What can we learn from mice lacking pro-survival BCL-2 proteins to advance BH3 mimetic drugs for cancer therapy?
In many human cancers the control of apoptosis is dysregulated, for instance as a result of the overexpression of pro-survival BCL-2 proteins. This promotes tumorigenesis by protecting nascent neoplastic cells from stress and renders malignant cells resistant to anti-cancer agents. Therefore, several BH3 mimetic drugs targeting distinct pro-survival proteins have been developed. The BCL-2 inhibitor Venetoclax/ABT-199, has been approved for treatment of certain blood cancers and tens of thousands of patients have already been treated effectively with this drug. To advance the clinical development of MCL-1 and BCL-XL inhibitors, a more detailed understanding of their distinct and overlapping roles in the survival of malignant as well as non-transformed cells in healthy tissues is required. Here, we discuss similarities and differences in pro-survival BCL-2 protein structure, subcellular localisation and binding affinities to the pro-apoptotic BCL-2 family members. We summarise the findings from gene-targeting studies in mice to discuss the specific roles of distinct pro-survival BCL-2 family members during embryogenesis and the survival of non-transformed cells in healthy tissues in adults. Finally, we elaborate how these findings align with or differ from the observations from the clinical development and use of BH3 mimetic drugs targeting different pro-survival BCL-2 proteins.


Impact of abiotic stressors on native rhizospheric bacterial community of Cajanus cajan.
Salinity and drought are the major abiotic stresses that limit agricultural productivity. Application of plant growth promoting rhizobacteria (PGPR) is an attractive technology but with the bottlenecks of reduced efficacy and survivability in the environment. For increased efficiency of PGPR strains, the impact of stresses on the native bacterial community needs to be studied. Experimentally induced stresses would be ideal to assess the immediate perturbances in the structure of soil bacterial community. Hence, the study focused on the effect of experimentally-induced salinity, and drought stress on rhizospheric bacterial community of Cajanus cajan. A plant growth experiment was set up to induce salinity and drought stresses. Shifts in the bacterial community were assessed by a culture-independent technique of denaturing gradient gel electrophoresis using 16S ribosomal RNA gene and transcript as markers, leading to a comparison of the resident with the active bacterial community. The impact on plant was evaluated by measurement of plant biometrics. Further, salinity and drought-stressed conditions led to distinct shifts in native and active rhizospheric bacterial community, corresponding to the higher decline at induction of stresses, and stabilization at later time points. The study encompasses the perturbations in the active and resident rhizospheric bacterial community caused by the induction of two different abiotic stresses along the plant's growth.


Phenotypic characterization, virulence, and immunogenicity of Edwardsiella tarda LSE40 aroA mutant.
Bacterial aro mutants are frequently used as live attenuated vaccines for domestic animals. In this study, we characterized Edwardsiella tarda strain LSE40 with a deletion in the aroA gene. In addition to autotrophy, the aroA mutant appeared to have delayed cell division and reductions in its swarming motility, biofilm formation, and production of translocator proteins in the type III secretory system. The mutant exhibited high virulence attenuation in turbot fish, Scophthalmus maximus (L.), where the 50 % lethal dose increased by more than 3 log₁₀ via intraperitoneal (i.p.) injection and by >2 log₁₀ via immersion exposure compared with the wild-type parent strain. A tissue persistence study showed that the mutant retained the ability to invade and spread in turbot and viable cells could be detected up to 28 days after i.p. infection and 21 days after immersion exposure. These results suggested a pleiotropic role for aroA in the physiological behavior of E. tarda. Turbot exhibited a good humoral response and the enhanced expression of innate immune factors, interleukin 1β and lysozyme, when vaccinated with aroA mutant at 10⁵ CFU via i.p. injection and at 10⁸ CFU via immersion exposure. However, the aroA mutant did not provide effective protection for turbot against edwardsiellosis following i.p. vaccination at doses of 10⁴-10⁶ CFU or immersion vaccination at doses of 10⁶-10⁸ CFU ml⁻¹. We hypothesized that the aroA mutant did not trigger an appropriate T cell-immune response in turbot against infection of E. tarda.


Balancing the Affinity and Pharmacokinetics of Antibodies by Modulating the Size of Charge Patches on Complementarity-Determining Regions.
A localized positive charge on IgG (referred to as a "charge patch") shows an adverse effect on pharmacokinetics (PK), so it would seem to be best practice to avoid charge patches during the discovery stage and closely monitor charge interactions during the development process. In certain circumstances, however, charge patches are required for target binding, in which case completely removing charge patches is not feasible. Therefore, quantitative measurement of a charge patch and its impact on PK is critical to the success of therapeutic antibody development. In this article, we generated mutations of a recombinant human antibody (referred to as mAb1) with disrupted charge patches to investigate how charge patches on IgG antibodies impact both target-binding affinity and PK-related factors. We conclude that it is important to modulate the size of the charge patch in order to balance target-binding affinity and PK.


Comparison of the inhibitory and excitatory effects of ADHD medications methylphenidate and atomoxetine on motor cortex.
Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in healthy adults, both stimulant and nonstimulant medications for ADHD decrease cortical inhibition and increase cortical facilitation. Cortical inhibition, shown previously to be abnormal in ADHD, may play a key role producing behavioral pathology.


Thermal cooling efficacy of a solar water pump using Oldroyd-B (aluminum alloy-titanium alloy/engine oil) hybrid nanofluid by applying new version for the model of Buongiorno.
Solar radiation, which is emitted by the sun, is required to properly operate photovoltaic cells and solar water pumps (SWP). A parabolic trough surface collector (PTSC) installation model was created to investigate the efficacy of SWP. The thermal transfer performance in SWP is evaluated thru the presence of warmth radiation and heat cause besides viscid dissipation. This evaluation is performed by measuring the thermal transmission proportion of the selected warmth transmission liquid in the PTSC, known as a hybrid nano-fluid. Entropy analysis of Oldroyd-B hybrid nano-fluid via modified Buongiorno's model was also tested. The functions of regulating parameters are quantitatively observed by using the Keller-box approach in MATLAB coding. Short terms define various parameters for tables in velocity, shear pressure and temperature, gravity, and Nusselt numbers. In the condition of thermal radiation and thermal conductivity at room temperature, the competence of SWP is proven to be enhanced. Unlike basic nano-fluids, hybrid nano-fluids are an excellent source of heat transfer. Additionally, with at least 22.56% and 35.01% magnitude, the thermal efficiency of AA7075-Ti-6Al-4 V/EO is higher than AA7075-EO.


Preschoolers' Beliefs, Emotions and Intended Responses toward Peer Behaviors: Do Children's Sex, Age, and Social Behavior Make a Difference?
Children's self-imposed isolation in the company of others (social withdrawal due to shyness or unsociability) and active isolation due to direct aggressive behaviors can challenge successful engagement in the peer group. The developmental attributional perspective acknowledges that children's intended affiliative responses are, in part, guided by their emotions and beliefs toward peers' social behaviors and may differ depending on children's sex, age group, and social behavior. This study aimed to (1) describe preschoolers' beliefs, emotions, and intended affiliative preferences toward aggressive, shy, and unsociable peers, depending on children's sex and age group, and (2) explore the associations between preschoolers' beliefs, emotions and intended affiliative preferences, depending on children's social behaviors and children's sex or age group. A total of 158 preschoolers aged 3-6 years were interviewed, using the Child Attributions Interview to assess their beliefs, emotions and intended affiliative preferences toward peers. Teachers completed the Social Competence and Behavior Evaluation Scale to assess children's prosocial behaviors, aggressive-anger, and anxious-withdrawal. Preschoolers' perspectives toward shy and unsociable peers were less negative than toward aggressive peers. However, participants in our sample were not fully aware of the different intentionality and social motivations of shy and unsociable peers. Higher levels of perceived social standing, social motivation and sympathy predicted higher affiliative preferences toward shy, unsociable, and aggressive peers. However, the magnitude of the associations between preschoolers' beliefs, emotions and intended affiliative preferences differed, depending on children's sex, age group and prosocial behavior, especially toward aggressive and shy peer behaviors. These findings are in line with the developmental attributional perspective, but highlight the need to account for developmental specificities, sex differences in peer relationships and children's individual differences in social behaviors.


Toolbox for Coronary Chronic Total Occlusion Percutaneous Coronary Intervention.
Since the publication of the hybrid algorithm there has been rapid development of new specialty wires, microcatheters, guide extensions, and low-profile balloons to facilitate successful coronary chronic total occlusion percutaneous coronary intervention. With development of new devices, it is best to categorize them by design and intended task. This enables a safe and systematic approach to coronary chronic total occlusion percutaneous coronary intervention and avoid overlap and waste. This article serves as a guide for tool selection for the interventional cardiologist performing coronary chronic total occlusion percutaneous coronary intervention.


Lower lid blepharoplasty with skin flap and muscle split.
A skin flap, muscle split lower eyelidplasty is recommended for the management of excess skin of the lower eyelids associated with herniated infraorbital fat pads. Precise fat pad removal and skin excision are necessary.


Biologically Defined or Biologically Informed Traits Are More Heritable Than Clinically Defined Ones: The Case of Oral and Dental Phenotypes.
The genetic basis of oral health has long been theorized, but little information exists on the heritable variance in common oral and dental disease traits explained by the human genome. We sought to add to the evidence base of heritability of oral and dental traits using high-density genotype data in a well-characterized community-based cohort of middle-age adults. We used genome-wide association (GWAS) data combined with clinical and biomarker information in the Dental Atherosclerosis Risk In Communities (ARIC) cohort. Genotypes comprised SNPs directly typed on the Affymetrix Genome-Wide Human SNP Array 6.0 chip with minor allele frequency of >5% (n = 656,292) or were imputed using HapMap II-CEU (n = 2,104,905). We investigated 30 traits including "global" [e.g., number of natural teeth (NT) and incident tooth loss], clinically defined (e.g., dental caries via the DMFS index, periodontitis via the CDC/AAP and WW17 classifications), and biologically informed (e.g., subgingival pathogen colonization and "complex" traits). Heritability (i.e., variance explained; h2) was calculated using Visscher's Genome-wide Complex Trait Analysis (GCTA), using a random-effects mixed linear model and restricted maximum likelihood (REML) regression adjusting for ancestry (10 principal components), age, and sex. Heritability estimates were modest for clinical traits-NT = 0.11 (se = 0.07), severe chronic periodontitis (CDC/AAP) = 0.22 (se = 0.19), WW17 Stage 4 vs. 1/2 = 0.15 (se = 0.11). "High gingival index" and "high red complex colonization" had h2 > 0.50, while a periodontal complex trait defined by high IL-1β GCF expression and Aggregatibacter actinomycetemcomitans subgingival colonization had the highest h2 = 0.72 (se = 0.32). Our results indicate that all GWAS SNPs explain modest levels of the observed variance in clinical oral and dental measures. Subgingival bacterial colonization and complex phenotypes encompassing both bacterial colonization and local inflammatory response had the highest heritability, suggesting that these biologically informed traits capture aspects of the disease process and are promising targets for genomics investigations, according to the notion of precision oral health.


