Analysis of noise generation and electric conduction at grain boundaries in CVD-grown MoS2 field effect transistors.
Grain boundaries in a chemical vapour deposition (CVD)-grown monolayer of MoS2 induce significant effects on the electrical and low frequency noise characteristics of the MoS2. Here, we investigated the electrical properties and noise characteristics of MoS2 field effect transistors (FETs) made with CVD-grown monolayer MoS2. The electrical and noise characteristics of MoS2 FETs were analysed and compared for the MoS2 channel layers with and without grain boundaries. The grain boundary in the CVD-grown MoS2 FETs can be the dominant noise source, and dependence of the extracted Hooge parameters on the gate voltage indicated the domination of the correlated number-mobility fluctuation at the grain boundaries. The percolative noise characteristics of the single grain regions of MoS2 were concealed by the noise generated at the grain boundary. This study can enhance understanding of the electrical transport hindrance and significant noise generation by trapped charges at grain boundaries of the CVD-grown MoS2 devices.


[Responses of soil organic carbon and microbial community structure to different tillage patterns and straw returning for multiple years.]
Soil organic carbon is essential for maintaining terrestrial ecosystem function and mitigating soil degradation. Soil microorganisms participate in soil carbon cycling. They are affected by tillage methods and straw returning. A split-plot design was adopted in this experiment. The whole-plot treatment had two tillage methods, subsoil tillage (ST) and rotary tillage (RT). The split-plot treatment included full straw returning (F) and no straw returning (0). The microbial community structure and carbon sequestration genes were assessed by Illumina sequencing technique. Soil organic carbon contents were measured during 2012-2017. The results showed that 1) subsoil tillage and straw returning significantly increased pH, microbial biomass carbon, total nitrogen, silt content, and clay content, while significantly decreased sand content; 2) during the test period (2012-2017), soil organic carbon (SOC) content under all treatments showed an increasing trend, but the increment for average SOC content under straw returning and subsoiling treatments was significantly higher than that of no straw returning and rotary tillage by 33.2 % and 30.6%, respectively; 3) Proteobacteria was the most abundant type of bacteria in the soil, followed by Acidobacteria and Gemmatadanetes; 4) STF treatment maintained high microbial diversity; 5) Excepted for soil sand content, soil pH, microbial biomass carbon, total nitrogen, silt content and clay content all caused the variation of soil microbial community structure under the STF treatment in the direction of SOC accumulation; 6) in addition to the gene abundance in the di- and oligosaccharides metabolic pathway, the gene abundance in the metabolic pathways for CO2 fixation, central carbohydrate metabolism, fermentation, one-carbon metabolism, organic acids, sugar alcohols and glycoside hydrolases showed that subsoil tillage was significantly higher than rotary tillage, with posi-tively correlation with soil organic carbon content. Therefore, the combination of subsoil tillage and straw returning could improve basic soil properties, affect soil microbial community structure, and increase the capacity of soil carbon fixation, thus providing a realistic basis for solving soil degradation.


[Preliminary research on the effect of antisense oligodeoxynucleotides of tankyrase 1 on tumor growth following intratumoral injection in mice].
To observe the suppressing effect of antisense oligodeoxynucleotides of tankyrase 1 (TANK1-ASODN) on murine tumor growth following intratumoral injection, and to explore its potential use in clinical treatment of lung cancer. After human lung cancer cells CALU had been inoculated subcutaneously to BALB/c nude mice and grew to tumor nodules, these mice were distributed randomly into three groups: four in the saline group, five in the TANK1-ASODN group, and another five in the sense oligodeoxynucleotides of tankyrase (TANK1-SODN) group. Multiple direct intratumoral injections of TANK1-ASODN, TANK1-SODN or saline were given into the tumor nodules, respectively. The tumor growth and the histopathological characteristics were observed and the expression of ki67 and telomerase hTERT in tumor cells were measured by SABC immunohistrochemical method. After 16 days of continuous injection, the tumor volume of the TANK1-ASODN group was significantly smaller than that of the TANK1-SODN (P < 0.01) and saline-treated groups (P < 0.01); tumor cell degeneration and necrosis were observed in mice treated with TANK1-ASODN. Moreover, a statistically significant decrease in Ki67 labeling index (P < 0.01) and the positive expression ratio of telomerase hTERT (P < 0.01) was observed in the TANK1-ASODN group. Human lung tumor cell lines express high telomerase activity. TANK1-ASODN can inhibit the activity of telomerase and suppress the proliferation of tumor cells.


Symptom shifting and associations with mental illness: A transdiagnostic approach applied to eating disorders.
Diagnostic comorbidity is common among psychiatric patients. One approach to obtain an improved understanding of this phenomenon is to explore diagnostic transitions, across time. In the present study, we aim to take this methodology further within the specific context of eating disorders by investigating whether there are individuals who shift not only between different eating disorder symptoms, but also shift to deliberate self-harm and substance use over time, and relations of this to other indicators of mental illness. Retrospective longitudinal registry data from the Swedish Stepwise national quality assurance platform for eating disorders were analyzed, including self-report measurements and clinical assessments. Individuals (N = 3,159 adults) were selected for analysis based on available data at admission and 12 months postadmission, and grouped based on occurrence of a "symptom shift" (defined as a decrease in one symptom and increase in another over time). In this sample of patients, 422 (13%) demonstrated symptom shifting among eating disorder symptoms. As hypothesized, "symptom shifters" were more prone to engage in deliberate self-harm and shifted to both deliberate self-harm and substance use across time. They had higher reported levels of symptoms indicative of mental illness (e.g., anxiety and compulsivity) and more pronounced functional impairment (clinician rated and self-rated), compared to nonshifters. Taken together, this study demonstrates that a subgroup of individuals diagnosed with eating disorder(s) shift between distinct psychiatric symptoms across time, indicating that they may share a common vulnerability to engaging in problem behaviors and a need for a more comprehensive and individualized treatment plan. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Going veggie: Identifying and overcoming the social and psychological barriers to veganism.
We conceptualize the journey to ethical veganism in the stages of the transtheoretical model of change, from precontemplation through contemplation, preparation, action, and maintenance. At each stage, we explore the psychological barriers to progressing towards veganism, discuss how they manifest, and explore ways to overcome them. It is hoped that this paper can be used as a guide for animal advocates to identify the stage an individual is at, and understand and overcome the social and psychological barriers they may face to progressing. We argue that, while many people are ignorant of the cruel practices entailed in animal farming, many deliberately avoid thinking about the issue, are unable to appreciate the scale of the issue, and simply tend to favour the status quo. When engaging with the issue of farm animal suffering, meat-eaters are largely driven by cognitive dissonance, which manifests as motivated reasoning aimed at protecting one's image of oneself and one's society. This is facilitated by confirmation bias and complicit media which cater to the preferred views of their meat-eating audience. Even once convinced of veganism, habit and willpower present further barriers to acting on those beliefs. This is all in the context of a speciesist and carnistic culture where meat consumption is normal, farming is noble, and vegans are 'others'. We locate and elucidate each of these biases within the stages of the transtheoretical model and discuss the implications of this model for animal advocates and for further research.


Machine learning reveals multiple classes of diamond nanoparticles.
Generating samples of nanoparticles with specific properties that allow for structural diversity, rather than requiring structural precision, is a more sustainable prospect for industry, where samples need to be both targeted to specific applications and cost effective. This can be better enabled by defining classes of nanoparticles and characterising the properties of the class as a whole. In this study, we use machine learning to predict the different classes of diamond nanoparticles based entirely on the structural features and explore the populations of these classes in terms of the size, shape, speciation and charge transfer properties. We identify 9 different types of diamond nanoparticles based on their similarity in 17 dimensions and, contrary to conventional wisdom, find that the fraction of sp2 or sp3 hybridized atoms are not strong determinants, and that the classes are only weakly related to size. Each class has been describe in such way as to enable rapid assignment using microanalysis techniques.


Treating agitation with dexmedetomidine in the ICU.
Patients in the intensive care unit frequently experience delirium, anxiety, and agitation, with a variety of treatments used. This article discusses the role of an alpha-adrenoceptor agonist, dexmedetomidine, and its clinical relevance and advantages for the agitated patient.


Evaluation of risk factors for house infestation by Triatoma infestans in Brazil.
An active entomologic survey was conducted by a team of trained health workers in a rural area endemic for Chagas' disease in central Brazil. They used pyrethrum as a flushing agent and 4,232 houses were inspected for triatomine bugs both inside and in the immediate environs. Houses with Triatoma infestans or evidence of an established colony were identified and defined as infested houses (cases). The building and environmental characteristics of 161 randomly selected infested houses were compared with 161 matched, noninfested houses (controls) that were the shortest distance from the infested house. Domestic and peridomestic potential risk factors associated with house infestation by Triatoma infestans were assessed by logistic regression analysis. Incomplete house construction (odds ratio [OR] = 2.5, 95% confidence interval [CI] = 1.5-4.1) was confirmed as a risk factor related to the presence or evidence of Triatoma infestans in the dwellings. The study also disclosed a statistically significant association between the presence of rats (OR = 1.6, 95% CI = 1.1-2.6) and indoor crop storage (OR = 2.3, 95% CI = 1.1-5.2) and house infestation. Further experimental field studies using tagged rodents should be conducted to assess their epidemiologic role in the domestic chain of Trypanosoma cruzi transmission.


Diabetes-induced alterations in the extracellular matrix and their impact on myocardial function.
Diabetes is an increasing public health problem that is expected to escalate in the future due to the growing incidence of obesity in the western world. While this disease is well known for its devastating effects on the kidneys and vascular system, diabetic individuals can develop cardiac dysfunction, termed diabetic cardiomyopathy, in the absence of other cardiovascular risk factors such as hypertension or atherosclerosis. While much effort has gone into understanding the effects of elevated glucose or altered insulin sensitivity on cellular components within the heart, significant changes in the cardiac extracellular matrix (ECM) have also been noted. In this review article we highlight what is currently known regarding the effects diabetes has on both the expression and chemical modification of proteins within the ECM and how the fibrotic response often observed as a consequence of this disease can contribute to reduced cardiac function.


