared., Results: Medial thigh was the preferrable site, and an ethanol-Tween 20 formulation of capsaicin was desirable. A 1-week washout for contralateral side or 2-week washout for ipsilateral side was necessary to eradicate capsaicin desensitization., Conclusions: With the established technicality in DBF measurements in cynomolgus macaques, the capsaicin-induced DBF model may be utilized in translational medical research in developing migraine therapeutics., (© 2021 John Wiley & Sons Ltd.)

No study has ever investigated how ambient temperature and PM 2.5 mediate rotavirus infection (RvI) in children. We used insurance claims data from Taiwan in 2006-2012 to evaluate the RvI characteristics in children aged ≤ 9. The RvI incidence rates were higher in colder months, reaching the highest in March (117.0/100 days), and then declining to the lowest in July (29.2/100 days). The age-sex-specific average incident cases were all higher in boys than in girls. Stratified analysis by temperature (<20, 20-24, and ≥25 °C) and PM 2.5 (<17.5, 17.5-31.4, 31.5-41.9, and ≥42.0 μg/m 3 ) showed that the highest incidence was 16.4/100 days at average temperatures of <20 °C and PM 2.5 of 31.5-41.9 μg/m 3 , with Poisson regression analysis estimating an adjusted relative risk (aRR) of 1.26 (95% confidence interval (CI) = 1.11-1.43), compared to the incidence at the reference condition (<20 °C and PM 2.5 < 17.5 μg/m 3 ). As the temperature increased, the incident RvI cases reduced to 4.84 cases/100 days (aRR = 0.40, 95% CI = 0.35-0.45) when it was >25 °C with PM 2.5 < 17.5 μg/m 3 , or to 9.84/100 days (aRR = 0.81, 95% CI = 0.77-0.93) when it was >25 °C with PM 2.5 > 42 μg/m 3 . The seasonal RvI is associated with frequent indoor personal contact among children in the cold months. The association with PM 2.5 could be an alternative assessment due to temperature inversion.

For facilitating risk communication in clinical management, such a ratio-based measure becomes easier to understand if expressed as a loss of life expectancy. The cohort, consisting of 543,410 adults in Taiwan, was recruited between 1994 and 2008. Health risks included lifestyle, biomarkers, and chronic diseases. A total of 18,747 deaths were identified. The Chiang's life table method was used to estimate a loss of life expectancy. We used Cox regression to calculate hazard ratios (HRs) for health risks. The increased mortality from cardio-metabolic risks such as high cholesterol (HR=1.10), hypertension (HR=1.48) or diabetes (HR=2.02) can be converted into a loss of 1.0, 4.4, and 8.9 years in life expectancy, respectively. The top 20 of the 30 risks were associated with a loss of 4 to 10 years of life expectancy, with 70% of the cohort having at least two such risk factors. Smoking, drinking, and physical inactivity each had 5-7 years loss. Individuals with diabetes or an elevated white count had a loss of 7-10 years, while prolonged sitting, the most prevalent risk factor, had a loss of 2-4 years. Those with diabetes (8.9 years) and proteinuria (9.1 years) present at the same time showed a loss of 16.2 years, a number close to the sum of each risk. Health risks, expressed as life expectancy loss, could facilitate risk communication. The paradigm shift in expressing risk intensity can help set public health priorities scientifically to promote a focus on the most important ones in primary care.

Pseudomonas aeruginosa causes life-threatening infections that are associated with antibiotic failure. Previously, we identified the antibiotic G2637, an analog of arylomycin, targeting bacterial type I signal peptidase, which has moderate potency against P. aeruginosa. We hypothesized that an antibody-antibiotic conjugate (AAC) could increase its activity by colocalizing P. aeruginosa bacteria with high local concentrations of G2637 antibiotic in the intracellular environment of phagocytes. Using a novel technology of screening for hybridomas recognizing intact bacteria, we identified monoclonal antibody 26F8, which binds to lipopolysaccharide O antigen on the surface of P. aeruginosa bacteria. This antibody was engineered to contain 6 cysteines and was conjugated to the G2637 antibiotic via a lysosomal cathepsin-cleavable linker, yielding a drug-to-antibody ratio of approximately 6. The resulting AAC delivered a high intracellular concentration of free G2637 upon phagocytosis of AAC-bound P. aeruginosa by macrophages, and potently cleared viable P. aeruginosa bacteria intracellularly. The molar concentration of AAC-associated G2637 antibiotic that resulted in elimination of bacteria inside macrophages was approximately 2 orders of magnitude lower than the concentration of free G2637 required to eliminate extracellular bacteria. This study demonstrates that an anti-P. aeruginosa AAC can locally concentrate antibiotic and kill P. aeruginosa inside phagocytes, providing additional therapeutic options for antibiotics that are moderately active or have an unfavorable pharmacokinetics or toxicity profile. IMPORTANCE Antibiotic treatment of life-threatening P. aeruginosa infections is associated with low clinical success, despite the availability of antibiotics that are active in standard microbiological in vitro assays, affirming the need for new therapeutic approaches. Antibiotics often fail in the preclinical stage due to insufficient efficacy against P. aeruginosa. One potential strategy is to enhance the local concentration of antibiotics with limited inherent anti-P. aeruginosa activity. This study presents proof of concept for an antibody-antibiotic conjugate, which releases a high local antibiotic concentration inside macrophages upon phagocytosis, resulting in potent intracellular killing of phagocytosed P. aeruginosa bacteria. This approach may provide new therapeutic options for antibiotics that are dose limited.

