A new cause of ischaemic priapism: Synthetic cannabinoids.
Priapism is a urological emergency that needs early intervention and may lead to irreversible cavernosal damage. Ischaemic priapism is the most common type, which is frequently idiopathic and commonly associated with haematological diseases, medications or recreational drugs. Synthetic cannabinoids (SCs) have been increasingly used all over the world, particularly among young-adult population. SCs can cause severe adverse effects on several organ systems. However, there are no studies in the literature which have stated the possible relationship between using of SCs and priapism. We present a case of 28-year-old man who was diagnosed with a 58-hr lasting priapism after regular administrations of SCs. The priapism did not resolve neither after applying aspiration with irrigation nor shunt surgery. Finally, penile prosthesis implantation was performed as last treatment option. The SCs have been increasingly used among young population in recent years; therefore, new SC-related ischaemic priapism cases might be encountered in the emergency departments.


Active lifestyle patterns reduce the risk of colorectal cancer in the Mecca region, Saudi Arabia: a case-control study.
We carried out a case-control study to investigate the effects of some lifestyle patterns on the occurrence of colorectal cancer (CRC) in the city of Mecca, Saudi Arabia. Parameters included BMI, employment, family income, educational level, family size, exercise, cancer awareness, diabetes, and hypertension. Individuals of both groups (n=164 for control group, n=137 for CRC group) completed a questionnaire with the help of trained dietitians. Results showed that limited cancer awareness was found to increase the risk of CRC [odds ratio (OR)=49.96, 95% confidence interval (CI): 11.45-217.9, P<0.001]. There was a linear trend (P-trend<0.001) of low educational level in increasing the risk of CRC. Mainly, illiterate individuals showed the highest risk of developing CRC (OR=116.8, 95% CI: 14.7-927.75, P<0.001). In addition, the results indicated a linear trend (P-trend<0.001) of low family income in increasing the risk of CRC. The highest risk of CRC was shown with family income less than 5000 Saudi riyals (OR=64.38, 95% CI: 12.82-323.28, P<0.001). Other risk factors included a sedentary lifestyle, unemployment, and diabetes. Surprisingly, low BMI was associated with increasing incidence of CRC (OR=0.92, 95% CI: 0.88-0.96, P<0.001). However, family size and hypertension had no effect (P>0.05) on the incidence of CRC. Our study emphasizes the effect of active lifestyle patterns and cancer awareness in decreasing the incidence of CRC in the Mecca region.


Abdominal Compartment Syndrome: diagnostic evaluation and possible treatment.
Abdominal compartment syndrome (ACS) is a clinical condition caused by an increase in intra-abdominal pressure. The incidence is variable, based on the type of patients taken into consideration, increasing exponentially in critical conditions, such as traumatized, burned patients in shock. The syndrome can also follow surgical procedures like transplantation of abdominal organs, for example configuring rare pictures such as RACS (post-transplant kidney syndrome). In most cases the symptoms are non-specific and varied according to the different etiology of the ACS, therefore the diagnosis may not be immediate. The aim of this work is to evaluate the best therapeutic approach based on the evidence in the literature. An early diagnosis, which can also identify the stages of intra-abdominal hypertension, is necessary to ensure the survival of the patient, implementing an integrated multidisciplinary treatment, expecially in the early stages of the development of the ACS. The definitive treatment is surgical and is based on the decompression of the abdomen.