A Sea-Sky Line Detection Method for Unmanned Surface Vehicles Based on Gradient Saliency.
Special features in real marine environments such as cloud clutter, sea glint and weather conditions always result in various kinds of interference in optical images, which make it very difficult for unmanned surface vehicles (USVs) to detect the sea-sky line (SSL) accurately. To solve this problem a saliency-based SSL detection method is proposed. Through the computation of gradient saliency the line features of SSL are enhanced effectively, while other interference factors are relatively suppressed, and line support regions are obtained by a region growing method on gradient orientation. The SSL identification is achieved according to region contrast, line segment length and orientation features, and optimal state estimation of SSL detection is implemented by introducing a cubature Kalman filter (CKF). In the end, the proposed method is tested on a benchmark dataset from the "XL" USV in a real marine environment, and the experimental results demonstrate that the proposed method is significantly superior to other state-of-the-art methods in terms of accuracy rate and real-time performance, and its accuracy and stability are effectively improved by the CKF.


Percutaneous transluminal angioplasty as a complement to surgery.
Transluminal angioplasty, a nonsurgical treatment for atherosclerotic occlusive disease, was performed on 56 arteries in 45 patients in conjunction with reconstructive vascular surgery. Twelve patients were treated presurgically, 12 patients were treated postsurgically, and 21 patients were treated intraoperatively. Some arteries were dilated to increase arterial inflow to the graft or to improve the distal runoff. In other cases, a major reconstructive surgical procedure was modified to a less traumatic or more favorable one. The long-term patency rate is still under investigation. The rate of success was 95%.


Collection optics for a Raman spectrometer based on the 90° geometry of scattered light collection.
In the present work, efficiency of classical lens, mirror-lens, and pure mirror variants of the collection optics for a Raman spectrometer based on 90° geometry of scattered light collection is investigated. It is experimentally established that, despite a smaller collection angle, in the case of a relatively narrow input slit of the spectrometer (<100 μm), the lens optics with corrected off-axis and chromatic aberrations allows larger signal intensities to be registered. However, the low f/# mirror collection optics described in the work provide a more stable adjustment and can be used to increase the Raman signal intensities in cases when the image of the scattering volume formed by them is commensurable with the sizes of the input slit of the spectrometer.


Direct magnitude estimates of speech intelligibility in dysarthria: effects of a chosen standard.
Direct magnitude estimation (DME) has been used frequently as a perceptual scaling technique in studies of the speech intelligibility of persons with speech disorders. The technique is typically used with a standard, or reference stimulus, chosen as a good exemplar of "midrange" intelligibility. In several published studies, the standard has been chosen subjectively, usually on the basis of the expertise of the investigators. The current experiment demonstrates that a fixed set of sentence-level utterances, obtained from 4 individuals with dysarthria (2 with Parkinson disease, 2 with traumatic brain injury) as well as 3 neurologically normal speakers, is scaled differently depending on the identity of the standard. Four different standards were used in the main experiment, three of which were judged qualitatively in two independent evaluations to be good exemplars of midrange intelligibility. Acoustic analyses did not reveal obvious differences between these four standards but suggested that the standard with the worst-scaled intelligibility had much poorer voice source characteristics compared to the other three standards. Results are discussed in terms of possible standardization of midrange intelligibility exemplars for DME experiments.


Myocellular Responses to Concurrent Flywheel Training during 70 Days of Bed Rest.
This investigation evaluated myocellular responses to an integrated resistance and aerobic training program during 70 d of bed rest. Training was 6 d·wk on a small-footprint gravity-independent flywheel resistance and aerobic device; 3 d of maximal flywheel supine quadriceps and calf exercises with continuous rowing separated by 4 to 6 h, and 3 d of interval rowing. Vastus lateralis (VL) and soleus (SOL) muscle biopsies were obtained from eight healthy males (age, 28 ± 4 yr; BMI, 25 ± 3 kg·m; V˙O2max, 42 ± 6 mL·kg·min) before and after 6° head-down tilt bed rest. Vastus lateralis and SOL myosin heavy chain (MHC) I and IIa single muscle fiber size and functional characteristics, as well as overall fiber type distribution, capillarization, and metabolic enzyme activities were evaluated. In the VL, MHC I size and power (absolute and normalized) were preserved. The MHC IIa fibers hypertrophied (+6%, P < 0.05) without a change in absolute power, so normalized power declined (-7%, P < 0.05). In the SOL, MHC I fibers atrophied (-9%) and absolute power declined (-17%) (P < 0.05), whereas normalized power was maintained. Size, absolute power, and normalized power were protected in the less-abundant MHC IIa fibers. Reduced MHC coexpressing hybrid fibers, generally indicative of an exercise training effect, was apparent in the VL, whereas fiber type was maintained in the SOL. Capillarization and metabolic enzymes were generally preserved or increased in VL and SOL. The integrated resistance and aerobic training protocol on a device maintains several key myocellular characteristics during prolonged unloading, but further refinement of the exercise approach to fully protect the SOL is warranted.


Enlargements of the distal third metacarpus and metatarsus in Thoroughbred foals at pasture from birth to 160 days of age.
To assess the relationship between the radiographic and microscopic appearance of the physeal regions of the distal third metacarpal (Mc3) and metatarsal (Mt3) bones of Thoroughbred foals at 160 days of age, and to clinically assess changes in contour of the distal Mc3 and Mt3 physeal regions from birth to 160 days of age. To assess relationships between maximum clinical physis scores and age, time of year, foal's sex, condition score, growth rate, copper (Cu) concentration in the liver of the foal, and supplementation of the dam with Cu in late gestation. Dams were given Cu (n=5 and n=11, in Years 1 and 2, respectively) or saline (n=5 and n=12, in Years 1 and 2, respectively) injections in late gestation. Liver biopsies were harvested from foals in the first week of life, and the whole liver homogenised after the animals were euthanised at around 160 days of age, to determine Cu concentrations. Pasture samples were collected every 4-8 weeks for analysis of mineral composition. During Year 1, 10 foals were weighed and examined every 2 weeks from birth to 160 days of age for evidence of pain and lameness in the distal Mc3/Mt3. In Year 2, 23 foals were weighed, condition-scored and examined for evidence of pain and lameness weekly for the first 5 weeks of life, then every 2 weeks from birth to 160 days of age, and a clinical physis score for the distal Mc3/Mt3 given. Cabinet radiographs of frontal slices of the physeal region of the distal Mc3/Mt3 at around 160 days of age were given a radiographic physis score. Physes were then examined histologically for evidence of abnormal endochondral ossification. Gross enlargements of the distal Mc3 and Mt3 were observed in all foals in this study, but were not associated with lameness, pain or inflammation. The most severe clinical physis scores occurred over 2 months in late summer/autumn, and were not influenced by the foal's growth rate, sex, or Cu concentration in the liver, or treatment of dams with Cu in late gestation. The clinical physis score was highly correlated to radiographic evidence of shouldering in the forelimb and hindlimb (both p<0.001). Focal disturbances in endochondral ossification were evident radiographically and histologically in the some of the physes at 160 days of age. The mineral composition of pasture was similar in Years 1 and 2, and concentrations of Cu and zinc were below those currently recommended for growing horses. Gross enlargements of the distal Mc3 and Mt3 were not consistent with previous descriptions of physitis. Results suggest that while many Thoroughbred foals at pasture will have visible boney enlargements of the distal Mc3/Mt3 in the first 5 months of life, few have physeal cartilage abnormalities or significant compromise of endochondral ossification. The importance of these clinical swellings may be overestimated, and they may more appropriately be called physiological enlargements associated with remodelling of bone.


Patterns of Ethylene and Carbon Dioxide Evolution during Cotton Explant Abscission.
The relationship between abscission and the evolution of ethylene and CO(2) was examined in explants and explant segments of cotton seedlings (Gossypium hirsutum L. cv. Acala SJ-1) under both static and flow system conditions, and in the presence and absence of mercuric perchlorate. Explant excision was immediately followed by increased ethylene evolution (wound ethylene); senescence was also accompanied by increased ethylene evolution (senescence ethylene). One or two ethylene peaks were found to interrupt the low background rate of ethylene evolution during the period between excision and senescence. The first intermediate ethylene peak coincided with a rise in CO(2) evolution; however, precedence could not be established. No statistical correlations were discovered between either intermediate ethylene peak and abscission. The best statistical correlation was found between wound ethylene and abscission at 12 hr after excision. No positive correlations were found between senescence ethylene and abscission. Implications of these results for the understanding of the role of ethylene in explant abscission are discussed.Relationships between a number of different explant treatments and ethylene evolution were also examined. Ethylene production in response to indoleacetic acid applications, abscisic acid applications, and different types of wounding is summarized. It was concluded that the results of the standard abscission bioassay (conducted in Petri dishes) have not been influenced by unnatural ethylene accumulations.


Transforming Life: A Broad View of the Developmental Origins of Health and Disease Concept from an Ecological Justice Perspective.
The influential scientist Rene J. Dubos (1901-1982) conducted groundbreaking studies concerning early-life environmental exposures (e.g., diet, social interactions, commensal microbiota, housing conditions) and adult disease. However, Dubos looked beyond the scientific focus on disease, arguing that "mere survival is not enough". He defined mental health as fulfilling human potential, and expressed concerns about urbanization occurring in tandem with disappearing access to natural environments (and elements found within them); thus modernity could interfere with health via "missing exposures". With the advantage of emerging research involving green space, the microbiome, biodiversity and positive psychology, we discuss ecological justice in the dysbiosphere and the forces-financial inequity, voids in public policy, marketing and otherwise-that interfere with the fundamental rights of children to thrive in a healthy urban ecosystem and learn respect for the natural environment. We emphasize health within the developmental origins of health and disease (DOHaD) rubric and suggest that greater focus on positive exposures might uncover mechanisms of resiliency that contribute to maximizing human potential. We will entrain our perspective to socioeconomic disadvantage in developed nations and what we have described as "grey space"; this is a mental as much as a physical environment, a space that serves to insidiously reinforce unhealthy behavior, compromise positive psychological outlook and, ultimately, trans-generational health. It is a dwelling place that cannot be fixed with encephalobiotics or the drug-class known as psychobiotics.


Three new Diels-Alder type adducts from the stem bark of Morus cathayana.
Three new Diels-Alder type adducts cathayanons C (1), D (2), and E (3), together with one known compound sanggenon C (4), were isolated from the stem bark of Morus cathayana. Their structures were fully elucidated by spectroscopic and chemical methods. Compound 2 showed good anti-oxidation activity with the inhibitory rate of malondialdehyde being 88% at a concentration of 10(- 6) mol/l.