Sensitization of human cells by inhibitors of DNA synthesis following the action of DNA-damaging agents.
Inhibitors of DNA synthesis 1-beta-arabinofuranosylcytosine (Ac) and hydroxyurea (Hu) taken together drastically sensitized human cells to the killing effect of DNA-damaging agents. For UV-irradiation this sensitization depended on the cells' ability for excision repair. By using viscoelastometric methods of measurement of double-strand breaks (DSB) in the genome, it was established that the first DSB were generated after incubation of the damaged cells in the mixture of inhibitors at about the same dose when sensitization appeared. A scheme is proposed to describe molecular events associated with the phenomenon studied.


Constitutive expression levels of CD95 and Bcl-2 as well as CD95 function and spontaneous apoptosis in vitro do not predict the response to induction chemotherapy and relapse rate in childhood acute lymphoblastic leukaemia.
CD95 (Fas/APO-1) expression and function and Bcl-2 expression, as well as spontaneous apoptosis in vitro, have been shown to be predictive markers for the in vivo response to chemotherapy in acute myeloid leukaemia (AML). To determine the clinical significance of apoptosis-regulating factors in acute lymphoblastic leukaemia (ALL), we investigated cell samples of children with ALL who had been included in the German ALL Berlin-Frankfurt-Münster (BFM) study using flow cytometry for constitutive expression levels of CD95 (n = 110) and Bcl-2 (n = 110). Furthermore, we determined the extent of spontaneous apoptosis in vitro (n = 102) and susceptibility to anti-CD95-induced apoptosis (CD95-sensitivity) (n = 97). We correlated these findings with the functional activity of the multidrug resistance (MDR)-associated P-glycoprotein (P-gp), as detected by the rhodamine123 efflux test, immunophenotype, cytogenetics and clinical data of the patients examined. Good responders to initial prednisone therapy ('prednisone response') revealed significantly higher Bcl-2 expression levels [5.4 +/- 3.4 relative fluorescence intensity (RFI), n = 68] than poor responders (3.7 +/- 2.6 RFI, n = 42; P = 0.002). There was no significant correlation between the other investigated parameters and prednisone response. Moreover, neither the CD95 and Bcl-2 expression levels nor the extent of spontaneous apoptosis in vitro, CD95 sensitivity or P-gp function were correlated with the response to induction chemotherapy or relapse rate, either for B-cell precursor ALL or T-cell ALL. No consistent pattern of change in CD95 (n = 10) and Bcl-2 expression (n = 9) was noted in cases studied at both initial diagnosis and relapse. In conclusion, our findings underline the different cell biological features of primary AML and ALL cells.


Implementation of a hospital antimicrobial stewardship program to improve vancomycin use in Cyprus: Challenges and opportunity.
The Republic of Cyprus is among the highest consumers of antibacterials for systemic use in Europe. The antimicrobial resistance of invasive isolates in Cyprus is also high compared to the European Union. Formal antimicrobial stewardship initiatives are scarce in Cyprus, raising an urgent need to address the challenges for implementing hospital antimicrobial stewardship. To implement an antimicrobial stewardship program and improve vancomycin use in a tertiary care hospital in Cyprus, through implementation of a protocol for treatment and therapeutic drug monitoring (TDM) and to discuss the current challenges present in Cyprus. Following a local audit of practices, we established a hospital antimicrobial stewardship program with limited resources, towards a model of stewardship which included a persuasive approach, education, selective reporting of antimicrobial susceptibility, providing comments on the microbiology results and regular microbiology clinical ward rounds. By implementing our vancomycin protocol, we achieved a statistically significant improvement (P<0.01) in achieving vancomycin therapeutic levels over a 2-year period, while improving administration practices. Meaningful steps toward implementing a local antimicrobial stewardship program are possible even in resource-limited and unfavourable settings.


A cross-sectional study of haemolytic disease of the newborn in Uganda.
Haemolytic disease of the newborn (HDN) is an immune haemolytic anaemia from maternal alloantibodies. Rh immunoglobulin (RhIg) prophylaxis can prevent alloimmunization to the D antigen. However, RhIg is not universally available in Uganda. ABO incompatibility also causes HDN. We determined the prevalence of HDN among newborn infants with jaundice in Uganda. We conducted a prospective cross-sectional study at Kawempe National Referral Hospital, Kampala, Uganda. Infants aged 0-14 days with neonatal jaundice (or total bilirubin >50 μmol/L) were enrolled. Clinical evaluation and laboratory testing, including ABO, RhD typing and maternal antibody screen, were performed. A total of 466 babies were enrolled. The mean (SD) age was 3.4 (1.5) days. Of newborn babies with jaundice, 17.2% (80/466) had HDN. Babies with HDN had lower haemoglobin (SD); 15.7 (2.7) compared with those without HDN; 16.4 (2.4) g/dL, p = 0.016; and a higher bilirubin (interquartile range); 241 (200-318) compared with those without HDN; 219 (191-263) μmol/L, p < 0.001. One baby had anti-D HDN, while 46/466 had HDN from an ABO incompatibility (anti-A 43.5% and anti-B 56.5%); 82% of babies with HDN also had suspected neonatal sepsis or birth asphyxia. About 79.2% (57/72) of mothers did not have ABO/Rh blood group performed antenatally. All infants with HDN survived except one. Among newborn infants with jaundice, HDN is not rare. The majority is due to ABO HDN affecting group A and group B babies equally. Ensuring routine ABO/Rh grouping for all pregnant women is an area for improvement.


First experience with enzyme replacement therapy during pregnancy and lactation in Pompe disease.
Enzyme replacement therapy (ERT) with alglucosidase alfa was registered as a treatment for Pompe disease in 2006. It is as yet unknown whether ERT can be safely applied during pregnancy and lactation. A primiparous 40-year-old woman diagnosed with Pompe disease continued receiving ERT during pregnancy and lactation. Before pregnancy, she had moderate limb-girdle weakness and used nocturnal ventilation. During pregnancy, her clinical condition remained fairly stable until the 25th gestational week. Thereafter she experienced more problems with mobility and respiration. Fetal growth was normal as monitored by regular ultrasound investigations. A healthy boy was born at a gestational age of 37 weeks and 5 days by elective Cesarean section. There were no maternal complications and the child developed normally. One year after delivery the mother's physical condition was similar as prior to her pregnancy. Pharmacokinetic studies following enzyme infusion showed that alglucosidase alfa was secreted into the breast milk. Activity levels in the milk (245 nmol/ml.h) peaked at 2.5h after the end of the infusion; which was 2h later than in the plasma (80 μmol/ml.h). Twenty-four hours after start of the infusion, the enzyme activity in the breast milk was back to the pre-infusion level. In this case report, the continuation of treatment with alglucosidase alfa during pregnancy and lactation has been safe for the mother and the child.


[Knowledge of and attitudes and adherence to the Spanish Guidelines for Asthma Management (GEMA) among Spanish health care professionals: the GEMA test Project].
Health care professionals' adherence to asthma guidelines is believed to be low. The aim of the present study was to determine the knowledge, attitudes, and adherence of Spanish health care professionals with respect to the Spanish Guidelines for Asthma Management (GEMA). A multiple choice test with 15 questions was constructed. Items assessed knowledge of and opinions and adherence to asthma guidelines in general and the GEMA in particular. Test completion was voluntary, individual, and anonymous. A total of 1,066 physicians and nurses took the test. The sample consisted of 241 (22.6%) respiratory medicine specialists and 244 (22.9%) nurses from the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), 221 (20.7%) pediatric pulmonologists from the Spanish Society of Pediatric Pulmonology (SENP), 220 (20.6%) general practitioners from the Spanish Society of Family and Community Medicine (semFYC), 181 (17%) general practitioners from the Spanish Society of Rural and General Medicine (SEMERGEN), and 38 (3.6%) others. Asthma guidelines were considered useful or very useful by 805 (76%), and 771 (72%) stated they were familiar with the GEMA. However, 388 (36%) admitted that they followed guidelines seldom or never. The level of adherence to the GEMA was poor for 243 (30.3%) respondents. The multivariate analysis revealed that low adherence was associated with the following characteristics: coming from the geographic center or south of Spain; being a primary care physician, unfamiliar with guidelines, or unconvinced of their utility; and not being a user of spirometry. Even though the majority of Spanish health care professionals surveyed seem to know of the GEMA, their adherence to those guidelines is very low. Educational programs that seek to improve knowledge of asthma guidelines should consider the profile of professionals with low adherence to the GEMA so as to include educational strategies that target them specifically.


Securing urethral catheters in patients undergoing urethrovesical anastomosis.
Securing urethral catheters for the optimal healing of and prevention of extravasation at the urethrovesical anastomosis. This article describes the technique that we use to help secure Foley catheters or replace them if necessary. In the rare patients where disruption of the anastomosis or loss of the catheter prematurely takes place, the nylon suture can be used to replace the catheter without jeopardizing the anastomotic line.


The widespread nature of phenotypic variability in hepatomas and cell lines, in the form of a geometric series.
The phenomenon of geometric phenotypic variability is described and its widespread occurrence is established by a new analysis of data from a literature survey of quantitative variation in 39 different enzymes and other cell products in hepatomas and cell lines. The range of variation from hepatoma to hepatoma or from cell line to cell line was between 3- and 700-fold, depending on the particular cell product. By collating together and normalizing the data for the enzymes and other cell products surveyed, it was demonstrated in a statistically valid manner that the quantitative variation for most, if not all, of the enzymes and serum albumin was not random, but followed a geometric series, the consecutive terms of which differed by a factor of square root 2. In addition, examples are presented to show that quantitative inheritance in normal tissues also occurs along this geometric series.