No association of TNFRSF1B variants with type 2 diabetes in Indians of Indo-European origin.
There has been no systematic evaluation of the association between genetic variants of type 2 receptor for TNFα (TNFR2) and type 2 diabetes, despite strong biological evidence for the role of this receptor in the pathogenesis of this complex disorder. In view of this, we performed a comprehensive association analysis of TNFRSF1B variants with type 2 diabetes in 4,200 Indo-European subjects from North India. The initial phase evaluated association of seven SNPs viz. rs652625, rs496888, rs6697733, rs945439, rs235249, rs17883432 and rs17884213 with type 2 diabetes in 2,115 participants (1,073 type 2 diabetes patients and 1,042 control subjects). Further, we conducted replication analysis of three associated SNPs in 2,085 subjects (1,047 type 2 diabetes patients and 1,038 control subjects). We observed nominal association of rs945439, rs235249 and rs17884213 with type 2 diabetes (P < 0.05) in the initial phase. Haplotype CC of rs945439 and rs235249 conferred increased susceptibility for type 2 diabetes [OR = 1.19 (95%CI 1.03-1.37), P = 0.019/Pperm = 0.076] whereas, TG haplotype of rs235249 and rs17884213 provided protection against type 2 diabetes [OR = 0.83 (95%CI 0.72-0.95, P = 7.2 × 10-3/Pperm = 0.019]. We also observed suggestive association of rs496888 with plasma hsCRP levels [P = 0.042]. However, the association of rs945439, rs235249 and rs17884213 with type 2 diabetes was not replicated in the second study population. Meta-analysis of the two studies also failed to detect any association with type 2 diabetes. Our two-stage association analysis suggests that TNFRSF1B variants are not the determinants of genetic risk of type 2 diabetes in North Indians.


Depressive symptoms and self-concept in young people with spina bifida.
Examined self-reported depressive symptoms in 72 young people with spina bifida, ages 9 to 18:11, and matched able-bodied comparison subjects, using the Dimensions of Depression Profile for Children and Adolescents (Harter & Nowakowski, 1987). Independent variables included gender, self-perceptions (including physical appearance), and perceived social support. Young people with spina bifida were at greater risk of depressive mood, low self-worth, and suicidal ideation. Girls, independent of disability, were at greater risk of depressive mood, low self-worth, and self-blame. Multiple regression analyses suggest that global self-worth serves as a mediating variable for the effect of physical appearance self-concept on depressed mood (particularly in young people with spina bifida), and that perceived parental social support has a direct effect on depressed mood (particularly in girls).


Supplementing calcium salts of soybean oil to beef steers early in life to enhance carcass development and quality1.
This study evaluated the effects of supplementing Ca salts of soybean oil (CSSO) to beef steers at 2 mo of age via creep-feeding, and/or during a 40-d preconditioning period on performance and carcass development responses. A total of 64 steers were enrolled in this study over 2 yr (32 steers per year), with 4 periods each year: creep-feeding (CF; day 0 to 60), preweaning (day 61 to weaning on day 124 and 127 of year 1 and 2, respectively), preconditioning (PC; day 132 to 172 in year 1 and day 135 to 175 of year 2), and feedlot (feedlot arrival to slaughter, day 173 to 378 in year 1 and day 176 to 385 in year 2). On day 0 steers were ranked by body weight (BW) and age (114 ± 4 kg of BW; 66.1 ± 0.9 d of age) and allocated to 1 of 16 pens. Pens were randomly assigned to receive CSSO during CF (80 g/d per steer) and/or PC (150 g/d per steer) in a 2 × 2 factorial arrangement of treatments. During CF and PC, nonsupplemented steers (CON) were provided an isolipidic prilled saturated fat supplement. Steer BW was recorded on day 0, 60, at weaning, and prior to feedlot shipping. Carcass traits were recorded upon slaughter. On day 0, 60, at weaning, prior to feedlot shipping, and during the feedlot period, blood samples were collected and longissimus muscle (LM) biopsies were collected. On day 60, steers that received CSSO during CF had greater (P < 0.01) plasma concentrations of linoleic and ω-6 compared with CON (CF treatment × day; P ≤ 0.05). Steers that received CSSO during PC had greater (P < 0.01) plasma concentrations of linoleic, ω-6, and total fatty acids compared with CON at feedlot shipping (PC treatment × day; P ≤ 0.05). A PC treatment × day interaction was also detected (P = 0.04) for mRNA expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), which was greater (P = 0.04) at feedlot shipping for steers receiving CSSO during PC. Interactions between CF treatment × day were detected (P ≤ 0.01) for mRNA expression of adipocyte fatty acid-binding protein, fatty acid synthase, PPAR-γ, and stearoyl-CoA desaturase, which were greater (P ≤ 0.02) in the feedlot in steers receiving CSSO during CF. No treatment differences were detected for (P ≥ 0.18) performance or carcass traits, including marbling and backfat thickness. Results from this study suggest that supplementing CSSO to suckled beef steers via creep-feeding upregulated mRNA expression of the adipogenic genes investigated herein later in life. These outcomes, however, were not translated into improved carcass quality.


