Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191.
Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88), which activates downstream NF-κB signaling through the Myddosome. As this pathway depends in part on activity of interleukin-1 receptor-associated kinases (IRAKs)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in preclinical models. Patient-derived cell lines and primary samples were used in both in vitro and in vivo experiments to model Waldenström's macroglobulinemia and its response to IRAK1/4 inhibitors. R191 induced a dose- and time-dependent reduction in viability of BCWM.1 and MWCL-1 Waldenström's cell lines, and suppressed activation of IRAK1/4. This was associated with cell-cycle arrest at G0-G1, reduced levels of cyclin-dependent kinases 4 and 6, and induction of apoptosis in cell lines and primary patient samples. Further downstream, R191 exposure led to reduced activation of NF-κB, and of protein kinase B/Akt/mammalian target of rapamycin signaling, whereas expression of a constitutively active Akt mutant induced R191 resistance. Gene expression profiling and gene set enrichment analysis revealed a signature consistent with inhibition of c-Myc and activation of the endoplasmic reticulum stress response. In both subcutaneous and systemic murine models of Waldenström's, R191 showed antitumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib. Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for patients with Waldenström's macroglobulinemia.


Triatomine dispersion rates and their association with socioeconomic and environmental conditions in Northeastern Brazil, from 2009 to 2013.
Triatomines are vectors of Trypanosoma cruzi , the etiological agent of Chagas disease, which affects between 6 and 12 million people in Latin America, with an incidence rate of 12 thousand cases per year. In the Ceara State, the predominance of the caatinga biome, coupled with a large rural area with precarious human habitations, provides several s shelters for these insects. In this study, we determined the spatiotemporal distribution of triatomine dispersion rates in the Cariri region, Southern Ceara and ascertained the possible association between these rates with socioeconomic and environmental factors. Dispersion rates (number of positive localities/number of searched localities × 100) were analyzed regarding 13 municipalities from the Ceara State, from 2009 to 2013. Socioeconomic and environmental variables collected from national research institutes were associated with the dispersion rates and their local empirical Bayesian estimates. All the municipalities recorded dispersion rates over 10% in all years, and 11 municipalities had average rates over 40% for the period of study. Significant differences were observed among the municipality means. The highest rates were observed in Antonina do Norte and Potengi. According to the correlation analysis, the proportion between the occupied population and the total population showed a significant negative correlation, as well as the percentage of the population who lives under adequate sanitary conditions. Both, the percentage of revenues from external sources and the percentage of urban households in reforested blocks had a significant positive correlation. Our results show that socioeconomic and environmental variables can be factors that contribute to both, the maintenance and the reduction of the elevated dispersion rates observed in the study area. Similar researches that encompass more municipalities from that region may reinforce Chagas disease surveillance and control in the Northeast of Brazil.


The cell biology of taste.
Taste buds are aggregates of 50-100 polarized neuroepithelial cells that detect nutrients and other compounds. Combined analyses of gene expression and cellular function reveal an elegant cellular organization within the taste bud. This review discusses the functional classes of taste cells, their cell biology, and current thinking on how taste information is transmitted to the brain.


Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study.
To date, all population-based epidemiologic data on gastrointestinal stromal tumor (GIST) in the United States predate the 2001 implementation of GIST-specific histology coding. As such, results from previous studies were limited because of inclusion of non-GIST abdominal or gastrointestinal sarcomas. We used a national cancer registry with modern day histologic codes to gain greater insight into the true epidemiology of GIST in the United States. We identified 6,142 patients diagnosed with GIST between 2001 and 2011 in the Surveillance, Epidemiology, and End Results database. Incidence, survival, demographic risk factors, and prognostic factors were analyzed. Annual age-adjusted incidence rose from 0.55/100,000 in 2001 to 0.78/100,000 in 2011 and increased with age, peaking among 70- to 79-year-olds (3.06/100,000). GIST was also more common in males than females [rate ratio (RR), 1.35], non-Hispanics than Hispanics (RR, 1.23), and blacks (RR, 2.07) or Asians/Pacific Islanders (RR, 1.50) than whites. The study period had 5-year overall and GIST-specific survival rates of 65% and 79%, respectively. The 5-year overall survival rates for those with localized, regional, and metastatic disease at diagnosis were 77%, 64%, and 41%, respectively. Multivariate analyses demonstrated that older age at diagnosis, male sex, black race, and advanced stage at diagnosis were independent risk factors for worse overall survival. Multivariate analysis also showed the four aforementioned characteristics, along with earlier year of diagnosis, to be independent risk factors for worse GIST-specific survival. As the first population-based, epidemiologic study of histologically confirmed disease, our findings provide a robust representation of GIST in the era of immunohistochemical diagnoses.


The gene G13 in the class III region of the human MHC encodes a potential DNA-binding protein.
G13 is a single-copy gene lying approx. 75 kb centromeric of the complement gene cluster in the class III region of the human MHC. The gene spans approx. 17 kb of DNA and has been shown to encode mRNA of approx. 2.7 kb that is present in cell lines representing lymphoid and non-lymphoid tissues, indicating that it is ubiquitously expressed. The complete nucleotide sequence of the 2.7 kb mRNA has been derived from cDNA and genomic clones. The longest open reading frame obtained for G13 codes for a 703 amino acid protein of approx. 77 kDa in molecular mass. Comparison of the putative G13 amino acid sequence with the protein databases revealed significant similarities with DNA-binding proteins of the leucine zipper class, including a human cAMP response element binding protein. G13 contains a bZIP motif, a region rich in basic amino acids adjacent to a coiled-coil leucine zipper domain, common to this class of proteins that is known to be involved in dimerization and DNA binding. Antibodies raised against a fragment encoding the C-terminal half of the putative G13 protein recognized a major polypeptide of approx. 86 kDa and a minor polypeptide of approx. 78 kDa on immunoblotting of U937 cell extracts; this has been confirmed by immunoprecipitation experiments. Even though it contained at least one potential bipartite nuclear localization signal, the G13 protein was present both in the cytoplasm and the nucleus of the fibroblast cells. Thus G13 might be a novel DNA-binding protein that is perhaps translocated to the nucleus in a regulated manner.


Physical activity, dietary calcium to magnesium intake and mortality in the National Health and Examination Survey 1999-2006 cohort.
Calcium and magnesium affect muscle mass and function. Magnesium and calcium are also important for optimal vitamin D status. Vitamin D status modifies the associations between physical activity and risk of incident cardiovascular disease (CVD) and CVD mortality. However, no study examined whether levels of magnesium and calcium and the ratio of dietary calcium to magnesium (Ca:Mg) intake modify the relationship between physical activity and mortality. We included 20,295 National Health and Nutrition Examination Survey participants (1999-2006) aged >20 years with complete dietary, physical activity and mortality data (2,663 deaths). We assessed physical activity based on public health guidelines and sex-specific tertiles of MET-minutes/week. We used Cox proportional hazards models adjusted for potential confounding factors and stratified by the intakes of magnesium, calcium, Ca:Mg ratio. We found higher physical activity was significantly associated with reduced risk of total mortality and cause-specific mortality, regardless of Ca:Mg ratio, magnesium or calcium intake. In contrast, both moderate and high physical activity were significantly associated with substantially reduced risks of mortality due to cancer when magnesium intake was above the RDA level. We also found higher physical activity was significantly associated with a reduced risk of mortality due to cancer only when Ca:Mg ratios were between 1.7 and 2.6, although the interaction was not significant. Overall, dietary magnesium and, potentially, the Ca:Mg ratio modify the relationship between physical activity and cause-specific mortality. Further study is important to understand the modifying effects of the balance between calcium and magnesium intake on physical activity for chronic disease prevention.


Scaling of Protein Function across the Tree of Life.
Scaling laws are a powerful way to compare genomes because they put all organisms onto a single curve and reveal nontrivial generalities as genomes change in size. The abundance of functional categories across genomes has previously been found to show power law scaling with respect to the total number of functional categories, suggesting that universal constraints shape genomic category abundance. Here, we look across the tree of life to understand how genome evolution may be related to functional scaling. We revisit previous observations of functional genome scaling with an expanded taxonomy by analyzing 3,726 bacterial, 220 archaeal, and 79 unicellular eukaryotic genomes. We find that for some functional classes, scaling is best described by multiple exponents, revealing previously unobserved shifts in scaling as genome-encoded protein annotations increase or decrease. Furthermore, we find that scaling varies between phyletic groups at both the domain and phyla levels and is less universal than previously thought. This variability in functional scaling is not related to taxonomic phylogeny resolved at the phyla level, suggesting that differences in cell plan or physiology outweigh broad patterns of taxonomic evolution. Since genomes are maintained and replicated by the functional proteins encoded by them, these results point to functional degeneracy between taxonomic groups and unique evolutionary trajectories toward these. We also find that individual phyla frequently span scaling exponents of functional classes, revealing that individual clades can move across scaling exponents. Together, our results reveal unique shifts in functions across the tree of life and highlight that as genomes grow or shrink, proteins of various functions may be added or lost.


(1-->3)-beta-D-glucan and endotoxin in house dust and peak flow variability in children.
House dust-associated bacterial endotoxins have been shown to be associated with asthma severity, and a similar role has been suggested for fungal (1-->3)-beta-D-glucans. In this study the relation between these agents and peak expiratory flow (PEF) variability was investigated in 148 children 7 to 11 yr of age of whom 50% had self- or parent-reported chronic respiratory symptoms. All children self-monitored twice daily their PEF for a period of 16 wk. Dust samples were collected from mattresses and from living room and bedroom floors, and endotoxin and (1-->3)-beta-D-glucan were measured in dust extracts. The relations with mean daily PEF variability (Ampl%mean) were investigated by linear regression analysis, adjusting for dust mite allergen levels, presence of pets, and type of floor cover. In unadjusted analyses the levels of both endotoxin and (1--> 3)-beta-D-glucan per square meter of living room floor were significantly associated with PEF-variability (but not when expressed per gram of sampled dust), particularly in atopic children with asthma symptoms. Adjusted analyses showed the same association for (1--> 3)-beta-D-glucan but not for endotoxin. Although no associations were found with microbial agent levels in bedroom floor or mattress dust, high levels of (1-->3)-beta-D-glucan in living room floor dust apparently increase PEF variability in asthmatic children.