Sex chromosome dosage compensation: definitely not for everyone.
Sex chromosomes often entail gene dose differences between the sexes, which if not compensated for, lead to differences between males and females in the expression of sex-linked genes. Recent work has shown that different organisms respond to sex chromosome dose in a variety of ways, ranging from complete sex chromosome dosage compensation in some species to active compensation of only a minority genes in other organisms. Although we still do not understand the implications of the diversity in sex chromosome dosage compensation, its realization has created exciting new opportunities to study the evolution, mechanism, and consequences of gene regulation. However, confusion remains as to what sorts of genes are likely to be dosage compensated, how dosage compensation evolves, and why complete dosage compensation appears to be limited to male heterogametic species. In this review, I survey the status of dosage compensation to answer these questions and identify current controversies in this fast-moving field.


Is mode of first birth a risk factor for subsequent preterm birth?
Previous preterm birth is a strong predictor of subsequent preterm birth, but less is known about the causes of preterm birth following a full-term first pregnancy. Recent research has highlighted previous caesarean section as a potential risk factor. To examine the relationship between mode of first birth and the risk of subsequent preterm birth in New South Wales (NSW), Australia. A population-based record-linkage study of NSW women who had a live singleton first birth at ≥37 weeks gestation, followed by a singleton second birth between 2005 and 2017. Relative risk (RR) and 95% CI of preterm birth in the subsequent pregnancy was calculated using modified Poisson regression, with mode of first birth as the exposure. Spontaneous preterm birth and preterm prelabour caesarean were secondary outcomes. Women who had either an intrapartum (RR: 1.26, 95% CI 1.19-1.32) or prelabour caesarean (RR: 1.26, 95% CI 1.18-1.35) first birth had a higher risk of subsequent preterm birth (any birth <37 weeks gestation), than those who birthed vaginally. Women who had a previous instrumental birth (RR: 0.85, 95% CI 0.79-0.91) or prelabour caesarean (RR: 0.74, 95% CI 0.67-0.82) had lower risks of subsequent spontaneous preterm birth. However, prior prelabour caesarean also greatly increased risk of subsequent preterm prelabour caesarean (RR: 5.25, 95% CI 4.65-5.93). The mode of first birth has differing effects on the risk of subsequent spontaneous preterm birth and preterm prelabour caesarean. Awareness of the risk of subsequent preterm birth following caesarean section may help inform clinical decisions around mode of first birth.


Methods for copy number aberration detection from single-cell DNA-sequencing data.
Copy number aberrations (CNAs), which are pathogenic copy number variations (CNVs), play an important role in the initiation and progression of cancer. Single-cell DNA-sequencing (scDNAseq) technologies produce data that is ideal for inferring CNAs. In this review, we review eight methods that have been developed for detecting CNAs in scDNAseq data, and categorize them according to the steps of a seven-step pipeline that they employ. Furthermore, we review models and methods for evolutionary analyses of CNAs from scDNAseq data and highlight advances and future research directions for computational methods for CNA detection from scDNAseq data.


Blood glucose levels in portal and peripheral circulation and their relation to food intake in the rat.
Rats weighing about 450 g were provided with permanent catheters in the portal vein and the right auricle. This method allows blood sampling from the portal and peripheral circulation at the same moment in the nondisturbed unanesthetized rat. In the ad lib condition the portal glucose level was higher than that in the general circulation before, during, and after the meal. After a fast of 22 hr premeal portal vein levels were equal to those of the general circulation. During the meal the portal glucose levels rose to about 150 mg per 100 ml whereas those of the general circulation did not exceed 130 mg/100 ml. Experiments with glucose infusions systemically and intraportally show that, under conditions of mild deprivation, the level of glucose in the portal vein plays no or only a very minor role in the termination of feeding.


Clinical manifestation and pathologic finding of unilateral acute hydrops after bilateral laser in situ keratomileusis.
We present a case of unilateral acute hydrops that developed in 25-year-old man 6 years after bilateral laser in situ keratomileusis (LASIK) for the correction of 2.75 diopters (D) of myopia. Preoperative corneal thickness using ultrasound pachymetry were 556 microm in the right eye and 554 microm in the left eye. Preoperative corneal topography of both eyes showed an asymmetric bow-tie pattern with inferior steepening. Forty-seven months after LASIK, the left eye developed astigmatism and enhancement excimer ablation was performed. Sixteen months after enhancement, a definite sign of keratectasia was detected in the left eye. Twenty-six months after enhancement, acute hydrops occurred in the left eye. The interface of the LASIK wound was separated and filled with aqueous humor. Penetrating keratoplasty was performed to avoid perforation. The keratocytes at the edge between the peripheral flap and remaining stroma showed mixoid degeneration and edematous change suggesting dying cells.


Thrive Health: a New Venture Connecting Patient Advocacy to Well-Being.
As part of the British Columbia government's response to the COVID-19 pandemic outbreak, an online self-assessment tool was launched to help with symptom assessment and to provide necessary health information for people. The tool was developed by Thrive Health, a company which has been working to improve the delivery of e-health in Canada since 2016, with an emphasis on well-being. This review captures this company's purpose and role in addressing the needs of patients and healthcare providers in the community, to change the definition of healthcare. In pursuing this goal, Thrive Health is innovating to make the long lost connection between physical and mental health through an online app with design features supported by research around subjective well-being, as a measurement of effective community development and human progress. This very characteristic is what establishes the company's uniqueness among other similar patient advocacy groups, and connects patient advocacy to happiness and well-being.


Nitrite-cured meats as a source of endogenously and exogenously formed N-nitrosoproline in the ferret.
Nitrite-cured meat containing 120 mg Na15NO2/kg was fed to male ferrets (Mustela putorius furo). During consumption of the meat, the animals were dosed orally with 0.87 mmol [2-2H]proline. All urine was collected throughout the study and analysed for total N-nitrosoproline (NPRO) and isotopic enrichment of NPRO by mass spectrometry. The cured-meat diet increased the urinary excretion of NPRO 14-fold. Isotope analyses indicated that approximately 70% of the NPRO came from the cured meat, the majority of which was analytically unavailable or 'bound' NPRO in the meat. A small portion of the excreted NPRO appeared to be formed in the stomach as a result of ingesting the cured meat. A minor amount of the excreted NPRO did not contain any isotopically labelled atoms. The administration of ascorbic acid did not significantly alter NPRO excretion. Animals dosed orally with 11.4 mumol of a peptide in which the N-terminal proline was nitrosated increased their excretion of NPRO by 385 nmol over the following 48 hr. These data indicate that nitrite-cured meat contains bound NPRO which contributes to the total amount of NPRO in the urine.


Nurse staffing laws: should you worry?
All 50 states could soon set mandates on RN staffing. Plans vary widely. In some states,,hospitals and nursing groups are uniting to shape the rules.


Ligand-Controlled Diastereoselective 1,3-Dipolar Cycloadditions of Azomethine Ylides with Methacrylonitrile.
Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.


Design and synthesis of aptamer-cyclometalated iridium(III) complex conjugate targeting cancer cells.
Targeted therapy showed broad application prospects in the treatment of various types of cancer. Through carriers such as aptamers, antibodies, proteins and peptides, targeted therapy can selectively deliver drugs into tumor cells. Compared with traditional treatment methods such as chemo- and radiotherapy, targeted drug delivery systems can reduce the toxic effects of drugs on normal cells and avoid adverse reactions. Herein, an aptamer-cyclometalated iridium(III) complex conjugate (ApIrC) has been designed and developed as a targeted anticancer agent. Owing to the targeting ability of aptamers, ApIrC specifically bound to nucleolin over-expressed on the surface of cancer cells and showed strong fluorescence signal for tumor imaging and diagnosis. ApIrC had more substantial cellular uptake in cancer cells than the iridium complex alone and exhibited favorable low toxicity to normal cells. After uptake by cells through endocytosis, ApIrC can selectively accumulated in mitochondria and induced caspase-3/7-dependent cell death. Remarkably, ApIrC can also specifically target 3D multicellular spheroids (MCSs) and show excellent tumor permeability. So, it can effectively reach the interior of MCSs and cause cell damage. To our knowledge, this is the first report of the aptamer-cyclometalated iridium(III) complex conjugate which studied for cancer targeted therapy. The developed conjugate has great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment.


Gray matter abnormalities in patients with social anxiety disorder: A voxel-based morphometry study.
The main objective of this study was to investigate the gray matter volume (GMV) differences between the patients with social anxiety disorder (SAD) and healthy controls, using VBM analysis. A total of 27 consecutive patients (15 women and 12 men) with SAD and 27 age and sex-matched healthy control subjects were included in this study. With magnetic resonance imaging, we examined GMV differences between SAD and healthy control groups. We found that GMV in the right middle and inferior temporal, left superior parietal, left precuneus and right fusiform areas were significantly greater in patients with SAD than in healthy controls. In addition, GMV in the right inferior and middle temporal regions were positively correlated with the social avoidance and total social anxiety scores of the participants in the SAD group. Lastly, greater GMV in the left superior parietal and precuneal regions were correlated with the higher disability in the social life of the patients with SAD. Our results suggest that the regions that showed significant GMV differences between the two groups play an important role in the pathophysiology of SAD and increased GMV in these regions might reflect a pathological process of neural abnormalities in this disorder.


Preventive effects of jiedu granules combined with cinobufacini injection versus transcatheter arterial chemoembolization in post-surgical patients with hepatocellular carcinoma: a case-control trial.
To investigate the therapeutic effects of Jiedu granules, a Chinese medicine (CM) compound, plus cinobufacini injection, which was extracted from skin of Bufo bufo gargarizans Cantor, to prevent the recurrence of hepatocellular carcinoma (HCC) after surgical resection. In this case-control trial, a total of 120 patients who stayed in Changhai Hospital were enrolled from December 2001 to December 2006. Sixty patients were treated with Jiedu granules plus cinobufacini injection to prevent tumor recurrence after operation (CM group) and 60 patients were treated with transcatheter arterial chemoembolization (TACE) after operation (TACE group). Progression-free survival (PFS) and overall survival (OS) rates were determined to evaluate the therapeutic effects of post-operative management of patients with HCC. PFS in the CM group was 18.07 months [95% confidence interval (CI): 12.49-23.65] and the 1-, 2-, 3-, 4- and 5-year PFS rates were 61%, 39%, 26%, 22% and 12%, respectively. PFS in the TACE group was 8.03 months (95% CI: 6.63-9.44) and the 1-, 2-, 3-, 4- and 5-year PFS rates were 34%, 11%, 7%, 2% and 0%, respectively. There was significant difference in survival rate between the two groups (P<0.01). The mean survival time (MST) of patients in the CM group was 49.53 months versus 39.90 months of the TACE group. The 1-, 2-, 3-, 4- and 5-year survival rates were 90%, 82%, 80%, 70% and 63%, respectively, in the CM group, and 79%, 70%, 60%, 60% and 36%, respectively, in the TACE group. There was significant difference in survival time between the two groups (P=0.045). Jiedu granules plus cinobufacini injection, a combination that is commonly used for post-operation management of HCC, can postpone tumor recurrence and metastasis, prolong the survival time and increase the survival rate of post-surgical patients with HCC. However, these findings need to be confirmed in a prospective, randomized controlled trial.


