High Sulfate Attack Resistance of Reinforced Concrete Flumes Containing Liquid Crystal Display (LCD) Waste Glass Powder.
To prevent chemical erosion of concrete and improve chemical resistance, reinforced concrete flumes were manufactured, conforming to the Korean Industrial Standards (KS). Two different sizes of liquid crystal display (LCD) waste glass powder (LWGP) particles were used (i.e., 5 and 12 µm) with two substitution types with cement in concrete (i.e., 10% and 20%). Changes in compressive strength, pore structure, weight, volume, and strength of the concrete flumes after immersion in two sulfate solutions (i.e., Na2SO4 and MgSO4) for 84 and 182 days were measured for sulfate attack resistance. The applicability of the LWGP concrete flume with a 0.5 mm crack width was also evaluated based on the bending strength results. The LWGP5, which has a smaller particle size among LWGPs, filled the smaller pores, thereby reducing the porosity and contributing to the compressive strength gain. Higher volume and weight change ratios for all specimens immersed in MgSO4 solution were found than those immersed in Na2SO4 solution under identical conditions. Flexural loads of all the LWGP concrete flumes with 0.05 mm crack widths were greater than 48.5 kN, as required by the KS code; however, these flexural loads were lower than those of ordinary Portland cement. The applicability was also validated via a flexural test complying with KS.


Physiological and pharmacokinetic effects of multilevel caging on Sprague Dawley rats under ketamine-xylazine anesthesia.
While the cage refinement is a necessary step towards improving the welfare of research rats, increasing the complexity and surface area of the living space of an animal may have physiological impacts that need to be taken into consideration. In this study, ketamine (80 mg/kg) and xylazine (10 mg/kg) caused a short duration anesthesia that was significantly decreased in Sprague-Dawley rats housed in multilevel cages (MLC), compared to rats housed in standard cages (SDC). The withdrawal reflex, the palpebral reflexes and the time-to-sternal all occurred earlier in MLC housed rats, suggesting an effect of housing on the physiology of the rats. In addition, during anesthesia, cardiac frequencies were increased in animals housed in the smaller SDC. Respiratory frequencies, the blood oxygen saturation and rectal temperatures during anesthesia did not vary between conditions during the anesthesia. While xylazine pharmacokinetics were unchanged with caging conditions, the clearance and half-lives of ketamine and its metabolite, norketamine, were altered in the rats housed in MLC. Finally, while no difference was ultimately seen in rat body weights, isolated liver and adrenal gland weights were significantly lighter in rats housed in the MLC. Increasing cage sizes, while having a positive impact on wellbeing in rats, can alter anesthetic drug metabolism and thus modify anesthesia parameters and associated physiological processes.


Impact of Cluster Nursing on Nursing on VAS Score and Urinary Function of Patients after Percutaneous Nephrolithotomy with Pneumatic Lithotripsy (PCNL).
To explore the effects of cluster nursing on VAS score and urinary system function of patients after percutaneous nephrolithotomy with pneumatic lithotripsy (PCNL). November 2019-January 2019, 114 patients with PCNL who received treatment in our hospital were selected and randomly divided into two groups: the control group and the study group. The study group received cluster nursing, and the control group received routine nursing. Compare the Barthel index (BI), between two groups, SAS score, complications rate, surgical outcomes, pain scores, quality of life scores, knowledge awareness rate, and satisfaction rate were compared. There were no significant variations in Bi and SAS scores before the nursing (P > 0.05). The BI ratings were clearly higher after nursing, whereas the SAS and pain levels were considerably lower, however, the research group altered more dramatically (P0.05). The study group's incidence of complications was lower (P0.05) than the control group's; the study group's hospitalization cost was lower, and the hospitalization and lower bed activity were shorter (P0.05); after the nursing, the organised quality score was significantly higher in both groups, but the research group changed more dramatically (P0.05). Compared with the control group, the knowledge of the research team was higher (P < 0.05); after the nursing, both group satisfaction scores were obviously high, but the study group changes more significantly (P < 0.05). After PCNL treatment, the patient receives cluster therapy, improving the patient's anxiety, reducing the degree of pain, and improving the quality of life in patients, and the patient satisfaction is high. Therefore, cluster nursing is worthy of extensive application in the postoperative care of patients with PCNL.


Occurrence, sources, and potential toxicity of polycyclic aromatic hydrocarbons in surface soils from the Yellow River Delta Natural Reserve, China.
A total of 46 surface soil samples collected from the experimental area, buffer area, and core area of the Yellow River Delta Natural Reserve (YRDNR), China, and an adjacent area outside the reserve were analyzed for 23 PAHs including highly carcinogenic dibenzopyrene isomers. The total concentrations ranged from 87.2 to 319 ng/g for ∑23PAHs and 79.2 to 311 ng/g for ∑16PAHs with average concentrations of 133 and 119 ng/g, respectively. Pearson correlation analysis implied that the total polycyclic aromatic compound (PAH) concentrations had a significant positive correlation with the total organic carbon content on the condition that four sites with abnormal values were removed. Low molecular-weight 2- to 3-ring PAHs predominated in the present study. Source diagnostics based on PAHs isomer ratios, principal component analysis, and multiple linear regression suggested that petroleum contributed most to the PAH contamination in the YRDNR, whereas a potential toxicity assessment using BaPeq indicated that the four dibenzopyrenes were the major carcinogenic PAH contributors in the area under investigation, although their concentrations only represented a small proportion of the total PAH concentrations.


The health of the nursing workforce. A survey of National Nurse Associations.
This investigation explored the extent to which nurses' own health is a priority for global National Nursing Associations. There is a growing body of evidence linking staff health and well-being and key dimensions of service quality, including patient safety, patient experience and the effectiveness of patient care. The International Council of Nurses is a federation of more than 130 National Nurses Associations, representing more than 20 million nurses worldwide. Representatives from these Associations attended a Congress in Singapore in 2019 at which a survey was conducted. A convenience sample of 37 leaders of National Nurse Associations from 33 countries and 61 nurse representatives took part in a survey. The majority of nurse leaders and participants believed that nurses' own health should be a priority to be addressed, principally because a healthy nurse is better able to provide good patient care. All of the examples offered about how these Associations address nurses' own health were about actions to prompt individual health behaviour change. The National Nurses Associations did not have a common terminology to talk about nurses' own health. Taking care of one's own health was included as part of the professional role and most nurse leaders thought that working conditions contributed to ill health. There is widespread agreement that nurses' own health matters but for most National Nurses Associations it is not a current priority. Going forward nurse health and wellbeing should be a core principle for health services and professional associations, and additional research is needed that demonstrates if improving working environments contributes to nurse retention and recruitment.


Recommendations for Prevention of Drug Re-Exposure in Toxic Epidermal Necrolysis
Drug re-exposure resulting in Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is a rare phenomenon and has scarcely been reported. With an aging population, polypharmacy, and a lack of a unified electronic medical record, standard recommendations to prevent or minimize the risk of re-exposure are necessary. We identified five patients, with diagnosis confirmed SJS/TEN, and determined the clinical characteristics and contributing risk factors leading to re-exposure. Polypharmacy, multiple prescribers, advanced age, medical illiteracy, retention of discontinued medications and self-prescribing all contributed to re-exposure in this cohort of patients. This case series demonstrates the potentially deadly effect of drug re-exposure, and the need for both streamlined and integrated medication allergy documentation systems. J Drugs Dermatol. 2019;18(10):1049-1052.


[An fMRI study on brain activation patterns of males and females during video sexual stimulation].
To investigate the difference in the brain activation patterns of males and females during video sexual stimulation by functional magnetic resonance imaging (fMRI). The participants were 20 adult males and 20 adult females, all healthy, right-handed, and with no history of sexual function disorder and physical, psychiatric or neurological diseases. Blood-oxygen-level-dependent fMRI was performed using a 1.5 T MR scanner. Three-dimensional anatomical image of the entire brain were obtained by using a T1-weighted three-dimensional anatomical image spoiled gradient echo pulse sequence. Each person was shown neutral and erotic video sequences for 60 s each in a block-study fashion, i.e. neutral scenes--erotic scenes--neutral scenes, and so on. The total scanning time was approximately 7 minutes, with a 12 s interval between two subsequent video sequences in order to avoid any overlapping between erotic and neutral information. The video sexual stimulation produced different results in the men and women. The females showed activation both in the left and the right amygdala, greater in the former than in the latter ([220.52 +/- 17.09] mm3 vs. [155.45 +/- 18.34] mm3, P < 0.05), but in the males only the left amygdala was activated. The males showed greater brain activation than the females in the left anterior cingulate gyrus ([420.75 +/- 19.37] mm3 vs. [310.67 +/- 10.53] mm3, P < 0.05), but less than the females in the splenium of the corpus callosum ([363.32 +/- 13.30] mm3 vs. [473.45 +/- 14.92] mm3, P < 0.01). Brain activation patterns of males and females during video sexual stimulation are different, underlying which is presumably the difference in both the structure and function of the brain between men and women.


[Sleep and psychotropic drugs].
After reviewing a number of recent concepts of the anatomy of the cerebral noradrenergic systems, the authors examines the effects of several representative drugs of each of the three major classes of psychotropic drugs (neuroleptics, antidepressants, tranquilizers) on sleep. The effects of the neuroleptics on the paradoxical phase of sleep can be explained by the particular features of the organization of the cerebral noradrenergic systems. The antidepressants reduce the paradoxical phase by a number of mechanisms related to their principal pharmacological properties of inhibition of monoamine uptake and the anticholinergic effect. The benzodiazepine tranquillizers have a complex action on sleep, probably acting via several mechanisms. Newly developed benzodiazepine receptor antagonists enable us to distinguish some of these effects. The sensitivity of sleep to a large number of drugs is a useful tool for the functional investigation of the central nervous system.