Maternally derived immunity to canine parvovirus infection: transfer, decline, and interference with vaccination.
Antibody to canine parvovirus (CPV) was transferred from an immune bitch to her pups through the placenta and colostrum. Colostral transfer accounted for approximately 90% of the maternally-derived CPV antibody. After suckling, pups and hemagglutination-inhibition titers that averaged 50% of their dam's titer. Maternally derived CPV antibody declined with a half-life of 9.7 days. Pups with hemagglutination-inhibition titers greater than or equal to 1:80 were immune to oronasal challenge with virulent CPV, but any detectable hemagglutination-inhibition antibody (titer greater than or equal to 1:10) interfered with active immunization by modified-liver feline panleukopenia virus, inactivated feline panleukopenia virus, or inactivated CPV vaccines.


Explaining variations in reported diabetes prevalence in general practice: how much variation is explained by differences between practice populations?
There are large variations in reported diabetes prevalence within United Kingdom (UK) populations. Linear regression was used to investigate whether population characteristics could explain the variation in prevalence between 19 practices with relatively complete diagnostic recording. Population obesity and South Asian ethnicity largely explained observed variation in prevalence (adjusted R2 = 0.80). When adjusted for obesity and ethnicity, the deprivation score was no longer a predictor of diabetes prevalence. If true variation in prevalence between practices is largely predicted by population ethnicity and obesity, these population characteristics could be used to predict expected prevalence and to assess the completeness of practice registers.


UNC-2 CaV2 Channel Localization at Presynaptic Active Zones Depends on UNC-10/RIM and SYD-2/Liprin-α in Caenorhabditis elegans.
Presynaptic active zone proteins couple calcium influx with synaptic vesicle exocytosis. However, the control of presynaptic calcium channel localization by active zone proteins is not completely understood. In a Caenorhabditis elegans (C. elegans) forward genetic screen, we find that UNC-10/RIM (Rab3-interacting molecule) and SYD-2/Liprin-α regulate presynaptic localization of UNC-2, the CaV2 channel ortholog. We further quantitatively analyzed live animals using endogenously GFP-tagged UNC-2 and active zone components. Consistent with the interaction between RIM and CaV2 in mammals, the intensity and number of UNC-2 channel puncta at presynaptic terminals were greatly reduced in unc-10 mutant animals. To understand how SYD-2 regulates presynaptic UNC-2 channel localization, we analyzed presynaptic localization of endogenous SYD-2, UNC-10, RIMB-1/RIM-BP (RIM binding protein), and ELKS-1. Our analysis revealed that although SYD-2 is the most critical for active zone assembly, loss of SYD-2 function does not completely abolish presynaptic localization of UNC-10, RIMB-1, and ELKS-1, suggesting an existence of SYD-2-independent active zone assembly. UNC-2 localization analysis in double and triple mutants of active zone components show that SYD-2 promotes UNC-2 localization by partially controlling UNC-10 localization, and ELKS-1 and RIMB-1 also contribute to UNC-2 channel localization. In addition, we find that core active zone proteins are unequal in their abundance. Although the abundance of UNC-10 at the active zone is comparable to UNC-2, SYD-2 and ELKS-1 are twice more and RIMB-1 four times more abundant than UNC-2. Together our data show that UNC-10, SYD-2, RIMB-1, and ELKS-1 control presynaptic UNC-2 channel localization in redundant yet distinct manners.SIGNIFICANCE STATEMENT Precise control of neurotransmission is dependent on the tight coupling of the calcium influx through voltage-gated calcium channels (VGCCs) to the exocytosis machinery at the presynaptic active zones. However, how these VGCCs are tethered to the active zone is incompletely understood. To understand the mechanism of presynaptic VGCC localization, we performed a C. elegans forward genetic screen and quantitatively analyzed endogenous active zones and presynaptic VGCCs. In addition to RIM, our study finds that SYD-2/Liprin-α is critical for presynaptic localization of VGCCs. Yet, the loss of SYD-2, a core active zone scaffolding protein, does not completely abolish the presynaptic localization of the VGCC, showing that the active zone is a resilient structure assembled by redundant mechanisms.


The role of inflammation and its related microRNAs in breast cancer: A narrative review.
Breast cancer is recognized as the most common type of cancer among women with a high rate of mortality all over the world. Over the past years, growing attention has been regarded to realize more about the mechanisms underlying the disease process. It is revealed that the progression of breast cancer may be strongly linked to chronic inflammation owing to the role of inflammatory factors in genetic instability and subsequent cancer predisposition. Although the association between breast cancer and inflammatory pathways has been well-defined now, only recent evidence pointed towards the inflammation-related microRNAs (miRNAs) as potential biomarkers and therapeutic targets involved in the crosstalk of multiple pathways during breast cancer development. Moreover, the practical interactions between these miRNAs and inflammatory factors are also a little characterized. In this review, we intended to describe the effects of predominant inflammatory pathways such as cytokines, phosphoinositide 3-kinase/protein kinase B, and nuclear factor kappa B in association with tumor promoting and tumor suppressing miRNAs on breast cancer progression. Providing new studies in the field of combining biomarkers for early diagnosis, prognosis, and monitoring breast cancer are very important. Notably, understanding the underlying mechanisms of miRNAs as a possible link between inflammation and tumorigenesis may offer a novel insight for combating this epidemic.


CHARTing a Path to Pragmatic Tobacco Treatment Research.
It is important to consider the degree to which studies are explanatory versus pragmatic to understand the implications of their findings for patients, healthcare professionals, and policymakers. Pragmatic trials test the effectiveness of interventions in real-world conditions; explanatory trials test for efficacy under ideal conditions. The Consortium of Hospitals Advancing Research on Tobacco (CHART) is a network of seven NIH-funded trials designed to identify effective programs that can be widely implemented in routine clinical practice. A cross-sectional analysis of CHART trial study designs was conducted to place each study on the pragmatic-explanatory continuum. After reliability training, six raters independently scored each CHART study according to ten PRagmatic Explanatory Continuum Indicator Summary (PRECIS) dimensions, which covered participant eligibility criteria, intervention flexibility, practitioner expertise, follow-up procedures, participant compliance, practitioner adherence, and outcome analyses. Means and SDs were calculated for each dimension of each study, with lower scores representing more pragmatic elements. Results were plotted on "spoke and wheel" diagrams. The rating process and analyses were performed in October 2014 to September 2015. All seven CHART trials tended toward the pragmatic end of the spectrum, although there was a range from 0.76 (SD=0.23) to 1.85 (SD=0.58). Most studies included some explanatory design elements. CHART findings should be relatively applicable to clinical practice. Funders and reviewers could integrate PRECIS criteria into their guidelines to better facilitate pragmatic research. CHART study protocols, coupled with scores reported here, may help readers improve the design of their own pragmatic trials.


Inferring cell junction tension and pressure from cell geometry.
Recognizing the crucial role of mechanical regulation and forces in tissue development and homeostasis has stirred a demand for in situ measurement of forces and stresses. Among emerging techniques, the use of cell geometry to infer cell junction tensions, cell pressures and tissue stress has gained popularity owing to the development of computational analyses. This approach is non-destructive and fast, and statistically validated based on comparisons with other techniques. However, its qualitative and quantitative limitations, in theory as well as in practice, should be examined with care. In this Primer, we summarize the underlying principles and assumptions behind stress inference, discuss its validity criteria and provide guidance to help beginners make the appropriate choice of its variants. We extend our discussion from two-dimensional stress inference to three dimensional, using the early mouse embryo as an example, and list a few possible extensions. We hope to make stress inference more accessible to the scientific community and trigger a broader interest in using this technique to study mechanics in development.


Defining clinically significant prostate cancer on the basis of pathological findings.
The definition of clinically significant prostate cancer is a dynamic process that was initiated many decades ago, when there was already evidence that a great proportion of patients with prostate cancer diagnosed at autopsy never had any clinical symptoms. Autopsy studies led to examinations of radical prostatectomy (RP) specimens and the establishment of the definition of significant cancer at RP: tumour volume of 0.5 cm3 , Gleason grade 6 [Grade Group (GrG) 1], and organ-confined disease. RP studies were then used to develop prediction models for significant cancer by the use of needle biopsies. The first such model was used to delineate the first active surveillance (AS) criteria, known as the 'Epstein' criteria, in which patients with a cancer Gleason score of 3 + 3 = 6 (GrG1) involving fewer than two cores, and <50% of any given core, and a prostate-specific antigen density of <0.15 ng/ml per cm3 had a minimal risk of significant cancer at RP. These were adopted as components of the 'very-low-risk category' of the National Comprehensive Cancer Network guidelines, in which AS is supported as a management option. With the increase in the popularity of AS, much research has been carried out to better define significant/insignificant cancer, in order to be able to safely offer AS to a larger proportion of patients without the risk of undertreatment. Research has focused on allowing higher volume tumours, focal extraprostatic extension, and a limited amount of Gleason pattern 4, and the significance of different morphological patterns of Gleason 4. Other areas of research that will probably impact on the field but that are not covered in this review include the molecular classification of tumours and imaging techniques.


Maternal vaccination: shaping the neonatal response to pertussis.
Antepartum maternal vaccination can protect highly sensitive newborns before they are old enough to receive their own vaccines. Two vaccines are currently recommended during pregnancy: the flu vaccine and the Tdap vaccine against tetanus, diphtheria, and pertussis. Although there is strong evidence that maternal vaccination works to protect the offspring, limitations in the understanding of vaccines and of maternal transfer of immunity compound to obscure our understanding of how they work. Here we focus on the example of pertussis to explore the possible mechanisms involved in the transfer of protection to offspring and how these may impact the newborn's response to future exposure to pertussis. For example, Tdap vaccines induce pathogen specific antibodies, and those antibodies are known to be transferred from mother to the fetus in utero and to the newborn via milk. But antibodies alone have modest impact on pertussis disease, and even less effect on colonization/transmission. Maternal immune cells can also be transferred to offspring and may play a direct role in protection from disease and/or influence the developing neonatal immune system. However, some of the transferred immunity may also blunt the offspring's response to subsequent vaccination. In this review we will summarize the protection conferred to offspring by maternal vaccination against pertussis and the likely mechanisms by which protection is transferred, identifying the many knowledge gaps that limit our most effective application of this approach.