An angiotensin II- and NF-kappaB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension.
Connexins (Cxs) play a role in the contractility of the aorta wall. We investigated how connexins of the endothelial cells (ECs; Cx37, Cx40) and smooth muscle cells (SMCs; Cx43, Cx45) of the aorta change during renin-dependent and -independent hypertension. We subjected both wild-type (WT) mice and mice lacking Cx40 (Cx40(-/-)), to either a two-kidney, one-clip procedure or to N-nitro-l-arginine-methyl-ester treatment, which induce renin-dependent and -independent hypertension, respectively. All hypertensive mice featured a thickened aortic wall, increased levels of Cx37 and Cx45 in SMC, and of Cx40 in EC (except in Cx40(-/-) mice). Cx43 was up-regulated, with no effect on its S368 phosphorylation, only in the SMCs of renin-dependent models of hypertension. Blockade of the renin-angiotensin system of Cx40(-/-) mice normalized blood pressure and prevented both aortic thickening and Cx alterations. Ex vivo exposure of WT aortas, carotids, and mesenteric arteries to physiologically relevant levels of angiotensin II (AngII) increased the levels of Cx43, but not of other Cx. In the aortic SMC line of A7r5 cells, AngII activated kinase-dependent pathways and induced binding of the nuclear factor-kappa B (NF-kappaB) to the Cx43 gene promoter, increasing Cx43 expression. In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-kappaB pathways.


Epstein-Barr virus load monitoring: its role in the prevention and management of post-transplant lymphoproliferative disease.
The Epstein-Barr virus load in the peripheral blood at the time of diagnosis of post-transplant lymphoproliferative disease (PTLD) is elevated 1000- to 10,000-fold compared to the level detected in normal latency. With the use of quantitative polymerase chain reaction (PCR), changes in the viral load over time can be measured with a two- to fourfold accuracy. This has allowed early detection of first-time infections and reactivations that may lead to PTLD and has provided an opportunity to intervene before symptomatic disease has occurred. Viral load monitoring has also been used to follow patients with PTLD and, along with other parameters, provided an assessment of the effectiveness of therapeutic protocols. Viral load monitoring has led to the discovery that at least two-thirds of transplant recipients become persistent viral load carriers. While the persistent load appears to be largely carried in latently infected memory B cells, more work is needed to clearly define this type of persistent infection and determine the risks associated with it. New diagnostic tests need to be developed to distinguish the persistent latent viral loads from viral loads that are likely to become symptomatic PTLD.


The cyclodextrin glycosyltransferase of Paenibacillus pabuli US132 strain: molecular characterization and overproduction of the recombinant enzyme.
The gene encoding the cyclodextrin glycosyltransferase (CGTase) of Paenibacillus pabuli US132, previously described as efficient antistaling agent and good candidate for cyclodextrins production, was cloned, sequenced, and expressed in Escherichia coli. Sequence analysis showed that the mature enzyme (684 amino acids) was preceded by a signal peptide of 34 residues. The enzyme exhibited the highest identity (94%) to the beta-CGTase of Bacillus circulans no. 8. The production of the recombinant CGTase, as active form, was very low (about 1 U/mL) in shake flasks at 37 degrees C. This production reached 22 U/mL after 22 hours of induction by mainly shifting the postinduction temperature from 37 to 19 degrees C and using 2TY instead of LB medium. High enzyme production (35 U/mL) was attained after 18 hours of induction in fermentor using the same culture conditions as in shake flask. The recombinant enzyme showed V(max) and K(m) values of 253 +/- 36 mumol of beta-cyclodextrin/mg/min and 0.36 +/- 0.18 g/L, respectively.


Repeatability of high-frequency bone conduction thresholds.
The purpose of this study was to determine the repeatability of high-frequency, bone conduction thresholds and to increase the data base concerning high-frequency, bone conduction threshold levels. Bone conduction thresholds were obtained on 30 subjects having normal, low, and mid frequency (0.25 to 8 kHz) hearing thresholds within and across five test sessions using a Pracitronic KH 70 bone vibrator referenced to a Brüel and Kjaer 4930 mechanical coupler at 1, 4, 8, 10, 12, 14, and 16 kHz. Within and across sessions, the bone conduction thresholds were not significantly (p greater than 0.05) different at each frequency indicating that repeated testing without replacing the bone vibrator (within session) and with replacing the bone vibrator (across session) did not influence the threshold measurements. Clinical implications concerning high-frequency, bone conduction audiometry are discussed.


Synergic Enhancement of Energy Storage Density and Efficiency in MnO2-Doped AgNbO3@SiO2 Ceramics via A/B-Site Substitutions.
Dielectric energy storage devices with high power density show great potential in applications of smart grids, electrical vehicles, pulsed power weapons, and so on. However, their limited recoverable energy density badly restricts their utilization and harms the miniaturization, portability, and integration of electronics. Herein, equivalent amounts of Bi2O3 and Sc2O3 were introduced to improve the energy storage property of 0.10 wt % MnO2-doped AgNbO3@SiO2 ceramics by simultaneously enhancing the maximum polarization, breakdown strength, and relaxation feature. It is particularly interesting that the AgNbO3-based ceramics with 4 mol % Bi2O3 and Sc2O3 demonstrate the recoverable energy storage density of 5.9 J/cm3 with the energy storage efficiency of 71%, exhibiting 1.9 and 1.4 times enhancement compared to 0.10 wt % MnO2-doped AgNbO3@SiO2 ceramics. In addition, the benign energy storage performance can be maintained at elevated temperatures and frequencies and up to 105 cycling, indicating great potential in advanced high-power applications.


Plasma albumin level as an indicator of severity of preeclampsia.
We propose that hypoalbuminemia in preeclampsia is the result of reduced hepatic blood flow which is secondary to hypovolemia created by higher filtration pressure in the capillaries. Thus, hypoalbuminemia can be identified as an early sign in developing preeclampsia. We reviewed the medical records of 60 patients, aged 22-28, admitted with a diagnosis of preeclampsia during the third trimester of pregnancy. Normotensive patients served as a control group. Albumin levels were correlated with severity of the disorder. Levels between 3.0-3.5 g/dl were seen in both groups. All patients with severe preeclampsia had values below 3.0 gm/dl. Serum albumin levels may serve as an indicator of the severity of preeclampsia.


[Rheological behavior of blood substitutes with a perfluorocarbon base].
Oxygen uptake and desoxygenation in blood take place in the capillary system of the organism so that flow characteristics of blood substitutes should be adapted to that of microcirculation. Therefore, appropriate viscosity of blood substitutes is required. In addition to this, studies on the viscosity of blood substitutes made on the basis of perfluorocarbons are also of interest for considering the deemulsificability during circulation. Viscosity measurements carried out on highly polymerized dextran solutions determining the colloid osmotic pressure in blood substitutes, perfluorocarbon emulsions as oxygen carriers, blood as well as mixtures of these components showed that the rheological behaviour of blood substitutes examined did not lead to organic disorders.


Comparison of patient-controlled analgesia with and without a background infusion after lower abdominal surgery in children.
Forty children aged 6-12 yr undergoing appendicectomy were allocated randomly to receive postoperative i.v. morphine by a patient-controlled analgesia (PCA) system (bolus dose 20 micrograms kg-1 with a lockout interval of 5 min) or the same PCA with a background infusion of morphine 20 micrograms kg-1 h-1. Patients breathed air and oxygen saturation was monitored by continuous pulse oximetry. Scores for pain, sedation and nausea were recorded hourly. Patients with PCA + background infusion received significantly more morphine than those with PCA only. Both groups self-administered similar amounts of morphine using the PCA machine. There were no significant differences in the pain scores of the two groups. Patients with PCA+background infusion suffered more nausea (P < 0.01), more sedation (P < 0.05) and hypoxaemia (P < 0.001) than those with PCA only. They also had a better sleep pattern than those with PCA only.


Immunotherapy for urothelial carcinoma: Metastatic disease and beyond.
For advanced and metastatic urothelial carcinomas (UCs), platinum (preferably cisplatin)-based chemotherapy has been the standard treatment for many years. However, many patients are ineligible for cisplatin-based chemotherapy because of poor performance status and/or other age-related conditions. At the other end of the spectrum, patients with localized non-muscle-invasive bladder cancer who are unresponsive to intravesical Bacillus Calmette-Guérin (BCG) treatment often face radical cystectomy as the only option. In recent years, the application of immunotherapy in the form of immune-checkpoint inhibitors has provided viable alternatives in the second-line postplatinum and first-line cisplatin-ineligible settings. Recent and ongoing clinical trials are also assessing the safety and efficacy of immunotherapy for neoadjuvant and adjuvant uses before/after cystectomy, for BCG-unresponsive cases, and for combination treatments that include the newer indoleamine 2,3-dioxygenase-1 inhibitors and/or BCG. This review summarizes recent developments in immunotherapy for UCs.


Improvement of Liver Cell Therapy in Rats by Dietary Stearic Acid.
Stearic acid is known as a potent anti-inflammatory lipid. This fatty acid has profound and diverse effects on liver metabolism. The aim of this study was to investigate the effect of stearic acid on markers of hepatocyte transplantation in rats with acetaminophen (APAP)-induced liver damage. Wistar rats were randomly assigned to 10-day treatment. Stearic acid was administered to the rats with APAP-induced liver damage. The isolated liver cells were infused intraperitoneally into rats. Blood samples were obtained to evaluate the changes in the serum liver enzymes, including activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and the level of serum albumin. To assess the engraftment of infused hepatocytes, rats were euthanized, and the liver DNA was used for PCR using sex-determining region Y (SRY) primers. The levels of AST, ALT and ALP in the serum of rats with APAP-induced liver injury were significantly increased and returned to the levels in control group by day six. The APAP-induced decrease in albumin was significantly improved in rats through cell therapy, when compared with that in the APAP-alone treated rats. SRY PCR analysis showed the presence of the transplanted cells in the liver of transplanted rats. Stearic acid-rich diet in combination with cell therapy accelerates the recovering of hepatic dysfunction in a rat model of liver injury.