ORION software tool for the geometrical calibration of all-sky cameras.
This paper presents the software application ORION (All-sky camera geOmetry calibRation from star positIONs). This software has been developed with the aim of providing geometrical calibration to all-sky cameras, i.e. assess which sky coordinates (zenith and azimuth angles) correspond to each camera pixel. It is useful to locate bodies over the celestial vault, like stars and planets, in the camera images. The user needs to feed ORION with a set of cloud-free sky images captured at night-time for obtaining the calibration matrices. ORION searches the position of various stars in the sky images. This search can be automatic or manual. The sky coordinates of the stars and the corresponding pixel positions in the camera images are used together to determine the calibration matrices. The calibration is based on three parameters: the pixel position of the sky zenith in the image; the shift angle of the azimuth viewed by the camera with respect to the real North; and the relationship between the sky zenith angle and the pixel radial distance regards to the sky zenith in the image. In addition, ORION includes other features to facilitate its use, such as the check of the accuracy of the calibration. An example of ORION application is shown, obtaining the calibration matrices for a set of images and studying the accuracy of the calibration to predict a star position. Accuracy is about 9.0 arcmin for the analyzed example using a camera with average resolution of 5.4 arcmin/pixel (about 1.7 pixels).


The effect of a water-dispersible beta-carotene formulation on the prevention of age-related lymphoid neoplasms in mice.
There is currently a great interest in the efficiency of micronutrients against age-associated disorders. The present study aimed to evaluate the efficacy of beta-carotene on the incidence of lymphoid neoplasia, a fatal pathology associated with OFI mouse ageing. Beta-carotene, given as a water-dispersible preparation to 8-month-old mice, on a four month follow-up study, significantly reduced the incidence of neoplasm (12.5% versus 50% for controls). Evaluation of the parameters of oxidative stress showed a highly-significant reduction of the antioxidant defenses in the liver of cancer mice when compared to healthy controls (78% decrease in GSH-Px activity and 47% decrease of the ratio GSH/GSSG). Liver GSH-Px activity was 35% higher in old than in young mice, which correlated with higher (41%) plasma Se level. In conclusion beta-carotene improved the antioxidant status of the mice, causing a 4.5-fold increase in the liver GSH/GSSG ratio, an effect which was probably responsible for the lowered incidence of neoplasia observed.


Continuous Bayesian network for studying the causal links between phosphorus loading and plankton patterns in Lake Simcoe, Ontario, Canada.
An ecosystem perspective to restoring beneficial uses in Areas of Concern can be interpreted as a shift from the traditional elucidation of simple cause-effect relationships to a multicausal way of thinking that more effectively accommodates ecosystem complexity. This holistic management paradigm has also pervaded the contemporary ecological modeling practice, making compelling the adoption of more sophisticated ecosystem modeling tools. In this study, our primary objective is to develop a Bayesian hierarchical network of simple ecological models for Lake Simcoe, Ontario, Canada, aiming to establish a realistic representation of the causal connections among exogenous nutrient loading, ambient nutrient conditions, and epilimnetic plankton dynamics. In particular, we used a spatially explicit simple mass-balance model forced with idealized sinusoidal loading to predict total phosphorus concentrations. A structural equation model was then used to delineate the interplay among nutrients, ambient light conditions, phytoplankton, and herbivorous biomass. Our analysis highlights the strength of the causal linkages between total phosphorus and water clarity with phytoplankton as well as the capacity of zooplankton grazing to modulate the algal standing crop. Our Bayesian network is also used to examine the exceedance frequency of threshold values for total phosphorus (15 μg/L) and chlorophyll a (4 μg/L) concentrations under scenarios of phosphorus loading reduction. Our study suggests that a 15% phosphorus loading decrease will still result in >25% violations of the 4 μg chla/L value in the two embayments of Lake Simcoe (Cook's Bay and Kempenfelt Bay). The TP levels will decrease in response to the exogenous loading reductions and this improvement will be primarily manifested in the northcentral segments of the system.


The Influence of Manganese Addition on the Properties of Biodegradable Zinc-Manganese-Calcium Alloys.
This study focuses on the preparation and characterization of zinc-based alloys containing magnesium, calcium, and manganese. The alloys were prepared by the melting of pure elements, casting them into graphite molds, and thermo-mechanically treating them via hot extrusion. The phase compositions of the samples were analyzed using X-ray diffraction technique and SEM/EDX analysis. The analysis confirmed that in addition to the Zn matrix, the materials are reinforced by the CaZn13, MgZn2, and Mn-based precipitates. The mechanical properties of the alloys were ascertained by tensile, compressive, and bending tests, measurement of the samples microhardness and elastic modulus. The results indicate that an increase in Mn content leads to an increase in the maximum stress experienced under both tension and compression. However, the plastic deformation of the alloys decreases with increasing Mn content. This study provides valuable insights into the microstructural changes and mechanical behavior of zinc-based alloys containing magnesium, calcium, and manganese, which can be used to design alloys for specific biomedical applications.


High performance coach cognition in the wild: using applied cognitive task analysis for practical insights-cognitive challenges and curriculum knowledge.
Despite significant empirical work in the sport coaching domain, there remains a paucity of evidence to inform practice in high-performance sport coaching. As a result, there are gaps in our understanding regarding coaching expertise at different levels of athlete performance. A significantly underutilized approach in coaching research is Cognitive Task Analysis and it's knowledge elicitation tools. Addressing these concerns, here we utilize applied Cognitive Task Analysis and a semi-structured interview protocol to elicit the cognitive challenges and use of knowledge by a group of N = 7 high-performance endurance sport coaches from a single national governing body. Analysis suggested prominent and ongoing challenges in day-to-day practice which, in turn require significant adaptive skill. In addition, results show how coaches used knowledge flexibly and conditionally to meet the demands of their role. A novel finding being the identification of the use of curriculum knowledge to mentally project the needs of athletes. The findings suggest opportunities for utilizing Cognitive Task Analysis to investigate the cognitive challenges of sport coaching and enhance coach development practice.


Thrombin-Activatable Fibrinolysis Inhibitor Gene Polymorphism (TAFI1040C/T) in Women With Recurrent Spontaneous Abortion.
Recurrent spontaneous abortion (RSA) is defined as 3 or more consecutive pregnancy failures. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that regulates both fibrinolysis and inflammation. The TAFI 1040C/T polymorphism could alter the circulating levels of TAFI with a reduced capacity to remove the fibrin clots from the circulation; therefore, it could be considered a molecular risk factor for RSA. The TAFI 1040C/T polymorphism was studied in 50 patients with RSA by polymerase chain reaction-restriction fragment length polymorphism technique and compared to 50 age- and gender-matched healthy volunteers as a control group to verify its possible association with RSA. In case group, the wild genotype (C/C) and heterozygous genotype (C/T) did not reduce the risk of RSA (odds ratio: 0.368 and 0.767, respectively), even when compared to the number of RSA ( P = .71). A higher frequency of C allele in the control group and a higher frequency of T allele in the case group were observed but with no statistical significance. In conclusion, our study revealed that TAFI 1040C/T could not be considered a molecular predictive factor for RSA in Egyptians.


Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes.
Chronic manganese (Mn) exposure induces neurotoxicity, which is characterized by Parkinsonian symptoms resulting from impairment in the extrapyramidal motor system of the basal ganglia. Mitochondrial dysfunction and oxidative stress are considered key pathophysiological features of Mn neurotoxicity. Recent evidence suggests astrocytes as a major target of Mn neurotoxicity since Mn accumulates predominantly in astrocytes. However, the primary mechanisms underlying Mn-induced astroglial dysfunction and its role in metal neurotoxicity are not completely understood. In this study, we examined the interrelationship between mitochondrial dysfunction and astrocytic inflammation in Mn neurotoxicity. We first evaluated whether Mn exposure alters mitochondrial bioenergetics in cultured astrocytes. Metabolic activity assessed by MTS assay revealed an IC50 of 92.68μM Mn at 24h in primary mouse astrocytes (PMAs) and 50.46μM in the human astrocytic U373 cell line. Mn treatment reduced mitochondrial mass, indicative of impaired mitochondrial function and biogenesis, which was substantiated by the significant reduction in mRNA of mitofusin-2, a protein that serves as a ubiquitination target for mitophagy. Furthermore, Mn increased mitochondrial circularity indicating augmented mitochondrial fission. Seahorse analysis of bioenergetics status in Mn-treated astrocytes revealed that Mn significantly impaired the basal mitochondrial oxygen consumption rate as well as the ATP-linked respiration rate. The effect of Mn on mitochondrial energy deficits was further supported by a reduction in ATP production. Mn-exposed primary astrocytes also exhibited a severely quiescent energy phenotype, which was substantiated by the inability of oligomycin to increase the extracellular acidification rate. Since astrocytes regulate immune functions in the CNS, we also evaluated whether Mn modulates astrocytic inflammation. Mn exposure in astrocytes not only stimulated the release of proinflammatory cytokines, but also exacerbated the inflammatory response induced by aggregated α-synuclein. The novel mitochondria-targeted antioxidant, mito-apocynin, significantly attenuated Mn-induced inflammatory gene expression, further supporting the role of mitochondria dysfunction and oxidative stress in mediating astrogliosis. Lastly, intranasal delivery of Mn in vivo elevated GFAP and depressed TH levels in the olfactory bulbs, clearly supporting the involvement of astrocytes in Mn-induced dopaminergic neurotoxicity. Collectively, our study demonstrates that Mn drives proinflammatory events in astrocytes by impairing mitochondrial bioenergetics.


Mutational analyses of trimethylguanosine synthase (Tgs1) and Mud2: proteins implicated in pre-mRNA splicing.
Yeast and human Tgs1 are orthologous RNA cap (guanine-N2) methyltransferases that convert m(7)G caps into the 2,2,7-trimethylguanosine (TMG) caps characteristic of spliceosomal snRNAs. TMG caps are dispensable for vegetative yeast growth, but are essential in the absence of Mud2, the putative yeast homolog of human splicing factor U2AF. Here we exploited the synthetic lethal interactions of tgs1Delta and mud2Delta mutations to identify essential structural features of the Tgs1 and Mud2 proteins. Thirty-two new mutations were introduced into human Tgs1 and surveyed for their effects on function in vivo in yeast and on the two sequential guanine-N2 methylation reactions in vitro. The structure-function data highlight a strictly essential pi-cation interaction between Trp766 and the m(7)G base and a network of important enzymic contacts to the cap triphosphate via Lys646, Tyr771, Arg807, and Lys836. Mud2 is a 527-amino acid polypeptide composed of a hydrophilic N-terminal domain and a C-terminal RRM domain. We found that the RRM domain is necessary but not sufficient for Mud2 function in complementing growth of tgs1Delta mud2Delta and mud1Delta mud2Delta strains. Other changes in Mud2 elicited distinct phenotypes in tgs1Delta versus mud1Delta backgrounds. mud2Delta also caused a severe growth defect in cells lacking the Tgs1-binding protein encoded by the nonessential gene YNR004w (now renamed SWM2, synthetic with mud2Delta). Mud2 mutational effects in the swm2Delta background paralleled those for mud1Delta. The requirements for Mud2 function are apparently more stringent when yeast cells lack TMG caps than when they lack Mud1 or Swm2.