Papaya Fruit Pulp and Resulting Lactic Fermented Pulp Exert Antiviral Activity against Zika Virus.
There are a several emerging and re-emerging RNA viruses that are prevalent around the world for which there are no licensed vaccines or antiviral drugs. Zika virus (ZIKV) is an example of an emerging virus that has become a significant concern worldwide because of its association with severe congenital malformations and neurological disorders in adults. Several polyphenol-rich extracts from plants were used as nutraceuticals which exhibit potent in vitro antiviral effects. Here, we demonstrated that the papaya pulp extracted from Carica papaya fruit inhibits the infection of ZIKV in human cells without loss of cell viability. At the non-cytotoxic concentrations, papaya pulp extract has the ability to reduce the virus progeny production in ZIKV-infected human cells by at least 4-log, regardless of viral strains tested. Time-of-drug-addition assays revealed that papaya pulp extract interfered with the attachment of viral particles to the host cells. With a view of preserving the properties of papaya pulp over time, lactic fermentation based on the use of bacterial strains Weissella cibaria 64, Lactobacillus plantarum 75 and Leuconostoc pseudomesenteroides 56 was performed and the resulting fermented papaya pulp samples were tested on ZIKV. We found that lactic fermentation of papaya pulp causes a moderate loss of antiviral activity against ZIKV in a bacterial strain-dependent manner. Whereas IC50 of the papaya pulp extract was 0.3 mg/mL, we found that fermentation resulted in IC50 up to 4 mg/mL. We can conclude that papaya pulp possesses antiviral activity against ZIKV and the fermentation process has a moderate effect on the antiviral effect.


Conversion of somatostatin-28 to somatostatin-14 during maturation of epithelial cells in the porcine jejunum.
Fractions of isolated epithelial cells were harvested from a segment of porcine jejunum by ten successive incubations with a chelating buffer. The cell fractions showed a progressive decrease in the activity of the brush-border enzymes, alkaline phosphatase and sucrase, with increasing incubation number but a progressive increase in the ability to incorporate labelled thymidine into DNA. Fractions enriched in cells from the crypt region (fractions 9 and 10) contained higher concentrations per mg protein of somatostatin-like immunoreactivity (1.8-fold), glucagon-like immunoreactivity (5.3-fold) and serotonin (3.0-fold) than fractions enriched in cells from the villus tip (fractions 1 and 2). Analysis of extracts of the fractions by gel filtration/radioimmunoassay showed that somatostatin-28 represented the predominant molecular form of somatostatin-like immunoreactivity in all cell fractions but the relative proportion of somatostatin-14 (and related metabolites) to somatostatin-28 was significantly higher (P less than 0.05) in fractions enriched in villus cells (fraction 1 and 2) than in fractions enriched in crypt cells (fractions 5-10). This result suggests that metabolism of somatostatin-28 to somatostatin-14 takes place during migration of the D cell from the crypt base to the villus tip. Heterogeneity in the somatostatin-14 region of the chromatograms indicates that the peptide may be further metabolized by the action of aminopeptidases.


Comparative visualization for parameter studies of dataset series.
This paper proposes comparison and visualization techniques to carry out parameter studies for the special application area of dimensional measurement using 3D X-ray computed tomography (3DCT). A dataset series is generated by scanning a specimen multiple times by varying parameters of an industrial 3DCT device. A high-resolution series is explored using our planar-reformatting-based visualization system. We present a novel multi-image view and an edge explorer for comparing and visualizing gray values and edges of several datasets simultaneously. Visualization results and quantitative data are displayed side by side. Our technique is scalable and generic. It can be effective in various application areas like parameter studies of imaging modalities and dataset artifact detection. For fast data retrieval and convenient usability, we use bricking of the datasets and efficient data structures. We evaluate the applicability of the proposed techniques in collaboration with our company partners.