Structural characterization of the complex between alpha-naphthoflavone and human cytochrome P450 1B1.
The atomic structure of human P450 1B1 was determined by x-ray crystallography to 2.7 Å resolution with α-naphthoflavone (ANF) bound in the active site cavity. Although the amino acid sequences of human P450s 1B1 and 1A2 have diverged significantly, both enzymes exhibit narrow active site cavities, which underlie similarities in their substrate profiles. Helix I residues adopt a relatively flat conformation in both enzymes, and a characteristic distortion of helix F places Phe(231) in 1B1 and Phe(226) in 1A2 in similar positions for π-π stacking with ANF. ANF binds in a distinctly different orientation in P450 1B1 from that observed for 1A2. This reflects, in part, divergent conformations of the helix B'-C loop that are stabilized by different hydrogen-bonding interactions in the two enzymes. Additionally, differences between the two enzymes for other amino acids that line the edges of the cavity contribute to distinct orientations of ANF in the two active sites. Thus, the narrow cavity is conserved in both P450 subfamily 1A and P450 subfamily 1B with sequence divergence around the edges of the cavity that modify substrate and inhibitor binding. The conservation of these P450 1B1 active site amino acid residues across vertebrate species suggests that these structural features are conserved.


Effect of extrusion cooking and amylase addition to gruels to increase energy density and nutrient intakes by Vietnamese infants.
Extrusion cooking and amylase addition are two processing methods used for the preparation of high energy dense (ED) gruels of suitable consistency. A quantitative study of energy and nutrient intakes of 67 infants aged 6 to 10 months in rural areas in Vietnam was carried out to compare the effects of these processes used alone or in combination. Twice a day, for a period of four days each, infants successively ate four gruels prepared from different flours based on a blend of rice, sesame and soybean: an instant flour obtained by extrusion cooking (gruel A), a ready-to-cook flour obtained by extrusion cooking plus alpha-amylase addition (gruel B), a flour produced by milling crude rice, sesame and roasted soybean plus alpha-amylase addition (gruel C) and without amylase (control gruel D). Gruels A, B and C had a high ED of respectively 94, 122 and 124 kcal/100 g while the control gruel D had a low ED (59 kcal/100 g). The intakes of the four gruels were inversely linked to their ED. However, despite the fact that gruels B and C had similar ED, larger intakes were obtained with gruel B, which was attributed to better acceptability. The average energy intakes of high ED gruels A, B and C, respectively 112, 134 and 117 kcal/meal, were significantly higher than that of gruel D (81 kcal/meal). Of the three processing methods, the one combining extrusion cooking and amylase addition gave the best results in terms of gruel acceptability and energy intake.


A coding method of chinese characters.
In this paper we propose a coding method of handprinted Chinese characters in which, defining a grammar, the process of block categorization is made to correspond to a process of sentential generation. We obtain two strings of production rules and block codes being equivalent to the descriptions of the structure and internal components of a character pattern, and a Chinese character is encoded effectively by the use of these two strings. It is shown that this coding method is available for the classification and discrimination of handprinted Chinese characters.


Investigation about the influence of longitudinal-mode structure of the laser on the relative intensity noise properties.
The influence of the longitudinal-mode structure (LMS) of the laser on the relative intensity noise (RIN) properties was investigated in this paper after an all-solid-state continuous-wave (CW) single-frequency 1064 nm laser with output power of 50.3 W was achieved. The LMS of the laser was manipulated by controlling the temperature of the nonlinear lithium triborate (LBO) crystal deliberately introduced to the resonator. When the laser worked with single-longitudinal-mode (SLM) operation, the stable RIN spectrum was observed and measured. Moreover, with the decrease of the nonlinear conversion efficiency (NCE), the frequency and amplitude of the resonant-relaxation oscillation (RRO) peak regularly shifted to the higher frequencies and increased, respectively. However, with further decrease of the NCE, the laser began to work with the multi-longitudinal-mode (MLM) or mode-hopping operation and the unstable RIN spectra of the laser were both observed not only at low frequencies but also at high frequencies. Once the NCE was moved away, the MLM or mode-hopping can only enhance the fluctuation of the laser RIN spectrum at the low frequencies (lower than the frequency of RRO). The experimental results directly revealed the relationship between the LMS of the laser and the RIN spectra, and confirmed definitely that the key to achieve a stable high power laser with low intensity noise was to realize single-frequency operation of the laser with free MLM and mode-hopping.


In Men with Castration-Resistant Prostate Cancer, Visceral Metastases Predict Shorter Overall Survival: What Predicts Visceral Metastases? Results from the SEARCH Database.
Although visceral metastases (VMs) are widely recognized to portend worse prognoses compared with bone and lymph metastases in men with metastatic castration-resistant prostate cancer (mCRPC), little is known about what predicts VMs and the extent to which men with VMs do worse. To determine whether men with VMs at initial mCRPC diagnosis have worse overall survival (OS) and identify predictors of VMs. We analyzed 494 men diagnosed with castration-resistant prostate cancer post-1999 and no known metastases from five Veterans Affairs hospitals of the Shared Equal Access Regional Cancer Hospital (SEARCH) database who later developed metastases. Radiology scans within 30 d of initial metastasis diagnosis were reviewed to collect information on bone, visceral, and lymph node metastases. We analyzed the 236 men who had a computed tomography scan performed. Predictors of VMs and OS were evaluated using logistic regression and Cox models, respectively. Of the 236 mCRPC patients, 38 (16%) had VMs. Regarding VMs, 19 patients (50%), 8 patients (21%), and 16 patients (42%) had metastases in the liver, lungs, and other locations, respectively. VMs were a predictor of OS on crude analysis (hazard ratio [HR]: 1.88; 95% confidence interval [CI], 1.30-2.72; p=0.001) and after risk adjustment (HR: 1.84; 95% CI, 1.24-2.72; p=0.002). Age, year, treatment center, prostate-specific antigen (PSA), and time from CRPC to metastases were significant in predicting OS (all p<0.05). None of the variables tested were associated with having VMs (all p > 0.09). Prospective studies and larger cohorts are needed to validate our findings. Demographic, tumor, and PSA kinetic characteristics were not predictive of having VMs, but VMs predicted worse OS. Because patients with VMs have worse overall survival, further research is needed to develop better biomarkers and thus diagnose those with VMs at earlier stages in their disease course.


Cancer mortality among French nuclear contract workers.
Nuclear workers from French contracting companies have received higher doses than workers from Electricité de France (EDF) or Commissariat à l'Energie Atomique (CEA). A cohort study of 9,815 workers in 11 contracting companies, monitored for exposure to ionizing radiation between 1967 and 2000 were followed up for a median duration of 12.5 years. Standardized mortality ratios (SMRs) were computed. Between 1968 and 2002, 250 deaths occurred. Our study demonstrated a clear healthy worker effect (HWE) with mortality attaining half that expected from national mortality statistics (SMR = 0.54, 95% CI = [0.47-0.61]). The HWE was lower for all cancers (SMR = 0.65) than for non-cancer deaths (SMR = 0.46). The analysis by cancer site showed no excess compared with the general population. Significant trends were observed according to the level of exposure to ionizing radiation for deaths from cancer, deaths from digestive cancer and deaths from respiratory cancer. The mortality of nuclear workers from contracting companies is very low compared to French national mortality.


Transfection and expression of hepatitis B virus x gene and its effect on apoptosis in HL-7702 cells.
To investigate the effects of hepatitis B virus x gene and its protein product HBxAg on apoptosis in hepatocyte line HL-7702. The reconstituted plasmid pcDNA3-x was established through recombination DNA technique; pcDNA3-X was transfected into HL-7702 cells by lipid-mediated trasfection. Positive clones were screened by G418, and HL-7702/HBx cells were analysed by the RT-PCR to confirm the steady expression of X gene in HL-7702 cells. The apoptosis rate in HL-7702 cells was determined by flow cytometry, TUNEL technology, electronic microscope. At the mean time, pcDNA3-X was transfected transiently into HL-7702 cells, and total RNA from HL-7702 cells was extracted 24, 48, 72, 96 and 120 h after the transient transfection, and semi-quantitative analysis was performed by RT-PCR to detect the expression of HBV X gene. Furthermore, apoptosis rate in HL-7702 cells was determined by flow cytometry analysis at the different times. RT-PCR analysis showed that HBV X gene could be expressed stably in HL-7702 cells. Both flow cytometry and TUNEL technology revealed that the apoptosis rates of HL-7702/HBx cells were much higher than those of HL-7702/pcDNA3 and HL-7702 cells. Furthermore, the apoptotic phenomena and apoptotic body were observed in HL-7702/HBx cells under electronic microscope, but not in HL-7702/pcDNA3 and HL-7702 cells. In the experiment of transient transfection, RT-PCR reveals that X gene was expressed most at 72 h after transfection; and the apoptosis rate reached the highest at the same time. After that, the apoptosis rate was reduced with the decrease of the X gene expression. HBV X gene and X protein can promote the apoptosis in hepatocyte. And there exist a quantity-effect relationship between the X gene expression and apoptosis rate in hepatocyte.


[Pain information pathways from the periphery to the cerebral cortex].
A recent PET study revealed that the first and second somatosensory cortices (SI, SII), and the anterior cingulate cortex are activated by painful peripheral stimulation in humans. It has become clear that painful signals (nociceptive information) evoked at the periphery are transmitted via various circuits to the multiple cerebral cortices where pain signals are processed and perceived. Human or clinical pain is not merely a modality of somatic sensation, but associated with the affect that accompanies sensation. Consequently, pain has a somatosensory-discriminative aspect and an affective-cognitive aspect that are processed in different but correlated brain structures in the ascending circuits. Considering the physiologic characteristics and fiber connections, the SI and SII cortices appear to be involved in somatosensory-discriminative pain, and the anterior cingulate cortex (area 24) in the affective-cognitive aspect of pain. This paper deals with the ascending pain pathways from the periphery to these cortices and their interconnections. Our recent findings on the protease-activated receptors 1 and 2 (PAR-1, and -2), which are confirmed to exist in the dorsal root ganglion cells, are also described. Activation of PAR-2 during inflammation or tissue injury at the periphery is pronociceptive, while PAR-1 appears to be antinociceptive. Based on the these findings, PAR-1 and PAR-2 are attracting interest as target molecules for new drug development.