This animal study aimed to elucidate the relationship of low-dose, narrow-band UVB at 308 nm with vitamin D synthesis. C57BL/6 female mice, at 3 weeks-of-age, were randomly divided into the following six groups (n = 6 at each time point of vitamin D measurement), which were: (1) normal diet without UVB irradiation; (2) VDd diet without UVB irradiation; and (3)-(6) VDd diet with 308 nm-UVB irradiation of 12.5, 25, 50, and 100 μω/cm 2 , respectively. All of the groups needing UVB irradiation received an exposure of 10 min per day, five days per week, and a duration of 3-5 weeks. The mice recovering from severe VDd (plasma total 25-hydroxyvitamin D level increasing from approximately 3 to over 30 ng/mL) only occurred in groups with a UVB irradiation dosage of either 50 or 100 μω/cm 2 . The optimal, estimated dosage for mice to recover from severe VDd was 355 mJ/cm 2 within 3 weeks. Low-dose, narrow-band UVB irradiation at 308 nm is effective in improving VDd in mice. The results obtained, in addition to the especially small side effects of the above UVB irradiation formula, could be further translated to treating VDd-related disorders.

Pigeon circovirus (PiCV) is the most recurrent virus diagnosed in pigeons and is among the major causative agents of young pigeon disease syndrome (YPDS). Due to the lack of an established laboratory protocol for PiCV cultivation, development of prophylaxis is hampered. Alternatively, virus-like particles (VLPs), which closely resemble native viruses but lack the viral genetic material, can be generated using a wide range of expression systems and are shown to have strong immunogenicity. Therefore, the use of VLPs provides a promising prospect for vaccine development. In this study, transfected human embryonic kidney (HEK-293) cells, a mammalian expression system, were used to express the PiCV capsid protein (Cap), which is a major component of PiCV and believed to contain antibody epitopes, to obtain self-assembled VLPs. The VLPs were observed to have a spherical morphology with diameters ranging from 12 to 26 nm. Subcutaneous immunization of pigeons with 100 µg PiCV rCap-VLPs supplemented with water-in-oil-in-water (W/O/W) adjuvant induced specific antibodies against PiCV. Observations of the cytokine expression and T-cell proliferation levels in spleen samples showed significantly higher T-cell proliferation and IFN- γ expression in pigeons immunized with VLPs compared to the controls ( p < 0.05). Experimentally infected pigeons that were vaccinated with VLPs also showed no detectable viral titer. The results of the current study demonstrated the potential use of PiCV rCap-VLPs as an effective vaccine candidate against PiCV.

In the United States, maternal mortality, defined as all deaths during pregnancy, childbirth, and up to 365 days after the end of pregnancy, is among the highest of all developed nations. For every 1 maternal death, there are more than 100 life-threatening complications that occur related to pregnancy. However, maternal morbidity and mortality do not affect all mothers equally. Black and indigenous people are at the highest risk for pregnancy-related complications and death-they are up to 5 times as likely to die from childbearing than white women. To understand this nationwide epidemic, cases of maternal death must be thoroughly reviewed, including the medical, social, and societal circumstances surrounding them. The state of Hawai'i formed the Maternal Mortality Review Committee in 2016 to review cases of maternal mortality, collect accurate data, and develop strategies for prevention. Twenty-five maternal deaths occurred in the state of Hawai'i from 2015 to 2017. More than half of these deaths were deemed preventable. Combined data show that mental health disorders played a significant role in maternal mortality, and approximately a quarter of cases involved substance use. Twenty-three percent of maternal deaths occurred in Native Hawaiian and Pacific Islander women, even though they make up a smaller proportion of women in the state. The collection and analysis of these data are the first steps toward understanding and reducing maternal morbidity and mortality in Hawai'i. Most notably, the striking ethnic disparities in maternal deaths and the preventable nature of many cases demand our immediate attention., (©Copyright 2020 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