First detection of TBE virus sequences in Ixodes ricinus from Friuli Venezia Giulia (Italy).
We report, for the first time, the presence of tick-borne encephalitis (TBE) virus in the tick Ixodes ricinus collected in the Friuli Venezia Giulia region of north-eastern Italy. Using molecular methods, we demonstrate that the TBE virus carried by ticks from FVG is a western European strain. Sequence analysis of the 5' NCR showed 98.4% identity to the Neudoerfl strain.


A serious game for engaging older adults in end-of-life care discussion: A mixed method study.
To examine the acceptability of a board game newly developed through a co-design process for promoting end-of-life care discussion among Chinese older adults. A multi-centre mixed method study, including a one group pre-test post-test study and focus group interviews, was conducted. Thirty older adults participated in a one-hour game session in a small group format. Acceptability was assessed by attrition rate and satisfaction with the game. Participants' experiences with the game were explored qualitatively. Within-subject changes in self-efficacy and readiness for advance care planning (ACP) behaviours were also examined. The players generally had positive experiences with the game, giving a low attrition rate. A significantly higher level of self-efficacy in sharing end-of-life care preferences with surrogates was reported after the game session (p = 0.008). There was a slight increase in the proportion of players indicated that they would complete ACP behaviours in the coming months immediately after the intervention. A serious game is acceptable by Chinese older adults to raise discussions regarding end-of-life matters. A game can be an ice-breaking tool to increase self-efficacy towards communicating end-of-life care preferences with surrogates, but follow-up support is needed to facilitate the uptake of ACP behaviours.


Default-mode network activity distinguishes amnestic type mild cognitive impairment from healthy aging: a combined structural and resting-state functional MRI study.
Resting-state functional magnetic resonance imaging (MRI), have revealed coactivation in a distributed network that characterizes the default-mode in the human brain. However, details from resting-state imaging in amnestic type mild cognitive impairment (aMCI) is poorly understand. Regional homogeneity, which characterizes low-frequency blood oxygenation level dependent fluctuation, after statistically controlling for the regional atrophy and age in resting-state, were examined and compared between the two groups. When regional atrophy was controlled, decreased regional homogeneity in posterior cingulate cortex and precuneus still remained significant in aMCI patients. In addition the aMCI subjects displayed several regions of increased homogeneity, typically in right inferior parietal lobule, right fusiform gyrus and bilateral putamen. The impairment of posterior cingulate and precuneus could be an important marker to distinguish aMCI from healthy aging in the resting-state. Moreover, the increased regional homogeneity changes would be consistent with compensation for damage to the medial temporal regions and limbic structures, perhaps by recruitment of alternative regions.


Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study.
Critical illness myopathy (CIM) and polyneuropathy (CIP), alone or in combination (CIP/CIM), are frequent complications in patients in the intensive care unit (ICU). There is no evidence that differentiating between CIP and CIM has any impact on patient prognosis. 1-year prospective cohort study of patients developing CIP, CIM or combined CIP and CIM during ICU stay. 28 out of 92 (30.4%) patients developed electrophysiological signs of CIP and/or CIM during their ICU stay, which persisted in 18 patients at ICU discharge. At hospital discharge, diagnoses in the 15 survivors were CIM in six cases, CIP in four, combined CIP and CIM in three and undetermined in two uncooperative patients. During the 1-year follow-up of six patients with CIM, one patient died and five recovered completely within 3 (three patients) to 6 (two patients) months. Of three patients with CIP/CIM, one died, one recovered and one with residual CIP remained tetraplegic. Of four patients with CIP, one recovered, two had persisting muscle weakness and one remained tetraparetic. CIM has a better prognosis than CIP. Differential diagnosis is important to predict long-term outcome in ICU patients.


Effect of early caffeine on neurodevelopmental outcome of very low-birth weight newborns.
The objective of this study is to evaluate the effect of early caffeine therapy started within the first 48 h of life on neurodevelopmental outcome in very low birth weight (VLBW) newborns. VLBW newborns received either caffeine therapy within first 48 h of life (Early group), after 3rd day of life (Late group) or no caffeine during first month of life as per clinical team. A cohort of these newborns (n = 160) who survived were evaluated using Bayley Scale of Infant Development III (BSID III) developmental testing between 18 and 22 months of corrected age. VLBW newborns in the "Early group" had significantly better composite, cognitive, language and motor BSID III scores as compared to those in "Late group" and no caffeine group. Composite BSID III scores were unchanged in the presence or absence of chorioamnionitis for "Early group", while the BSID III scores were significantly lower in the presence of acute chorioamnionitis in "Late group" and no caffeine group. Early caffeine therapy was associated with better BSID III scores in a cohort of VLBW newborns. Newborns with acute chorioamnionitis benefited from early caffeine therapy.


Physicochemical characterisation of depleted uranium (DU) particles at a UK firing test range.
Depleted uranium (DU) particles were isolated from soils at Eskmeals, UK, where DU munitions have been tested against hard targets and unfired DU buried in soils for corrosion studies. Using electron microscopy and X-ray analyses, three classes of particles were identified: (1) DU aerosols and fragments, typically 1-20 μm diameter, composed mainly of uranium as UO(2) and U(3)O(8), (2) solidified molten particles, typically 200-500 μm diameter, composed of U, mixed with Fe from target materials and (3) deposits and coatings, often of metaschoepite on sand grains up to 500 μm diameter. The first two particle types are derived from firing impacts, the last from corrosion of buried uranium metal. Alpha and mass spectrometry allowed quantitative elemental and isotopic characterisation of DU-containing particulate environmental samples.


Improved insulin receptor assay: effects of an antidiabetic sulphonylurea on liver membrane insulin receptors from obese hyperglycaemic mice.
1 A simple assay of liver membrane insulin receptors is described, under conditions which apparently stabilized the insulin-receptor complex. The receptor population was measured in the presence of physiological doses of radioactive hormone under conditions which minimized negative co-operativity effects. 2 Equilibrium between receptor and hormone was attained in vitro within 60 min of incubation time at 13 degrees C with no apparent loss of binding sites after 3 h of incubation. 3 Liver membranes from lean mice possessed 8.8 times the receptor number per mg membrane protein measured in membranes from obese hyperglycaemic (ob/ob) littermates. After treatment of ob/ob mice with ARDF-26 (Gliquidon; Boehringer Ingelheim Ltd) the concentration of liver membrane insulin receptors was increased 5 fold.


Signals from the lysosome: a control centre for cellular clearance and energy metabolism.
For a long time, lysosomes were considered merely to be cellular 'incinerators' involved in the degradation and recycling of cellular waste. However, now there is compelling evidence indicating that lysosomes have a much broader function and that they are involved in fundamental processes such as secretion, plasma membrane repair, signalling and energy metabolism. Furthermore, the essential role of lysosomes in autophagic pathways puts these organelles at the crossroads of several cellular processes, with significant implications for health and disease. The identification of a master regulator, transcription factor EB (TFEB), that regulates lysosomal biogenesis and autophagy has revealed how the lysosome adapts to environmental cues, such as starvation, and targeting TFEB may provide a novel therapeutic strategy for modulating lysosomal function in human disease.


Conformation of mononucleotides and dinucleoside monophosphates. P[H] and H[H] nuclear Overhauser effects.
The phosphorus-proton nuclear Overhauser effect (NOE) was used to investigate the quantitative distribution of rotamers about the C3'--O3' bond (phi') of 3'-AMP and 2',3'-cyclic-CMP and the C4'--C5', C5'--O5' bonds (psi, phi) of 5'-AMP. Phosphorus-proton and proton-proton NOE's were used to provide a qualitative insight into the backbone conformation and the glycosyl angle torsions of adenosylyl-(3' leads to 5')-adenosine (ApA). The major psi rotamer in 5'-AMP is the 60 degree (gg) form, while the major phi rotamer is the 180 degrees (g'g') form. The constrained model, 2',3'-cyclic-CMP, manifests the C3'endo furanose pucker predominantly. The results from these two models are consistent with nuclear magnetic resonance (NMR) J coupling analyses. The phi; distribution of 3'-AMP is dominated (77%) by the 180 degrees g- rotamer. The 3'-AMP results are consistent with phosphorus-hydrogen coupling constant analyses, but do not accord with phosphorus-carbon coupling constant results. The phosphorus-proton NOE reveals that the phosphorus of ApA occupies a region of conformation space not seen in 5'-AMP. The proton-proton NOE on APA shows a significant portion of syn rotamer in both X distributions and detects a cross-purine ring interaction consistent with base stacking known to exist in this system.


African swine fever virus MGF505-11R inhibits type I interferon production by negatively regulating the cGAS-STING-mediated signaling pathway.
African swine fever (ASF) is an acute, hemorrhagic, and highly contact infectious disease caused by African swine fever virus (ASFV) infecting domestic pigs or wild boars, the mortality rate up to 100 %. Evasion of host innate immunity plays a vital role in the pathogenesis of ASFV. Studies have showed that the MGF505 genes involve in regulating the IFN-I response, but its mechanism of action remains poorly understood. In our present study, ASFV MGF505-11R inhibited IFN-β and ISRE activation induced by cGAS, IRF7, IRF3-5D, STING, IKKε and TBK1 accompanied by decreases of IFN-β, ISG15 and ISG56 mRNA transcription. ASFV MGF505-11R interacted with STING, degrading STING expression by the lysosomal, ubiquitin-proteasome and autophagy pathways. Moreover, ASFV MGF505-11R could inhibit the phosphorylation of TBK1 and IRF3 stimulated by cGAS/STING overexpression. Finally, the truncation mutation analysis indicated that the 1-191 aa and 182-360 aa of ASFV MGF505-11R could inhibit cGAS-STING-mediated activation of IFN-β promoters. In short, these results demonstrated that ASFV MGF505-11R involved in regulating the IFN-I response by negatively regulating the cGAS signaling pathway. In summary, this study preliminarily clarified the molecular mechanism of ASFV MGF505-11R gene antagonizing IFN-I-mediated antiviral, which will helpfully provide new strategies for treatment and prevention of ASF.