Evidence of the symptomatic and structural efficacy of methotrexate in daily practice as the first disease-modifying drug in rheumatoid arthritis despite its suboptimal use: results from the ESPOIR early synovitis cohort.
To describe the use of MTX in early arthritis (EA) in daily clinical practice and to evaluate its 6-month symptomatic efficacy and 12-month structural efficacy. Patients included in the French observational ESPOIR cohort were assessed. Evaluation of the symptomatic and structural efficacy was performed by generalized linear regression after adjustment on propensity score (PS) in the group of patients receiving at least 3 months of MTX vs the ones receiving any other treatment except LEF, SSZ or TNF inhibitors. Within the first 6 months of follow-up of 777 EA patients, 59% received a DMARD, which was MTX in 68% (N = 313) of patients. The mean dose of MTX was 12.7 ± 3.8 mg/week. Only 53.7% of the patients received folic acid supplementation. MTX was initiated in patients with more active and severe disease. At 6 months, in unadjusted analysis, patients starting MTX had a significantly higher DAS-28 (3.58 vs 3.23; P = 0.001) and a significantly higher HAQ (0.60 vs. 0.48; P = 0.01) compared with controls. After adjustment by PS, there were no significant differences. Adjustment for the PS also revealed a statistically significant decrease in the radiological progression at 12 months in the MTX group [total Sharp-van der Heijde score (SHS), 1.05 ± 0.29 vs 2.02 ± 0.29, P = 0.025]. This study confirms the symptomatic and structural efficacy of MTX in EA in daily practice despite the non-optimal use of MTX, including low doses and infrequent concomitant folic acid supplementation.


The impact of uterine leiomyomas: a national survey of affected women.
We sought to characterize the impact of uterine leiomyomas (fibroids) in a racially diverse sample of women in the United States. A total of 968 women (573 white, 268 African American, 127 other races) aged 29-59 years with self-reported symptomatic uterine leiomyomas participated in a national survey. We assessed diagnosis, information seeking, attitudes about fertility, impact on work, and treatment preferences. Frequencies and percentages were summarized. The χ(2) test was used to compare age groups. Women waited an average of 3.6 years before seeking treatment for leiomyomas, and 41% saw ≥2 health care providers for diagnosis. Almost a third of employed respondents (28%) reported missing work due to leiomyoma symptoms, and 24% believed that their symptoms prevented them from reaching their career potential. Women expressed desire for treatments that do not involve invasive surgery (79%), preserve the uterus (51%), and preserve fertility (43% of women aged <40 years). Uterine leiomyomas cause significant morbidity. When considering treatment, women are most concerned about surgical options, especially women aged <40 years who want to preserve fertility.


Activating parabrachial cannabinoid CB1 receptors selectively stimulates feeding of palatable foods in rats.
The endocannabinoid system is emerging as an integral component in central and peripheral regulation of feeding and energy balance. Our investigation analyzed behavioral roles for cannabinoid mechanisms of the pontine parabrachial nucleus (PBN) in modulating intake of presumably palatable foods containing fat and/or sugar. The PBN serves to gate neurotransmission associated with, but not limited to, the gustatory properties of food. Immunofluorescence and in vitro [(35)S]GTPgammaS autoradiography of rat tissue sections containing the PBN revealed the presence of cannabinoid receptors and their functional capability to couple to their G-proteins after incubation with the endocannabinoid 2-arachidonoyl glycerol (2-AG). The selective cannabinoid 1 receptor (CB(1)R) antagonist AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] prevented the response, demonstrating CB(1)R mediation of 2-AG-induced coupling. Microinfusions of 2-AG into the PBN in behaving rats robustly stimulated feeding of pellets high in content of fat and sucrose (HFS), pure sucrose, and pure fat (Crisco), during the first 30 min after infusion. In contrast, 2-AG failed to increase consumption of standard chow, even when the feeding regimen was manipulated to match baseline intakes of HFS. Orexigenic responses to 2-AG were attenuated by AM251, again indicating CB(1)R mediation of 2-AG actions. Furthermore, responses were regionally specific, because 2-AG failed to alter intake when infused into sites approximately 500 mum caudal to infusions that successfully stimulated feeding. Our data suggest that hedonically positive sensory properties of food enable endocannabinoids at PBN CB(1)Rs to initiate increases in eating, and, more generally, these pathways may serve a larger role in brain functions controlling behavioral responses for natural reward.


Usefulness of Forensic Dental Symbols© and Dental Encoder© database in forensic odontology.
A new universal graphic dental system, Forensic Dental Symbols(©), has been created to provide precision in the construction of dental records, improve standardization, and increase efficiency in dental identification procedures. Two hundred and thirty-four different graphic symbols representing the most frequent clinical status for each tooth were designed. Symbols can be then converted to a typographic font and then are ready to use in any computer. For the appropriate use, manipulation, and storage of dental information generated by the Forensic Dental Symbols(©), Dental Encoder(©) database has been created. The database contains all the information required by INTERPOL Disaster Victim Identification (DVI)-dental-forms. To explore the possibilities that Dental Encoder(©) offers, an antemortem dental database from a Spanish population of 3920 military personnel had been constructed. Data generated by Dental Encoder(©) were classified into sex and age groups. The program can perform an automatic search of the database for cases that match a selected clinical status presented in a single tooth or a combination of situations for several teeth. Moreover, Dental Encoder(©) allows information to be printed on INTERPOL DVI-dental-forms, or the inclusion of any completed form into any document, technical report, or identification of dental report.


Evidence for a multistep pathogenesis of chronic myelogenous leukemia.
To study the relationship of the Philadelphia chromosome (Ph1) to the pathogenesis of chronic myelogenous leukemia, multiple B-lymphoid cell lines were established from a patient with Ph1-positive leukemia who was heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase. Both A and B types of enzyme were found in a 1:1 proportion in normal tissues, but 45 of 63 (71%) Ph1-negative B-lymphoid cells lines derived from this patient showed only the single glucose-6-phosphate dehydrogenase (type B) found in the Ph1-positive leukemic clone. Furthermore, 8 of 33 analyzable lines with B-type enzyme had chromosomal aberrations compared to 0 of 14 lines with A-type glucose-6-phosphate dehydrogenase. These results provide evidence for the suggestion that some cells of the abnormal clone do not express the Ph1 abnormality. Thus, acquisition of Ph1 may not be a sufficient cause for the disease. It is possible that at least two steps are involved in the pathogenesis of Ph1-positive chronic myelogenous leukemia, one causing abnormal proliferation of a clone of pluripotent hematopoietic stem cells and the other inducing Ph1 in descendants of these progenitors.


Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4(+) T cells.
A.SW and B10.S mice share the same major histocompatibility complex (MHC) haplotype (H-2(s)). However, A.SW mice are susceptible to experimental autoimmune myocarditis (EAM) and develop severe disease after immunization with myosin, whereas B10.S mice are resistant. We found that naive A.SW mice have intrinsically increased total CD4(+) T cell counts and increased proportions of CD4(+) T cells in their spleens compared to B10.S mice. Among total CD4(+) T cells, naive A.SW mice have a lower relative frequency of forkhead box protein 3 (FoxP3(+))CD25(+) regulatory T cells (T(regs)). A.SW mice also had a higher proportion of CD4(+) T cells and a lower proportion of T(regs) in their hearts and spleen during EAM, with greater T cell activation and proliferation, compared to B10.S mice. These differences in the T cell compartment were not antigen-specific, as ovalbumin/complete Freund's adjuvant (OVA/CFA) or CFA immunization elicited the same differences in CD4(+) T cells and T(regs) between A.SW and B10.S mice. Moreover, A.SW mice had more T helper type 17 (Th17) cells and B10.S had more Th1 cells in their hearts. The higher percentage of CD4(+) T cells and their enhanced potential to differentiate towards the Th17 pathway was also observed in naive A.SW mice. Interleukin (IL)-6 is required for Th17 induction. Interestingly, IL-6Rα expression was greater on naive A.SW CD4(+) T cells, compared to B10.S CD4(+) T cells, indicating that this intrinsic difference, together with a relatively lower T(reg) proportion of CD4(+) T cells, might lead to heightened Th17 responses and greater susceptibility to autoimmunity in A.SW mice.


A multi-patient analysis of the center of rotation trajectories using finite element models of the human mandible.
Studying different types of tooth movements can help us to better understand the force systems used for tooth position correction in orthodontic treatments. This study considers a more realistic force system in tooth movement modeling across different patients and investigates the effect of the couple force direction on the position of the center of rotation (CRot). The finite-element (FE) models of human mandibles from three patients are used to investigate the position of the CRots for different patients' teeth in 3D space. The CRot is considered a single point in a 3D coordinate system and is obtained by choosing the closest point on the axis of rotation to the center of resistance (CRes). A force system, consisting of a constant load and a couple (pair of forces), is applied to each tooth, and the corresponding CRot trajectories are examined across different patients. To perform a consistent inter-patient analysis, different patients' teeth are registered to the corresponding reference teeth using an affine transformation. The selected directions and applied points of force on the reference teeth are then transformed into the registered teeth domains. The effect of the direction of the couple on the location of the CRot is also studied by rotating the couples about the three principal axes of a patient's premolar. Our results indicate that similar patterns can be obtained for the CRot positions of different patients and teeth if the same load conditions are used. Moreover, equally rotating the direction of the couple about the three principal axes results in different patterns for the CRot positions, especially in labiolingual direction. The CRot trajectories follow similar patterns in the corresponding teeth, but any changes in the direction of the force and couple cause misalignment of the CRot trajectories, seen as rotations about the long axis of the tooth.