The characteristic signs and symptoms of mania and depression according to Kraepelin circa 1905: a comparison with DSM-III.
Although the rise of operationalized diagnostic criteria and the creation of DSM-III were influenced in the USA by a neo-Kraepelinian 'revival' of interest in psychiatric nosology, Kraepelin was only a distal influence on the specific diagnostic criteria proposed. The historical origins of the DSM-III criteria for mania and major depression (MD) are traceable back to the 1950s and contain no direct link to Kraepelin's writings. George Dreyfus, a student and assistant to Kraepelin, authored in 1907 a monograph on Involutional Melancholia which reviewed cases seen by Kraepelin in Heidelberg. In this monograph, Dreyfus presents the 'characteristic' symptoms for mania and depression 'as described by Kraepelin.' This historical finding provides the unprecedented opportunity to examine the resemblance between the criteria proposed for mania and depression in DSM-III, inspired by Kraepelin's nosologic vision, and those specifically suggested by Kraepelin 73 years earlier. Kraepelin's symptoms and signs for mania paralleled seven of the eight DSM-III criteria (except the decreased need for sleep), with two not included in DSM-III (increased mental activity and short bursts of sadness). Kraepelin's signs and symptoms paralleled six of the nine DSM-III criteria for MD, lacking suicidal ideation and changes in appetite/weight and sleep but including obsessions, reduced expressive movements, and decreased mood responsiveness. Although Kraepelin's overall approach to mania and depression emphasized their close inter-relationship in the cyclic course of manic-depressive illness, it is noteworthy Kraepelin's 'characteristic' symptoms for mania and depression as described by Dreyfus, bear substantial but incomplete resemblance to the criteria proposed in DSM-III.


Two data bases in every garage: information quality systems.
Enterprises, including Federal agencies such as the U.S. Environmental Protection Agency (EPA), are now identifying their information as a strategic resource. As part of a new strategy, enterprises address quality system planning. This technical paper presents some of EPA's approaches and techniques for reconciling quality system considerations for science and technical activities with quality system considerations for information technology and resources. Identification of key information quality indicators, management processes, and assessment processes are addressed.


Appendage morphogenesis in Drosophila: a developmental study of the rotund (rn) gene.
The phenotype of rotund (rn) null alleles is described, and compared to wild type. The mutants are expressed zygotically and cause position specific defects in certain imaginal discs (antenna, legs, wing, haltere and proboscis) and their corresponding adult derivatives. In the discs, specific folds are absent in rn mutants compared to wild type. Clonal analysis shows that the rn + gene is partially autonomous in its expression in cells destined to form certain distal parts of the adult appendages. The results are consistent with the idea that the rn + gene is required for normal morphogenesis of specific distal parts of the adult appendages.


Patterns of Telehealth Use for Mental Health Treatment Among Hispanic Veterans.
Background: Video-to-home telehealth (VTH) is promising for increasing access to mental health (MH) services. VA Video Connect (VVC) facilitates video-based teleconferencing between patients and providers and can reduce barriers while maintaining clinical effectiveness. Little is known about the preferences of Hispanic veterans for VTH. Methods: A retrospective cohort investigation of VTH for MH care utilization among veterans having at least one MH visit from October 2019 to September 2020. The veterans consisted of 155,492 Hispanic/Latino and 1,544,958 non-Hispanic/Latino. VVC involved face-to-face synchronous video-based teleconferencing between patients and providers, enabling care at home or another private location. The main measures included the percentage of MH encounters delivered through VVC. Results: Compared with non-Hispanic veterans, Hispanic veterans had 3.28% greater percentage of VVC MH encounters. Furthermore, there was a 2.65% increase per month in percentage of VVC MH encounters. Conclusions: Contrary to preconceived notions, Hispanic veterans access VTH at higher rates than their non-Hispanic counterparts.


High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA.
Because of the unparalleled efficiency and universal utility in treating a variety of disease types, siRNA agents have evolved as the future drug-of-choice. Yet, the inability of the polyanionic siRNA macromolecules to cross the cell membrane remains as the bottleneck of possible clinical applications. With the cell penetrating peptides (CPP) being discovered lately, the most effective tactic to achieve the highest intracellular siRNA delivery deems to be by covalently conjugating the drug to a CPP; for instance, the arginine-rich Tat or low molecular weight protamine (LMWP) peptides. However, construction of such a chemical conjugate has been referred by scientists in this field as the "Holy Grail" challenge due to self-assembly of the cationic CPP and anionic siRNA into insoluble aggregates that are deprived of the biological functions of both compounds. Based on the dynamic motion of PEG, we present herein a concise coupling strategy that is capable of permitting a high-yield synthesis of the cell-permeable, cytosol-dissociable LMWP-siRNA covalent conjugates. Cell culture assessment demonstrates that this chemical conjugate yields by far the most effective intracellular siRNA delivery and its corresponded gene-silencing activities. This work may offer a breakthrough advance towards realizing the clinical potential of all siRNA therapeutics and, presumably, most anionic macromolecular drugs such as anti-sense oligonucleotides, gene compounds, DNA vectors and proteins where conjugation with the CPP encounters with problems of aggregation and precipitation. To this end, the impact of this coupling technique is significant, far-reaching and wide-spread.


[Study of the most significant for the correction components of the functional condition of elderly hockey players.]
Presents the results of a dynamic integrated study of the vegetative, metabolic and psycho-physiological components of the functional state of elderly hockey players before and after participating in competitions. The study involved 42 male hockey players aged 55-64 years. It has been established that the indicators of the vegetative regulation of cardiac activity are the most stable component of the functional state in the group of elderly athletes. At the same time, after participating in competitions, a statistically significant decrease in the simple sensorimotor response and an increase in lipid peroxidation processes were revealed. It is proved that the use of therapeutic regulators of the functional state (in particular, pharmaco-, psycho- and physiotherapeutic) should be directed to the components of the central nervous system and the antioxidant defense system, as the most sensitive and susceptible to suffering.


Analysis of conjugated bile acids in human biological fluids. Synthesis of hyodeoxycholic acid 3- and 6-glycosides and related compounds.
The glucuronide, glucoside and N-acetylglucosaminide conjugates of hyodeoxycholic acid were synthesized. In addition, murideoxycholic acid 3-glycosides and some of their C-5 epimeric analogs were also prepared. The principal reactions used are 1) the Koenigs-Knorr condensation reaction of 3-oxo-6 alpha-hydroxy and 6-oxo-3 alpha-hydroxy esters with an appropriate alpha-acetohalosugar catalyzed by cadmium carbonate in benzene under reflux, 2) reduction of the resulting bile acid glycoside methyl ester-acetates with tert-butylamine-borane complex, and 3) subsequent hydrolysis with aqueous lithium hydroxide.


[Build of focal cerebral ischemia model in different varieties of mice with modification monofilament].
To establish a general method of focal cerebral ischemia model in different varieties of mice. Each group of healthy adult KM and C57BL/6 mice were randomly divided into control group (n = 10) and MCAO group (n = 10). The mice in MCAO group were applied in the preparation of the MCAO model by intraluminal occlusion using monofilament. Twenty-four hours after operation,the neurologic function was evaluated,middle cerebral artery blood flow was monitored and the infarction volume was calculated by TTC staining, to evaluate the reliability of the model. In the MCAO group, the base value of the cerebral blood flow down of KM and C57BL/6 mice respectively was (81.65 ± 4.59)%, (83.68 ± 6.25)%. The neurological deficit score respectively was (2.30 ± 0.82), (2.50 ± 0.80). TTC staining can clearly show the infarction area, and relatively stable, 24 hours of the survival rate of KM and C57BL/6 mice were 100% and 80% respectively. The key link is the optimization and improvement of monofilament, temperature, anesthesia and so on. The modified intraluminal occlusion of MCAO using monofilament is a kind of reliable and simple method to establish experimental cerebral ischemia model in mice.


13C-labeled D-ribose: chemi-enzymic synthesis of various isotopomers.
Current interest in the use of heteronuclear multidimensional NMR methods to assess the structures, conformations and/or dynamics of oligonucleotides in solution has created an immediate need for nucleosides and their derivatives labeled in various ways with stable isotopes (13C, 2H, 15N and/or 17,18O). This short review focuses exclusively on chemienzymic methods to introduce one or more 13C labels into D-ribose, a precursor to ribo- and 2'-deoxyribonucleosides. It will be demonstrated that five convenient reactions, applied in specific sequences, provide access to 26 of the 32 13C-labeled isotopomers of D-ribose in acceptable yields. While not explicitly discussed herein, these same reactions, appropriately modified, can also be used to insert one or more 2H and/or 17,18O isotopes into this aldopentose.


Geographic distribution of burn in an Australian setting.
To investigate the geographic distribution and temporal trends of burn admissions in an Australian setting. Health administrative data of all persons hospitalised for a first burn in Western Australia for the period 2000-2012 were used. Crude and standardised incident rates were generated for each region. Maps of crude rates were generated for state regions and postcode-suburbs of Perth, the capital city. Standardised incidence rates were generated for Western Australia, total and regions, and for sub-cohorts defined by age (<20years; ≥20 years), TBSA burn severity and major causes of burns (fire, scalds and contact). Negative binomial regression was used to examine temporal changes and generate incidence rate ratios (IRR) with 95% confidence intervals (CI). Perth had the lowest burn admission rate per population; clusters of suburbs of lower social advantage and higher immigrant settlement were identified as being at high risk. While the highest observed admission rates were found in Kimberley and Goldfields (remote) regions, after adjustment for the regional demographic structures, the Wheatbelt and Mid-West (rural) regions were found to have the highest adjusted rates of burn admissions. Significant annual declines in admission rates were found for the Kimberley, Pilbara and Goldfields (remote regions); however, stable admission rates were identified for all other regions. The Mid-West and Wheatbelt rural regions were found to have the highest risk of burn admissions raising concerns about farming-related injury. Safety awareness and burn prevention strategies need to be continued, with specific attention to these high risk areas, to reduce burn admissions in Western Australia.