Chloral hydrate anesthesia and lens opacification in mice.
To study the effect of chloral hydrate in the eye lens in mice. We instilled tropicamide in the eyes of two groups of eight 129 strain wild-type mice and injected chloral hydrate intraperitoneally (400 mg/kg). A drop of hypromellosum solution was additionally instilled in the eye of the second group to reduce corneal dehydration. The lens was inspected at several time intervals with a standard slit lamp biomicroscope after the injection. No lens opacification was found in any animal after the topical administration of tropicamide. On the contrary, the intraperitoneal administration of chloral hydrate produced lens opacification in both groups of animals. We show that chloral hydrate, when used intraperitoneally, induces acute and reversible lens opacification in all animals. In addition, we found that instillation of hypromellose solution does not prevent the lens opacification caused by chloral hydrate injection. We hypothesized some plausible explanations for these findings.


Extrasynaptic release of GABA by retinal dopaminergic neurons.
GABA release by dopaminergic amacrine (DA) cells of the mouse retina was detected by measuring Cl- currents generated by isolated perikarya in response to their own neurotransmitter. The possibility that the Cl- currents were caused by GABA release from synaptic endings that had survived the dissociation of the retina was ruled out by examining confocal Z series of the surface of dissociated tyrosine hydroxylase-positive perikarya after staining with antibodies to pre and postsynaptic markers. GABA release was caused by exocytosis because 1) the current events were transient on the millisecond time scale and thus resembled miniature synaptic currents; 2) they were abolished by treatment with a blocker of the vesicular proton pump, bafilomycin A1; and 3) their frequency was controlled by the intracellular Ca2+ concentration. Because DA cell perikarya do not contain presynaptic active zones, release was by necessity extrasynaptic. A range of depolarizing stimuli caused GABA exocytosis, showing that extrasynaptic release of GABA is controlled by DA cell electrical activity. With all modalities of stimulation, including long-lasting square pulses, segments of pacemaker activity delivered by the action-potential-clamp method and high-frequency trains of ramps, discharge of GABAergic currents exhibited considerable variability in latency and duration, suggesting that coupling between Ca2+ influx and transmitter exocytosis is extremely loose in comparison with the synapse. Paracrine signaling based on extrasynaptic release of GABA by DA cells and other GABAergic amacrines may participate in controlling the excitability of the neuronal processes that interact synaptically in the inner plexiform layer.


Surface-initiated activators generated by electron transfer for atom transfer radical polymerization in detection of DNA point mutation.
Amplification-by-Polymerization reportedly offers a sensitive and detector-free approach for DNA detection. However, the requirement for an oxygen-free environment when classic radical polymerization reactions are used in signal amplification significantly limits the mobility of this approach for point-of-need applications. We report here the employment of a purge-free controlled/"living" polymerization reaction, activators generated by electron transfer for atom transfer radical polymerization (AGET ATRP), to achieve signal amplification upon DNA hybridization. Its aptitude in simplifying assay procedure and shortening assay turn-around has been demonstrated in this report, which substantiates the feasibility of using Amplification-by-Polymerization for high throughput or portable screening of genetic mutations. In addition, employment of water-soluble ascorbic acid as the reducing agent has overcome the hurdles encountered by heterogeneous AGET ATRP reactions. Optimization of AGET ATRP in the presence of oligonucleotides has been conducted where tris[(2-pyridyl)methyl]amine (TPMA) was selected as the catalyst ligand for its mild reaction rate. Effective polymer growth has been achieved when the concentration of the Cu(II) catalyst was controlled at 20 mM and ascorbic acid at 18 mM. The propagation and termination reaction constants have been derived, purporting the speculated controlled growth kinetics during polymer grafting. A linear relationship between the grafted polymer film thickness and the amount of captured DNA target sequences has been established, which provides the quantification basis during DNA detection. Detection of DNA sequences with single-point mutations has been successful regardless of the mutation site.


Androgen signaling disruption during fetal and postnatal development affects androgen receptor and connexin 43 expression and distribution in adult boar prostate.
To date, limited knowledge exists regarding the role of the androgen signaling during specific periods of development in the regulation of androgen receptor (AR) and connexin 43 (Cx43) in adult prostate. Therefore, in this study we examined mRNA and protein expression, and tissue distribution of AR and Cx43 in adult boar prostates following fetal (GD20), neonatal (PD2), and prepubertal (PD90) exposure to an antiandrogen flutamide (50 mg/kg bw). In GD20 and PD2 males we found the reduction of the luminal compartment, inflammatory changes, decreased AR and increased Cx43 expression, and altered localization of both proteins. Moreover, enhanced apoptosis and reduced proliferation were detected in the prostates of these animals. In PD90 males the alterations were less evident, except that Cx43 expression was markedly upregulated. The results presented herein indicate that in boar androgen action during early fetal and neonatal periods plays a key role in the maintenance of normal phenotype and functions of prostatic cells at adulthood. Furthermore, we demonstrated that modulation of Cx43 expression in the prostate could serve as a sensitive marker of hormonal disruption during different developmental stages.


HACE2-Exosome-Based Nano-Bait for Concurrent SARS-CoV-2 Trapping and Antioxidant Therapy.
Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is seriously threatening human health. Following SARS-CoV-2 infection, immune cell infiltration creates an inflammatory and oxidative microenvironment, which can cause pneumonia, severe acute respiratory syndrome, kidney failure, and even death. Clinically, a safe and effective treatment strategy remains to be established. Herein, a nano-bait strategy for inhibition of SARS-CoV-2 infection by redirecting viral attack while simultaneously relieving inflammation is developed. Specifically, the nano-bait was based on the exosome-sheathed polydopamine (PDA@Exosome) nanoparticles, which were generated by exocytosis of the PDA nanoparticles from H293T cells. In this approach, PDA@Exosome inherits from the source cells of H293T cells a surface display of ACE2 through pre-engineered expression. The resulting PDA@Exosome can compete with ACE2-expressing epithelial cells for S protein binding, in either the pre-exposure or post-exposure route. Moreover, relying on the ability of PDA to intercept and deactivate radical species, the PDA@Exosome can significantly attenuate the level of inflammatory cytokines by mediating oxidative stress, a major cause of organ injury. Due to its high trapping, multiple antioxidant ability, and good biocompatibility, the HACE2-exosome based nano-bait is a promising robust antiviral nanotherapeutics for the ongoing COVID-19 pandemic.


Advances in Exosomes-Based Drug Delivery Systems.
Exosomes, a subgroup of extracellular vesicles, are important mediators of long-distance intercellular communication and are involved in a diverse range of biological processes such as the transport of lipids, proteins, and nucleic acids. Researchers, seeing the problems caused by the toxic effects and clearance of synthetic nanoparticles, consider exosomes as an interesting alternative to such nanoparticles in the specific and controlled transport of drugs. In recent years, there have been remarkable advances in the use of exosomes in cancer therapeutics or for treating neurological diseases, among other applications. The objective of this work is to analyze studies focused on exosomes used in drug delivery system, present and future applications in this field of research are discussed based on the results obtained.


The 22 to 25-Year Survival of Cemented and Cementless Total Knee Arthroplasty in Young Patients.
Despite cementless total knee arthroplasties (TKAs) have potential advantages over cemented TKAs, there are conflicting results. The purpose of the present study is to determine the long-term clinical and radiographic results, the survival rate, and the prevalence of osteolysis of cemented vs cementless TKAs. A total of 261 patients (522 knees) who underwent bilateral simultaneous TKAs were included in the present study (mean age, 62.5 ± 5.5 years). Patients were evaluated clinically, radiographically, and also using computed tomography scans. A mean follow-up period was 23.8 years (range, 22-25 years). There were no significant differences between the Knee Society total score, change in total score, knee function score, and Western Ontario and McMaster Universities Osteoarthritis Index score in the 2 groups. In total, 8 knees (3%) were revised in the cementless group and 5 knees (2%) in the cemented group. Radiographs and computed tomography scans showed no femoral, tibial, or patellar osteolysis in either group. The rate of survival at 25 years was 97% (95% confidence interval [CI], 92%-100%) in the cementless group and 98% (95% CI, 94%-100%) in the cemented group, with reoperation for any reason as the end point. The rate of survival at 25 years was 98% (95% CI, 94%-100%), with reoperation for aseptic loosening as the end point in both groups. At this length of follow-up, cementless TKA has comparable outcomes and survivorship to cemented TKA.


Safety, mucosal and systemic immunopotency of an aerosolized adenovirus-vectored vaccine against SARS-CoV-2 in rhesus macaques.
Mucosal immunity provides a potential for preventing initial infection and stopping subsequent transmission of SARS-CoV-2. Here, we examined the safety and immunogenicity of a replication-defective adenovirus type-5 vectored vaccine (Ad5-nCov) encoding SARS-CoV-2 spike protein delivered by nebulization inhalation in rhesus macaques. The vaccine-associated clinical pathology and toxicity were not observed in the NHP model. The extensive safety study indicated that Ad5-nCoV was mainly confined to the organs related to respiratory system and was rapidly cleared away from the system. Our results showed that Ad5-nCoV delivered by inhalation robustly elicited both systematic and mucosal immune responses against SARS-nCoV-2 and variants. Thus, Ad5-nCoV inhalation may provide an effective, safe and non-invasive vaccination strategy for the control of SARS-CoV-2.


On the use of Ethephon as abscising agent in cv. Crimson Seedless table grape production: combination of Fruit Detachment Force, Fruit Drop and metabolomics.
The effect of 2-chloroethylphosphonic acid (Ethephon, in the following ETH) as abscising agent on cv. Crimson Seedless table grape was investigated by means of Fruit Detachment Force (FDF) and Fruit Drop (FD) analyses combined with a metabolomic study carried out by High Resolution Mass Spectrometry (HRMS) and Nuclear Magnetic Resonance (NMR) spectroscopy. The effectiveness of ETH as abscising agent was ascertained with ETH concentration ranging from 1.4 to 4.0 g/L in a two-year study. The ETH treatments caused berry drops higher than 40% and induced an increase of tartaric acid, procyanidin P2, terpenoid derivatives and peonidin-3-glucoside as well as a decrease of catechin and epicatechin. HRMS-NMR covariance analysis was carried out to correlate the fluctuations of tartaric acid NMR signals to those of MS peaks of the secondary metabolites affected by ETH treatments.