On the modeling of DCT and subband image data for compression.
Image subband and discrete cosine transform coefficients are modeled for efficient quantization and noiseless coding. Quantizers and codes are selected based on Laplacian, fixed generalized Gaussian, and adaptive generalized Gaussian models. The quantizers and codes based on the adaptive generalized Gaussian models are always superior in mean-squared error distortion performance but, generally, by no more than 0.08 bit/pixel, compared with the much simpler Laplacian model-based quantizers and noiseless codes. This provides strong motivation for the selection of pyramid codes for transform and subband image coding.


Biological activities and phytochemical profiles of extracts from different parts of bamboo (Phyllostachys pubescens).
Besides being a useful building material, bamboo also is a potential source of bioactive substances. Although some studies have been performed to examine its use in terms of the biological activity, only certain parts of bamboo, especially the leaves or shoots, have been studied. Comprehensive and comparative studies among different parts of bamboo would contribute to a better understanding and application of this knowledge. In this study, the biological activities of ethanol and water extracts from the leaves, branches, outer culm, inner culm, knots, rhizomes and roots of Phyllostachys pubescens, the major species of bamboo in Japan, were comparatively evaluated. The phytochemical profiles of these extracts were tentatively determined by liquid chromatography-mass spectrometry (LC-MS) analysis. The results showed that extracts from different parts of bamboo had different chemical compositions and different antioxidative, antibacterial and antiallergic activities, as well as on on melanin biosynthesis. Outer culm and inner culm were found to be the most important sources of active compounds. 8-C-Glucosylapigenin, luteolin derivatives and chlorogenic acid were the most probable compounds responsible for the anti-allergy activity of these bamboo extracts. Our study suggests the potential use of bamboo as a functional ingredient in cosmetics or other health-related products.


Targeting antigen-independent proliferation in chronic lymphocytic leukemia through differential kinase inhibition.
The clinical success of B-cell receptor (BCR) signaling pathway inhibitors in chronic lymphocytic leukemia (CLL) is attributed to inhibition of adhesion in and migration towards the lymph node. Proliferation of CLL cells is restricted to this protective niche, but the underlying mechanism(s) is/are not known. Treatment with BCR pathway inhibitors results in rapid reductions of total clone size, while CLL cell survival is not affected, which points towards inhibition of proliferation. In vitro, BCR stimulation does not induce proliferation of CLL, but triggering via Toll-like receptor, tumor necrosis factor or cytokine receptors does. Here, we investigated the effects of clinically applied inhibitors that target BCR signaling, in the context of proliferation triggered either via CD40L/IL-21 or after CpG stimulation. CD40L/IL-21-induced proliferation could be inhibited by idelalisib and ibrutinib. We demonstrate this was due to blockade of CD40L-induced ERK-signaling. Targeting JAKs, but not SYK, blocked CD40L/IL-21-induced proliferation. In contrast, PI3K, BTK as well as SYK inhibition prevented CpG-induced proliferation. Knockdown experiments showed that CD40L/IL-21 did not co-opt upstream BCR components such as CD79A, in contrast to CpG-induced proliferation. Our data indicate that currently applied BTK/PI3K inhibitors target antigen-independent proliferation in CLL, and suggest that targeting of JAK and/or SYK might be clinically useful.


Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for the potential treatment of T-cell lymphomas and asthma.
Mogamulizumab (KW-0761; AMG-761), under development by Kyowa Hakko Kirin and Amgen, is a defucosylated humanized IgG1 mAb against C-C chemokine receptor 4 (CCR4) for the potential intravenous treatment of T-cell lymphomas and asthma. Chemokines and their receptors are signaling molecules constitutively responsible for lymphocyte and neutrophil chemotaxis, which can also be involved in pathogenic mechanisms of various diseases. In particular, CCR4 has been demonstrated to play a major role in adult T-cell leukemia/lymphoma (ATL), in which it is a marker of poor prognosis. Consequently, CCR4 blockade might have therapeutic potential in treating ATL, a disease that is most often aggressive in course, and for which existing therapies are not always effective. Mogamulizumab reduced tumor load via enhanced antibody-dependent cell cytotoxicity in preclinical studies and demonstrated promising efficacy in early clinical trials in patients with ATL. In addition, CCR4 also has a role in maintaining T-helper cell type 2 airways inflammation in asthma, and Amgen have acquired the rights to develop mogamulizumab for this indication and other non-oncology indications; however, at the time of publication, no data were available from Amgen's investigations. This is a review on the potential use of mogamulizumab for the treatment of T-cell lymphomas and asthma, with specific emphasis on the treatment of ATL.


Video game training and the reward system.
Video games contain elaborate reinforcement and reward schedules that have the potential to maximize motivation. Neuroimaging studies suggest that video games might have an influence on the reward system. However, it is not clear whether reward-related properties represent a precondition, which biases an individual toward playing video games, or if these changes are the result of playing video games. Therefore, we conducted a longitudinal study to explore reward-related functional predictors in relation to video gaming experience as well as functional changes in the brain in response to video game training. Fifty healthy participants were randomly assigned to a video game training (TG) or control group (CG). Before and after training/control period, functional magnetic resonance imaging (fMRI) was conducted using a non-video game related reward task. At pretest, both groups showed strongest activation in ventral striatum (VS) during reward anticipation. At posttest, the TG showed very similar VS activity compared to pretest. In the CG, the VS activity was significantly attenuated. This longitudinal study revealed that video game training may preserve reward responsiveness in the VS in a retest situation over time. We suggest that video games are able to keep striatal responses to reward flexible, a mechanism which might be of critical value for applications such as therapeutic cognitive training.


BETA-GLUCOSIDASE SYSTEM OF NEUROSPORA CRASSA. I. BETA-GLUCOSIDASE AND CELLULASE ACTIVITIES OF MUTANT AND WILD-TYPE STRAINS.
Eberhart, Bruce (University of North Carolina, Greensboro), David F. Cross, and Lewis R. Chase. beta-Glucosidase system of Neuspora crassa. I. beta-Glucosidase and cellulose activities of mutant and wild-type strains. J. Bacteriol. 87:761-770. 1964.-A mutant strain, gluc-1, of Neurospora crassa was isolated and characterized by its low level of beta-glucosidase activity. The mutant was selected by testing irradiated colonies for extracellular beta-glucosidase activity. Strains containing the gluc-1 gene were also visibly detected by their reduced ability to destroy esculin in their growth media. The mutant strain grew at wild-type rates with cellobiose or carboxymethylcellulose as carbon sources. This auxotrophic similarity with wild type is explained by the presence of at least two beta-glucosidases (and possibly two cellulases) in Neurospora that act complementarily. The thermolabile beta-glucosidase was destroyed after 1 min of incubation at 60 C. This enzyme was present in mycelia but absent in conidial extracts. A second beta-glucosidase that is comparatively stable at 60 C was present in both mycelia and conidia. A partial separation of these enzymes was achieved with ammonium fractionation of mycelial extracts of gluc-1 and wild-type strains. Thermolabile beta-glucosidase and cellulase activity appear not to be affected by the gluc-1 mutation, whereas the thermostable glucosidase is greatly reduced in gluc-1 strains.


Associations between depressive syndromes and HIV risk behaviors among San Francisco men who have sex with men.
HIV prevention plans for men who have sex with men (MSM) are often multifaceted. They involve reduction of sexual risk behaviors, such as condomless intercourse, but also often include pharmaceutical approaches, such as early treatment of HIV-infected individuals with antiretroviral therapy (ART). Effectiveness is possibly threatened by individual-level factors, such as depression. In this study of 322 San Francisco MSM (240 HIV-uninfected individuals and 82 HIV-infected individuals, according to self-report), we examine associations between depressive syndromes and HIV risk behaviors (sexual risk behaviors and ART non-adherence). Our study failed to find evidence that depressive syndromes lead to increases in ART non-adherence (risk difference, RD: 27.9; 95% confidence interval, CI: -3.5, 59.3). However, the study does suggest an association between depressive syndromes and concurrence of non-adherence and potentially HIV-discordant condomless receptive anal intercourse (RD: 36.0; 95% CI: 5.2, 66.8). Among HIV-uninfected MSM, our study suggests negative associations between depressive syndromes and sexual risk behaviors. We recommend screening and treatment of depression among HIV-infected MSM.


Cross-sectional and case-control analyses of the association of kidney function staging with adverse postoperative outcomes in general and vascular surgery.
This study aimed to assess kidney dysfunction in general surgical patients and examine the effect on postoperative mortality and morbidity. An estimated 13% of the US population has chronic kidney disease (CKD), but awareness among patients and caregivers is lacking. The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) data sets for 2005-2007 were analyzed. Preoperative kidney function was assessed by the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate (eGFR) and staged according to National Kidney Foundation. Cross-sectional analyses were performed for 30-day mortality (Cox proportional hazard) and incidence of major complications (nominal logistic regression). A case-control cohort of colectomy cases was analyzed comparing patients in the stage 4 CKD group and the no CKD group (no-CKD). Sixty-four percent of evaluable patients had reduced eGFR, but eGFR was not evaluable in 28% of the surgical cases. In the 260,352 evaluable cases, adjusted hazard ratio for 30-day mortality was 2.30 [95% confidence interval (CI), 2.11-2.51] for stage 3 CKD; 3.37 (95% CI, 3.01-3.76) for stage 4 CKD; and 3.05 (95% CI, 2.68-3.47) for stage 5 CKD compared with no-CKD (P < 0.0001). CKD was an independent risk factor for having major complications postsurgery [stage 3, odds ratio (OR) = 1.24 (95% CI, 1.19-1.29); stage 4, OR = 1.65 (95% CI, 1.52-1.78); and stage 5 CKD, OR = 1.40 (95% CI, 1.30-1.51); P < 0.0001]. The case-control for colectomy was confirmatory: increased 30-day mortality in stage 4 CKD versus no-CKD (hazard ratio = 2.58, 95% CI, 1.13-5.92; P = 0.025). Renal insufficiency may be underrecognized in the general and vascular (noncardiac) surgery population, is a leading independent predictor of poor early postoperative outcomes, and should be routinely assessed in the preoperative setting.