A triphenylene-based triptycene with large free volume synthesized by zirconium-mediated biphenylation.
Biphenylation using (Li(THF)(4))(2) x Zr(biphe)(3) of hexabromotriptycenes bearing H (1-H) or Bu (1-Bu) at the bridgeheads gave triptycenes with triphenylene blades. The blades extend both perpendicular and parallel to the 3-fold axis and generate a large intramolecular free volume (IMFV) (1-H, AM1, 710 A(3); cf. triptycene, AM1 71 A(3)). Crystals of 1-H could not be obtained. Triptycene 1-Bu, in which the Bu groups fill the voids near the bridgehead, was crystalline. X-ray diffraction analysis revealed crystal packing with alternating, interlocked corrugated and distorted hexagonal layers.


Development of a real-time quantitative PCR assay to enumerate Yersinia pestis in fleas.
A real-time quantitative polymerase chain reaction (qPCR) assay was developed for Yersina pestis. The qPCR assay was developed utilizing a conserved region of the Y. pestis ferric iron uptake regulator gene (fur) to design primers and a fluorescent (FAM-labeled) TaqMan probe. The assay was optimized using cultured Y. pestis (UG05-0454) and was confirmed to work with strains from 3 Y. pestis biovars. The optimized assay was capable of detecting a single organism of cultured Y. pestis and as little as 300 bacteria in infected flea triturates. This qPCR assay enables rapid enumeration of Y. pestis bacterium in laboratory-infected fleas when compared with conventional serial dilution plating.


Effective chemomobilization with etoposide and cytarabine (EC regimen) in lymphoma patients: a single-center, retrospective, observational study.
Autologous stem cell transplantation is an important strategy for patients with relapsed or refractory lymphoma. Although various regimens for peripheral blood stem cell collection have been used, the optimal regimen has not yet been established. We aimed to evaluate the mobilization efficacy and safety of the regimen consisted of etoposide and cytarabine (EC regimen). We retrospectively analyzed the clinical data of 46 lymphoma patients who received peripheral blood stem cell mobilization with the EC regimen [etoposide (100 mg/m2/day, days 1-4) and cytarabine (100 mg/m2/day, days 1-4)] at Toyohashi municipal hospital from 2004 to 2013. The median age of the patients was 55 years. The most common underlying diseases were diffuse large B-cell lymphoma (46%) and follicular lymphoma (26%). Three-quarters of patients were in their second complete or partial remission. The median total number of collected CD34+ cells was 10.6 × 106 kg-1. Forty-two patients (91%) yielded at least 2 × 106 kg-1 CD34+ cells within a median of 2 apheresis days, and 33 patients (72%) achieved it with only one apheresis. Successful mobilization was observed in five of six patients who failed to mobilize previously. Although febrile neutropenia occurred in 22 patients (48%), no fatal infection was observed. The EC regimen was highly effective in lymphoma patients, including patients who mobilized poorly with other regimens.


Interleukin-8 in the pathogenesis of primary central nervous system lymphoma in association with HIV infection.
The pathogenesis of acquired immunodeficiency syndrome-associated primary central nervous system lymphoma (AIDS-associated PCNSL) remains unclear. However, cell adhesion molecules have been reported to be strongly associated with PCNSL. In this study, we established Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) from HIV-positive patients (LCL(HIV)) and normal individuals (LCL(N)). The expression of CD18 antigen by LCL(HIV) was stronger than that by LCL(N). We performed a cell adhesion assay using ISO-HAS, which is the human hemangiosarcoma cell line and expresses intercellular adhesion molecule 1 (CD54). The binding rates of LCL(HIV) and ISO-HAS without stimulation were higher than those of LCL(N). Further, we demonstrated that azidothymidine or simvastatin inhibited the binding rates of LCL(HIV) and ISO-HAS more significantly than those of LCL(N). Further, the levels of interleukin (IL)-8, a CD18 inducer, were higher in LCL(HIV) than in LCL(N). We conclude that interaction between IL-8 and CD18 may be critical to AIDS-related PCNSL.


Motion sickness and sense of presence in a virtual reality environment developed for manual wheelchair users, with three different approaches.
Visually Induced Motion Sickness (VIMS) is a bothersome and sometimes unsafe experience, frequently experienced in Virtual Reality (VR) environments. In this study, the effect of up to four training sessions to decrease VIMS in the VR environment to a minimal level was tested and verified through explicit declarations of all 14 healthy participants that were recruited in this study. Additionally, the Motion Sickness Assessment Questionnaire (MSAQ) was used at the end of each training session to measure responses to different aspects of VIMS. Total, gastrointestinal, and central motion sickness were shown to decrease significantly by the last training session, compared to the first one. After acclimatizing to motion sickness, participants' sense of presence and the level of their motion sickness in the VR environment were assessed while actuating three novel and sophisticated VR systems. They performed up to four trials of the Illinois agility test in the VR systems and the real world, then completed MSAQ and Igroup Presence Questionnaire (IPQ) at the end of each session. Following acclimatization, the three VR systems generated relatively little motion sickness and high virtual presence scores, with no statistically meaningful difference among them for either MSAQ or IPQ. Also, it was shown that presence has a significant negative correlation with VIMS.


Evaluation of the Clinical and Sociodemographic Features of Turkish Patients with Vitiligo.
Vitiligo is an acquired, pigmentary skin disorder that affects about 0.1-4.0% of the population. In this study, we aimed to investigate the disease features such as age of onset, disease duration, clinical and sociodemographic characteristics, and laboratory parameters of patients with vitiligo. A hundred patients who were in follow-up for vitiligo between the period of June 2013 and May 2014 were included in the study. The clinical features and laboratory parameters were retrospectively obtained from the records of the patients. The mean age was 34.9±16.8 years. The most common clinical types were focal and acrofacial. Facial involvement was the most common localization. Forty-five (45%) patients had an associated systemic disease. Autoimmune thyroid disease, essential hypertension, and alopecia areata, which were observed in 28%, 8%, and 5% of patients, respectively, were the most common associated diseases. Twenty-one percent of the patients had low ferritin levels, 20% had low iron levels, 12% had low vitamin B12 levels, and 1% had low folic acid levels. The prevalence of anti-TG (anti-thyroglobulin) and anti-TPO (anti-thyroid peroxidase) antibodies were found 17% and 27% of the patients, respectively. We found that the clinical characteristics of vitiligo in our patients were similar to those in other studies. We observed laboratory abnormalities and accompanying diseases associated with vitiligo. Therefore we conclude that laboratory examinations including thyroid antibodies and regular follow-up of these patients are essential.


Porencephalic congenital cysts with hydrocephalus.
The therapeutic criteria according to tomographic findings are reviewed. 10 children, 6 male and 4 female, with porencephalic congenital cysts were studied. Early symptoms began within the first 6 months of life in 9 cases, and at the age of 5 years in 1. The most frequent symptoms were: seizures in 3; motor deficit in 5; retarded psychomotor development in 7; endocranial hypertension syndrome in 7; symmetric macrocrania in 7; paresis of the motor ocular nerves in 4. Preoperative studies: X-ray films-1 each patient-showed diastasis of sutures in 6 and cranial asymmetry in 2. Electroencephalograms-6 patients-were abnormal and diffuse in 3, hipsarrhythmic in 2, and focal in 1. CT-1 each patient-showed porencephalic cysts in all the patients; ventricular dilatation in 9; a single ventricle in 1, and a shift of the midline in 5. Postoperative studies: EEG, 1 each patient; CT, 1 each patient. 8 patients underwent peritoneal shunts and 2 atrial shunts. Plastic surgery of the dysraphy was also performed. Postsurgical treatment: Rehabilitation and anti-convulsive treatment-4 patients. There were no deaths among the patients. The morbidity improved.


Sampling Methods and their Prospects in Liquid-Based Cytology of Oral Mucosa: A Comparative Study.
Examining epithelial cells in the mouth cavity is simple and non-invasive with exfoliative cytology. Liquid-based cytology is an additional diagnostic technique that can improve the specificity and sensitivity of conventional cytology. The purpose of our study was to describe the consistency of normal oral mucosa samples obtained with three different tools: the Cytobrush®, dermatological curette, and OralCDx® for liquid-based cytology. Literature review was done, and reporting of the improvements in the field of investigation and diagnosis has been reported. The present communication aims toward comparing three different sampling instruments such as Cytobrush, curette, and OralCDx for liquid-based cytology of the oral mucosa.


Thrombolamban, the 22-kDa platelet substrate of cyclic AMP-dependent protein kinase, is immunologically homologous with the Ras family of GTP-binding proteins.
Platelet inhibition by agents that increase intracellular levels of cAMP is associated with cAMP-dependent phosphorylation of specific intracellular proteins, including a membrane-associated 22-kDa microsomal protein called thrombolamban. In view of recent studies suggesting that platelets also contain 22-kDa GTP-binding proteins that are homologous with ras-encoded p21 proteins, the present work was undertaken to examine the possibility that thrombolamban and the Ras-like proteins were the same. Platelet microsomes were labeled with [gamma-32P]ATP and the labeled proteins were examined by autoradiography of sodium dodecyl sulfate/polyacrylamide gels. On Western blots of both one-dimensional and two-dimensional gels, thrombolamban immunoreacted with M90, a monoclonal antibody that recognizes the GTP-binding domain of Ras p21 proteins, but not with Y13-259, a monoclonal antibody that recognizes another domain and is specific for Ras proteins. Overlay experiments with unlabeled platelet microsomes demonstrated numerous low molecular weight proteins that bound [alpha-32P]GTP, although none could be identified as thrombolamban. Finally, thrombolamban was immunoprecipitated by M90. These studies show that thrombolamban is a low molecular weight protein that is immunologically related to the Ras family of GTP-binding proteins.