We have recently shown that exogenous administration of extracellular heat shock protein HSC70, a previously recognized intracellular chaperone protein, can protect against LPS-induced cardiac dysfunction through anti-inflammatory actions. However, whether it can also exert anti-hypertrophic effect is unknown. The present study was aimed to investigate the efficacy of HSC70 against cardiac hypertrophy and its underlying molecular mechanisms. Cardiomyocytes were isolated from the cardiac ventricles of neonatal Wistar rats and LPS (1 μg/mL) was used to induce the hypertrophic responses. We found that HSC70 (0.1, 1 and 5 μg/mL) pretreatment attenuated LPS-induced cardiomyocyte hypertrophy dose-dependently. In addition, HSC70 mitigated LPS-induced inflammatory mediators including TNF-α, IL-6, NO, iNOS and COX-2, with down-regulated protein expression of MMP-2 and MMP-9. Moreover, HSC70 repressed LPS-induced signaling of MAPK and Akt. Finally, HSC70 inhibited NF-κB subunit p65, and the DNA binding activity of NF-κB. Taken together, these findings suggest that in vitro HSC70 can exert anti-hypertrophic effects through inhibition of pro-inflammatory mediators, which are potential mediated by the down-regulation of MAPK, Akt and NF-κB signaling pathways. In conclusion, extracellular HSC70 may be a novel pharmacologic strategy in the management of cardiac hypertrophy., Competing Interests: Declaration of Competing Interest To the best of our knowledge, all authors have no conflict of interest, financial or otherwise., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Haemophilia A and B are disorders caused by the lack of clotting factors VIII and IX, respectively. Repeated bleeding into the same joint leads to haemophilic arthropathy (HA). Interleukin (IL)-1β is responsible for the pro-inflammatory response and IL-37 is induced by IL-1β stimuli to have an anti-inflammatory response and prevent uncontrolled inflammation and tissue damage. Our objective was to investigate plasma levels of IL-1β and IL-37 in patients with severe haemophilia with different severities of HA., Methods: Peripheral blood samples were collected from 14 patients with severe haemophilia A and 6 with severe haemophilia B, and 18 healthy individuals. Plasma levels of IL-1β and IL-37 were detected by immunoassay, and severity of HA was evaluated using the Pettersson scoring system. Plasma levels of IL-1β and IL-37 were analysed in patients with severe haemophilia grouped by Pettersson score and in healthy individuals., Results: Plasma levels of IL-1β and IL-37 were significantly higher in patients with severe haemophilia compared with healthy individuals and significantly lower in those with moderate to severe HA than in those with no or mild HA., Conclusions: Plasma levels of IL-1β and IL-37 may be useful to track HA progression in patients with severe haemophilia.

For antibody-drug conjugates to be efficacious and safe, they must be stable in circulation to carry the payload to the site of the targeted cell. Several components of a drug-conjugated antibody are known to influence stability: 1) the site of drug attachment on the antibody, 2) the linker used to attach the payload to the antibody, and 3) the payload itself. In order to support the design and optimization of a high volume of drug conjugates and avoid unstable conjugates prior to testing in animal models, we wanted to proactively identify these potential liabilities. Therefore, we sought to establish an in vitro screening method that best correlated with in vivo stability. While traditionally plasma has been used to assess in vitro stability, our evaluation using a variety of THIOMAB TM antibody-drug conjugates revealed several disconnects between the stability assessed in vitro and the in vivo outcomes when using plasma. When drug conjugates were incubated in vitro for 24 h in mouse whole blood rather than plasma and then analyzed by affinity capture LC-MS, we found an improved correlation to in vivo stability with whole blood (R 2 = 0.87, coefficient of determination) compared to unfrozen or frozen mouse plasma (R 2 = 0.34, 0.01, respectively). We further showed that this whole blood assay was also able to predict in vivo stability of other preclinical species such as rat and cynomolgus monkey, as well as in human. The screening method utilized short (24 h) incubation times, as well as a custom analysis software, allowing increased throughput and in-depth biotransformation characterization. While some instabilities that were more challenging to identify remain, the method greatly enhanced the process of screening, optimizing, and lead candidate selection, resulting in the substantial reduction of animal studies.