A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened.
Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Bardet-Biedl Syndrome (BBS) proteins are involved in maintaining ciliary function by mediating protein trafficking to the cilia. However, the mechanisms governing ciliary trafficking by BBS proteins are not well understood. Here, we show that a novel protein, Leucine-zipper transcription factor-like 1 (LZTFL1), interacts with a BBS protein complex known as the BBSome and regulates ciliary trafficking of this complex. We also show that all BBSome subunits and BBS3 (also known as ARL6) are required for BBSome ciliary entry and that reduction of LZTFL1 restores BBSome trafficking to cilia in BBS3 and BBS5 depleted cells. Finally, we found that BBS proteins and LZTFL1 regulate ciliary trafficking of hedgehog signal transducer, Smoothened. Our findings suggest that LZTFL1 is an important regulator of BBSome ciliary trafficking and hedgehog signaling.


Compression and Reswelling of Microgel Particles after an Osmotic Shock.
We use dedicated microfluidic devices to expose soft hydrogel particles to a rapid change in the externally applied osmotic pressure and observe a surprising, nonmonotonic response: After an initial rapid compression, the particle slowly reswells to approximately its original size. We theoretically account for this behavior, enabling us to extract important material properties from a single microfluidic experiment, including the compressive modulus, the gel permeability, and the diffusivity of the osmolyte inside the gel. We expect our approach to be relevant to applications such as controlled release, chromatography, and responsive materials.


Assessment model for the justification of intrusive lifestyle interventions: literature study, reasoning and empirical testing.
In many countries health insurers, employers and especially governments are increasingly using pressure and coercion to enhance healthier lifestyles. For example by ever higher taxes on cigarettes and alcoholic beverages, and ever stricter smoke-free policies. Such interventions can enhance healthier behaviour, but when they become too intrusive, an unfree society can emerge. Which lifestyle interventions that use pressure or coercion are justifiable and which are not? We tried to develop an assessment model that can be used for answering this question, on a generally acceptable way, for all sorts of lifestyle interventions. The intended assessment model was developed in three phases. In the first phase the model was theoretically developed on the basis of literature study and reasoning. In the second phase the model was empirically tested by assessing two detailed cases from everyday practice using the model. The model was improved again and again. In the third phase (publication phase) the 10(th) version of the model was developed while writing this article. An assessment model for the justification of intrusive lifestyle interventions. It comprises three components: (1) 12 assessment criteria (necessity, causality, responsibility, appropriate design, effectiveness, intrusiveness, burdens-benefits-ratio, fairness, support, complementary policies, verifiability, implementation capacity); (2) an assessment structure with three filters (design logic, effects and side effects, implementation); (3) a way of assessing (based on reasonableness and transparency). We have developed an assessment model for the justification of lifestyle interventions that use pressure or coercion to promote health. The correctness, completeness and practicality of the model are likely. Important principles for the justification are the logic and completeness of the underlying argumentation and the proper use of the available scientific information. Parties for and against a particular intervention could use the model to test and strengthen their argumentation and to improve the quality of the intervention.


Regulation of Nicotiana tabacum osmotic stress-activated protein kinase and its cellular partner GAPDH by nitric oxide in response to salinity.
Several studies focusing on elucidating the mechanism of NO (nitric oxide) signalling in plant cells have highlighted that its biological effects are partly mediated by protein kinases. The identity of these kinases and details of how NO modulates their activities, however, remain poorly investigated. In the present study, we have attempted to clarify the mechanisms underlying NO action in the regulation of NtOSAK (Nicotiana tabacum osmotic stress-activated protein kinase), a member of the SNF1 (sucrose non-fermenting 1)-related protein kinase 2 family. We found that in tobacco BY-2 (bright-yellow 2) cells exposed to salt stress, NtOSAK is rapidly activated, partly through a NO-dependent process. This activation, as well as the one observed following treatment of BY-2 cells with the NO donor DEA/NO (diethylamine-NONOate), involved the phosphorylation of two residues located in the kinase activation loop, one being identified as Ser158. Our results indicate that NtOSAK does not undergo the direct chemical modifications of its cysteine residues by S-nitrosylation. Using a co-immunoprecipitation-based strategy, we identified several proteins present in immunocomplex with NtOSAK in salt-treated cells including the glycolytic enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Our results indicate that NtOSAK directly interacts with GAPDH in planta. Furthermore, in response to salt, GAPDH showed a transient increase in its S-nitrosylation level which was correlated with the time course of NtOSAK activation. However, GADPH S-nitrosylation did not influence its interaction with NtOSAK and did not have an impact on the activity of the protein kinase. Taken together, the results support the hypothesis that NtOSAK and GAPDH form a cellular complex and that both proteins are regulated directly or indirectly by NO.


[Lithium therapy in patients with mild mental retardation].
In the psychiatric treatment of patients with mild learning disabilities or borderline intellectual functioning, signs and symptoms of psychiatric disorders are sometimes misinterpreted as behaviour that reflects problems that are known to patients with mental retardation. We report on two case studies in which lithium therapy made a substantial contribution to (partial) recovery. One patient had bipolar disorder and the other had a major depressive disorder combined with suicidal behaviour. Each patient also had a mild learning disability or borderline intellectual functioning.


A Universal Bacteriophage T4 Nanoparticle Platform to Design Multiplex SARS-CoV-2 Vaccine Candidates by CRISPR Engineering.
A "universal" vaccine design platform that can rapidly generate multiplex vaccine candidates is critically needed to control future pandemics. Here, using SARS-CoV-2 pandemic virus as a model, we have developed such a platform by CRISPR engineering of bacteriophage T4. A pipeline of vaccine candidates were engineered by incorporating various viral components into appropriate compartments of phage nanoparticle structure. These include: expressible spike genes in genome, spike and envelope epitopes as surface decorations, and nucleocapsid proteins in packaged core. Phage decorated with spike trimers is found to be the most potent vaccine candidate in mouse and rabbit models. Without any adjuvant, this vaccine stimulated robust immune responses, both T H 1 and T H 2 IgG subclasses, blocked virus-receptor interactions, neutralized viral infection, and conferred complete protection against viral challenge. This new type of nanovaccine design framework might allow rapid deployment of effective phage-based vaccines against any emerging pathogen in the future.


QTc interval prolongation during recovery from brief high-intensity intermittent exercise in obese adults.
The risk of malignant arrhythmias is higher during extremely intense exercise and after its cessation. It is still unclear whether high-intensity interval exercise (HIE), an increasingly popular option in preventive and rehabilitative medicine, can lead to an impaired electrophysiological milieu, as revealed by QT interval prolongation on an electrocardiogram. This study investigated heart rate-corrected QT interval (QTc) dynamics during recovery from HIE in obese adults. In total, 13 obese males (age: 24.3 ± 4.6 years old; body mass index: 31.6 ± 4.1 kg/m2) underwent: (1) HIE: an HIE session of four 30-s all-out cycling efforts interspersed with 4‑min recovery periods; (2) REC: a recovery session 24 h after HIE; and (3) CON: a control session of no treatment. The QT interval was measured before HIE, REC, and CON, and then at 30-min intervals thereafter, for up to 3 h. QTc values were obtained using Bazett, Fridericia, Framingham, Hodges, and Rautaharju correction formulas. Acute HIE led to a significant increase in QTc for each correction (by 5-47 ms, all p < 0.05), and QTc was significantly longer during early recovery from acute exercise (HIE) compared with CON corrected with the Bazett (by 49 ms), Fridericia (by 11 ms), Hodges (by 27 ms), and Rautaharju (by 15 ms) formulas (all p < 0.05). Further, the QTc for each correction at most of the observation points in the REC trial was significantly longer (by 5-10 ms, all p < 0.05) than the corresponding value of the CON. In conclusion, in obese adults, the risk of QTc prolongation increased after brief HIE, and the risk may be sustained for more than 24 h.


Tree shrew lavatories: a novel nitrogen sequestration strategy in a tropical pitcher plant.
Nepenthes pitcher plants are typically carnivorous, producing pitchers with varying combinations of epicuticular wax crystals, viscoelastic fluids and slippery peristomes to trap arthropod prey, especially ants. However, ant densities are low in tropical montane habitats, thereby limiting the potential benefits of the carnivorous syndrome. Nepenthes lowii, a montane species from Borneo, produces two types of pitchers that differ greatly in form and function. Pitchers produced by immature plants conform to the 'typical' Nepenthes pattern, catching arthropod prey. However, pitchers produced by mature N. lowii plants lack the features associated with carnivory and are instead visited by tree shrews, which defaecate into them after feeding on exudates that accumulate on the pitcher lid. We tested the hypothesis that tree shrew faeces represent a significant nitrogen (N) source for N. lowii, finding that it accounts for between 57 and 100 per cent of foliar N in mature N. lowii plants. Thus, N. lowii employs a diversified N sequestration strategy, gaining access to a N source that is not available to sympatric congeners. The interaction between N. lowii and tree shrews appears to be a mutualism based on the exchange of food sources that are scarce in their montane habitat.


Hidden threat in familial Mediterranean fever: subclinical inflammation, oxidative stress and their relationship with vitamin D status.
Vitamin D levels have been investigated in children with familial Mediterranean fever (FMF), but the relationship between vitamin D status and inflammation/oxidative stress indicators could not be clearly demonstrated. This study aimed to investigate the relationship between subclinical inflammation/oxidative stress and vitamin D status in children with FMF during an attack-free period. In the cross-sectional study, ninety children with FMF in the attack-free period and 30 healthy children were included. Patients were grouped according to their vitamin D status (< 20, 20-29, and 30-100 ng/mL). The groups were compared in terms of pentraxin 3 (PTX-3), total oxidant status (TOS), and total antioxidant status (TAS). Multivariable linear regression analysis was performed to identify factors associated with vitamin D status. PTX-3 levels were significantly higher in patients with vitamin D insufficiency (20-29 ng/mL) than in the group with vitamin D sufficient (30-100 ng/mL). Patients with vitamin D deficiency (< 20 ng/mL) had higher TOS. A strong negative correlation was observed between vitamin D levels and TOS (p = 0.003). Subclinical inflammation (PTX-3 ≥ 0.640) and high TOS levels were negatively associated with vitamin D levels.