Suberanilohydroxamic acid prevents TGF-β1-induced COX-2 repression in human lung fibroblasts post-transcriptionally by TIA-1 downregulation.
Cyclooxygenase-2 (COX-2), with its main antifibrotic metabolite PGE2, is regarded as an antifibrotic gene. Repressed COX-2 expression and deficient PGE2 have been shown to contribute to the activation of lung fibroblasts and excessive deposition of collagen in pulmonary fibrosis. We have previously demonstrated that COX-2 expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) is epigenetically silenced and can be restored by epigenetic inhibitors. This study aimed to investigate whether COX-2 downregulation induced by the profibrotic cytokine transforming growth factor-β1 (TGF-β1) in normal lung fibroblasts could be prevented by epigenetic inhibitors. We found that COX-2 protein expression and PGE2 production were markedly reduced by TGF-β1 and this was prevented by the pan-histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) and to a lesser extent by the DNA demethylating agent Decitabine (DAC), but not by the G9a histone methyltransferase (HMT) inhibitor BIX01294 or the EZH2 HMT inhibitor 3-deazaneplanocin A (DZNep). However, chromatin immunoprecipitation assay revealed that the effect of SAHA was unlikely mediated by histone modifications. Instead 3'-untranslated region (3'-UTR) luciferase reporter assay indicated the involvement of post-transcriptional mechanisms. This was supported by the downregulation by SAHA of the 3'-UTR mRNA binding protein TIA-1 (T-cell intracellular antigen-1), a negative regulator of COX-2 translation. Furthermore, TIA-1 knockdown by siRNA mimicked the effect of SAHA on COX-2 expression. These findings suggest SAHA can prevent TGF-β1-induced COX-2 repression in lung fibroblasts post-transcriptionally through a novel TIA-1-dependent mechanism and provide new insights into the mechanisms underlying its potential antifibrotic activity.


Orbitofrontal, dorsal striatum, and habenula functional connectivity in psychiatric patients with substance use problems.
Substance abuse is commonly defined as the persistence of drug use despite negative consequences. Recent preclinical work has shown that higher input from the orbitofrontal cortex (OFC) to the dorsal striatum was associated with compulsive reward-seeking behavior despite negative effects. It remains unknown whether drug use is associated with the connectivity between the OFC and dorsal striatum in humans. We studied the resting state functional connectivity (RSFC) between the OFC, dorsal striatum, and habenula (and the whole brain in a separate analysis) in psychiatric inpatients with high (PU, problem users) and low (LU, low users) substance use. We matched PU and LU for psychiatric comorbidities. We found that PU showed higher RSFC between the left OFC and the left dorsal striatum than LU. RSFC between the habenula and both OFC and dorsal striatum was also higher in PU, which suggests the habenula may be a part of the same circuit. Finally, higher RSFC between the OFC and insula was also observed in PU. Our data shows that OFC, habenula, dorsal striatum, and insula may play an important role in PU. Furthermore, we postulate that the habenula may link the mesolimbic and cortico-striatal systems, which are altered in PU.


[Clinical features of 10 cases with phlyctenular keratitis].
We investigated 15 eyes of 10 patients with phlyctenular keratitis. The patients were 6 men and 4 women, and their ages ranged between 3 and 56 years (mean, 17.8 years). The follow-up periods ranged from 0.5 to 48 months (mean, 14 months). Clinically, complications in many cases were papillary hyperplasia in palpebral conjunctiva, meibomian gland infarct, chalazion, and blepharitis. Microbial examination from the lid margin before treatment revealed bacteria in 4 eyes of 4 patients out of 9 eyes of 8 patients. The level of serum specific IgE antibody was high in only 1 patient out of 6. We classified the clinical course into 3 stages, namely, infiltrative, nodule, and cicatricial stages. We also investigated the transition of the disease among the stages. All the cases of the infiltrative stage progressed to the nodule stage, and 92% of the nodule stage went on to the cicatricial stage. However 14% of the cicatricial stage cases reverted to the infiltrative stage and 7% to the nodule stage.


A review of barriers and facilitators of HIV treatment among injection drug users.
Globally, injection drug use continues to account for a substantial proportion of HIV infections. There have not, however, been any evidence-based reviews of the barriers and facilitators of HIV treatment among injection drug users. For this review, published studies were extracted from nine academic databases, with no language or date specified in the search criteria. Existing evidence demonstrates that, although injection drug users often have worse outcomes from HIV treatment than non-injection drug users, major antiretroviral-associated survival gains still have been observed among this population. Inferior outcomes are explained by a range of barriers to antiretroviral access and adherence, which often stem from the negative influences of illicit drug policies, as well as issues within medical systems, including lack of physician education about substance abuse. Evidence demonstrates that several under-utilized interventions and novel antiretroviral delivery modalities have helped to greatly address these barriers in several settings, and there is sufficient evidence to support immediate scale-up of these programmes. These interventions include coupling antiretroviral therapy with opioid substitution therapies as well as directly administered antiretroviral therapy programmes. Of particular interest for future evaluation is the coupling of HIV treatment programmes within comprehensive services, which also provide low-threshold (harm reduction) HIV prevention programmes. Scale-up of evidence-based HIV treatment and prevention to injection drug users, however, will require increasing political will among both national policy-makers and international public health agencies.


A Novel in vitro Human Macrophage Model to Study the Persistence of Mycobacterium tuberculosis Using Vitamin D(3) and Retinoic Acid Activated THP-1 Macrophages.
Mycobacterium tuberculosis (Mtb) replicates within the human macrophages and we investigated the activating effects of retinoic acid (RA) and vitamin D(3) (VD) on macrophages in relation to the viability of intracellular Mtb. A combination of these vitamins (RAVD) enhanced the levels of DC-SIGN and mannose receptors on THP-1 macrophages that increased mycobacterial uptake but inhibited the subsequent intracellular growth of Mtb by inducing reactive oxygen species and autophagy. RAVD also enhanced antigen presenting and chemotactic receptors on THPs suggesting an activated phenotype for RAVD activated THPs. RAVD mediated activation was also associated with a marked phenotypic change in Mtb infected THPs that fused with adjacent THPs to form multinucleated giant cells (MNGCs). Typically, MNGCs occurred over 30 days of in vitro culture and contained non-replicating persisting Mtb for more than 60 days in culture. Latent tuberculosis occurs in over a third of mankind and we propose that RAVD mediated induction of persistent Mtb within human macrophages provides a novel model to develop therapeutic approaches and investigate pathogenesis of latency.


Enhancing the sensitivity of magnetic sensors by 3D metamaterial shells.
Magnetic sensors are key elements in our interconnected smart society. Their sensitivity becomes essential for many applications in fields such as biomedicine, computer memories, geophysics, or space exploration. Here we present a universal way of increasing the sensitivity of magnetic sensors by surrounding them with a spherical metamaterial shell with specially designed anisotropic magnetic properties. We analytically demonstrate that the magnetic field in the sensing area is enhanced by our metamaterial shell by a known factor that depends on the shell radii ratio. When the applied field is non-uniform, as for dipolar magnetic field sources, field gradient is increased as well. A proof-of-concept experimental realization confirms the theoretical predictions. The metamaterial shell is also shown to concentrate time-dependent magnetic fields upto frequencies of 100 kHz.


Muscarinic receptors control postprandial release of glucagon-like peptide-1: in vivo and in vitro studies in rats.
Plasma levels of glucagon-like peptide-1 (GLP-1) rise rapidly after nutrient ingestion through an indirect mechanism triggered from the proximal intestine and involving the vagus nerve that stimulates the L cell in the distal gut. The role of muscarinic receptors in this pathway was thus investigated using the anesthetized rat and fetal rat intestinal cells (FRIC) in culture. GLP-1 secretion from the distal gut increased 5-fold after 3 ml corn oil were placed into the proximal duodenum (P < 0.001). Atropine (a nonspecific muscarinic receptor antagonist) completely inhibited fat-induced GLP-1 secretion in vivo (P < 0.01). Pirenzepine (an M1 muscarinic receptor antagonist) also inhibited fat-induced GLP-1 secretion in vivo, by 91 +/- 6% (P < 0.01). Gallamine (an M2 muscarinic receptor antagonist) and 4-diphenylacetoxy-N-methylpiperidine (an M3 muscarinic receptor antagonist) had no effect. Incubating FRIC cultures with bethanechol (a muscarinic receptor agonist) stimulated GLP-1 secretion to 200 +/- 22% of control (P < 0.01). Pirenzepine and gallamine significantly inhibited bethanechol-stimulated GLP-1 secretion, by 96 +/- 12% and 98 +/- 8%, respectively (P < 0.01). Unexpectedly, 4-diphenylacetoxy-N-methylpiperidine stimulated GLP-1 secretion by FRIC cells, to 324 +/- 52% of the control value (P < 0.01). Double immunofluorescent staining using GLP-1 and M1, M2, and M3 muscarinic receptor antibodies showed expression of the three subtypes of muscarinic receptors by the L cells in rat ileal sections and FRIC cultures. These results demonstrate the role of M1 muscarinic receptors expressed by L cells in the control of postprandial secretion of GLP-1. M2 muscarinic receptors also seem to play a role in controlling GLP-1 secretion by fetal, but not adult, L cells.


A contextual model of adolescent alcohol use across the rural-urban continuum.
In the research presented here, we develop and test with respondents from a broad range of contexts a multilevel social control model of adolescent substance use, integrating macro- and microsociological and criminological perspectives. Specifically, this research examines the individual-level social control processes or mechanisms thought to lead to alcohol use embedded in school contexts in different community settings along the rural-urban continuum. In this way we determine 1) the main effects of individual- and contextual school-level variables and 2) the conditioning or moderating influences of school climate on individual alcohol use and on individual-level processes leading to alcohol use. Furthermore, given that our sample contains students from a broad range of settings along the rural-urban continuum, our findings address the appropriateness of conceptualizing rural and urban drug use and their respective etiologies as dichotomous. In this respect our findings suggest that heterogeneity in drug use exists within rural school settings as well as within urban school settings, and that examining rural drug use as separate from urban drug use is not justified.


Matrix metalloproteinases 2, 7, and 9 and tissue inhibitor of metalloproteinases-1 in tumors and serum of patients with ovarian neoplasms.
The content of matrix metalloproteinases 7 and 9 was significantly increased, while the content of metalloproteinase 2 was reduced in ovarian cancer tissue compared to benign tumors. In blood serum from patients with ovarian cancer, the concentrations of matrix metalloproteinases 7 and 9 and their type 1 tissue inhibitor were significantly elevated, while the concentration of matrix metalloproteinase 2 was reduced compared to the corresponding parameters in healthy women. After chemotherapy, tissue and serum concentrations of metalloproteinases and their inhibitor in patients practically returned to normal. A significant positive correlation between serum levels of matrix metalloproteinases 7 and 9 and tissue inhibitor of metalloproteinases-1 in patients with ovarian cancer and the size of primary tumor (ultrasound examination) and a positive correlation between these parameters and the concentration of classical ovarian cancer marker CA-125 were demonstrated.