Comparison of separation modes for microchip electrophoresis of proteins.
Separation of a set of model proteins was tested on a microchip electrophoresis analytical platform capable of sample injection by two different electrokinetic mechanisms. A range of separation modes-microchip capillary zone electrophoresis, microchip micellar electrokinetic chromatography, and nanoparticle-based sieving-was tested on glass and polydimethylsiloxane/glass microchips and with silica-nanoparticle colloidal arrays. The model proteins calmodulin (18 kiloDalton), bovine serum albumin (66 kDa), and concanavalin (106 kDa) were labeled with Alexa Fluor 647 for laser-induced fluorescence detection. The best separation and resolution were obtained in a silica-nanoparticle colloidal array chip.


Improvement of the C-glycosylation Step for the Synthesis of Remdesivir.
The bulk supply of the antiviral C-nucleoside analogue remdesivir is largely hampered by a low-yielding C-glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodology for this critical transformation. By utilizing diisopropylamine as a cost-effective additive, the addition reaction furnishes an optimal yield of 75% of the desired ribofuranoside adduct, representing the highest yield obtained thus far for this key step. The method proved suitable for hectogram scale synthesis without column chromatographic operations.


Identification of an acid-lipase in human serum which is capable of solubilizing glycophosphatidylinositol-anchored proteins.
A lipase has been identified in human serum which can convert the membrane form of the variant surface glycoprotein of Trypanosoma brucei to a water soluble form. The conversion can be monitored by loss of [3H] myristic acid incorporated into the diacylglycerol of the glycophosphatidylinositol membrane anchor of the protein, but does not lead to the exposure of the antigenic determinant in the polar head group of the glycolipid. The serum lipase is a glycoprotein, and is optimally active at pH 5.4. Treatment at 62 degrees for one hour does not inactivate the enzyme, which is inhibited by chelating agents.


Population distributions of plant size and light environment of giant ragweed (Ambrosia trifida L.) at three densities.
Plots in a naturally occurring population of giant ragweed (Ambrosia trifida L.) near Ames, Iowa, USA were left unthinned (high density,=693 plants/m2) or were thinned in early June 1989 to create low and medium densities of 10 and 50 plants/m2. Size and light environment of individual plants were measured at monthly intervals from June to September. By September, low density plants had 15 times greater biomass/plant and 30 times greater leaf area/plant than high density plants, although biomass and leaf area per unit land area decreased with decreasing density. Plants at high density allocated more biomass to stem growth, but plants at medium and low density had successively higher leaf area ratios, higher potential photosynthetic rates, higher allocation to leaves, and higher growth rates. Average light on leaves decreased with increasing density and also decreased over the growing season in the low and medium densities. The distribution of light environments of individual plants was non-normal and skewed to the left in most months, in contrast to the rightwards skew of distributions of plant size parameters. Inequality in the distributions, as measured by coefficient of variation and Gini coefficients, increased over most of the growing season. There was little effect of density on inequality of stem diameter, height, or estimated dry weight, but inequality in reproductive output greatly increased with density. There was greater inequality in number of staminate flowers produced than in number of pistillate flowers and seeds produced. Path analysis indicated that early plant size was the most important predictor of final plant size and reproductive output; photosynthesis, conductance, and light environment were also significantly correlated with size and reproduction but usually were of minor importance. Variation in growth rate apparently increased inequality in plant size at low density, whereas belowground competition and death of smaller plants may have limited increases in inequality at high density.


Assessing the impact of national level interventions on workplace respiratory disease in the UK: part 1--changes in workplace exposure legislation and market forces.
The 2004 amendment to the Control of Substances Hazardous to Health 2002 regulations (COSHH 2004) introducing workplace exposure limits (WELs) was enacted in the UK in 2005. This study aimed to determine whether introducing this legislation coincided with a reduction in the incidence of work-related short latency respiratory disease (SLRD) attributed to the agents with a WEL. The second objective was to determine whether changes in legislation, WELs and market forces coincided with a reduction in the incidence of SLRD attributed to glutaraldehyde and latex. Reports of SLRD made to the Surveillance of Work-related and Occupational Respiratory Disease scheme were used to estimate the change in incidence within reporters between two time periods (interrupted time series design) using a longitudinal, negative binomial regression model with β distributed random effects. A statistical interaction term was included in the model to make comparisons between the groups defined by suspected causal agent and/or occupation, essentially comparing two interrupted time series. Time periods were defined prospectively representing the changes in legislation or market forces. The introduction of the COSHH 2004 legislation in the UK coincided with a significant reduction in reports of SLRD attributed to agents with a WEL relative to those without a WEL (ratio of incidence rate ratios: 0.70; 95% CI 0.52 to 0.93) and a significant reduction in SLRD attributed to glutaraldehyde in healthcare workers (0.20; 0.07 to 0.57) and latex in all workers (0.37; 0.16 to 0.85). These data are consistent with a beneficial effect of legislation aiming to reduce workplace exposures.


Impact of comorbidity on overall survival in patients surgically treated for renal cell carcinoma.
Although the classification of cancer has traditionally focused on the gross and microscopic characteristics of the tumor, the overall health of patients can affect their survival. Because patients with renal cell carcinoma often have other medical conditions, we explored the effect of preexisting medical disease on survival after radical and partial nephrectomy. From January 1995 to August 2003, the comorbidity status of 697 patients with nonmetastatic renal cell carcinoma who had undergone radical or partial nephrectomy was prospectively coded using the Adult Comorbidity Evaluation-27. Histopathologic review of all slides was performed according to the 2004 World Health Organization scheme. Other variables analyzed included age, sex, ethnicity, pathologic stage, Fuhrman grade, and tumor size. The effect of these factors on overall survival (OS) was analyzed using Cox proportional hazards regression model. The median follow-up was 32.2 months for survivors and 36.5 months for all patients. The OS rate at 1, 3, and 5 years was 92.0% (641 patients), 75.3% (525 patients), and 52.7% (367 patients), respectively. Univariate analyses demonstrated that age, comorbidity, tumor size, Fuhrman grade, and pathologic stage were significant predictors of OS. Multivariate analysis revealed that age (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.10 to 1.82, P = .0067), comorbidity (HR 1.37, 95% CI 1.16 to 1.63, P = .0002), pathologic stage (HR 1.97, 95% CI 1.60 to 2.41, P < .0001), and grade (HR 1.83, 95% CI 1.28 to 2.59, P = .0008) predicted for OS. The results of this study have demonstrated that comorbidity is an independent prognostic factor for OS in patients with renal cell carcinoma. Capturing the comorbidity information using validated instruments can improve the preoperative evaluation of patients by providing more accurate prognostic information.


Fabrication of chitosan/graphene oxide composite aerogel microspheres with high bilirubin removal performance.
Functional chitosan/graphene oxide (CS/GO) composite aerogel microspheres were fabricated via CO2 supercritical drying, which displayed excellent performance for bilirubin removal. The morphology and chemical structure of CS/GO composite aerogel microspheres were characterized, which illustrated a nanoporous structure with a maximum specific surface area of 174.69 m2/g, and a special pore size distribution at 20-40 nm, also a good mechanical property. Importantly, the composite aerogel microspheres (10% GO) revealed a large adsorption capacity (178.25 mg/g) for bilirubin within 2 h. Dynamic adsorption experiment illustrated that the aerogel microspheres adsorbed much more bilirubin with a shorter equilibrium time of about 30 min. Besides, the adsorption mechanism of bilirubin by the CS/GO composite aerogel microspheres was investigated through the relevant model fitting, including adsorption kinetics and adsorption isotherm, which illustrated that the mechanism included both physical and chemical processes, but chemical adsorption was dominated. Adsorption isotherm indicated that bilirubin adsorption by the microspheres was fitted well with Freundlich isotherm, which ascribed to multilayer adsorption. After five adsorption-desorption cycles, the adsorption capacity still maintains large adsorption capacity. In addition, the hemolysis rate and coagulation time tests presented the good blood compatibility for the adsorbents. Therefore, the CS/GO composite aerogel microspheres with rapid, high adsorption capacity and good blood compatibility might be promising for hyperbilirubinemia treatment.


Formation of extracellular and intracellular ice during warming of vitrified mouse morulae and its effect on embryo survival.
In vitrified solutions, ice can form during warming if the concentration of the cryoprotectant is insufficient. For the cryopreservation of cells, ice is innocuous when it remains outside the cell, but intracellular ice (ICI) is lethal. We tried to estimate the conditions in which ICI forms in vitrified mouse morulae during warming. The solutions for the experiments (EFS10-EFS50) contained 10-50% ethylene glycol plus Ficoll plus sucrose. When vitrified EFS20, EFS30, and EFS40 were kept at -80 degrees C, they remained transparent after 3 min, but turned opaque after 60 min (EFS20, EFS30) or 24h (EFS40). Morulae were vitrified with EFS solutions after exposure for 30-120 s at 25 degrees C. They were warmed by various methods and survival was assessed in culture. After rapid warming (control), survival was high with EFS30 (79-93%) and EFS40 (96-99%). After slow warming, survival decreased with both EFS30 (48-62%) and EFS40 (44-64%). This must be from the formation of ICI. To examine the temperature at which ICI formed during slow warming, vitrified embryos were kept at various sub-zero temperatures during warming. Survival with EFS30 and EFS40 decreased on keeping samples for 3 min at -80 (25-75%), -60 (7-49%), -40 (0-41%), or -20 degrees C (26-60%). When samples were kept at -80 degrees C for 24h, the survival decreased to 0-14%. These results suggest that ICI forms at a wide range of temperatures including -80 and -20 degrees C, more likely between -60 and -40 degrees C, and the ice forms not only quickly but also slowly.