Disulfide-linked bioconjugates allow the delivery of pharmacologically active or other cargo to specific tissues in a redox-sensitive fashion. However, an understanding of the kinetics, subcellular distribution, and mechanism of disulfide cleavage in such bioconjugates is generally lacking. Here, we report a modular disulfide-linked TAMRA-BODIPY based FRET probe that can be readily synthesized, modified, and conjugated to a cysteine-containing biomolecule to enable real-time monitoring of disulfide cleavage during receptor-mediated endocytosis in cells. We demonstrate the utility of this probe to study disulfide reduction during HER2 receptor-mediated uptake of a Cys-engineered anti-HER2 THIOMAB antibody. We found that introduction of positive, but not negative, charges in the probe improved retention of the BODIPY catabolite. This permitted the observation of significant disulfide cleavage in endosomes or lysosomes on par with proteolytic cleavage of a similarly charged valine-citrulline peptide-based probe. In general, the FRET probe we describe should enable real-time cellular monitoring of disulfide cleavage in other targeted delivery systems for mechanistic or diagnostic applications. Furthermore, modifications to the released BODIPY moiety permit evaluation of physicochemical properties that govern lysosomal egress or retention, which may have implications for the development of next-generation antibody-drug conjugates.

Interfacial quantum states are drawing tremendous attention recently because of their importance in design of low-dimensional quantum heterostructures with desired charge, spin, or topological properties. Although most studies of the interfacial exchange interactions were mainly performed across the interface vertically, the lateral transport nowadays is still a major experimental method to probe these interactions indirectly. In this Letter, we fabricated a graphene and hydrogen passivated silicon interface to study the interfacial exchange processes. For the first time we found and confirmed a novel interfacial quantum state, which is specific to the 2D-3D interface. The vertically propagating electrons from silicon to graphene result in electron oscillation states at the 2D-3D interface. A harmonic oscillator model is used to explain this interfacial state. In addition, the interaction between this interfacial state (discrete energy spectrum) and the lateral band structure of graphene (continuous energy spectrum) results in Fano-Feshbach resonance. Our results show that the conventional description of the interfacial interaction in low-dimensional systems is valid only in considering the lateral band structure and its density-of-states and is incomplete for the ease of vertical transport. Our experimental observation and theoretical explanation provide more insightful understanding of various interfacial effects in low-dimensional materials, such as proximity effect, quantum tunneling, etc. More important, the Fano-Feshbach resonance may be used to realize all solid-state and scalable quantum interferometers.

Objectives: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are 2 commonly ordered liver function tests, and ALT has long been considered more liver-specific than AST. Between the 2, the one which is better in predicting liver or non-liver-related mortality remains unsettled., Methods: The cohort, 416,122 adults, came from a self-paying comprehensive health surveillance program during 1994-2008 and was followed up till 2008. Mortality came from National Death Index, with 10,412 deaths identified. Hazard ratios (HRs), computed by Cox model, and life expectancy, by life table method, were presented for 5 levels of AST and ALT with elevated AST or ALT defined as ≥40 IU/L. Liver disease included liver cancer and other liver conditions., Results: There were 3 times more elevated ALT (15.4%) than AST (5.7%). However, those with elevated AST had higher mortality for all-cause (HR = 2.44), for liver disease (HR = 27.2), and for liver cancer (HR = 47.6) than its ALT counterparts (HR = 1.69, 10.8, and 20.2, respectively). Elevated AST also lost more years of life expectancy (10.2) than those lost by ALT (5.2) and larger than most common risks. Elevated AST had increased mortality from all cancers (HR = 3.57), stroke (HR = 1.36), respiratory diseases (HR = 1.34), and injuries (HR = 1.82), other than just liver disease. All-cause mortality remained significantly increased, when high risk groups were excluded, such as frequent drinkers, hepatitis carriers, those died from nonmedical conditions, those died in the first 3 years, or advanced fibrosis index based on 4 factors or aspartate transaminase-to-platelet ratio index. Results were consistent between those returned for second visits and those analyzed in initial visits., Discussion: Those with elevated AST (≥40 IU/L) had life expectancy cut short by 10.2 years, doubled the number of years lost with elevated ALT. For all-cause and for liver-related mortality, AST was an important predictor, better than ALT.