Developmental patterns of selected characteristics of the gastrointestinal tract of young turkeys.
Developing embryos and hatchling poults were sampled (n = 4) at Days 22, 24, 26, and 28 of incubation and at 1, 2, 4, 6, and 8 days after hatching, and selected characteristics of the gastrointestinal tract (GIT) were measured. Body weight increased linearly up to day of hatching and also from 2 to 8 days posthatching. Residual yolk weight decreased rapidly starting on Day 26 of incubation and was nearly depleted by 4 days posthatching. Changes in weight of segments of the GIT nearly paralleled the increase in body weight until day of hatching. Thereafter, weights of the proventriculus, small intestine, and pancreas increased more rapidly than body weight until 6 days after hatching. At this time, change in weight of small intestine and pancreas seemed to parallel that of body weight, whereas proventriculus weight continued to increase more rapidly. Gizzard weight, as a percentage of body weight, increased until Day 4 posthatching and then remained relatively constant through 8 days. Specific activities (SA) of pancreatic amylase, lipase, and trypsin were low until after hatching. Subsequently, amylase SA increased nearly threefold by Day 6. Lipase SA remained nearly constant between Days 1 and 8, and trypsin SA increased only slightly. Total activities of pancreatic enzymes, however, increased substantially after hatching, mainly because of increased pancreas weight. Jejunal maltase SA was high at hatching but decreased markedly by Day 4. This decrease in SA resulted in a notable reduction in total maltase activity of the jejunum despite an increase in jejunum weight.


A combined epigenetic and non-genetic approach for reprogramming human somatic cells.
Reprogramming of somatic cells to different extents has been reported using different methods. However, this is normally accompanied by the use of exogenous materials, and the overall reprogramming efficiency has been low. Chemicals and small molecules have been used to improve the reprogramming process during somatic cell nuclear transfer (SCNT) and induced pluripotent stem (iPS) cell generation. We report here the first application of a combined epigenetic and non-genetic approach for reprogramming somatic cells, i.e., DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and human embryonic stem cell (hESC) extracts. When somatic cells were pretreated with these inhibitors before exposure to hESC (MEL1) extracts, morphological analysis revealed a higher rate of hESC-like colony formation than without pretreatment. Quantitative PCR (qPCR) demonstrated that pluripotency genes were upregulated when compared to those of somatic cells or treated with hESC extracts alone. Overall changes in methylation and acetylation levels of pretreated somatic cells suggests that epigenetic states of the cells have an effect on reprogramming efficiency induced by hESC extracts. KnockOutserum replacement (KOSR) medium (KO-SR) played a positive role in inducing expression of the pluripotency genes. hESC extracts could be an alternative approach to reprogram somatic cells without introducing exogenous materials. The epigenetic pre-treatment of somatic cells could be used to improve the efficiency of reprogramming process. Under differentiation conditions, the reprogrammed cells exhibited differentiation ability into neurons suggesting that, although fully reprogramming was not achieved, the cells could be transdifferentiated after reprogramming.


Determination of the Possible Target Genes of Hepatoma-derived Growth Factor in Hepatoma Cells.
We identified a new growth factor, hepatoma-derived growth factor (HDGF), which is a presumed growth-stimulating factor of hepatocellular carcinoma (HCC). Recently, we identified two microRNAs (miR-6072 and miR-3137) induced by HDGF, which were also found to be associated with the prognosis of HCC patients. This study aimed to identify the target genes of these HDGF-related microRNAs. A public database was searched for candidate target genes of HDGF-related microRNAs. Using the microarray system, the genes whose expression changed in response to HDGF administration were determined. Finally, a public cancer genomics database was searched for genes that were induced by HDGF and associated with the prognosis of HCC. A total of 1,132 genes were identified as common target genes of the 2 HDGF-related microRNAs. Among these genes, a microarray system showed that the expression of 6 genes was increased (≥1.5-fold) or decreased (≤0.67-fold) after HDGF administration. Using a cancer genomics database, two of the six genes were found to be related to the prognosis of HCC. A high expression of alkylglycerone phosphate synthase (AGPS) was significantly associated with a poor survival (p=0.0025, 0.0063 and 0.0081 for the 1-, 3- and 5-year survival, respectively). A high expression of the shroom family member 4 (SHROOM4) gene was found to be significantly associated with a better survival (p=0.003, 0.0006 and 0.0006 for the 1-, 3- and 5-year survival, respectively). This study identified potential target genes of HDGF-related microRNAs that were associated with the prognosis of HCC.


Correlates of Pediatric CPAP Adherence.
Obstructive sleep apnea (OSA) is a common pediatric condition characterized by recurrent partial or complete cessation of airflow during sleep, typically due to inadequate upper airway patency. Continuous positive airway pressure (CPAP) is a therapeutic option that reduces morbidity. Despite efforts to promote use, CPAP adherence is poor in both pediatric and adult populations. We sought to determine whether demographics, insurance status, OSA severity, therapeutic pressure, or comorbid conditions were associated with pediatric CPAP adherence. A retrospective review of adherence download data was performed on all pediatric patients with initiation or adjustment of CPAP treatment over a one-year period with documented in-laboratory CPAP titration. Patients were grouped as CPAP adherent or non-adherent, where adherence was defined as > 70% nightly use and average usage ≥ 4 hours per night. Differences between the groups were analyzed by χ(2) test. Overall, nearly half of participants were CPAP adherent (49%, 69/140). Of the demographic data collected (age, ethnicity, sex, insurance status), only female sex was associated with better adherence (60.9% vs 39.5% of males adherent; odds ratio [OR] = 2.41, 95%CI = 1.20-4.85; p = 0.01). Severity of OSA (diagnostic apnea-hypopnea index [AHI] and degree of hypoxemia), therapeutic pressure, and residual AHI did not impact CPAP adherence (p > 0.05). Patients with developmental delay (DD) were more likely to be adherent with CPAP than those without a DD diagnosis (OR = 2.55, 95%CI = 1.27-5.13; p = 0.007). Female patients with trisomy 21 tended to be more adherent, but this did not reach significance or account for the overall increased adherence associated with female sex. Our study demonstrates that adherence to CPAP therapy is poor but suggests that female sex and developmental delay are associated with better adherence. These findings support efforts to understand the pathophysiology of and to develop adherence-promoting and alternative interventions for pediatric OSA.


The Perspective of Nectarine Fruit as a Sugar Substituent in Puddings Prepared with Corn and Rice Starch.
It has been long recognized that fruits are healthy diet compounds as they are excellent sources of health-beneficial bioactive components (polyphenols, minerals, vitamins, organic acids, etc.). The diversification of the consumer's taste calls for an expansion of food options and novel ingredients. Puddings are a well-known food choice introduced in the human diet at a very early age because of their easy and high digestion. Four formulations with two types of starch (corn and rice) were selected as object of analysis. Nectarines were incorporated as a purée, and lyophilized powder. The nectarine variety "Gergana", used for the preparations, is a local variety with proven beneficial properties. The study aimed at analyzing the physical (moisture, ash, color, water-holding capacity, water activity, density and syneresis), textural (firmness, gumminess, cohesiveness, springiness, and chewiness), nutritional, and sensory characteristics of the nectarine-enriched puddings. The outcomes obtained from this study provided significant information about the possible application of the formulations in the children's daily menus. All four formulations had distinct peachy aroma. The formulations prepared with nectarine purée resulted in a better sensory perception about their texture, and better water-holding capacity. At this point, the formulation prepared with lyophilized fruit and rice starch has the most promising results. Sufficient evidence leads to further exploration of the perspective of fruit-enriched puddings in order to improve their technological and health-promoting properties.


[ATPase activity of rat liver mitochondria in acute tetrachloromethane poisoning].
The ATPase activity (proton ATPase) of rat liver mitochondria was studied 2, 24, 28, 96 and 168 h after acute tetrachloromethane poisoning. It is established that the tetrachloromethane poisoning. It is established that the tetrachloromethane poisoning is accompanied by a considerable activation of mitochondrial H+-ATPase and a decrease of the DNP and Ca+, Na+ and K+ activating influence on it. Maximum changes in the H+-ATPase activity is observed 24 h after poisoning. Changes in the H+-ATPase properties are accompanied by a fall in the alpha-ketoglutarate dehydrogenase and succinate dehydrogenase activities and by disturbance of the liver mitochondria contractile properties. The electrochemical membrane potential of the mitochondria under the effect of tetrachloromethane is supposed to be reduced due to a primary damage of the phospholipid matrix of the coupling membrane and an increase in its proton conductivity.


Surgeon General's Conference on Agricultural Safety and Health, 1991.
On April 30-May 3, 1991, CDC's National Institute for Occupational Safety and Health (NIOSH) convened the Surgeon General's Conference on Agricultural Safety and Health in Des Moines, Iowa. The theme for this conference was "FarmSafe 2000: A National Coalition for Local Action." Agricultural safety and health professionals, equipment manufacturers, farmer and migrant health organizations, rural health-care professionals, and agricultural youth organizations met to deliberate on methods to reduce health and safety risks in agriculture. More than 700 persons attended and represented 41 states and Puerto Rico. Through small-group interactive discussions, the conference addressed surveillance, research, and intervention--three public health activities necessary to meet year 2000 national health objectives (1). This report summarizes the issues considered at the conference and recommendations proposed by attendees.


A novel narrow surface cage for full endoscopic oblique lateral lumbar interbody fusion: A finite element study.
To evaluate the mechanical response of a narrow surface cage that we designed for full endoscopic oblique lateral lumbar interbody fusion (FE-OL-LIF). A finite element (FE) model of lumbar spine was developed and validated. To simulate the FE-OL-LIF, the functional spinal unit (FSU) L4-L5 was assembled with a narrow surface polyetheretherketone (PEEK) cage, two rods and four screws. 500N load combined with 7.5Nm moment was applied to the surgical models. Effect of the cage width on the stress was studied. Range of motion (ROM) in the surgical models significantly decreased by 88% in flexion, 91% extension, 85% in right and left lateral bending, 75% in right and left axial rotation as compared to the intact model. Width of the cage slightly decreased the ROM in all loading scenarios. Flexion produced the highest stress in the cages and endplates. In all loading cases, the maximum stresses of cages and endplates were both lower than their yield stress. In engineering analysis, the novel narrow-surface cage had a strength to support spine activities. 9 mm width cage was recommended in FE-OL-LIF. This study provided engineering evidence and technical advice to improve the design of minimally invasive cage. Fatigue test and cadaver trial shall be improved.