Firing rate distributions and efficiency of information transmission of inferior temporal cortex neurons to natural visual stimuli.
The distribution of responses of sensory neurons to ecological stimulation has been proposed to be designed to maximize information transmission, which according to a simple model would imply an exponential distribution of spike counts in a given time window. We have used recordings from inferior temporal cortex neurons responding to quasi-natural visual stimulation (presented using a video of everyday lab scenes and a large number of static images of faces and natural scenes) to assess the validity of this exponential model and to develop an alternative simple model of spike count distributions. We find that the exponential model has to be rejected in 84% of cases (at the p < 0.01 level). A new model, which accounts for the firing rate distribution found in terms of slow and fast variability in the inputs that produce neuronal activation, is rejected statistically in only 16% of cases. Finally, we show that the neurons are moderately efficient at transmitting information but not optimally efficient.


Rainfall and child weight in Uganda.
We combine data from the 2006 and 2011 Uganda Demographic and Health Surveys (UDHS) with rainfall data and two waves of the Ugandan National Household Survey (UNHS) to study patterns in child weight, as measured by weight-for-height z scores (WHZ), among 3492 rural children below age 5 in Uganda. We focus on rainfall as a nutrition driver along agriculture and disease pathways. We find a positive and significant association between crop yield and WHZ, but the magnitude of this association diminishes as we control for covariates, especially the use of productivity-enhancing agricultural inputs. We find diarrheal disease to have a negative and significant association with WHZ, and modifying effects of social and environmental factors along the disease pathway. Contemporaneous rainfall is associated with a lower likelihood of diarrheal disease in areas with excess rainfall and a higher likelihood of diarrheal disease in rainfall deficit areas. Our findings reinforce calls for targeted and situation-sensitive policies to promote child nutrition.


The Burdens, Concerns, and Quality of Life of Patients with Gastroparesis.
The impact of gastroparesis on patients from the patient's viewpoint is needed to better address treatment priorities. The aims of this study were to: (1) Delineate burdens and concerns of patients with gastroparesis; (2) investigate specific symptoms contributing to impaired quality of life (QOL) in gastroparesis. The International Foundation for Functional GI Disorders gastroparesis survey questionnaire was developed to describe patients' viewpoint about their experience with gastroparesis and included Patient Assessment of Upper GI Symptoms (PAGI-SYM) and SF-36 QOL survey. A total of 1423 adult patients with gastroparesis completed the survey. Average duration of gastroparesis symptoms was 9.3 years with time from onset to diagnosis 5.0 years. Patients felt that they receive good information regarding treatment options from physicians, the Internet, and Facebook. Patients rated their satisfaction with available treatment for their gastroparesis as dissatisfied (33%), somewhat dissatisfied (27%), neutral (14%), somewhat satisfied (15%), and satisfied (4%). Patients felt that gastroparesis symptoms that are most important to improve with treatment are nausea, stomach pain, and vomiting. Overall, there was a decreased quality of life by SF-36. Physical health QOL score was negatively correlated with symptoms including nausea (r = -0.37), upper abdominal pain (r = -0.37), and early satiety (r = -0.37). This large series of patients with gastroparesis describes their burdens, concerns, and QOL. Nausea, vomiting, early satiety, and abdominal pain are important symptoms for treatment. Many patients are not satisfied with current treatments, wanting specific treatments for their disorder. Interestingly, a large number of patients find out about treatments, not only from their physician, but also using the Internet including social media.


Mn4+,Li+ co-doped SrMgAl10O17 phosphor-in-glass: application in high-power warm w-LEDs.
Currently, the shortage of red components and easy aging of organic silicone still remain challenges for high-power phosphor-converted warm white light-emitting diodes (w-LEDs). Aiming to alleviate these issues, phosphor-in-glass (PiG), fabricated by co-sintering red- and yellow-emitting phosphors and low-melting glass, has been regarded as a promising color converter for w-LEDs. In this study, a Li+,Mn4+ co-doped SrMgAl10O17 red phosphor was synthesized via a conventional solid-state reaction. The as-prepared phosphor exhibits a deep red emission, ascribed to Mn4+:2Eg→4A2g spin-forbidden transition in the range of 600-700 nm with a narrow-band full width at half maximum of 55 nm, and provides an ideal broadband excitation extending from 250 to 530 nm. Impressively, the Li+ additive used as charge compensation was beneficial to enhance the Mn4+ luminescence by allowing more Mn4+ to replace Al3+. Furthermore, the developed SrMgAl10O17:Mn4+,Li+ red phosphor and commercial YAG:Ce3+ yellow phosphor co-doped inorganic PiG were successfully fabricated as color converters to substitute organic silicone. The w-LED was fabricated by combining an InGaN blue LED chip with a PiG plate. Importantly, the constructed w-LEDs exhibited superior optical performance and tuned chromaticity feature with the correlated color temperature evolved from bluish cool white (6903 K) to yellowish warm white (3717 K), and the color rendering index increased from 69.4 to 85.5, meeting the requirements for indoor lighting.