Prognostic factors for the surgery for mesial temporal lobe epilepsy: longitudinal analysis.
Determining long-term prognostic factors of surgery for mesial temporal lobe epilepsy (MTLE) is important for identifying ideal candidates and predicting the prognosis for individual patients. We tried to identify the prognostic factors of anterior temporal lobectomy (ATL) for MTLE with longitudinal multivariate analysis. Two hundred twenty-seven patients with MTLE were included in this study. The primary outcome variable was patient status 1-5 years after surgery: seizure free, or not. Clinical characteristics and recent diagnostic modalities were considered as prognostic factors. Univariate and standard multiple logistic-regression analysis for outcome at 1 and 5 years after surgery and the generalized estimation equation (GEE) model for longitudinal multiple logistic regression of the 5-year follow-up period were used. The seizure-free rate at 1 year was 81.1% and decreased to 75.2% at 5 years after surgery. By the univariate or standard multiple logistic-regression analysis, age at surgery or hippocampal sclerosis on magnetic resonance imaging (MRI) ipsilateral to surgery was significant for the postsurgical outcome. However, the longitudinal analysis by the GEE model revealed that younger age at surgery [odds ratio (OR), 0.59; 95% confidence interval (CI), 0.43-0.81], absence of secondarily generalized tonic-clonic seizure (2 degrees GTCS; OR, 0.45; 95% CI, 0.26-0.79), and hippocampal sclerosis on MRI (OR, 2.44; 95% CI, 1.11-5.26) were significant predictors of a good surgical outcome. Age at surgery, presence of 2 degrees GTCS, and hippocampal sclerosis on MRI are independent prognostic factors for ATL in MTLE. These findings suggest that MTLE is a progressive disorder, and surgical outcome is better when early ATL is performed.


Bayesian pedigree inference with small numbers of single nucleotide polymorphisms via a factor-graph representation.
We develop a computational framework for addressing pedigree inference problems using small numbers (80-400) of single nucleotide polymorphisms (SNPs). Our approach relaxes the assumptions, which are commonly made, that sampling is complete with respect to the pedigree and that there is no genotyping error. It relies on representing the inferred pedigree as a factor graph and invoking the Sum-Product algorithm to compute and store quantities that allow the joint probability of the data to be rapidly computed under a large class of rearrangements of the pedigree structure. This allows efficient MCMC sampling over the space of pedigrees, and, hence, Bayesian inference of pedigree structure. In this paper we restrict ourselves to inference of pedigrees without loops using SNPs assumed to be unlinked. We present the methodology in general for multigenerational inference, and we illustrate the method by applying it to the inference of full sibling groups in a large sample (n=1157) of Chinook salmon typed at 95 SNPs. The results show that our method provides a better point estimate and estimate of uncertainty than the currently best-available maximum-likelihood sibling reconstruction method. Extensions of this work to more complex scenarios are briefly discussed.


Peer-Assisted Learning (PAL): Perceptions and Wellness of First-Year Medical Students.
Medical education is oftentimes stressful and has been documented to compromise student well-being, hinder performance, and contribute to burnout. Many medical schools aim to foster students' sense of well-being. This can be accomplished by peer-assisted learning (PAL), which has the potential to improve student wellness and performance in medical school. The PAL program at Nova Southeastern University Dr. Kiran C. Patel College of Allopathic Medicine provides first-year medical students with educational sessions related to their curriculum, led by second-year medical students. The goal of this study was to determine the efficacy of PAL in promoting wellness and enhancing knowledge. Pre- and post-program surveys were distributed to students prior to and after the completion of PAL. Data analysis included frequencies of responses, qualitative analysis, and chi-square analysis. Thirty-eight out of 51 first-year medical students responded to the pre-program survey (response rate 75%) and 23 out of 51 responded to the post-program survey (response rate 45%). A majority of respondents from the pre-survey believed that PAL would provide them with tools necessary to be successful. These findings were similar in the post-program survey with a majority of attendees sharing that PAL enhanced their knowledge, reduced test-taking anxiety, and provided useful skills. Results from the pre- and post-program surveys suggest that PAL can enhance student well-being while improving knowledge of the material taught in medical school. The online version contains supplementary material available at 10.1007/s40670-021-01381-0.


Effects of phenytoin on sympathetic reflex responses in the cat.
Phenytoin (DPH), in a low dose (2 mg/kg) was found to potentiate reflex elevations in blood pressure and responses of the nictitating membrane induced either by the electrical stimulation of the sciatic nerve or by intravenously applied pentetrazol in light anaesthetized cats. Pressor responses to carotid occlusion under chloralose anaesthesia were also potentiated. In contrast a high dose (20 mg/kg) of DPH exerted an inhibitory effect on these responses. These effects of DPH on sympathetic reflex responses proved to be long-lasting. Intravenously applied picrotoxin (0.05 mg/kg) or the same dose of ouabain, injected into the vertebral artery, partially reversed the inhibitory effect of DPH (20 mg/kg). Our data support the suggestion that DPH exerts its inhibitory action by effecting ionic fluxes in the CNS, mostly in inhibitory structures.


Correction: Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression.
[This corrects the article DOI: 10.1371/journal.pone.0153682.].


Colon capsule endoscopy compared with other modalities in the evaluation of pediatric Crohn's disease of the small bowel and colon.
Data on colon capsule endoscopy (CCE) in evaluating the small bowel and colon concurrently are rare. This study aimed to evaluate the accuracy of CCE in assessing disease activity of the small bowel and colon in pediatric Crohn's disease (CD) by comparison with magnetic resonance enterography (MRE), small-intestine contrast US (SICUS), and ileocolonoscopy. We prospectively enrolled 40 consecutive patients (22 male, 18 female, mean age 13.1 ± 3.1 years) with CD of the small bowel and colon. All underwent SICUS, MRE, CCE, and ileocolonoscopy sequentially over 5 days. All investigators were blinded to patient history and test results. Patients were classified as active or inactive for the small bowel and the colon according to specific criteria for each tool (simple endoscopic score for CD, Lewis score, US and magnetic resonance parameters of activity). For colon mucosa evaluation, ileocolonoscopy was the comparator. For the small bowel, a consensus panel was convened. Sensitivity of CCE to detect colon inflammation was 89%, and specificity was 100%. The positive predictive value (PPV) and negative predictive value (NPV) of CCE for colon inflammation were 100% and 91%, respectively. In the small bowel, CCE showed 90% sensitivity, 94% specificity, with PPV and NPV of 95% and 90%, respectively. Accuracy parameters for SICUS (sensitivity 90%, specificity 83%) and MRE (sensitivity 85%, specificity 89%) were lower than those for CCE. No serious adverse events related to the CCE procedure or preparation were reported. CCE is of great usefulness in evaluating both small bowel and colon mucosa in pediatric CD. This single, noninvasive tool makes it possible to evaluate the small-bowel and the colon concurrently with high diagnostic accuracy. Future multicenter studies need to define the role of CCE in the routine management of pediatric patients with CD. ( NCT02199626.).


The training of junior doctors for accident and emergency work: a case for urgent treatment?
The experience of casualty officers at the time of appointment has been compared, by questionnaire survey, with abilities and responsibilities 3 months after starting work in Accident and Emergency Medicine. Initial clinical and practical knowledge frequently did not match the demands of the new post. Some doctors felt unable to assume initial responsibility for important and commonplace clinical conditions. Many expressed dissatisfaction with the teaching they received. Only one-fifth of respondents had received any form of introductory course. Accident and Emergency work provides useful training for Senior House Officers pursuing a variety of careers, but adequate preparation is essential. This is not provided in the preregistration year. It is recommended that medical schools make greater efforts to ensure relevant comprehensive experience amongst their students before graduation. Introductory courses should be arranged for all new casualty officers and greater emphasis placed on the immediate availability of experienced supervisory staff in Accident and Emergency Departments.


Portuguese wild hop diversity assessment by fast SNP genotyping using high-resolution melting.
A set of seven SNP markers was used to evaluate the genetic diversity of wild Portuguese hops in comparison with commercial cultivars. A collection of 110 wild genotypes and 33 cultivars was characterized by a high-resolution melting analysis of short amplicons targeting SNP loci. Most of the 143 genotypes (75%) could be differentiated. Phylogenetic analysis showed three main clusters, one included almost exclusively (98%) wild accessions, being the others constituted of both wild and commercial genotypes. The study of population genetic structure placed the accessions into three genetic units, being one exclusively of Portuguese genotypes. The study showed the great biodiversity of the Portuguese hop germplasm and the notable differences (FST = 0.163, p<0.00001) from commercial hops. Results support the usefulness of the use of these seven markers for hop discrimination, with the fast and high-throughput HRMA technique for allele calling and contribute to the affirmation of the high richness breeding potential of Portuguese wild hops.


Monitoring of methylene blue monomers and dimers to control the bacterialogical water quality including application to photocatalysis.
In this study, we propose the development of a rapid and reliable method to control and to monitor microbial water quality. The methylene blue (MB) decolorization assay was based on the analysis of spectral profiles of dye in interaction with a different bacterial concentration. The determination of dye decolorization rate (DDR) shows a correlation between the MB reduction rate and the bacterial density. Moreover, the kinetic of the monomer and dimer equilibrium of MB in water mainly, the monitoring of bounded MB species in relationship with a knowed concentration of target bacteria, was allowed to establish a relationship between MB decolorization rate and bacterial density. Furthermore, this method was applied to evaluate the water quality after photocatalysis. Based on this method, the photocatalytic effects on bacterial density was highlighted by the decrease in DDR after photocatalytic treatment with fractioned times (0 to 5 h); this increase was followed by a decrease of bounded MB species and, an increase in free MB forms miming the reduction of bacterial density due to the biocide effects of photocatalysis process. However, the analysis of spectra profiles shows a weak but a continuous decrease in bounded MB dimer and monomer forms in the treated water samples exempt of culturable bacteria. Moreover, the MB spectra profiles were tended toward a negative control spectrum without superposition. Thus, the possibility of the presence of viable but non-culturable bacteria was expected; therefore, to optimize this tertiary water treatment process, an extending on proceeding time was recommended to avoid the bacterial resuscitation after photocatalysis.


Lamaze breathing: what every pregnant woman needs to know.
Lamaze breathing historically is considered the hallmark of Lamaze preparation for childbirth. This column discusses breathing in the larger context of contemporary Lamaze. Controlled breathing enhances relaxation and decreases perception of pain. It is one of many comfort strategies taught in Lamaze classes. In restricted birthing environments, breathing may be the only nonpharmacological comfort strategy available to women. Conscious breathing and relaxation, especially in combination with a wide variety of comfort strategies, can help women avoid unnecessary medical intervention and have a safe, healthy birth.