Central Attention Network for Hyperspectral Imagery Classification.
In this article, the intrinsic properties of hyperspectral imagery (HSI) are analyzed, and two principles for spectral-spatial feature extraction of HSI are built, including the foundation of pixel-level HSI classification and the definition of spatial information. Based on the two principles, scaled dot-product central attention (SDPCA) tailored for HSI is designed to extract spectral-spatial information from a central pixel (i.e., a query pixel to be classified) and pixels that are similar to the central pixel on an HSI patch. Then, employed with the HSI-tailored SDPCA module, a central attention network (CAN) is proposed by combining HSI-tailored dense connections of the features of the hidden layers and the spectral information of the query pixel. MiniCAN as a simplified version of CAN is also investigated. Superior classification performance of CAN and miniCAN on three datasets of different scenarios demonstrates their effectiveness and benefits compared with state-of-the-art methods.


Cranberry: Chemical Composition, Antioxidant Activity and Impact on Human Health: Overview.
Cranberries are a rich source of bioactive compounds that comprise a healthy diet. Cranberry is abundant in nutritional components and many bioactive compounds that have antioxidant properties. Both American (Vaccinium macrocarpon) and European (Vaccinium oxycoccus) cranberry species are rich in polyphenols such as phenolic acids, anthocyanins and flavonoids, and is one of the few fruits that is high in proanthocyanidins, which is linked to many health benefits. The review systematizes information on the chemical composition of cranberry, its antioxidant effect, and the beneficial impact on human health and disease prevention after cranberry consumption, and in particular, its effect against urinary tract inflammation with both adults and children, cardiovascular, oncology diseases, type 2 diabetes, metabolic syndrome, obesity, tooth decay and periodontitis, Helicobacter pylori bacteria in the stomach and other diseases. Additional research needs to study cranberry proteomics profiling, polyphenols interaction and synergism with other biologically active compounds from natural ingredients and what is important in formulation of new functional foods and supplements.


Evaluation of water-mimicking solid phantom materials for use in HDR and LDR brachytherapy dosimetry.
In modern HDR or LDR brachytherapy with photon emitters, fast checks of the dose profiles generated in water or a water-equivalent phantom have to be available in the interest of patient safety. However, the commercially available brachytherapy photon sources cover a wide range of photon emission spectra, and the range of the in-phantom photon spectrum is further widened by Compton scattering, so that the achievement of water-mimicking properties of such phantoms involves high requirements on their atomic composition. In order to classify the degree of water equivalence of the numerous commercially available solid water-mimicking phantom materials and the energy ranges of their applicability, the radial profiles of the absorbed dose to water, D w, have been calculated using Monte Carlo simulations in these materials and in water phantoms of the same dimensions. This study includes the HDR therapy sources Nucletron Flexisource Co-60 HDR (60Co), Eckert und Ziegler BEBIG GmbH CSM-11 (137Cs), Implant Sciences Corporation HDR Yb-169 Source 4140 (169Yb) as well as the LDR therapy sources IsoRay Inc. Proxcelan CS-1 (131Cs), IsoAid Advantage I-125 IAI-125A (125I), and IsoAid Advantage Pd-103 IAPd-103A (103Pd). Thereby our previous comparison between phantom materials and water surrounding a Varian GammaMed Plus HDR therapy 192Ir source (Schoenfeld et al 2015) has been complemented. Simulations were performed in cylindrical phantoms consisting of either water or the materials RW1, RW3, Solid Water, HE Solid Water, Virtual Water, Plastic Water DT, Plastic Water LR, Original Plastic Water (2015), Plastic Water (1995), Blue Water, polyethylene, polystyrene and PMMA. While for 192Ir, 137Cs and 60Co most phantom materials can be regarded as water equivalent, for 169Yb the materials Plastic Water LR, Plastic Water DT and RW1 appear as water equivalent. For the low-energy sources 106Pd, 131Cs and 125I, only Plastic Water LR can be classified as water equivalent.


[Progress of metagenomics next-generation sequencing in the detection of drug-resistant phenotypes of Gram-negative bacteria].
The ongoing spread of drug-resistant bacterial infections poses a significant threat to public health, and early diagnosis and targeted treatment are the keys to successful treatment. Traditional bacterial culture and drug susceptibility testing is time-consuming and insensitive, and cannot meet the needs of clinical diagnosis and treatment, so molecular detection technologies, such as metagenomics next-generation sequencing, have become a new research direction. This article reviewed recent advances in high-throughput sequencing for the diagnosis and treatment of drug resistance in Gram-negative bacteria.


Elevated E2: oocyte ratio in women undergoing IVF and tubal ET. Correlation with a decrease in the implantation rate.
To investigate the influence of various estradiol (E2): oocyte ratios on reproductive outcome in women undergoing in vitro fertilization and tubal embryo transfer (IVF-TET). Two hundred seven women undergoing 251 IVF-TET cycles were recruited in this retrospective study. All the women received a flare-up gonadotropin releasing hormone agonist (GnRHa) protocol to achieve ovarian hyperstimulation. Oocyte retrieval was performed 34-36 hours after human chorionic gonadotropin (hCG) injection, followed by TET two days later. An E2: oocyte ratio > or = 350 pg/mL had a higher E2 level (2,213 +/- 2,258 vs. 1,553 +/- 972 pg/mL, P < .05) and fertilization rate (77 +/- 23 vs. 64 +/- 23%, P < .001) but a lower oocyte number (4.8 +/- 4.7 vs. 7.6 +/- 4.8, P < .001) than in those with a ratio < 350 pg/mL. The pregnancy (17.9% vs. 32.8%, P = .03) and implantation (5.3% vs. 12.9%, P = .008) rates were significantly decreased in cycles with an E2: oocyte ratio > or = 350 pg/mL as compared to those with a ratio < 350 pg/mL. IVF-TET cycles with an elevated E2: oocyte ratio correlated with lower pregnancy and implantation rates. The poor reproductive outcome possibly was due to the relatively high E2 concentration, which might have a detrimental effect on endometrial receptivity.


Sterile inflammation in acute liver injury: myth or mystery?
Inflammation during liver injury normally serves as a mechanism for cleaning up debris and as a stimulant for regeneration. However, aberrant levels of inflammation can provoke further liver injury and inhibit regeneration through the release of damaging reactive oxygen species. Considerable effort has gone into understanding the mechanisms that control the switch between healthy and pathological inflammation. The identification of a receptor system that detects damage-associated molecular patterns and stimulates inflammation has led to the idea of sterile inflammation. This article will focus on the role of sterile inflammation during liver injury in three models where sterile inflammation has been presumed to mediate a portion of the injury mechanism and its potential relevance for the human pathophysiology.


Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings.
Liver tissue from 16 patients with rheumatoid arthritis was studied. The patients had received low dose methotrexate weekly for a minimum of 12 months between two liver biopsies. The progression of pericellular fibrosis was measured by computerised image analysis. Extracts of these liver biopsy specimens were pooled into five samples according to the progression of hepatic fibrosis and analysed by high performance liquid chromatography. The concentrations of methotrexate, 2,4 diamino-N(10)-methylpteroic acid, and methotrexate polyglutamate were markedly increased in the samples obtained from the three patients who recorded the greatest increase in fibrosis. These preliminary data suggest that progression of hepatic fibrosis is related to the retention of methotrexate and metabolites in the liver.


Oxidative stress and the JNK pathway as a potential therapeutic target for diabetes.
Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic beta-cell dysfunction found in diabetes. Possibly due to low levels of antioxidant enzyme expressions, beta-cells are vulnerable to oxidative stress. When beta-cell-derived cell lines or isolated rat islets were exposed to oxidative stress, insulin gene expression was markedly decreased. Furthermore, when diabetic C57BL/ KsJ-db/db mice were treated with antioxidants, glucose tolerance was ameliorated. Histological analyses of the pancreata revealed that the beta-cell mass is significantly larger in the mice treated with the antioxidants. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA. As a possible mechanism underlying the phenomena, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), an important transcription factor for the insulin gene, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. Furthermore, oxidative stress induces nucleocytoplasmic translocation of PDX-1 through activation of the c-Jun N-terminal kinase (JNK) pathway, which leads to suppression of insulin gene expression. Taken together, oxidative stress and consequent activation of the JNK pathway are involved in progression of beta-cell dysfunction found in diabetes, and thus are a therapeutic target for diabetes.


Tuning the lipophilic nature of pyclen-based 90Y3+ radiopharmaceuticals for β-radiotherapy.
Pyclen-dipicolinate chelates proved to be very efficient chelators for the radiolabeling with β--emitters such as 90Y. In this study, a pyclen-dipicolinate ligand functionalized with additional C12 alkyl chains was synthesized. The radiolabeling with 90Y proved that the addition of saturated carbon chains does not affect the efficiency of the radiolabeling, whereas a notable increase in lipophilicity of the resulting 90Y radiocomplex was observed. As a result, the compound could be extracted in Lipiodol® and encapsulated in biodegrable pegylated poly(malic acid) nanoparticles demonstrating the potential of lipophilic pyclen-dipicolinate derivatives as platforms for the design of radiopharmaceuticals for the treatment of liver or brain cancers by internal radiotherapy.


Initial experience with hepatic intraarterial fotemustine and interferon alpha 2b combination for treatment of liver tumors.
Locoregional treatments represent a good option for patients suffering from hepatocellular carcinoma (HCC) not eligible for resection or transplantation. Locoregional approaches include a wide spectrum of therapeutic methods and hepatic intra-arterial drug infusion is also considered. Fotemustine is a chemotherapy drug usually administered intravenously according to standard administration schedules. Interferon alpha 2b (IFNα2b), a biological response modifier conventionally administered by a systemic route, has been employed in the treatment of both virus-related hepatitis and HCC. Nonetheless, both drugs can also be infused into the hepatic artery. We report on five patients with liver cancer, not suitable for conventional therapies, treated with hepatic intra-arterial administration of fotemustine in combination with IFNα2b. They received fotemustine at a dose of 30 mg/m(2) and IFNα2b at a starting dose of 2,000,000 IU (increasing up to 3,000,000 IU for subsequent administrations) weekly for three consecutive weeks, followed by two weeks of rest. Among the patients suffering from HCC, the first patient showed a partial response, two patients had almost stable disease and one patient was not assessable. A patient with an intrahepatic biliary tract cancer experienced disease progression. The therapeutic regimen used showed acceptable tolerability profiles and lack of life-threatening side-effects. Further evaluation with a larger patient cohort will be required to clarify if fotemustine and IFNα2b administered into the hepatic artery could be beneficial in treating patients with HCC.