AxCe9(IO3)36 (A = K, La): the effects of a change in the intermediate valence on the second-harmonic generation response.
Two new isostructural non-centrosymmetric cerium iodates KxCe9(IO3)36 (x≈ 3) and LaxCe9(IO3)36 (x≈ 0.3) were synthesized via a hydrothermal method and systematically characterized. They are intermediate valence compounds with the same band gap, showing similar microscopic net dipole moments per unit volume, but different macroscopic second-harmonic generation (SHG) responses under 1064 nm laser irradiation. This research gives a new view for understanding the effects of electronic structure on the SHG response.


Amphibian transcription factor IIIA proteins contain a sequence element functionally equivalent to the nuclear export signal of human immunodeficiency virus type 1 Rev.
The human immunodeficiency virus type 1 (HIV-1) Rev protein is required for nuclear export of late HIV-1 mRNAs. This function is dependent on the mutationally defined Rev activation domain, which also forms a potent nuclear export signal. Transcription factor IIIA (TFIIIA) binds to 5S rRNA transcripts and this interaction has been proposed to play a role in the efficient nuclear export of 5S rRNA in amphibian oocytes. Here it is reported that amphibian TFIIIA proteins contain a sequence element with homology to the Rev activation domain that effectively substitutes for this domain in inducing the nuclear export of late HIV-1 mRNAs. It is further demonstrated that this TFIIIA sequence element functions as a protein nuclear export signal in both human cells and frog oocytes. Thus, this shared protein motif may play an analogous role in mediating the nuclear export of both late HIV-1 RNAs and 5S rRNA transcripts.


The potential role of Th17 in mediating the transition from acute to chronic autoimmune inflammation: rheumatoid arthritis as a model.
T helper 17 cells (Th17) have arisen in the last 15 years as major effector cells in several chronic inflammatory states. In synovitis associated with rheumatoid arthritis (RA), Th17 emerged as being involved in driving the active acute phases and correlated with local and systemic parameters of inflammation; in particular, TCRζ(dim) Th17 appear to be the greatest producers of IL-17 at the single-cell level. IL-1beta and IL-6, along with IL-23, arose as the major drivers of differentiation and local development of Th17, while IL-15 and cell-cell contact can trigger the local production of IL-17. TNF-alpha inhibition can reversibly block the migration of pathogenic effector memory TCRzeta(dim) T cells and CCR6+ Th17 from peripheral blood to inflamed tissues. IL-17 is a potent chemoattractant for pre-committed CD4+ T cells and neutrophils, and may promote the migration of B cells to lymphoid follicles in the chronic phase of synovial inflammation. Importantly, IL-17 drives osteoclastogenesis and neoangiogenesis in the RA joint. These data strongly suggest that Th17 are key effector cells in driving the transition from the acute to the chronic phase of RA inflammation.


Promoting cancer screening among churchgoing Latinas: Fe en Acción/faith in action.
Cancer screening rates among Latinas are generally low, reducing the likelihood of early cancer detection in this population. This article examines the effects of a community intervention (Fe en Acción/Faith in Action) led by community health workers (promotoras) on promoting breast, cervical and colorectal cancer screening among churchgoing Latinas. Sixteen churches were randomly assigned to a cancer screening or a physical activity intervention. We examined cancer knowledge, barriers to screening and self-reported mammography, clinical breast exam, Pap test, fecal occult blood test and sigmoidoscopy or colonoscopy at baseline and 12 months follow-up. Participants were 436 adult Latinas, with 16 promotoras conducting a cancer screening intervention at 8 out of 16 churches. The cancer screening intervention had a significant positive impact on self-reported mammography (OR = 4.64, 95% CI: 2.00-10.75) and breast exams in the last year (OR= 2.82, 95% CI: 1.41-5.57) and corresponding reductions in perceived (87.6%) barriers to breast cancer screening (P < .008). Cervical and colorectal cancer screening did not improve with the intervention. These findings suggest Fe en Acción church-based promotoras had a significant impact on promoting breast cancer screening among Latinas. Colon cancer screening promotion, however, remains a challenge.


Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer.
The efficacy and safety of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Overall, 170 patients were randomly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) on day 1 of up to six 21-day cycles (arm I); axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin (arm II); or pemetrexed/cisplatin alone (arm III). The primary endpoint was progression-free survival (PFS). Median PFS was 8.0, 7.9, and 7.1 months in arms I, II, and III, respectively (hazard ratio: arms I vs. III, 0.89 [P = 0.36] and arms II vs. III, 1.02 [P = 0.54]). Median overall survival was 17.0 months (arm I), 14.7 months (arm II), and 15.9 months (arm III). Objective response rates (ORRs) for axitinib-containing arms were 45.5% (arm I) and 39.7% (arm II) compared with 26.3% for pemetrexed/cisplatin alone (arm III). Gastrointestinal disorders and fatigue were frequently reported across all treatment arms. The most common all-causality grade ≥3 adverse events were hypertension in axitinib-containing arms (20% and 17%, arms I and II, respectively) and fatigue with pemetrexed/cisplatin alone (16%). Axitinib in combination with pemetrexed/cisplatin was generally well tolerated. Axitinib combinations resulted in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC. ClinicalTrials.gov: NCT00768755 (October 7, 2008).


Identification of typical miRNAs and target genes in hepatocellular carcinoma by DNA microarray technique.
The purpose of this study was to identify featured miRNAs of hepatocellular carcinoma (HCC) by comparing normal and cancer cell line samples and find potential utility as biomarkers for early diagnosis and treatment of HCC. We downloaded the gene expression profile GSE41077 from Gene Expression Omnibus database which included 6 HCC cell lines samples and 2 controls. Differentially expressed miRNAs were identified by multtest package in R language after the data normalization. The selected differentially expressed miRNAs were further analyzed using bioinformatics methods. Target genes of these miRNAs were predicted using miRTarBase and miRecords databases. STRING software was used to construct the interaction network of target genes. Finally, we made module analysis by using Cytoscape software and its plugins--MCODE and BiNGO. A total of 40 differentially expressed miRNAs were identified and the remarkably down-regulated miRNA was hsa-miR-122 which included 29 high confident target genes. The interaction network of target genes was constructed among 629 interaction pairs. Four functional modules in the network were obtained, from which EGLN3, ALDOA, NCAM1 and AACS were the high confident target genes, respectively. Genes in the modules most related to biological functions of signal transmission, regulation of macromolecule metabolic process. Low level of expression of hsa-miR-122 in HCC cell line is consistent with the existed previous studies. It is not only confirm the importance role of such miRNA in HCC cells, but also provide important help in identifying specific biomarker of HCC cells.


The herpes simplex virus type 1 DNA polymerase gene: site of phosphonoacetic acid resistance mutation in strain Angelotti is highly conserved.
By comparative sequence analysis of the herpes simplex virus type 1 DNA polymerase gene of strain Angelotti and a phosphonoacetic acid-resistant (PAAr) derivative, the site of the PAAr mutation was identified as a single nucleotide (C----T) conversion within the mapping limits of the known PAAr mutations of strains KOS and 17. The conservative amino acid change at residue 719 from alanine to valine results in a radical change in the properties of the polymerase, rendering the mutant enzyme resistant to PAA and various antiviral compounds. Amino acid homologies as well as secondary structure analysis reveal that the PAAr mutation is contained in a 14 amino acid sequence which is highly conserved, and detected in the central domain of prokaryotic and eukaryotic DNA polymerases.