Quality of life in postmenopausal women with osteoporosis: a systematic review and meta-analysis.
Postmenopausal osteoporosis has become a global trend, which seriously affects women's quality of life. However, the differences remain unclear in health-related quality of life (HRQoL) among postmenopausal women with normal bone mineral density, osteoporosis, and osteoporotic fractures. The aim of this study was to assess health-related quality of life in women with three different bone states. Databases of PubMed, Embase, Cochrane, and Web of Science were based on the search terms, and the search time was set from the inception of each database to January 2022. A study was included if the researchers used a validated quality of life questionnaire to investigate the quality of life of postmenopausal women with osteoporosis or osteoporotic fractures. The random-effect model was used for meta-analysis, and the mean difference with a 95% confidence interval (95%CI) was calculated. Thirteen studies that met the inclusion criteria were systematically reviewed, involving 2897 postmenopausal women, and 12 of them were included in the meta-analysis. Postmenopausal women with osteoporosis had worse overall HRQoL and different HRQoL dimensions compared with postmenopausal women with normal bone density. Compared with postmenopausal women with osteoporosis, postmenopausal women with osteoporotic fractures had worse overall HRQoL and individual dimensions of HRQoL, especially physical component summary (SMD = - 0.61, 95% CI, - 0.98 to - 0.24). Bone mineral density was positively associated with HRQoL, while fragility fracture severity was negatively associated with HRQoL. Postmenopausal osteoporosis and fragility fractures reduce HRQoL to varying degrees in women. More research should be done to reduce the incidence of the disease.


Early B-lymphocyte precursors and their regulation by sex steroids.
This review describes an improved characterization of early B-lymphocyte precursors in mice and the remarkable sensitivity of the same cells to hormones. The nuclear enzyme terminal deoxynucleotidyl transferase (TdT) was used as a marker to image and characterize bone marrow cells lacking all lineage-associated markers. Most early TdT+ precursors have a distinctive density of c-kit and express the interleukin-7Ralpha chain, as well as flt-3/flk2, but lack CD34. An understanding of those cell surface properties made it possible to obtain highly enriched, viable cells with the potential to give rise to CD19+ lymphocytes in culture. A series of other flow cytometry and culture experiments suggested a possible differentiation sequence for these early pro-B cells. This new model was used to advantage in our studies of sex steroids. It appears that early precursors represent a hormone-sensitive control point for determining numbers of new B lymphocytes that are produced within bone marrow. We also compare and contrast these findings with B lymphopoiesis in humans.


Applied biomechanics of bone: functional and clinical perspectives.
Proper locomotion depends on the presence of a strong, intact skeletal system that is able to withstand the stresses and strains of everyday life. In this article, the authors discuss the function of force on bones from a clinical and biomechanical viewpoint. As is presented, bone is a living, viable organ that responds to both external and internal stimuli.


Large-scale ecological networks do work in an ecologically complex biodiversity hotspot.
Landscape-scale ecological networks (ENs) are interconnected conservation corridors of high-quality habitat used to mitigate the adverse effects of landscape fragmentation and to connect with protected areas. The effectiveness of ENs for biodiversity conservation and ecosystem function has been challenged. Here we show how an extensive system of ENs of remnant historic land was put in place at a large spatial scale (>0.5 million ha) in a plantation forestry context in a global biodiversity hotspot in southern Africa. These ENs can maintain indigenous and historic compositional and functional biodiversity, even in an area prone to the challenging effects of El Niño. Furthermore, ENs increase the effective size of local protected areas. Socio-ecological solutions and financial viability are also integrated as part of practical implementation of ENs. By adopting a retrospective analytical approach, biodiversity is maintained while also having productive forestry, making this a powerful agro-ecological approach on a large conservation-significant scale.


Brush-like gold nanowires-anchored g-C3N4 nanosheets with tunable geometry for ultrasensitive and regenerative SERS detection of gaseous molecules.
Strapping plasmonic substrate with a reliable ability to anchor molecules and achieve reproducible result provides trustworthy opportunities for flourishing surface-enhanced Raman scattering (SERS) technique. Herein, a facile controllable in-situ anisotropic growth strategy was exploited to anchor gold nanowires (Au NWs) onto two-dimensional g-C3N4 nanosheets (g-C3N4/Au NWs), facilitating a sensitive and recyclable SERS sensor for gaseous analytes. Benefiting from the attractive enrichment effect of the brush-like surface formed by numerous small Au NWs as well as their rich nanotips-mediated enhancement capability, the hybrid substrate showed an outstanding performance in SERS-based detection of trace 4-Aminothiophenol (4-ATP) molecules, demonstrating a monitoring limitation down to 10-8 M even in atmosphere. Satisfyingly, under visible light illumination, the efficient green photocatalytic ability derived from the g-C3N4 supporting matrix rendered reusable capability for the substrate, whose SERS signal was kept at a persistent high level throughout 6 cycles. Attributed to the narrow line width of SERS spectrum, the 4-ATP assay under the interference of 2-naphthalenethiol (2-NAT) was acquired in gas phase and the dependable recovery rates from 85.4 to 93.9% were confirmed as well. Thanks to the intriguing features including excellent sensitivity and recyclability, the g-C3N4/Au NWs substrate proposed here will pave the way toward the potential application of SERS technique in multiplexed gaseous detection.


Advantages of low pH and limited oxygenation in arsenite removal from water by zero-valent iron.
The removal of toxic arsenic species from contaminated waters by zero-valent iron (ZVI) has drawn considerable attention in recent years. In this approach, arsenic ions are mainly removed by adsorption to the iron corrosion products. Reduction to zero-valent arsenic on the ZVI surface is possible in the absence of competing oxidants and can reduce arsenic mobility and sludge formation. However, associated removal rates are relatively low. In the current study, simultaneous high reduction and removal rates of arsenite (H3AsO3), the more toxic and mobile environmentally occurring arsenic species, was demonstrated by reacting it with ZVI under limited aeration and relatively low pH. 90% of the removed arsenic was attached to the ZVI particles and 60% of which was in the elemental state. Under the same non-acidic conditions, only 40-60% of the removed arsenic was attached to the ZVI with no change in arsenic oxidation state. Under anaerobic conditions, reduction occurred but total arsenic removal rate was significantly lower and ZVI demand was higher. The effective arsenite removal under acidic oxygen-limited conditions was explained by formation of Fe(II)-solid intermediate on the ZVI surface that provided high surface area and reducing power.


Classical command of quantum systems.
Quantum computation and cryptography both involve scenarios in which a user interacts with an imperfectly modelled or 'untrusted' system. It is therefore of fundamental and practical interest to devise tests that reveal whether the system is behaving as instructed. In 1969, Clauser, Horne, Shimony and Holt proposed an experimental test that can be passed by a quantum-mechanical system but not by a system restricted to classical physics. Here we extend this test to enable the characterization of a large quantum system. We describe a scheme that can be used to determine the initial state and to classically command the system to evolve according to desired dynamics. The bipartite system is treated as two black boxes, with no assumptions about their inner workings except that they obey quantum physics. The scheme works even if the system is explicitly designed to undermine it; any misbehaviour is detected. Among its applications, our scheme makes it possible to test whether a claimed quantum computer is truly quantum. It also advances towards a goal of quantum cryptography: namely, the use of 'untrusted' devices to establish a shared random key, with security based on the validity of quantum physics.


Sol-Gel Prepared Spinel HTLs for Assembling 20% Efficiency Perovskite Solar Cell in Air Without Using Anti-Solvent and Toxic Solvent.
Low-temperature sol-gel prepared ZnCo2 O4 spinel-based thin films are developed as high-performance hole transporting layer (HTL) for coating perovskite film (NA-Psk) from the basic MAPbI3 /ACN/CH3 NH2 solution in air without using anti-solvent. Inverted PSC based on 2 mole% (vs Zn) Cu2+ doped ZnCo2 O4 (2%Cu@ZnCo2 O4 ) HTL and NA-Psk absorber exhibit the maximum power conversion efficiency (PCE) of 20.0% with no current hysteresis while the cell based on ZnCo2 O4 and PEDOT:PSS HTL (using NA-Psk absorber) achieves the PCE of 15.79% and 12.3% with a current hysteresis index of 9.8% and 32.4%, respectively. Without encapsulation, PSCs based on 2%Cu@ZnCo2 O4 , ZnCo2 O4 , and PEDOT:PSS HTLs maintain 90%, 77%, and 12%, respectively of the original efficiency by standing in ambient atmosphere (temperature: 20-25 °C, RH:30%-40%) for 1800 h. Large area (10 cm × 10 cm substrate) perovskite mini-module (PSM) with PCE over 15% is also demonstrated by using sol-gel prepared 2%Cu@ZnCo2 O4 HTL. The poor photovoltaic performance of PEDOT:PSS HTL is due to the basic MAPbI3 /ACN/CH3 NH2 solution will deprotonate the acidic PEDOT:PSS to reduce its conductivity whereas ZnCo2 O4 HTL are not affected by basic perovskite precursor solution.


Clavulanic acid: a review.
Natural antibiotics are almost universal secondary metabolites, not essential for the growth of the producing organisms generally produced at low growth rates or after growth has ceased. Clavulanic acid (CA), a naturally occurring powerful inhibitor of bacterial beta-lactamases is a major beta-lactam antibiotic produced by organism Streptomyces clavuligerus and is active against a wide spectrum of Gram-positive and Gram-negative bacteria. The review discusses the biosynthetic pathway, fermentative production, downstream processing and applications of CA.


[Congenital cystic adenomatoid malformation of the lung with systemic circulation (author's transl)].
A new observation of CCAML which systemic circulation is presented. At this occasion authors update literature review published in 1973. The total number of cases reported is 78 which our case has to be added. The existence of a systemic artery has only been demonstrated previously in three patients.