A New Method for Estimating the Incidence of Infectious Diseases.
Ambitious World Health Organization targets for disease elimination require monitoring of epidemics using routine health data in settings of decreasing and low incidence. We evaluated 2 methods commonly applied to routine testing results to estimate incidence rates that assume a uniform probability of infection between consecutive negative and positive tests based on 1) the midpoint of this interval and 2) a randomly selected point in this interval. We compared these with an approximation of the Poisson binomial distribution, which assigns partial incidence to time periods based on the uniform probability of occurrence in these intervals. We assessed bias, variance, and convergence of estimates using simulations of Weibull-distributed failure times with systematically varied baseline incidence and varying trend. We considered results for quarterly, half-yearly, and yearly incidence estimation frequencies. We applied the methods to assess human immunodeficiency virus (HIV) incidence in HIV-negative patients from the Treatment With Antiretrovirals and Their Impact on Positive and Negative Men (TAIPAN) Study, an Australian study of HIV incidence in men who have sex with men, between 2012 and 2018. The Poisson binomial method had reduced bias and variance at low levels of incidence and for increased estimation frequency, with increased consistency of estimation. Application of methods to real-world assessment of HIV incidence found decreased variance in Poisson binomial model estimates, with observed incidence declining to levels where simulation results had indicated bias in midpoint and random-point methods.


Reorganization of the GABAergic system following brain extirpation in the earthworm (Eisenia fetida, Annelida, Oligochaeta).
The reorganization of the GABAergic system was studied by means of immunohistochemistry after the symmetrical and asymmetrical (unilateral) extirpation of the brain of the annelid Eisenia fetida. GABA-immunoreactive neurons were first observed in the wound tissue on the 3rd postoperative day. Thereafter the number of labelled cells gradually increased, and by postoperative days 76-80 all GABA-immunoreactive cells (approx. 140 neurons) could be found in their final positions in the symmetrically regenerated brain. After asymmetrical brain extirpation, nearly all cells (70-75) could be detected in the regenerating hemisphere by postoperative days 50-56. In the early stages of the asymmetrical regeneration of the brain, more GABAergic cells were concentrated dorsally and laterally in the preganglion than during the symmetrical type of regeneration. In both types of regeneration, the immunoreactive neurons in the regenerated brain originated in part from undifferentiated neuroblasts situated in different parts of the body, and in part from dividing neurons localized mainly in the pharyngeal nerve plexus. Both exogenous GABA and picrotoxin, applied during the early stages (days 10- 12) of brain regeneration, inhibited the development of the wound tissue and the migration of the neuroblasts and the enteric neurons. At the same time, exogenous GABA application accelerated the proliferation of the pharyngeal neurons. No effect on the process of regeneration could be demonstrated when exogenous GABA and picrotoxin were given together.


Use of an antisense oligonucleotide to inhibit expression of a mutated human procollagen gene (COL1A1) in transfected mouse 3T3 cells.
A series of antisense oligonucleotides were developed to inhibit specifically expression of a mutated exogenous gene for collagen without inhibiting expression of an endogenous gene for the same protein. The test system consisted of mouse NIH 3T3 cells that were stably transfected with an internally deleted construct of the human gene for the pro alpha 1(I) chain of type I procollagen [Olsen et al. (1991) J. Biol. Chem. 266, 1117]. The target site was a region at the 3' end of exon 1 and the first few nucleotides of intron 1 of the exogenous human gene that differed in sequence by nine nucleotides from the sequence of the endogenous mouse gene. Expression of the two genes was assayed by Western blot with cross-reacting antibodies and by steady-state levels of mRNAs. None of the oligonucleotides were effective in concentrations up to 25 microM when administered without any carrier. However, when administered with 5 or 10 micrograms/mL lipofectin, one of the oligonucleotides in concentrations of 0.1-0.2 microM inhibited expression of the exogenous gene from 50% to 80% without significant inhibition of expression of the endogenous gene. Also, a missense version of the same oligonucleotide had no significant effect, and the inhibition observed with the most effective oligonucleotide was abolished by a single base change. Time course experiments indicated that, after a 4-h treatment, inhibition appeared at 8 h and persisted for at least 22 h.(ABSTRACT TRUNCATED AT 250 WORDS)


Dismal Survival in COVID-19 Patients Requiring ECMO as Rescue Therapy after Corticosteroid Failure.
(1) Background: COVID-19 may lead to refractory hypoxemia requiring venovenous extracorporeal membrane oxygenation (ECMO). Survival rate if ECMO is implemented as rescue therapy after corticosteroid failure is unknown. We aimed to investigate if ECMO implemented after failure of the full-recommended 10-day corticosteroid course can improve outcome. (2) Methods: We conducted a three-center cohort study including consecutive dexamethasone-treated COVID-19 patients requiring ECMO between 03/2020 and 05/2021. We compared survival at hospital discharge between patients implemented after (ECMO-after group) and before the end of the 10-day dexamethasone course (ECMO-before group). (3) Results: Forty patients (28M/12F; age, 57 years (51-62) (median (25th-75th percentiles)) were included, 28 (70%) in the ECMO-before and 12 (30%) in the ECMO-after group. In the ECMO-before group, 9/28 patients (32%) received the 6 mg/day dexamethasone regimen versus 12/12 (100%) in the ECMO-after group (p < 0.0001). The rest of the patients received an alternative dexamethasone regimen consisting of 20 mg/day during 5 days followed by 10 mg/day during 5 days. Patients in the ECMO-before group tended to be younger (57 years (51-59) versus 62 years (57-67), p = 0.053). In the ECMO-after group, no patient (0%) survived while 12 patients (43%) survived in the ECMO-before group (p = 0.007). (4) Conclusions: Survival is poor in COVID-19 patients requiring ECMO implemented after the full-recommended 10-day dexamethasone course. Since these patients may have developed a particularly severe presentation, new therapeutic strategies are urgently required.


Dosimetric factors and Lyman normal-tissue complication modelling analysis for predicting radiation-induced lung injury in postoperative breast cancer radiotherapy: a prospective study.
To investigate the relationship between dosimetric factors, including Lyman normal-tissue complication (NTCP) parameters and radiation-induced lung injury (RILI), in postoperative breast cancer patients treated by intensity modulated radiotherapy (IMRT). 109 breast cancer patients who received IMRT between January 2012 and December 2013 were prospectively enrolled. A maximum likelihood analysis yielded the best estimates for Lyman NTCP parameters. Ten patients were diagnosed with RILI (primarily Grade 1 or Grade 2 RILI); the rate of RILI was 9.17% (10/109). Multivariate analysis demonstrated that ipsilateral lung V20 was an independent predictor (P=0.001) of RILI. Setting V20=29.03% as the cut-off value, the prediction of RILI achieved high accuracy (94.5%), with a sensitivity of 80% and specificity of 96%. The NTCP model parameters for 109 patients were m=0.437, n=0.912, and TD50(1)=17.211 Gy. The sensitivity of the modified Lyman NTCP model to predict the RILI was 90% (9/10), the specificity was 69.7% (69/99), and the accuracy was 71.6% (78/109). The RILI rate of the NTCP<9.62% in breast cancer patients was 1.43% (1/70), but the RILI rate of the NTCP>9.62% in patients with breast cancer was 23.08% (9/39), (P=0.001). In conclusion, V20 is an independent predictive factor for RILI in patients with breast cancer treated by IMRT; V20=29.03% could be a useful dosimetric parameter to predict the risk of RILI. The Lyman NTCP model parameters of the new value (m=0.437, n=0.912, TD50 (1) =17.211 Gy) can be used as an effective biological index to evaluate the risk of RILI.


[Pain mechanisms in Complex Regional Pain Syndrome Type 1--a review].
The phenomenon of pain in the course of Complex Regional Pain Syndrome Type 1 is interesting, because its mechanism of its development and maintaining has not been definitively explain. The objective of this article was to review of contemporary knowledge in this issue. The following hypotheses were mentioned: 1) sensitization of dorsal root neurons on afferent barrage form site of injury, of which each, also non-nociceptive, can induce an activation of the nociceptive pathway; 2) interactions between the nervous and immune systems, when pain stimulation as a result of injury or inflammation activate microglia cells in central nerve system, what probably is responsible for development of spontaneous pain; 3) the role of of glutamatergic N-metyl-D-asparagin receptor (NMDA), which increased activity reduces pain experience due to changes of conductance and number of AMPA receptors, that mediate fast pain transmission; 4) the phenomenon of allodynia, when a touch stimuli, temperature or limb position change is experienced as a pain. This is probably caused by false interpretation of the stimuli due to its disturbed processing in the dorsal root ganglia; 5) a contribution of the cerebral cortex in the perception and processing of the pain, as a part of complex, homeostatic matrix; 6) a role of sympathetic pain component in Complex Regional Pain Syndrome. Afore-mentioned hypotheses do not allow to definitive identification of the major patophysiological mechanism which contribute in the development and maintaining of pain in CRPS, but they show a complexity of these processes.


Dedicated small animal scanners: a new tool for drug development?
Nuclear imaging techniques can provide information about the time course of uptake, the spatial distribution, and the functional effects of a drug in the human body. Recently, PET has also acquired the potential to affect the drug development process during a very early stage, when a drug is undergoing animal testing. The development of dedicated small animal scanners with high resolution has made it possible to assess the time course of uptake of a drug within a single animal, providing that the drug is labelled with a positron-emitting isotope. Dedicated small animal scanners may therefore prove to be very useful, especially in those parts of the drug development process that require a longitudinal study design. However, in the case of receptor and enzyme studies, there may be pharmacological constraints and specific radioactivity of the radiopharmaceuticals may become an important issue. This paper will assess the potential and also the limitations of high-resolution PET in animal testing of therapeutic drugs.


Identification of the Different Gene Expression Characteristics from Liver Cirrhosis to Hepatocellular Carcinoma Using Single-Cell Sequencing Analyses.
The occurrence of hepatocellular carcinoma (HCC) is closely related to the chronic inflammation which caused liver fibrosis and cirrhosis, and the interaction between HCC and its microenvironment further drives tumorigenesis. However, the single-cell resolution in vivo study is lacking, which limits our molecular understanding of tumour biology in the liver. Here, using published single-cell sequencing technology (scRNA-seq) database, we analyzed the liver microenvironment at high resolution in an unbiased manner and demonstrated the transcriptomic comparison between various cell populations and subpopulations in HCC and cirrhosis tissues. We found that eight genes that are specifically expressed in the endothelial cell and stellate cell of the HCC patients and correlated them with their survival rate, which may provide novel diagnosis and treatment targets for the clinical application.