How Determinants of Employee Innovation Behavior Matter During the COVID-19 Pandemic: Investigating Cross-Regional Role via Multi-Group Partial Least Squares Structural Equation Modeling Analysis.
The COVID-19 pandemic cropping up at the end of 2019 started to pose a threat to millions of people's health and life after a few weeks. Nevertheless, the COVID-19 pandemic gave rise to social and economic problems that have changed the progress steps of individuals and the whole nation. In this study, the work conditions for employees from Taiwan, Malaysia, and the Chinese mainland are explored and compared, and the relationship between support mechanisms and innovation behaviors (IB) is evaluated with a view of the social cognitive career theory. This study adopts the cross-sectional survey and purposive sampling to collect questionnaires. A total of 623 copies of a questionnaire from Taiwanese, 440 copies from Malaysians, and 513 copies from mainlanders were collected in this study to compare the three groups in developing employees' IBs. Smart-partial least squares for partial least squares structural equation modeling was applied in the structural model to conduct a verification of the hypotheses and comparative analysis in this study. According to the findings, compared with employees from the Chinese mainland, the Taiwanese and Malaysian samples show more significant paths regarding employee employability, IB, prior knowledge, perceived organizational support, self-efficacy, and job performance. Our results will offer more insights and advice concerning theories of human resource.


Effect of Micro-Nano Bubble Water and Silica Fume on Properties of C60 Concrete.
Micro-nano bubble water (WNBW) in concrete is relatively uncommon due to its newness as a technology. This paper presents the preparation of C60 concrete with 35% fly ash (FA) through WNBW and varying amounts of silica fume (0%, 4%, 7%, and 10% SF). The study examines the impact of WNBW and SF on the working performance, compressive strength, and durability of concrete. The findings indicate that applying WNBW and SF independently or jointly deteriorates the working performance of fresh concrete. However, compared to regular mixing water, WNBW reduces the concrete passing time through the V-funnel, decreasing by 40%, 39.1%, 42.9%, and 50.5% for the four varying SF contents. Furthermore, using WNBW, SF, or both resulted in the increased compressive strength of concrete at 7 days and 28 days, with 7% SF content yielding a 12.2% and 6.6% increase, respectively. Using a combination of WNBW and SF has been shown to decrease the impermeability of concrete effectively. The addition of 4% SF results in the lowest electric flux when using regular mixing water, with a discernible decrease of 30.1% compared to the control group. Conversely, using WNBW as mixing water yields a decrease in electric flux at each SF content, with the maximum decrease being 39.7%. Furthermore, both the single and combined use of these materials can contribute to the reduction in the carbonation resistance of the concrete. C60 concrete mixed with 7% SF and 100% WNBW boasts enhanced frost resistance, as indicated by the mass loss and dynamic elastic modulus loss being the least following freeze-thaw under the same SF content. According to the findings of the tests, there is evidence that the incorporation of 7% SF and 100% WNBW into C60 concrete results in lowered viscosity, a highly advantageous attribute for actual construction. Additionally, this mixture displays impressive compressive strength and durability properties. These results provide technical support regarding the integration of WNBW and SF in C60 concrete.


Site-directed mutations near transmembrane domain 1 alter conformation and function of norepinephrine and dopamine transporters.
The human dopamine and norepinephrine transporters (hDAT and hNET, respectively) control neurotransmitter levels within the synaptic cleft and are the site of action for amphetamine (AMPH) and cocaine. We investigated the role of a threonine residue within the highly conserved and putative phosphorylation sequence RETW, located just before transmembrane domain 1, in regulating hNET and hDAT function. The Thr residue was mutated to either alanine or aspartate. Similar to the inward facing T62D-hDAT, T58D-hNET demonstrated reduced [(3)H]DA uptake but enhanced basal DA efflux compared with hNET with no further effect of AMPH. The mutations had profound effects on substrate function and binding. The potency of substrates to inhibit [(3)H]DA uptake and compete with radioligand binding was increased in T→A and/or T→D mutants. Substrates, but not inhibitors, demonstrated temperature-sensitive effects of binding. Neither the functional nor the binding potency for hNET blockers was altered from wild type in hNET mutants. There was, however, a significant reduction in potency for cocaine and benztropine to inhibit [(3)H]DA uptake in T62D-hDAT compared with hDAT. The potency of these drugs to inhibit [(3)H](-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane-1,5-napthalenedisulfonate (WIN35,428) binding was not increased, demonstrating a discordance between functional and binding site effects. Taken together, these results concur with the notion that the T→D mutation in RETW alters the preferred conformation of both hNET and hDAT to favor one that is more inward facing. Although substrate activity and binding are primarily altered in this conformation, the function of inhibitors with distinct structural characteristics may also be affected.


Assemblies of salen-type oxidovanadium(IV) complexes: substituent effects and in vitro protein tyrosine phosphatase inhibition.
Oxidovanadium(IV) complexes with substituted chiral tetradentate dianionic N,N'-bis-o-hydroxybenzylidene-1,2-propylenediamines were synthesized and their physicochemical properties were characterized using single crystal X-ray diffraction, elemental analysis, ATR FTIR, UV-VIS and EPR spectroscopy, cyclic voltammetry, spectroelectrochemistry and preliminary in vitro protein-tyrosine phosphatase inhibition activity studies. Different 5-substituents in the salicylaldehyde (condensed with 1,2-diaminopropane; 2 : 1) were tested, namely 5-Br (complex 1), 5-Cl (2), 5-NO2 (3) and 5-OCH3 (4). The crystal structures of 1 and 2 show square pyramidal coordination of vanadium and parallel arrangement of monomeric exo isomers in supramolecular dimers. The halogen-halogen interaction of substituents in 5,5'-positions leads to weakening of axial interaction between phenolate O and V in 2, compared to 1. The Br atom takes part in halogen bonding with a vanadyl group in 1. Complex 3 has a linear polymeric structure with a V-O-V asymmetric bridge motif (IR absorption band at 873 cm(-1), separated d-d bands and broad EPR band structure in frozen solution pointing to oligomeric nature) while 4 is monomeric (V=O stretching at 976 cm(-1), broad d-d band structure). Redox potentials of the V(4+)/V(5+) couple lie in the range of -0.14 to 0.21 V (vs. Fc/Fc(+)) and show substantial dependence on the electron withdrawing properties of the substituents. The charge transfer character of the bands present in the range 365-395 nm was confirmed based on UV-VIS spectroelectrochemical experiments. Different assemblies of complex molecules are influenced by the electron withdrawing properties of the 5,5'-substituents, leading to supramolecular dimers (1, 2 and 4) and linear polymeric self-assembly (3). An in vitro study of representative complex 1 showed protein tyrosine phosphatase activity inhibition higher than that of suramin but lower than those of oxidovanadium(IV) sulphate and bis(maltolato)oxidovanadium(IV).


A tall order: Small area mapping and modelling of adult height among Swiss male conscripts.
Adult height reflects an individual's socio-economic background and offers insights into the well-being of populations. Height is linked to various health outcomes such as morbidity and mortality and has consequences on the societal level. The aim of this study was to describe small-area variation of height and associated factors among young men in Switzerland. Data from 175,916 conscripts (aged between 18.50 and 20.50 years) was collected between 2005 and 2011, which represented approximately 90% of the corresponding birth cohorts. These were analysed using Gaussian hierarchical models in a Bayesian framework to investigate the spatial pattern of mean height across postcodes. The models varied both in random effects and degree of adjustment (professional status, area-based socioeconomic position, and language region). We found a strong spatial structure for mean height across postcodes. The range of height differences between mean postcode level estimates was 3.40cm according to the best fitting model, with the shorter conscripts coming from the Italian and French speaking parts of Switzerland. There were positive socioeconomic gradients in height at both individual and area-based levels. Spatial patterns for height persisted after adjustment for individual factors, but not when language region was included. Socio-economic position and cultural/natural boundaries such as language borders and mountain passes are shaping patterns of height for Swiss conscripts. Small area mapping of height contributes to the understanding of its cofactors.


Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study.
Interleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6Rα. In TARGET (NCT01709578), a phase 3 study in adults with moderate-to-severe RA and inadequate response or intolerance to tumour necrosis factor inhibitors, subcutaneous sarilumab 200 mg or 150 mg every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) significantly reduced disease activity versus placebo plus csDMARDs. Circulating levels of biomarkers associated with synovial inflammation (matrix metalloproteinase 3 (MMP-3), collagen type I MMP-cleaved fragment (C1M), collagen type III MMP-cleaved fragment (C3M)), myeloid (soluble intercellular adhesion molecule 1 (sICAM-1), IL-8 and calprotectin) and lymphoid activation (chemokine, CXC motif, ligand 13 (CXCL13), CXCL10, B cell-activating factor) and bone remodelling (receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin and osteocalcin) were evaluated in patients from a TARGET substudy. Sarilumab significantly decreased C1M, C3M, CXCL13, MMP-3 and total RANKL levels at week 24 versus placebo; some markers were significantly suppressed at week 2 and normalised to levels in healthy controls. Levels of sICAM-1 were predictive of disease activity score by C-reactive protein and clinical disease activity index low disease activity (LDA) response in the sarilumab 200 mg q2w group at week 12. A trend was observed in which patients with lower sICAM-1 levels at baseline had better response compared with patients with higher sICAM-1. Sarilumab plus csDMARDs decreased circulating biomarkers of synovial inflammation and bone resorption; sICAM-1 was predictive of achieving LDA with sarilumab. NCT01709578; Post-results.