In Saccharomyces cerevisiae, Sir proteins mediate heterochromatin epigenetic gene silencing. The assembly of silent heterochromatin requires histone deacetylation by Sir2, conformational change of SIR complexes, and followed by spreading of SIR complexes along the chromatin fiber to form extended silent heterochromatin domains. Sir2 couples histone deacetylation and NAD hydrolysis to generate an epigenetic metabolic small molecule, O-acetyl-ADP-ribose (AAR). Here, we demonstrate that AAR physically associates with Sir3 and that polySir3-AAR formation has a specific and essential role in the assembly of silent SIR-nucleosome pre-heterochromatin filaments. Furthermore, we show that AAR is capable of stabilizing binding of the Sir3 BAH domain to the Sir3 carboxyl-terminal region. Our data suggests that for the assembly of SIR-nucleosome pre-heterochromatin filament, the structural rearrangement of SIR-nucleosome is important and result in creating more stable interactions of Sir3, such as the inter-molecule Sir3-Sir3 interaction, and the Sir3-nucleosome interaction within the filaments. In conclusion, our results reveal the importance of AAR, indicating that it not only affects the conformational rearrangement of SIR complexes but also might function as a critical fine-tuning modulatory component of yeast silent SIR-nucleosome pre-heterochromatin by stabilizing the intermolecular interaction between Sir3 N- and C-terminal regions., (Copyright © 2019. Published by Elsevier Inc.)

In Taiwan, most students with disabilities receive education in an inclusive setting. Literature has documented the effects of interventions in increasing students' positive behaviors in inclusive settings, including students with disabilities in Western countries; however, effectiveness of such interventions in an Asian context remains unclear. The Class-Wide Function-Related Intervention Teams (CW-FIT) is one of the interventions that applies reinforcement-based strategies and provides multi-tiered supports to students with various severity of challenging behaviors. This study investigates the effects of CW-FIT Tier I (i.e. class-wide intervention) and Tier II (i.e. self-management) on the on-task and disruptive behaviors of a student with Autism Spectrum Disorder in an inclusive elementary classroom in Taiwan. Across nine weeks of intervention, the researchers used a reversal single-case design A-B-C-B-C to demonstrate experimental control over five phases. In addition, the researchers administered interviews and questionnaires to collect social validity data from the teacher and peers' perceptions toward the intervention. Findings from this study support that the CW-FIT is an effective intervention in increasing a student's on-task behaviors and decreasing disruptive behaviors in an inclusive classroom in an Asian context. The effect of implementing multiple tiers of CW-FIT was much more effective than implementing solely Tier I (class-wide intervention). The intervention was also well-received by the general education teacher and students., (© The British Society of Developmental Disabilities 2019.)

O-acetyl-ADP-ribose (AAR) is a metabolic small molecule relevant in epigenetics that is generated by NAD-dependent histone deacetylases, such as Sir2. The formation of silent heterochromatin in yeast requires histone deacetylation by Sir2, structural rearrangement of SIR complexes, spreading of SIR complexes along the chromatin, and additional maturation processing. AAR affects the interactions of the SIR-nucleosome in vitro and enhances the chromatin epigenetic silencing effect in vivo. In this study, using isothermal titration calorimetry (ITC) and dot blotting methods, we showed the direct interaction of AAR with Sir3. Furthermore, through chromatin immunoprecipitation (ChIP)-on-chip and chromatin affinity purification (ChAP)-on chip assays, we discovered that AAR is capable of increasing the extended spreading of Sir3 along telomeres, but not Sir2. In addition, the findings of a quantitative real-time polymerase chain reaction (qRT-PCR) and examinations of an in vitro assembly system of SIR-nucleosome heterochromatin filament were consistent with these results. This study provides evidence indicating another important effect of AAR in vivo. AAR may play a specific modulating role in the formation of silent SIR-nucleosome heterochromatin in yeast., Competing Interests: The authors declare no conflict of interest.

Background: The genetic background of patients with hemoglobin (Hb) H disease in Taiwan has been investigated; however, the clinical features and treatment outcomes were not reported., Objective: To analyze the clinical features and genotypes of patients with HbH who reside in Taiwan., Methods: We conducted a retrospective analysis of the clinical and molecular characteristics of 38 patients with HbH disease who were undergoing treatment at Kaohsiung Medical University Hospital, Taiwan., Results: Initial Hb levels were lower and the numbers of patients requiring iron-chelation therapy were higher in the nondeletional HbH group than in the deletional HbH group (P <.05). Compared with the healthy population, the patients with HbH disease exhibited short body length, low body weight, and low body mass index (BMI)., Conclusions: Patients with nondeletional HbH disease had lower Hb levels and a higher requirement for splenectomy and iron-chelation therapy than did those with deletional HbH disease. Also, growth status was compromised in patients with HbH disease., (© American Society for Clinical Pathology 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Convergent beam electron diffraction (CBED) in transmission electron microscopy (TEM) was applied to determine local carbon concentrations in low-carbon transformation-induced plasticity (TRIP) steels. High-order Laue-zone (HOLZ) lines were experimentally obtained for comparison with simulation results. A new procedure for calculating carbon content is thus proposed. Retained austenite (RA) is classified into three types by morphology; the relationship between the carbon content and the corresponding RA morphology is discussed based on CBED results. Furthermore, results of X-Ray diffractometry measurements are also used for comparison., (© 2018 Wiley Periodicals, Inc.)