Multi-Omics Analysis of the Gut-Liver Axis Reveals the Mechanism of Liver Injury in Colitis Mice.
Liver injury is a common complication of inflammatory bowel disease (IBD). However, the mechanisms of liver injury development are not clear in IBD patients. Gut microbiota is thought to be engaged in IBD pathogenesis. Here, by an integrated analysis of host transcriptome and colonic microbiome, we have attempted to reveal the mechanism of liver injury in colitis mice. In this study, dextran sulfate sodium (DSS) -induced mice colitis model was constructed. Liver transcriptome showed significant up- and down-regulation of pathways linked to immune response and lipid metabolism, respectively. Whilst the colon transcriptome exhibited dramatic alterations in immune response and pathways associated with cell growth and death. The microbiota of DSS-treated mice underwent strong transitions. Correlation analyses identified genes associated with liver and colon injury, whose expression was associated with the abundance of liver and gut health-related bacteria. Collectively, the results indicate that the liver injury in colitis mice may be related to the intestinal dysbiosis and host-microbiota interactions. These findings may provide new insights for identifying potential targets for the treatment of IBD and its induced liver injury.


Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis.
Antineutrophil cytoplasmic autoantibody (ANCA) causes vascular injury that leads to small-vessel vasculitis. Patients with ANCA aberrantly express neutrophil granule-encoding genes, including 2 that encode autoantigens: proteinase 3 (PR3) and myeloperoxidase (MPO). To uncover a potential transcriptional regulatory mechanism for PR3 and MPO disrupted in patients with ANCA vasculitis, we examined the PR3 and MPO loci in neutrophils from ANCA patients and healthy control individuals for epigenetic modifications associated with gene silencing. We found that levels of the chromatin modification H3K27me3, which is associated with gene silencing, were depleted at PR3 and MPO loci in ANCA patients compared with healthy controls. Interestingly, in both patients and controls, DNA was unmethylated at a CpG island in PR3, whereas in healthy controls, DNA was methylated at a CpG island in MPO. Consistent with decreased levels of H3K27me3, JMJD3, the demethylase specific for H3K27me3, was preferentially expressed in ANCA patients versus healthy controls. In addition, we describe a mechanism for recruiting the H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) to PR3 and MPO loci mediated by RUNX3. RUNX3 message was decreased in patients compared with healthy controls, and may also be under epigenetic control. DNA methylation was increased at the RUNX3 promoter in ANCA patients. These data indicate that epigenetic modifications associated with gene silencing are perturbed at ANCA autoantigen-encoding genes, potentially contributing to inappropriate expression of PR3 and MPO in ANCA patients.


Nuclear-Cytoplasmic Partitioning of Phytochrome-Regulated Transcripts in Pisum sativum.
Nuclear and cytoplasmic mRNAs for several phytochrome-regulated genes were examined in Pisum seedlings in order to investigate possible light effects on mRNA partitioning between the nucleus and cytoplasm. Transcripts from each of five light-regulated genes exhibited different responses to a variety of light treatments, but for each transcript we observed a characteristic linear relationship between nuclear and cytoplasmic levels over a wide range of total transcript abundance. Different mRNAs are characterized by different nuclear-cytoplasmic ;partitioning coefficients', indicating that post-transcriptional events play a significant role in regulating the accumulation of these mRNAs during light induction.


CHL1 suppresses tumor growth and metastasis in nasopharyngeal carcinoma by repressing PI3K/AKT signaling pathway via interaction with Integrin β1 and Merlin.
Deletion of Chromosome 3p is one of the most frequently detected genetic alterations in nasopharyngeal carcinoma (NPC). We reported the role of a novel 3p26.3 tumor suppressor gene (TSG) CHL1 in NPC. Down-regulation of CHL1 was detected in 4/6 of NPC cell lines and 71/95 (74.7%) in clinical tissues. Ectopic expressions of CHL1 in NPC cells significantly inhibit colony formation and cell motility in functional study. By up-regulating epithelial markers and down-regulating mesenchymal markers CHL1 could induce mesenchymal-epithelial transition (MET), a key step in preventing tumor invasion and metastasis. CHL1 could also cause the inactivation of RhoA/Rac1/Cdc42 signaling pathway and inhibit the formation of stress fiber, lamellipodia, and filopodia. CHL1 could co-localize with adhesion molecule Integrin-β1, the expression of CHL1 was positively correlated with Integrin-β1 and another known tumor suppressor gene (TSG) Merlin. Down-regulation of Integrin-β1 or Merlin was significantly correlated with the poor survival rate of NPC patients. Further mechanistic studies showed that CHL1 could directly interact with integrin-β1 and link to Merlin, leading to the inactivation of integrin β1-AKT pathway. In conclusion, CHL1 is a vital tumor suppressor in the carcinogenesis of NPC.


Constructive On-DNA Abramov Reaction and Pudovik Reaction for DEL Synthesis.
Organophosphonic compounds are distinctive among natural products in terms of stability and mimicry. Numerous synthetic organophosphonic compounds, including pamidronic acid, fosmidromycin, and zoledronic acid, are approved drugs. DNA encoded library technology (DELT) is a well-established platform for identifying small molecule recognition to target protein of interest (POI). Therefore, it is imperative to create an efficient procedure for the on-DNA synthesis of α-hydroxy phosphonates for DEL builds.


Influence of disease stage on polyethylenimine-mediated plasmid DNA delivery in murine hepatitis.
In order to determine the influence of hepatic disease-stage on polyethylenimine-mediated gene delivery, we investigated branched and linear polyethylenimine (B-PEI, L-PEI)-mediated plasmid DNA delivery with time in murine hepatitis induced by a subcutaneous injection of tetrachloro carbon (CCl(4)). Plasmid DNA (pDNA) encoding firefly luciferase was used as the model reporter gene. We determined luciferase activity in various organs of CCl(4)-treated mice and control mice after an intravenous administration of B-PEI and L-PEI/pDNA complexes. Both B-PEI and L-PEI/pDNA complexes showed significantly lower gene expression in the liver, spleen, and lung at the stage of severe hepatitis (18 h after CCl(4) injection), whereas the complexes induced gene expression in the liver at the liver regeneration stage (48 h after CCl(4) injection). Significant differences in gene expressions between CCl(4)-treated mice and control mice vanished in most organs at the hepatitis subsidence stage (168 h after CCl(4) injection), indicating that the influence of hepatitis induced by CCl(4) was reversible with PEI-mediated gene delivery. Our findings demonstrated that murine hepatitis induced by CCl(4) could influence polyethylenimine-mediated plasmid DNA delivery according to the disease stage. These results indicate the necessity of considering the timing and dose of gene therapy according to the disease stage.


Endocrine role of the decidual tissue: decidual luteotropin regulation of luteal adenylyl cyclase activity, luteinizing hormone receptors, and steroidogenesis.
We have recently reported that the decidual tissue of pseudopregnant and pregnant rats produces a luteotropic substance, decidual luteotropin, which can sustain luteal function in the absence of PRL. However, the luteotropic activity of the decidua depends on the presence of LH in the circulation. The objective of the present investigation was to determine whether decidual luteotropin sustains luteal function by maintaining the luteal cell content of LH receptors and LH-responsive adenylyl cyclase. Pseudopregnant adult rats had their uteri scratched on day 5 to induce decidual tissue formation. Both day 5 hysterectomized and intact pseudopregnant animals were used as controls. On day 7, rats were injected with 0.4 mg 2-bromo-ergocryptine (CB-154) to suppress PRL secretion. Within 48 h, CB-154 administration to either control group not possessing decidual tissue induced a dramatic decrease in progesterone production, LH receptor content, and LH-stimulated adenylyl cyclase in luteal cells. In contrast, suppression of PRL secretion in rats with decidualized uteri had no effect on progesterone secretion, luteal cell LH receptor content, or LH-stimulated adenylyl cyclase. Removal of the decidual tissue immediately after CB-154 treatment caused a significant decline in LH receptors, whereas administration of PRL to control rats without decidual tissue reversed the detrimental effect of CB-154 on both receptor content and LH-stimulated adenylyl cyclase. Examination of the time course (0, 24, and 48 h) of CB-154 action in rats lacking decidual tissue indicated that the decrease in serum progesterone preceded any detectable loss in luteal LH receptor content and LH-stimulated adenylyl cyclase activity. The results also suggest that the decline in LH-stimulated cyclase activity is largely due to the decrease in LH-binding sites and not to an alteration in the cyclase system. PRL withdrawal does not decrease but, rather, enhances epinephrine-stimulated cyclase activity. In summary, results of these investigations have revealed that decidual luteotropin can maintain the luteal content of LH receptors and LH-responsive cyclase and can sustain luteal cell production of progesterone in the absence of PRL; the synergism between decidual luteotropin (or PRL) and LH on luteal steroidogenesis involves more than the maintenance of LH receptors; and PRL withdrawal has opposite effects on LH- and catecholamine-responsive adenylyl cyclases, decreasing the former and stimulating the latter.


The Hsp90-dependent proteome is conserved and enriched for hub proteins with high levels of protein-protein connectivity.
Hsp90 is one of the most abundant and conserved proteins in the cell. Reduced levels or activity of Hsp90 causes defects in many cellular processes and also reveals genetic and nongenetic variation within a population. Despite information about Hsp90 protein-protein interactions, a global view of the Hsp90-regulated proteome in yeast is unavailable. To investigate the degree of dependency of individual yeast proteins on Hsp90, we used the "stable isotope labeling by amino acids in cell culture" method coupled with mass spectrometry to quantify around 4,000 proteins in low-Hsp90 cells. We observed that 904 proteins changed in their abundance by more than 1.5-fold. When compared with the transcriptome of the same population of cells, two-thirds of the misregulated proteins were observed to be affected posttranscriptionally, of which the majority were downregulated. Further analyses indicated that the downregulated proteins are highly conserved and assume central roles in cellular networks with a high number of protein interacting partners, suggesting that Hsp90 buffers genetic and nongenetic variation through regulating protein network hubs. The downregulated proteins were enriched for essential proteins previously not known to be Hsp90-dependent. Finally, we observed that downregulation of transcription factors and mating pathway components by attenuating Hsp90 function led to decreased target gene expression and pheromone response, respectively, providing a direct link between observed proteome regulation and cellular phenotypes.