Effects of graphene on morphology, microstructure and transcriptomic profiling of Pinus tabuliformis Carr. roots.
Graphene has shown great potential for improving growth of many plants, but its effect on woody plants remains essentially unstudied. In this work, Pinus tabuliformis Carr. bare-rooted seedlings grown outdoors in pots were irrigated with a graphene solution over a concentration range of 0-50 mg/L for six months. Graphene was found to stimulate root growth, with a maximal effect at 25 mg/L. We then investigated root microstructure and carried out transcript profiling of root materials treated with 0 and 25 mg/L graphene. Graphene treatment resulted in plasma-wall separation and destruction of membrane integrity in root cells. More than 50 thousand of differentially expressed genes (DEGs) were obtained by RNA sequencing, among which 6477 could be annotated using other plant databases. The GO enrichment analysis and KEGG pathway analysis of the annotated DEGs indicated that abiotic stress responses, which resemble salt stress, were induced by graphene treatment in roots, while responses to biotic stimuli were inhibited. Numerous metabolic processes and hormone signal transduction pathways were altered by the treatment. The growth promotion effects of graphene may be mediated by encouraging proline synthesis, and suppression of the expression of the auxin response gene SMALL AUXIN UP-REGULATED RNA 41 (SAUR41), PYL genes which encode ABA receptors, and GSK3 homologs.


Mapping cellular routes of Ras: a ubiquitin trail.
The three mammalian Ras isoforms: HRas, NRas and KRas have been widely implicated in the control of cell proliferation, survival, motility and transformation. Although nearly identical with respect to their catalytic and effector-binding properties, HRas, NRas and KRas lead to different biological outcomes in development, cell growth and cancer. This functional distinction is believed to result at least in part from the differential membrane compartmentalization of Ras isoforms. The different distribution of Ras proteins in cellular membranes dictates unique spatio-temporal patterns of activation of effector pathways. This perspective focuses on the factors that control membrane compartmentalization of Ras with an emphasis on a recently discovered novel posttranslational modification of Ras--ubiquitination. The properties of Ras ubiquitination, its contribution to the regulation of Ras intracellular trafficking and finally the influence of Ras ubiquitination on its signaling potential are discussed.


Economic Evaluation of Fidaxomicin for the Treatment of Clostridium Difficile Infection (C. difficile-associated diarrhoea) in Ireland.
Background: Clostridium difficile is associated with 20-30% of cases of antibiotic-associated diarrhoea. The incidence of C. difficile infection (CDI) is higher in Ireland than in other countries in Europe, and it is associated with considerable morbidity. Previously recommended standard therapeutic options were vancomycin and metronidazole, but the macrocyclic antibiotic fidaxomicin has recently been recommended for use in adults with CDI in Ireland. Objectives: To perform a cost-utility analysis of fidaxomicin compared to oral metronidazole (used to treat initial non-severe disease and first non-severe recurrence) and oral vancomycin (used to treat severe disease and any non-severe recurrence beyond the first) for the treatment of CDI. Methods: A Markov model was used to determine the cost-utility of fidaxomicin in the treatment of all adult CDI patients (base case), patients with severe CDI and patients with initial CDI recurrences, respectively. Patients enter the model in the CDI health state and are treated either with fidaxomicin or current standard of care (oral metronidazole for non-severe CDI; vancomycin for severe CDI) for 10 days. The time horizon was 1 year. Deterministic and probabilistic sensitivity analyses were performed. Health state utilities were derived from the literature. The perspective was that of the Irish Health Service Executive (HSE). Results: In the base case, fidaxomicin was dominant to current standard-of-care therapy, with cost savings of €2,904 and incremental quality-adjusted life year (QALY) gain of 0.031. The main drivers of costeffectiveness were recurrence rates and cost of hospitalization. Fidaxomicin was also dominant for all patient subgroups. The probability of fidaxomicin being cost-effective in all patients with CDI at a willingness to pay threshold of €45,000 per QALY gained was 82%. Conclusion: Fidaxomicin was dominant to the current standard-of-care therapy for CDI. Based on this analysis, fidaxomicin has received reimbursement for CDI treatment under the High Tech Drug Scheme in Ireland.


Genome-wide DNA methylation profiles in hematopoietic stem and progenitor cells reveal overrepresentation of ETS transcription factor binding sites.
DNA methylation is an essential epigenetic mark that is required for normal development. Knockout of the DNA methyltransferase enzymes in the mouse hematopoietic compartment reveals that methylation is critical for hematopoietic differentiation. To better understand the role of DNA methylation in hematopoiesis, we characterized genome-wide DNA methylation in primary mouse hematopoietic stem cells (HSCs), common myeloid progenitors (CMPs), and erythroblasts (ERYs). Methyl binding domain protein 2 (MBD) enrichment of DNA followed by massively parallel sequencing (MBD-seq) was used to map genome-wide DNA methylation. Globally, DNA methylation was most abundant in HSCs, with a 40% reduction in CMPs, and a 67% reduction in ERYs. Only 3% of peaks arise during differentiation, demonstrating a genome-wide decline in DNA methylation during erythroid development. Analysis of genomic features revealed that 98% of promoter CpG islands are hypomethylated, while 20%-25% of non-promoter CpG islands are methylated. Proximal promoter sequences of expressed genes are hypomethylated in all cell types, while gene body methylation positively correlates with gene expression in HSCs and CMPs. Elevated genome-wide DNA methylation in HSCs and the positive association between methylation and gene expression demonstrates that DNA methylation is a mark of cellular plasticity in HSCs. Using de novo motif discovery, we identified overrepresented transcription factor consensus binding motifs in methylated sequences. Motifs for several ETS transcription factors, including GABPA and ELF1, are overrepresented in methylated regions. Our genome-wide survey demonstrates that DNA methylation is markedly altered during myeloid differentiation and identifies critical regions of the genome and transcription factor programs that contribute to hematopoiesis.


Ultrastructural localization of keratin and alpha-L-fucose in human eccrine sweat glands.
Human eccrine sweat glands were embedded in Lowicryl K4M. Cytokeratin proteins and blood group H antigen were localized by applying a postembedding immunogold method using a monoclonal antikeratin antibody and the lectin Ulex europaeus I. The antikeratin antibody labeled intermediate filaments in the secretory coil and dermal duct. Within dark secretory cells bundles of filaments criss-crossing the cell were labeled. Within the luminal cells of the dermal duct filaments arranged parallel to the cell surface and lying in the apex of the cell were labeled, too. The association of keratin filaments with desmosomes was visualized demonstrating their subcellular connection with other cell organelles. The desmosomes themselves remained unlabeled. The lectin Ulex europaeus I is a blood group H specific lectin and binds to alpha-L-fucosyl-containing glycoproteins. Dark cells of the secretory coil reacted with the lectin. Here the secretory granules, the lateral cell membranes, and the microvilli membranes were labeled. The endoplasmatic reticulum, the Golgi complex, and transport vesicles were not labeled, although the glycoprotein synthesis is considered to be located in the Golgi complex. Thus, either the number of alpha-L-fucose molecules in the Golgi is too low to be detected by the technique employed or the determinant of blood group H antigen is released after the secretory granules and transport vesicles leave the Golgi complex.


Endosomal recruitment of the WASH complex: active sequences and mutations impairing interaction with the retromer.
The Wiskott-Aldrich syndrome protein and scar homolog (WASH) complex is the major Arp2/3 activator at the surface of endosomes. The branched actin network, that the WASH complex induces, contributes to cargo sorting and scission of transport intermediates destined for most endosomal routes. A major challenge is to understand how the WASH molecular machine is recruited to the surface of endosomes. The retromer endosomal machinery has been proposed by us and others to play a role in this process. In this work, we used an unbiased approach to identify the endosomal receptor of the WASH complex. We have delineated a short fragment of the FAM21 subunit that is able to displace the endogenous WASH complex from endosomes. Using a proteomic approach, we have identified the retromer cargo selective complex (CSC) as a partner of the active FAM21 sequence displacing the endogenous WASH complex. A point mutation in FAM21 that abolishes CSC interaction also impairs WASH complex displacement activity. The CSC is composed of three subunits, VPS35, VPS29 and VPS26. FAM21 directly binds the VPS35 subunit of the retromer CSC. Additionally, we show that a point mutant of VPS35 that blocks binding to VPS29 also prevents association with FAM21 and the WASH complex revealing a novel role for the VPS35-VPS29 interaction in regulating retromer association with the WASH complex. This novel approach of endogenous WASH displacement confirms previous suggestions that the retromer is the receptor of the WASH complex at the surface of endosomes and identify key residues that mediate this interaction. The interaction between these two endosomal machineries, the WASH complex and the retromer, is likely to play a critical role in forming platforms at the surface of endosomes for efficient sorting of cargoes.


Machine learning-based guilt detection in text.
We introduce a novel Natural Language Processing (NLP) task called guilt detection, which focuses on detecting guilt in text. We identify guilt as a complex and vital emotion that has not been previously studied in NLP, and we aim to provide a more fine-grained analysis of it. To address the lack of publicly available corpora for guilt detection, we created VIC, a dataset containing 4622 texts from three existing emotion detection datasets that we binarized into guilt and no-guilt classes. We experimented with traditional machine learning methods using bag-of-words and term frequency-inverse document frequency features, achieving a 72% f1 score with the highest-performing model. Our study provides a first step towards understanding guilt in text and opens the door for future research in this area.


Doppler sonography enhances rtPA-induced fibrinolysis in an in vitro clot model of spontaneous intracerebral hemorrhages.
Transcranial Doppler (TCD) was shown to enhance intravascular fibrinolysis by rtPA in ischemic stroke. Studies revealed that catheter-based administration of rtPA induces lysis of intracerebral hemorrhages (ICH). However, it is unknown whether TCD would be suitable to enhance rtPA-induced fibrinolysis in patients with ICH. The aim of this study was to assess the potential of TCD to enhance rtPA-induced fibrinolysis in an in vitro clot system. Reproducible human blood clots of 25 ml were incubated in a water bath at 37°C during treatments. They were weighed before and after 6 different treatments: (I) control (incubation only), (II) rtPA only, (III) one Doppler probe, (IV) two Doppler probes placed vis-à-vis, (V) one probe and rtPA and (VI) two probes and rtPA. To quantify lysis of the blood clots and attenuation of the Doppler through a temporal squama acoustic peak rarefaction pressure (APRP) was measured in the field of the probes. Temperature was assessed to evaluate possible side effects. Clot weight was reduced in all groups. The control group had the highest relative end weight of 70.2%±7.2% compared to all other groups (p<0,0001). Most efficient lysis was achieved using (VI) 2 probes and rtPA 36.3%±4.4% compared to (II, III, IV) (p<0.0001; p = 0.0002; p = 0.048). APRP was above lysis threshold (535.5±7.2 kPa) using 2 probes even through the temporal squama (731.6±32.5 kPa) (p = 0.0043). There was a maximal temperature elevation of 0.17±0.07°C using both probes. TCD significantly enhances rtPA-induced lysis of blood clots, and the effect is amplified by using multiple probes. Our results indicate that bitemporal TCD insonation of hematomas could be a new and safe approach to enhance fibrinolysis of ICH´s treated with intralesional catheter and rtPA.