Purpose: Congenital hemolytic anemia caused by red blood cell (RBC) membrane defects is a heterogeneous group of disorders. The present study aimed to search the causative gene mutations in patients with RBC membrane disorders in Taiwan., Materials and Methods: Next-generation sequencing approach using whole-exome sequencing (WES) was performed. Sanger sequencing was performed for confirmation of variants detected in WES in patients and their family members., Results: Five causative variants, including two ANK1, two SPTA and one SPTB variants, were detected in four patients. All these variants, except one SPTA1 variant c.83G > A (p.R28H), are novel variants. Their pedigree analysis showed one de novo SPTA1 mutation c.83G > A (p.R28H) combined with α LELY , one de novo ANK1 mutation c.1034C > A (p.A345E), one autosomal dominant combined SPTA1 c.4604A > C (p.Q1535P) and SPTB c.6203 T > C (p.L2068P) mutations and one autosomal dominant ANK1 c.4462C > T (p.R1488X) mutation., Conclusions: Our data demonstrated that WES is an efficient tool for determining genetic etiologies of RBC membrane disorders and can facilitate accurate diagnosis and genetic counseling. Additional studies should be conducted on larger cohorts to investigate the distribution of gene mutations in patients with RBC membrane disorders in Taiwan., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Thiodiglycolic acid (TDGA) is a major metabolite of vinyl chloride monomer (VCM), and it has been suggested as an exposure biomarker for VCM. The validity of this biomarker when the level of VCM is less than 5 ppm, however, is questionable. The objective of this article is to evaluate the feasibility of using urinary TDGA as a biomarker of VCM exposure in a community health risk assessment setting where the concentration of VCM in air is typically very low (likely below 1 ppm). To achieve this objective, we examine the fraction of urinary TDGA associated with different levels of VCM exposures of three studies from different countries, using estimations of the TDGA metabolite predicted by a PBPK model. It is demonstrated that differences in background TDGA have considerable effect on the adequacy of TDGA as a biomarker of VCM. We conclude that, in a community health assessment setting, TDGA should not be used as an exposure biomarker for VCM without having a proper control group, and a PBPK model can be used first to determine whether or not the amount of TDGA in urine is of concern., (Copyright © 2018. Published by Elsevier Inc.)

Despite the recent success of antibody-drug conjugates (ADCs) in cancer therapy, a detailed understanding of their entry, trafficking, and metabolism in cancer cells is limited. To gain further insight into the activation mechanism of ADCs, we incorporated fluorescence resonance energy transfer (FRET) reporter groups into the linker connecting the antibody to the drug and studied various aspects of intracellular ADC processing mechanisms. When comparing the trafficking of the antibody-FRET drug conjugates in various different model cells, we found that the cellular background plays an important role in how the antigen-mediated antibody is processed. Certain tumor cells showed limited cytosolic transport of the payload despite efficient linker cleavage. Our FRET assay provides a facile and robust assessment of intracellular ADC activation that may have significant implications for the future development of ADCs.

Neuregulin 1 (NRG1) is required for development of the central and peripheral nervous system and regulates neurotransmission in the adult. NRG1 and the gene encoding its receptor, ERBB4, are risk genes for schizophrenia, although how alterations in these genes disrupt their function has not been fully established. Studies of knockout and transgenic mice have yielded conflicting results, with both gain and loss of function resulting in similar behavioral and electrophysiological phenotypes. Here, we used high affinity antibodies to NRG1 and ErbB4 to perturb the function of the endogenous proteins in adult mice. Treatment with NRG1 antibodies that block receptor binding caused behavioral alterations associated with schizophrenia, including, hyper-locomotion and impaired pre-pulse inhibition of startle (PPI). Electrophysiological analysis of brain slices from anti-NRG1 treated mice revealed reduced synaptic transmission and enhanced paired-pulse facilitation. In contrast, mice treated with more potent ErbB4 function blocking antibodies did not display behavioral alterations, suggesting a receptor independent mechanism of the anti-NRG1-induced phenotypes. We demonstrate that anti-NRG1 causes accumulation of the full-length transmembrane protein and increases phospho-cofilin levels, which has previously been linked to impaired synaptic transmission, indicating enhancement of non-canonical NRG1 signaling could mediate the CNS effects.