Combinatorial effect of Si4+, Ca2+, and Mg2+ released from bioactive glasses on osteoblast osteocalcin expression and biomineralization.
Osteocalcin (OCN) expression is an essential osteogenic marker of successful bone regeneration therapies. This study hypothesizes that Si(4+) and Ca(2+) combinatorial released by bioactive glass enhance osteoblast biomineralization through up-regulation of OCN expression; and Mg(2+) release delays such enhancement. Osteoblasts (MC3T3-E1) were treated with ionic products of bioactive glass dissolution (6P53-b experimental bioactive glass and 45S5 commercial Bioglass™). Results showed that gene expressions, including OCN and its up-stream transcription factors (Runx2, ATF4, MSX1, SP7/OSX), growth factors and signaling proteins (BMP2, BMP6, SMAD3), were enhanced in both 45S5 and 6P53-b glass conditioned mediums (GCMs). This up-regulation led to enhanced mineral formation by 45S5 glass conditioned mediums ([GCM], Si(4+)+Ca(2+)) after 20 days, and by 45S5 GCM and 6P53-b GCM (Si(4+)+Ca(2+)+Mg(2+)) after 30 days. In examining the extracellular matrix generated by cells when exposed to each GCM, it was found that 45S5 GCM had slightly elevated levels of mineral content within ECM as compared to 6P53-b GCM after 30 days while control treatments exhibited no mineral content. The formation of well-defined mineralized nodules (distinct PO4(3-) [960 cm(-1)] and CO3(2-) [1072 cm(-1)] peaks from Raman Spectra) was observed for each GCM as the soluble glass content increased. In examining the individual and combined ion effects between Si(4+), Ca(2+), and Mg(2+), it was found Mg(2+) down-regulates OCN expression. Thus, ions released from both 45S5 and 6P53-b bioactive glasses up-regulate OCN expression and biomineralization while 6P53-b GCM Mg(2+) release down-regulated OCN expression and delayed osteoblast biomineralization. These results indicate that Si(4+), Ca(2+), and Mg(2+) combinatorially regulate osteoblast OCN expression and biomineralization.


Source contribution analysis of surface particulate polycyclic aromatic hydrocarbon concentrations in northeastern Asia by source-receptor relationships.
We analyzed the source-receptor relationships for particulate polycyclic aromatic hydrocarbon (PAH) concentrations in northeastern Asia using an aerosol chemical transport model. The model successfully simulated the observed concentrations. In Beijing (China) benzo[a]pyren (BaP) concentrations are due to emissions from its own domain. In Noto, Oki and Tsushima (Japan), transboundary transport from northern China (>40 °N, 40-60%) and central China (30-40 °N, 10-40%) largely influences BaP concentrations from winter to spring, whereas the relative contribution from central China is dominant (90%) in Hedo. In the summer, the contribution from Japanese domestic sources increases (40-80%) at the 4 sites. Contributions from Japan and Russia are additional source of BaP over the northwestern Pacific Ocean in summer. The contribution rates for the concentrations from each domain are different among PAH species depending on their particulate phase oxidation rates. Reaction with O3 on particulate surfaces may be an important component of the PAH oxidation processes.


Constructing origami power generator from one piece of electret thin film and application in AI-enabled transmission line vibration monitoring.
One of the crucial issues for applying electret/triboelectric power generators in the Internet of Things (IoT) is to take full advantage of specific high voltage signals and enable self-powered sensing. Therefore, inspired by Miura-origami, we present an innovative origami power generator (OPG) constructed from only one piece of electret thin film. The Miura-origami architecture realizes a generator with excellent deformability and stretchability and makes it unnecessary for any auxiliary support structure during the compress-release cycle. Various parameters of the generator are intensively investigated, including the excitation accelerations, excitation displacements, numbers of power generation units and deformation degree of the device. When stimulated with 5.0 g acceleration at 15 Hz frequency, the generator with 8 generation units can obtain an instantaneous peak-to-peak voltage and a remarkable optimum peak power of 328 V and 2152 μW at 50 MΩ, respectively. In addition, the regulable shape and multiple generation modes of the device greatly improve its applicability in various vibration energy collection requirements. Based on the above results, a hexagonal electret generator integrated with six-phase OPGs is developed as a "Buoy on Sky," after which the signal waveforms generated from internal power generators are recognized with 92% accuracy through a neural network algorithm that identifies the vibration conditions of transmission lines. This work demonstrates that a fusion of origami art and energy conversion techniques can achieve a multifunctional generator design satisfying the requirements for IoT applications.


Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells.
Most patients suffering from breast carcinoma do not die due to the primary tumor but from the development of metastases. Active migration of cancer cells is a prerequisite for development of these metastases. We used time-lapse videomicroscopy and computer-assisted cell tracking of MDA-MB-468 human breast carcinoma cells, which were incorporated into a three-dimensional collagen matrix, in order to analyze the migratory activity of these cells in response to different neurotransmitters. Our results show that met-enkephalin, substance P, bombesin, dopamine, and norepinephrine have a stimulatory effect on the migration of the breast cancer cells; moreover, these cells show positive chemotaxis towards norepinephrine as was analyzed by the directionality and persistence on a single-cell basis. Gamma-aminobutyric acid (GABA) however has an inhibitory effect. Endorphin and leu-enkephalin, as well as histamin and acetylcholine, had no influence on the migratory activity of the cells. In summary, we provide evidence for a strong regulatory involvement of neurotransmitters in the regulation of breast cancer cell migration, which might provide the basis for the use of the pharmacological agonists and antagonists for the chemopreventive inhibition of metastasis development.


The ultrasound diagnosis of hydatidiform mole.
Experience with ultrasound compound 'B' scanning in 18 cases of hydatidiform mole is presented. The scan appearances are analysed with respect to the presence or absence of transonic areas, and to the uniformity of echogenicity elsewhere in the uterus. The differential diagnosis is discussed. The commonest appearance seen in a hydatidiform mole is the combination of multiple small transonic areas with uneven echogenicity in the remainder of the uterine cavity. The condition most likely to cause diagnostic confusion is early normal pregnancy with a bulky decidua, but incomplete abortion and uterine fibroid may also be confused with hydatidiform mole.


Multiple primary carcinomas of the upper aerodigestive tract.
Multiple primary squamous cell carcinomas in the upper aerodigestive tract are well described but rare. To be recognised as distinct primary tumours, such malignancies must fulfil a number of anatomical and histological criteria as defined by Warren and Gates. Classification is based on the temporal sequence of tumour diagnosis into three groups; simultaneous, synchronous and metachronous. Second and subsequent primary tumours may escape early detection if not actively searched for. We present a very unusual case of three synchronous tumours in the oral cavity and oropharynx. The literature is reviewed emphasising the importance of thorough investigation of the entire upper aerodigestive tract in patients with a squamous cell carcinoma in this region. Recommendations regarding follow up are also discussed.


Effect of urogastrone on intestinal regeneration is dose-dependent.
Urogastrone (UG) increases the rate of intestinal regeneration in intestinal defects patched with adjacent serosal surfaces by increasing the rate of epithelial cell migration and proliferation. It also inhibits contraction of the patched intestinal defect. The purpose of this study was to determine the effect of the dose of UG on these processes. Twenty male New Zealand white rabbits (1.9-2.9 kg) had 2 x 5 cm ileal defects patched with adjacent caecal serosal surface. Group I (n = 6) served as the control group. Group II (n = 5), Group III (n = 5) and Group IV (n = 4) received UG 0.15, 1.5 and 4.5 micrograms/kg/h i.v. via mini-osmotic pumps. Seven days after patching, both epithelialization of the patched defect and neomucosal surface area were significantly increased by UG and the increases were dose-dependent. Contraction was not inhibited by the lowest dose of UG but was diminished by 1.5 micrograms/kg/h. Proliferative activity in both neomucosa and adjacent normal mucosa were increased in UG-treated animals with the greatest increase in rabbits receiving 1.5 and 4.5 micrograms/kg/h UG. The effect of UG on both epithelialization and contraction of patched intestinal defects is dose-dependent. Since the lowest dose of urogastrone increased epithelialization without increasing proliferative activity, stimulated cell migration appears to be the earliest effect of UG.


Effect of reinforcement, reinforcer omission and extinction on a communicative response in domestic dogs (Canis familiaris).
There is a controversy about the mechanisms involved in the interspecific communicative behaviour in domestic dogs. The main question is whether this behaviour is a result of instrumental learning or higher cognitive skills are required. The present investigations were undertaken to study the effect of learning processes upon the gaze towards the human's face as a communicative response. To such purpose, in Study 1, gaze response was subjected to three types of reinforcement schedules: differential reinforcement, reinforcer omission, and extinction in a situation of "asking for food". Results showed a significant increase in gaze duration in the differential reinforcement phase and a significant decrease in both the omission and extinction phases. These changes were quite rapid, since they occurred only after three training trials in each phase. Furthermore, extinction resulted in animal behaviour changes, such as an increase in the distance from the experimenter, the back position and lying behaviour. This is the first systematic evaluation of the behavioural changes caused by reward withdrawal (frustration) in dogs. In Study 2, the gaze response was studied in a situation where dogs walked along with their owners/trainers. These results show that learning plays an important role in this communicative response. The possible implications of these results for service dogs are discussed.


Intra-coronary administration of L-arginine aggravates myocardial stunning through production of peroxynitrite in dogs.
The aim of this study was to investigate how the enhanced nitric oxide (NO) production by intra-coronary infusion of L-arginine acts in myocardial stunning in dogs by focusing on the involvement of peroxynitrite, a reaction product of NO and superoxide anion. Dogs were divided into six groups; a control non-treated group (CON, n = 9), and NG-nitro L-arginine methyl ester (L-NAME, n = 6), 1 mM L-arginine (L-ARG, n = 8), D-arginine (D-ARG, n = 6), L-arginine plus superoxide dismutase (L-ARG + SOD, n = 6), and SOD alone (SOD, n = 6) treated groups. L-NAME, or L- or D-arginine was continuously infused into the left anterior descending coronary artery (LAD) starting just prior to reperfusion, whereas SOD was intravenously injected before occlusion. During 120 min of reperfusion after 15 min occlusion of LAD, myocardial contractile function in the ischemic region gradually recovered and reached approximately 70% of the preischemic level in CON, D-ARG and SOD, but it remained dyskinetic (-46%) in L-ARG. On the other hand, it was improved in L-NAME (90%). Tissue malondialdehyde was elevated (p < 0.005) after reperfusion, and myocardial NO metabolites measured by an intratissue-microdialyzer increased (approximately 150%, p < 0.05) in the ischemic region during reperfusion in L-ARG but not in the CON, L-NAME, D-ARG or SOD groups. In the L-ARG + SOD group, L-arginine-induced contractile dysfunction and elevation of malondialdehyde were prevented, but the increase in NO metabolites remained. These results suggest that L-arginine aggravated myocardial stunning through oxidative stress and the cytotoxicity was caused by NO derivatives but not by NO itself. The formation of nitrotyrosine, a footprint of peroxynitrite, was immunohistochemically confirmed in the ischemic region of L-ARG. Our results demonstrate for the first time in vivo that NO has a detrimental role in myocardial stunning through the production of peroxynitrite.