TFIIA and the transactivator Rap1 cooperate to commit TFIID for transcription initiation.
Transcription of eukaryotic messenger RNA (mRNA) encoding genes by RNA polymerase II (Pol II) is triggered by the binding of transactivating proteins to enhancer DNA, which stimulates the recruitment of general transcription factors (TFIIA, B, D, E, F, H) and Pol II on the cis-linked promoter, leading to pre-initiation complex formation and transcription. In TFIID-dependent activation pathways, this general transcription factor containing TATA-box-binding protein is first recruited on the promoter through interaction with activators and cooperates with TFIIA to form a committed pre-initiation complex. However, neither the mechanisms by which activation signals are communicated between these factors nor the structural organization of the activated pre-initiation complex are known. Here we used cryo-electron microscopy to determine the architecture of nucleoprotein complexes composed of TFIID, TFIIA, the transcriptional activator Rap1 and yeast enhancer-promoter DNA. These structures revealed the mode of binding of Rap1 and TFIIA to TFIID, as well as a reorganization of TFIIA induced by its interaction with Rap1. We propose that this change in position increases the exposure of TATA-box-binding protein within TFIID, consequently enhancing its ability to interact with the promoter. A large Rap1-dependent DNA loop forms between the activator-binding site and the proximal promoter region. This loop is topologically locked by a TFIIA-Rap1 protein bridge that folds over the DNA. These results highlight the role of TFIIA in transcriptional activation, define a molecular mechanism for enhancer-promoter communication and provide structural insights into the pathways of intramolecular communication that convey transcription activation signals through the TFIID complex.


Role-playing in the problem-based learning class.
Learning and teaching have been conceptualized and executed in many styles, such as self-learning, peer learning, and interaction between the learner and mentor. Today, openness to alternative ideas and embracing innovative approaches in nursing education are encouraged in order to meet students' learning interests and needs, and to address ever-changing healthcare requests. Problem-based learning has been widely adopted in nursing education, with various positive effects on students' learning, such as motivated learning, team work, problem-solving skills and critical thinking. Role-plays have been demonstrated as an effective learning strategy that includes an active and experiential feature that facilitates students' autonomy in their health-related learning. However, there is a lack of discussion of whether and how role-play can be used in problem-based learning (PBL). This paper shows the development of a classroom-based innovation using role-play in the PBL class for higher diploma year-one nurse students (a total of 20 students, five per group). This paper consists of five sections: a) the literature on PBL and nurse education, and role-plays as the innovation; b) the PBL case scenario with the illustration of the two role-play scripts, c) student evaluation on role-play in the PBL class; d) discussions on both achievements and limitations of this innovation, and e) the conclusion. It is hoped that this paper will be an example to other nurse educators who are keen on exploring interactive and student-driven learning and teaching strategies in the PBL class.


Investigating the Feasibility of Epicranial Cortical Stimulation Using Concentric-Ring Electrodes: A Novel Minimally Invasive Neuromodulation Method.
Invasive cortical stimulation (ICS) is a neuromodulation method in which electrodes are implanted on the cortex to deliver chronic stimulation. ICS has been used to treat neurological disorders such as neuropathic pain, epilepsy, movement disorders and tinnitus. Noninvasive neuromodulation methods such as transcranial magnetic stimulation and transcranial electrical stimulation (TES) show great promise in treating some neurological disorders and require no surgery. However, only acute stimulation can be delivered. Epicranial current stimulation (ECS) is a novel concept for delivering chronic neuromodulation through subcutaneous electrodes implanted on the skull. The use of concentric-ring ECS electrodes may allow spatially focused stimulation and offer a less invasive alternative to ICS. Demonstrate ECS proof-of-concept using concentric-ring electrodes in rats and then use a computational model to explore the feasibility and limitations of ECS in humans. ECS concentric-ring electrodes were implanted in 6 rats and pulsatile stimulation delivered to the motor cortex. An MRI based electro-anatomical human head model was used to explore different ECS concentric-ring electrode designs and these were compared with ICS and TES. Concentric-ring ECS electrodes can selectively stimulate the rat motor cortex. The computational model showed that the concentric-ring ECS electrode design can be optimized to achieve focused cortical stimulation. In general, focality was less than ICS but greater than noninvasive transcranial current stimulation. ECS could be a promising minimally invasive alternative to ICS. Further work in large animal models and patients is needed to demonstrate feasibility and long-term stability.


Predicting cardiovascular disease risk from gut microbial genes.
Gut bacteria-driven production of trimethylamine (TMA) is strongly associated with cardiovascular disease. Borton et al. (mBio 14:e01511-23, 2023, https://doi.org/10.1128/mbio.01511-23) introduce the Methylated Amine Gene Inventory of Catabolism database (MAGICdb), comprehensively cataloging pathways involved in TMA metabolism. By integrating transcriptomics, proteomics, and metagenomic data, this work identifies key bacterial players in the process and can link gut microbial gene content to fecal TMA concentrations. This work shows that methylated amine metabolism is a keystone microbiome process carried out by a small proportion of the community. Proatherogenic pathways are more widely distributed among the gut microbiota, and new TMA-reducing genera were identified that might offer new potential for probiotic strategies or targeted microbiome interventions. Remarkably, MAGICdb's power to predict cardiovascular disease risk matches an approach using more traditional lipid risk factors. This open source will be a valuable tool for the community to link methylated amine metabolism to gut microbiome-related human health conditions.


Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study.
Histological subtyping of pulmonary adenocarcinoma has recently been updated based on predominant pattern, but data on reproducibility are required for validation. This study first assesses reproducibility in subtyping adenocarcinomas and then assesses further the distinction between invasive and non-invasive (wholly lepidic) pattern of adenocarcinoma, among an international group of pulmonary pathologists. Two ring studies were performed using a micro-photographic image-based method, evaluating selected images of lung adenocarcinoma histologic patterns. In the first study, 26 pathologists reviewed representative images of typical and 'difficult' histologic patterns. A total number of scores for the typical patterns combined (n=94) and the difficult cases (n=21) were 2444 and 546, respectively. The mean kappa score (±s.d.) for the five typical patterns combined and for difficult cases were 0.77±0.07 and 0.38±0.14, respectively. Although 70% of the observers identified 12-65% of typical images as single pattern, highest for solid and least for micropapillary, recognizing the predominant pattern was achieved in 92-100%, of the images except for micropapillary pattern (62%). For the second study on invasion, identified as a key problem area from the first study, 28 pathologists submitted and reviewed 64 images representing typical as well as 'difficult' examples. The kappa for typical and difficult cases was 0.55±0.06 and 0.08±0.02, respectively, with consistent subdivision by the same pathologists into invasive and non-invasive categories, due to differing interpretation of terminology defining invasion. In pulmonary adenocarcinomas with classic morphology, which comprise the majority of cases, there is good reproducibility in identifying a predominant pattern and fair reproducibility distinguishing invasive from in-situ (wholly lepidic) patterns. However, more precise definitions and better education on interpretation of existing terminology are required to improve recognition of purely in-situ disease, this being an area of increasing importance.


Biosynthesis of proteoglycans in cartilage slices. Fractionation by gel chromatography and equilibrium density-gradient centrifugation.
The kinetics of incorporation of [(35)S]sulphate into slices of pig laryngeal cartilage in vitro was linear with time up to 6h. The specific radioactivities of the extracted proteoglycans (containing about 80% of the uronic acid of the cartilage) and the glycosaminoglycans remaining in the tissue after extraction were measured after various times of continuous and ;pulse-chase' radioactivity incorporation. Radioactivity was present in the isolated chondroitin sulphate after 2 min, but there was a 35min delay in its appearance in the extractable proteoglycan fraction. Fractionation of the proteoglycans by gel chromatography showed that the smallest molecules had the highest specific radioactivity, but ;pulse-chase' experiments over 5h did not demonstrate any precursor-product relationships between fractions of different size. Equilibrium density-gradient centrifugation in 4m-guanidine hydrochloride showed that among the proteoglycan fractions the specific radioactivity increased as the chondroitin sulphate content decreased, but with preparations from ;pulse-chase' experiments there was again no evidence for precursor-product relationships between the different fractions. Differences in radioactive incorporation would seem to reflect metabolic heterogeneity within the proteoglycans extracted from cartilage. This may be due either to a partial separation of different types of proteoglycans or to differences in the rates of degradation of the molecules of different size and composition as a result of the nature and specificity of the normal degrading enzymes. The results suggest that molecules of all sizes were formed at the same time.


Evaluation of performance and microbial ecology of sequencing batch reactor and membrane bioreactor treating thin-film transistor liquid crystal display wastewater.
In Taiwan, a substantial amount of thin-film transistor liquid crystal display (TFT-LCD) wastewater is produced daily due to an increasing production of the opto-electronic industry in recent years. The main components of TFT-LCD wastewater include dimethyl sulphoxide (DMSO), monoethanolamine (MEA), and tetra-methyl ammonium hydroxide (TMAH), which are recognized as non-or slow-biodegradable organic compounds and limited information is available regarding their biological treatablility. This study was conducted to evaluate the long-term performance of two bioreactors, anaerobic-aerobic (A/O) sequencing batch reactor (SBR) and aerobic membrane bioreactor (MBR), treating synthetic TFT-LCD wastewater containing DMSO, MEA, and TMAH with different loadings. For the A/O SBR, the influent wastewater was composed of 800 mg MEA/L, 430 mg DMSO/L, and 90 mg TMAH/L, respectively. After reaching steady-state, SBR was able to achieve more than 99% degradation efficiencies for the three compounds examined. For the case of aerobic MBR, the influent wastewater was composed of 550 mg MEA/L, 270 mg DMSO/L, and 330 mg TMAH/L, respectively, and degradation efficiencies for the three compounds achieved more than 99%. Although both different reactors shared similar and satisfactory degradation efficiencies for DMSO, MEA, and TMAH, the microbial ecology of these two reactors, as elucidated with molecular methods, was apparently different. The 16S rDNA-based cloning/sequencing results indicated that the dominant sequences retrieved from the aerobic MBR, including Hyphomicrobium denitrificans, Hyphomicrobium zavarzinii, Rhodobacter sp., and Methyloversatilis universalis, showed a clear linkage to their physiological properties of DMSO and TMAH degradation. On the other hand, Zoogloea sp., Chlorobium chlorochromatii, Agricultural soil bacterium, and Flavosolibacter ginsengiterrae were proliferated in the A/O SBR Run1, while Thiobacillus sp., Nitrosomonas sp., Thauera aromatica and Azoarcus sp. became dominant in Run2. Furthermore, the sequences retrieved from different reactors were used to establish the terminal restriction fragment length polymorphism (TRFLP) fingerprint methodology for monitoring the dynamics of dominant degrading bacteria in the aerobic MBR treating TFT-LCD wastewater.