THIOMAB antibody technology utilizes cysteine residues engineered onto an antibody to allow for site-specific conjugation. The technology has enabled the exploration of different attachment sites on the antibody in combination with small molecules, peptides, or proteins to yield antibody conjugates with unique properties. As reported previously ( Shen , B. Q. , et al. ( 2012 ) Nat. Biotechnol. 30 , 184 - 189 ; Pillow , T. H. , et al. ( 2017 ) Chem. Sci. 8 , 366 - 370 ), the specific location of the site of conjugation on an antibody can impact the stability of the linkage to the engineered cysteine for both thio-succinimide and disulfide bonds. High stability of the linkage is usually desired to maximize the delivery of the cargo to the intended target. In the current study, cysteines were individually substituted into every position of the anti-HER2 antibody (trastuzumab), and the stabilities of drug conjugations at those sites were evaluated. We screened a total of 648 THIOMAB antibody-drug conjugates, each generated from a trastuzamab prepared by sequentially mutating non-cysteine amino acids in the light and heavy chains to cysteine. Each THIOMAB antibody variant was conjugated to either maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E (MC-vc-PAB-MMAE) or pyridyl disulfide monomethyl auristatin E (PDS-MMAE) using a high-throughput, on-bead conjugation and purification method. Greater than 50% of the THIOMAB antibody variants were successfully conjugated to both MMAE derivatives with a drug to antibody ratio (DAR) of >0.5 and <50% aggregation. The relative in vitro plasma stabilities for approximately 750 conjugates were assessed using enzyme-linked immunosorbent assays, and stable sites were confirmed with affinity-capture LC/MS-based detection methods. Highly stable conjugation sites for the two types of MMAE derivatives were identified on both the heavy and light chains. Although the stabilities of maleimide conjugates were shown to be greater than those of the disulfide conjugates, many sites were identified that were stable for both. Furthermore, in vitro stabilities of selected stable sites translated across different cytotoxic payloads and different target antibodies as well as to in vivo stability.

Vertical integration of van der Waals (vdW) materials with atomic precision is an intriguing possibility brought forward by these two-dimensional (2D) materials. Essential to the design and analysis of these structures is a fundamental understanding of the vertical transport of charge carriers into and across vdW materials, yet little has been done in this area. In this report, we explore the important roles of single layer graphene in the vertical tunneling process as a tunneling barrier. Although a semimetal in the lateral lattice plane, graphene together with the vdW gap act as a tunneling barrier that is nearly transparent to the vertically tunneling electrons due to its atomic thickness and the transverse momenta mismatch between the injected electrons and the graphene band structure. This is accentuated using electron tunneling spectroscopy (ETS) showing a lack of features corresponding to the Dirac cone band structure. Meanwhile, the graphene acts as a lateral conductor through which the potential and charge distribution across the tunneling barrier can be tuned. These unique properties make graphene an excellent 2D atomic grid, transparent to charge carriers, and yet can control the carrier flux via the electrical potential. A new model on the quantum capacitance's effect on vertical tunneling is developed to further elucidate the role of graphene in modulating the tunneling process. This work may serve as a general guideline for the design and analysis of vdW vertical tunneling devices and heterostructures, as well as the study of electron/spin injection through and into vdW materials.

Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.

High-frequency operation with ultrathin, lightweight, and extremely flexible semiconducting electronics is highly desirable for the development of mobile devices, wearable electronic systems, and defense technologies. In this work, the experimental observation of quasi-heterojunction bipolar transistors utilizing a monolayer of the lateral WSe 2 -MoS 2 junctions as the conducting p-n channel is demonstrated. Both lateral n-p-n and p-n-p heterojunction bipolar transistors are fabricated to exhibit the output characteristics and current gain. A maximum common-emitter current gain of around 3 is obtained in our prototype two-dimensional quasi-heterojunction bipolar transistors. Interestingly, we also observe the negative differential resistance in the electrical characteristics. A potential mechanism is that the negative differential resistance is induced by resonant tunneling phenomenon due to the formation of quantum well under applying high bias voltages. Our results open the door to two-dimensional materials for high-frequency, high-speed, high-density, and flexible electronics.