Motivations for social withdrawal and academic adjustment in emerging adulthood.
While social withdrawal in childhood is typically associated with lower academic functioning, little is known about how motivations for social withdrawal may be connected to academic adjustment in emerging adulthood. The purpose of the present study was to examine associations between social withdrawal motivations (i.e., shyness, avoidance and unsociability) and indices of academic adjustment, including academic achievement (i.e., grade point average [GPA]) and academic motivation (i.e., intrinsic value, self-efficacy and test anxiety), while accounting for gender and conscientiousness. Participants were 623 emerging adults between the ages of 18 and 25 (Mage = 20.15, SD = 1.67; 79% female) who were currently attending university. Hierarchical regression results showed that shyness was negatively associated with intrinsic value and self-efficacy. Whereas shyness was positively associated with test anxiety, avoidance was negatively associated with test anxiety. Social withdrawal motivations were not associated with GPA. The findings suggest that some motivations for social withdrawal play a role in university students' academic motivation, but not their academic achievement.


Prevalence of Dirofilaria immitis in cats in Japan.
The prevalence of Dirofilaria immitis in cats in Japan has been examined since 1957. Twenty surveys involving a total of 3775 cats, conducted in two islands of Japan (Honshu and Kyushu), were studied. The surveys evaluated both stray (3617) and house (158) cats. Presence of D. immitis was detected at necropsy. The results show a prevalence of D. immitis varying from 0.5 to 9.5% for stray cats and from 3.0 to 5.2% for house cats on the two islands.


Thymic Stromal Lymphopoietin: To Cut a Long Story Short.
Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform.


Effects of marrow donor and recipient age on immune responses.
This report describes treatments to restore diminished splenic immune responses of old mice. Lethal irradiation, followed by young bone marrow and infant thymus transplants, restored the T cell mitogen response and the antibody-forming cell response against sheep red blood cells in the old mice. Although old bone marrow cells restore these immune responses in young recipients, as well as do young bone marrow cells, old bone marrow in old recipients did not improve their levels of response. Longevities of old recipients with rejuvenated responses were not increased, and aging of tail tendon collagen was not affected. The effect of lethal irradiation before the marrow transplant was shown to be minimal, by the use of unirradiated old W-anemic recipients. Parabiosing young mice with old partners caused impairment of these two immune responses in the young partners without enhancing them in the old partners. The old partners did not have increased longevities. To explain these results, we suggest the following hypothesis: old bone marrow contains precursors that produce suppressive factors or cells when in an old environment but not when in a young environment. However, these factors, if allowed to develop in an old environment, can function in a young parabiosed partner.


The determinants of financial inclusion from the households' perspectives in Vietnam.
Various studies have been conducted to measure financial inclusion at the country level. However, measuring financial inclusion at the household level has largely been neglected in the existing literature, particularly for emerging markets such as Vietnam. This study constructs an index of financial inclusion at the household level using the Vietnam Household Living Standard Surveys (VHLSS) in 2014, 2016, and 2018. We also identify the determinants of financial inclusion from the perspective of Vietnamese households. Our study also utilizes an ordered logit model to examine the effects of the determinants on each level of financial inclusion. Our empirical results reveal three key determinants, including (i) total income per household, (ii) relative income representing the difference between the average income of the province that the household currently lives in and the total income of this household, and (iii) the distance from the household to the nearest bank branch, are crucial factors driving the financial inclusion. While the total income per household positively enhances financial inclusion, relative income appears to reduce the degree of financial inclusion. Besides, distance to the nearest bank branch poses another challenge in achieving the financial inclusion goals in Vietnam in the future.


Comet fluorescence in situ hybridization analysis for oxidative stress-induced DNA damage in colon cancer relevant genes.
Our objective was to study whether products of oxidative stress, such as hydrogen peroxide (H(2)O(2)), trans-2-hexenal, and 4-hydroxy-2-nonenal (HNE), cause DNA damage in genes, relevant for human colon cancer. For this, total DNA damage was measured in primary human colon cells and colon adenoma cells (LT97) using the single-cell gel electrophoresis assay, known as "Comet Assay." APC, KRAS, and TP53 were marked in the comet images using fluorescence in situ hybridization (Comet FISH). The migration of APC, KRAS, or TP53 signals into the comet tails was quantified and compared to total DNA damage. All three substances were clearly genotoxic for APC, KRAS, and TP53 genes and total DNA in both types of cells. In primary colon cells, TP53 gene was more sensitive toward H(2)O(2), trans-2-hexenal, and HNE than total DNA was. In LT97 cells, the TP53 gene was more sensitive only toward trans-2-hexenal and HNE. APC and KRAS genes were more susceptible than total DNA to both lipid peroxidation products but only in primary colon cells. This suggests genotoxic effects of lipid peroxidation products in APC, KRAS, and TP53 genes. In LT97 cells, TP53 was more susceptible than APC and KRAS toward HNE. Based on the reported gatekeeper properties of TP53, which in colon adenoma is frequently altered to yield carcinoma, this implies that HNE is likely to contribute to cancer progression. This new experimental approach facilitates studies on effects of nutrition-related carcinogens in relevant target genes.


Postoperative Care of a Liver Transplant Recipient Using a Classification System: Type A (Stable) Versus Type B (Unstable).
Liver transplantation has become an effective and valuable option for patients with end-stage liver disease and hepatocellular carcinoma. Liver failure, an acute or chronic condition, results in impaired bile production and excretion, clotting factor production, protein synthesis, and regulation of metabolism and glucose. Some acute conditions of liver disease have the potential to recover if the liver heals on its own. However, chronic conditions, such as cirrhosis, often lead to irreversible disease and require liver transplantation. In this publication, we review the pathophysiology of liver failure, examine common conditions that ultimately lead to liver transplantation, and discuss the postoperative management of patients who are either hemodynamically stable (type A) or unstable (type B).


Decellularized material as scaffolds for tissue engineering studies in long gap esophageal atresia.
Esophageal atresia refers to an anomaly in foetal development in which the esophagus terminates in a blind end. Whilst surgical correction is achievable in most patients, when a long gap is present it still represents a major challenge associated with higher morbidity and mortality. In this context, tissue engineering could represent a successful alternative to restore oesophageal function and structure. Naturally derived biomaterials made of decellularized tissues retain native extracellular matrix architecture and composition, providing a suitable bed for the anchorage and growth of relevant cell types. Areas covered: This review outlines the various strategies and challenges in esophageal tissue engineering, highlighting the evolution of ideas in the development of decellularized scaffolds for clinical use. It explores the interplay between clinical needs, ethical dilemmas, and manufacturing challenges in the development of a tissue engineered decellularized scaffold for oesophageal atresia. Expert opinion: Current progress on oesophageal tissue engineering has enabled effective repair of patch defects, whilst the development of a full circumferential construct remains a challenge. Despite the different approaches available and the improvements achieved, a gold standard for fully functional tissue engineered oesophageal constructs has not been defined yet.


The Role of the Transcriptional Response to DNA Replication Stress.
During DNA replication many factors can result in DNA replication stress. The DNA replication stress checkpoint prevents the accumulation of replication stress-induced DNA damage and the potential ensuing genome instability. A critical role for post-translational modifications, such as phosphorylation, in the replication stress checkpoint response has been well established. However, recent work has revealed an important role for transcription in the cellular response to DNA replication stress. In this review, we will provide an overview of current knowledge of the cellular response to DNA replication stress with a specific focus on the DNA replication stress checkpoint transcriptional response and its role in the prevention of replication stress-induced DNA damage.


Intravenous maternal -arginine administration to twin-bearing ewes, during late pregnancy, is associated with increased fetal muscle mTOR abundance and postnatal growth in twin female lambs.
The aims of this study were to determine whether parenteral Arg administered to well-fed twin-bearing ewes from 100 to 140 d of pregnancy influences fetal skeletal muscle growth, the abundance and activation of mechanistic target of rapamycin (mTOR) protein, and postnatal muscle growth of the offspring. Ewes fed 100% of NRC-recommended nutrient requirements for twin-bearing ewes were administered an intravenous bolus of either 345 μmol Arg HCl/kg BW or saline solution (Control) 3 times per day. At 140 d of pregnancy (P140), a group of 11 Control and 9 Arg-treated ewes were euthanized and hind leg muscles and longissimus dorsi (LD) were excised and weighed. A sample of LD was snap frozen in liquid nitrogen for later analysis of free AA (FAA) concentration, mTOR abundance and phosphorylation, and biochemical indices (DNA, RNA, and protein content). For the remaining 25 ewes (Arg, = 13, and Control, = 12), Arg administration was continued until the initiation of parturition and ewes were allowed to lamb. Lambs were weaned at postnatal Day 82 and grazed on pasture until postnatal day 153 (PN153), when a subset of 20 lambs ( = 10 per group) was euthanized. At P140, only the psoas major was heavier in the Arg-administered group compared with the Control group. Female lambs from ewes supplemented with Arg (Arg-F) had increased abundance of total mTOR, RNA concentration, and RNA:DNA ratio in LD compared with female lambs from Control ewes (Con-F), whereas males did not differ. At PN153, Arg-F were heavier than Con-F and had heavier LD and plantaris and a trend for heavier psoas major muscles compared with Con-F. In contrast, BW and individual muscle weights did not differ in male lambs. Lambs from Arg-treated ewes had heavier semimembranosus and tended to have heavier biceps femoris compared with Control lambs. The RNA concentration in LD was greater in Arg-F compared with Con-F, and DNA concentration was greater in the Arg group compared with the Control group. In conclusion, Arg administration to the ewe during gestation increases female lamb weight and muscle weight after birth and these changes are associated with altered mTOR protein abundance and have potential implications for sheep production.