Zingiber officinale Roscoe prevents acetaminophen-induced acute hepatotoxicity by enhancing hepatic antioxidant status.
A large number of xenobiotics are reported to be potentially hepatotoxic. Free radicals generated from the xenobiotic metabolism can induce lesions of the liver and react with the basic cellular constituents - proteins, lipids, RNA and DNA. Hepatoprotective activity of aqueous ethanol extract of Zingiber officinale was evaluated against single dose of acetaminophen-induced (3g/kg, p.o.) acute hepatotoxicity in rat. Aqueous extract of Z. officinale significantly protected the hepatotoxicity as evident from the activities of serum transaminase and alkaline phosphatase (ALP). Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and ALP activities were significantly (p<0.01) elevated in the acetaminophen alone treated animals. Antioxidant status in liver such as activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase and glutathione-S-transferase (GST), a phase II enzyme, and levels of reduced glutathione (GSH) were declined significantly (p<0.01) in the acetaminophen alone treated animals (control group). Hepatic lipid peroxidation was enhanced significantly (p<0.01) in the control group. Administration of single dose of aqueous extract of Z. officinale (200 and 400mg/kg, p.o.) prior to acetaminophen significantly declines the activities of serum transaminases and ALP. Further the hepatic antioxidant status was enhanced in the Z. officinale plus acetaminophen treated group than the control group. The results of the present study concluded that the hepatoprotective effect of aqueous ethanol extract of Z. officinale against acetaminophen-induced acute toxicity is mediated either by preventing the decline of hepatic antioxidant status or due to its direct radical scavenging capacity.


Reactive oxygen species generated by thiopurine/UVA cause irreparable transcription-blocking DNA lesions.
Long-term treatment with the anticancer and immunosuppressant thiopurines, azathioprine or 6-mercaptopurine, is associated with acute skin sensitivity to ultraviolet A (UVA) radiation and a high risk of skin cancer. 6-thioguanine (6-TG) that accumulates in the DNA of thiopurine-treated patients interacts with UVA to generate reactive oxygen species. These cause lethal and mutagenic DNA damage. Here we show that the UVA/DNA 6-TG interaction rapidly, and essentially irreversibly, inhibits transcription in cultured human cells and provokes polyubiquitylation of the major subunit of RNA polymerase II (RNAPII). In vitro, 6-TG photoproducts, including the previously characterized guanine-6-sulfonate, in the transcribed DNA strand, are potent blocks to RNAPII transcription whereas 6-TG is only slightly inhibitory. In vivo, guanine-6-sulfonate is removed poorly from DNA and persists to a similar extent in the DNA of nucleotide excision repair-proficient and defective cells. Furthermore, transcription coupled repair-deficient Cockayne syndrome cells are not hypersensitive to UVA/6-TG, indicating that potentially lethal photoproducts are not selectively excised from transcribed DNA. Since persistent transcription-blocking DNA lesions are associated with acute skin responses to sunlight and the development of skin cancer, our findings have implications for skin cancer in patients undergoing thiopurine therapy.


Fitting a model to categorical response data with application to species extrapolation of toxicity.
The evaluation of toxicity data for noncarcinogens is complicated by the multiplicity of possible end points, and variations in both severity of effect and response rate. Often the response rates are not reported, so that "dose-response" analysis involves the relation between dose and severity of effect. Severity is usually reported as a description of the nature of the effects; measured values are rare. One approach is to then assign severity descriptions to ordered categories and to model the dose-category relationship. The application presented here is to interspecies scaling, i.e., the estimation of parameters in the model used to convert animal doses into equally toxic human doses.


A review of modeling interacting transient phenomena with non-equilibrium Green functions.
As experimental probes have matured to observe ultrafast transient and high frequency responses of materials and devices, so to have the theoretical methods to numerically and analytically simulate time- and frequency-resolved transport. In this review article, we discuss recent progress in the development of the time-dependent and frequency-dependent non-equilibrium Green function (NEGF) technique. We begin with an overview of the theoretical underpinnings of the underlying Kadanoff-Baym equations and derive the fundamental NEGF equations in the time and frequency domains. We discuss how these methods have been applied to a variety of condensed matter systems such as molecular electronics, nanoscale transistors, and superconductors. In addition, we survey the application of NEGF in fields beyond condensed matter, where it has been used to study thermalization in ultra-cold atoms and to understand leptogenesis in the early universe. Throughout, we pay special attention to the challenges of incorporating contacts and interactions, as the NEGF method is uniquely capable of accounting for such features.


Estimating the potential impact and diagnostic requirements for SARS-CoV-2 test-and-treat programs.
Oral antivirals have the potential to reduce the public health burden of COVID-19. However, now that we have exited the emergency phase of the COVID-19 pandemic, declining SARS-CoV-2 clinical testing rates (average testing rates = ≪10 tests/100,000 people/day in low- and-middle income countries; <100 tests/100,000 people/day in high-income countries; September 2023) make the development of effective test-and-treat programs challenging. We used an agent-based model to investigate how testing rates and strategies affect the use and effectiveness of oral antiviral test-to-treat programs in four country archetypes of different income levels and demographies. We find that in the post-emergency phase of the pandemic, in countries where low testing rates are driven by limited testing capacity, significant population-level impact of test-and-treat programs can only be achieved by both increasing testing rates and prioritizing individuals with greater risk of severe disease. However, for all countries, significant reductions in severe cases with antivirals are only possible if testing rates were substantially increased with high willingness of people to seek testing. Comparing the potential population-level reductions in severe disease outcomes of test-to-treat programs and vaccination shows that test-and-treat strategies are likely substantially more resource intensive requiring very high levels of testing (>>100 tests/100,000 people/day) and antiviral use suggesting that vaccination should be a higher priority.


Excessive occupational heat exposure: a significant ergonomic challenge and health risk for current and future workers.
Occupational heat exposure threatens the health of a worker not only when heat illness occurs but also when a worker's performance and work capacity is impaired. Occupational contexts that involve hot and humid climatic conditions, heavy physical workloads and/or protective clothing create a strenuous and potentially dangerous thermal load for a worker. There are recognized heat prevention strategies and international thermal ergonomic standards to protect the worker. However, such standards have been developed largely in temperate western settings, and their validity and relevance is questionable for some geographical, cultural and socioeconomic contexts where the risk of excessive heat exposure can be high. There is evidence from low- and middle-income tropical countries that excessive heat exposure remains a significant issue for occupational health. Workers in these countries are likely to be at high risk of excessive heat exposure as they are densely populated, have large informal work sectors and are expected to experience substantial increases in temperature due to global climate change. The aim of this paper is to discuss current and future ergonomic risks associated with working in the heat as well as potential methods for maintaining the health and productivity of workers, particularly those most vulnerable to excessive heat exposure.


[Determination of Se, Fe, Si in electrolytic manganese metal by ICP-AES].
The method was established for the simultaneous determination of Se, Fe and Si in electrolytic manganese metal by inductively coupled plasma atomic emission spectrometry (ICP-AES). The sample was dissolved by light sulphuric acid. The analysis conditions were obtained by studying dissolved acid, Mn matrix and background. The recommended method not only proved to be simple and rapid but showed satisfying precision and accuracy as well. The relative standard deviation is less than 2.68% and the recovery is 98%-105%. The t-test showed that no conspicuous difference with typical methods was found.


[Cowden syndrome (multiple hamartoma syndrome). Role of the dentist in early detection].
First lesions of Cowden syndrome appear in the oral cavity and on the skin. Malignant transformation is a late, common event in thyroid and breast. The early diagnosis of Cowden disease prior to the development of internal malignancy, particularly of the breast and the thyroid gland, is very important. We emphasize that the dentist may be the first health care professional who recognizes the syndrome, and this is a crucial step in the prevention and cure of the predictable malignancy. This article presents a typical case of Cowden disease.


Drugs for treating neurocysticercosis (tapeworm infection of the brain).
Anthelminthic drugs may shrink brain cysts in neurocysticercosis, but can also cause severe adverse effects. The objective of this review was to assess the effects of drug treatment in human neurocysticercosis in relation to survival, cyst persistence, subsequent seizures and hydrocephalus. We searched the Cochrane Infectious Diseases Group trials register and Medline. We contacted researchers and experts in the field and drug manufacturers. Randomised or quasi-randomised trials comparing a cysticidal drug with a placebo or a control group receiving symptomatic therapy, in patients with neurocystercosis. Assessment of trial quality and data extraction was done independently by two reviewers. Four studies involving 305 people met the inclusion criteria. None reported on withdrawal of anticonvulsant therapy, headache relief, disability or death as outcomes. A difference just approaching significance was detected between cysticidal therapy and placebo in relation to cyst persistence up to six months (relative risk 0.83, 95% confidence interval 0.70 to 0.99). Two trials reported on seizures after one to two years follow-up and found no difference (relative risk 0.95, 95% 0.59 to 1.51). There was no difference detected for hydrocephalus (relative risk 2.19, 95% confidence interval 0.29 to 16.55). There is insufficient evidence to assess whether cysticidal therapy in neurocysticerosis is associated with beneficial effects.