This study aimed to identify the excess risks associated with diabetic patients with early kidney involvement (early diabetic kidney disease). The mortality risks of early diabetic kidney disease, defined as diabetes in early stages 1-3 chronic kidney disease (CKD), were assessed from a cohort of 512,700 adults in Taiwan participating in a health surveillance program from 1994-2008. Three related groups were identified and compared: diabetes without CKD, early diabetic kidney disease, and early CKD without diabetes. Deaths were ascertained through the National Death Registry. One-third of diabetics had early kidney disease, and approximately two-thirds of patients were classified with early CKD due to proteinuria. Patients with early diabetic kidney disease had more lifestyle risks such as inactivity or obesity, which characteristically amplified excess mortality by up to five times. The three-fold increase in all-cause mortality (hazard ratio 3.16) and a 16-year loss in life expectancy made early diabetic kidney disease a serious and yet often overlooked disease, with most patients unaware of their kidney involvement. Mortality for early diabetic kidney disease was nearly twice as high as that for early CKD (hazard ratio 2.01) or diabetes without CKD (hazard ratio 1.79). The 16-year life span loss is much worse than individually from early CKD (six years) or diabetes (ten years). Thus, identifying early proteinuria among diabetic patients and realizing the importance of reducing lifestyle risks like inactivity is a clinical challenge, but can save lives., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Previous studies have reported inconsistent results of the associations of alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) with incident type 2 diabetes (diabetes hereafter). We aimed to resolve the controversy by taking nonalcoholic fatty liver disease (NAFLD) into account. The study population comprised 132,377 non-diabetic individuals (64,875 men and 67,502 women) aged 35-79 who had two or more health examinations during 1996-2014. A total of 6,555 incident diabetes (3,734 men and 2,821 women) were identified, on average, over 5.8 years of follow-up. Cox regression was used to calculate the hazard ratio (HR) for incident diabetes, adjusting for classical confounders. The risk of incident diabetes was significantly associated with NAFLD [HR = 2.08 (men) and 2.65 (women)]. Elevated ALT, AST, GGT and ALP were also significantly associated with the increased risk of diabetes, with HRs of 1.27, 1.23, 1.58 and 1.37, respectively, in men, and 1.56, 1.18, 1.48 and 1.44, respectively in women. Our results suggest that NAFLD, ALT, AST, GGT and ALP are independent predictors for incident diabetes in both men and women.

Background/aims: Transfusion dependent subjects are at a great risk of viral hepatitis infection. We aimed to evaluate the prevalence and factors associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among transfusion-dependent patients in Taiwan., Methods: A total of 140 patients (67 thalassemic patients, 70 hemophilic patients, two patients with hereditary spherocytosis and one patient with von Willebrand disease) were prospectively enrolled to evaluate the prevalence and factors associated with viral hepatitis and spontaneous HCV clearance. All patients were tested for HBV and HCV serology and virology. Two consecutive serum samples, at least 1 year apart, were collected to clarify HCV seroclearance., Results: The seropositivity rate of hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV), and both HBsAg/anti-HCV were 6.4%, 45.7% and 5%, respectively. Logistic regression analysis of factors associated with anti-HCV seropositivity included age (odds ratio/95% confidence interval [OR/CI]: 1.12/1.07-1.18, P<0.001), serum alanine aminotransferase (ALT) (OR/CI: 1.04/1.02-1.06, P<0.001) and platelet counts (OR/CI: 0.995/0.991-0.998, P = 0.002). Age was the only factor independently associated with HBsAg seropositivity (OR/CI: 1.08/1.02-1.14.4, P = 0.007). Compared to patients born before 1992, the seroprevalence of HCV among thalassemic patients decreased dramatically in those born after 1992 (46.0% vs. 11.8%, p = 0.012). The seroprevalence of HCV among hemophilic patients also decreased significantly when comparing patients born before 1987 to those born after 1987 (79.5% vs. 11.5%, p<0.001). Similarly, the seroprevalence of HBV decreased significantly in the post-vaccination cohort compared to its counterpart (13.1%, vs. 1.3%, p = 0.005). The spontaneous clearance of HCV was observed in 25.4% (15/59) of patients, and ALT was the only factor associated with it (OR/CI 0.98/0.96-1.00, P = 0.02)., Conclusions: Both HBV and HCV infections are prevalent among transfusion-dependent thalassemic and hemophilic patients in Taiwan. Nevertheless, seroprevalence decreased significantly and dramatically for HCV after universal blood screening and for HBV after implementation of a universal mass vaccination program.