Phylogenetic Diversity of Nitrogenase Reductase Genes and Possible Nitrogen-Fixing Bacteria in Thermophilic Chemosynthetic Microbial Communities in Nakabusa Hot Springs.
Chemosynthetic microbial communities develop and form dense cell aggregates in slightly alkaline sulfidic hot springs in the temperature range of 70-86°C at Nakabusa, Japan. Nitrogenase activity has recently been detected in the microbial communities collected. To identify possible members capable of nitrogen fixation, we examined the diversities of 16S rRNA and nitrogenase reductase (NifH) gene sequences in four types of chemosynthetic communities with visually different colors and thicknesses. The results of a 16S rRNA gene analysis indicated that all four microbial communities had similar bacterial constituents; the phylum Aquificae was the dominant member, followed in abundance by Thermodesulfobacteria, Firmicutes, and Thermotogae. Most of the NifH sequences were related to sequences reported in hydrothermal vents and terrestrial hot springs. The results of a phylogenetic analysis of NifH sequences revealed diversity in this gene among the communities collected, distributed within 7 phylogenetic groups. NifH sequences affiliated with Aquificae (Hydrogenobacter/Thermocrinis) and Firmicutes (Caldicellulosiruptor) were abundant. At least two different energy metabolic pathways appeared to be related to nitrogen fixation in the communities analyzed; aerobic sulfur/hydrogen-oxidizing bacteria in Aquificae and fermentative bacteria in Firmicutes. The metabolic characteristics of these two dominant phyla differed from those previously inferred from nitrogenase activity assays on chemosynthetic communities, which were associated with hydrogen-dependent autotrophic sulfate reduction. These assays may correspond to the observed NifH sequences that are distantly related to the known species of Thermodesulfovibrio sp. (Nitrospirae) detected in the present study. The activities of nitrogen-fixing organisms in communities may depend on redox states as well as the availability of electron donors, acceptors, and carbon sources.


Preeclampsia and brain damage among preterm infants: a changed panorama in a 20-year analysis.
The purpose of this study was to compare the rates of preterm infant brain damage between preeclamptic and normotensive pregnancies during a 20-year period. A cohort study was performed of 1201 singleton pregnancies between 24 and 35 weeks gestation delivered at a single institution during the period 1984-2003. Preeclampsia was diagnosed according to standard criteria. Periventricular/intraventricular hemorrhage (PV-IVH) and periventricular leukomalacia were diagnosed by postnatal cranial ultrasound. Severe infant brain damage was defined as the presence of cystic periventricular leukomalacia and/or intraparenchymal hemorrhage or IVH with ventricular dilation. Logistic regression analysis was used to compute the rates of neonatal brain damage adjusting for potential confounders and to perform an interaction study. The crude rates of severe brain damage among the 329 preeclamptic pregnancies were 11.6% (five of 43) in the period 1984 to 1988 and 0.86% (one of 116) in the period 1999 to 2003 ( P for trend < 0.001). The adjusted decrement in the rate of severe brain damage per 5-year period was 65.7% (95% confidence interval [CI], 35.1 to 81.9). The crude rates of severe brain damage among the 872 normotensive pregnancies were 6.1% (eight of 132) in the period 1984 to 1988 and 3.4% (10 of 298) in the period 1999 to 2003 ( P for trend = 0.03). The adjusted decrement per 5-year period was 21.7 (95% CI, 10.6 to 31.4; P = 0.001 compared with infants born to mothers with preeclampsia). Multivariable analysis of interaction confirmed that, during the period of the study, the decrement in the rates of PV-IVH ( P for interaction = 0.04) and of severe brain damage ( P for interaction = 0.03) was higher among preeclamptic than normotensive pregnancies. At our institution, in the last two decades the decrement in the rates of PV-IVH and severe brain damage among preterm infants was significantly higher in preeclamptic than normotensive pregnancies.


Case report: Venetoclax plus Azacitidine in treatment of acute undifferentiated leukemia.
Acute undifferentiated leukemia (AUL) is a clinical rare leukemia with an overall poor prognosis. Currently, there are no well-established treatment guidelines for AUL, further exploration of optimal treatment options is now required. We report an AUL patient who was complicated by a NRAS mutation and del5q was admitted to our hospital and we present the clinical features. In addition, we conducted a literature review. The "VA" scheme combines agents Venetoclax and Azacitidine that have synergistic therapeutic effect with a tolerable safety profile. There is no previous report of the "VA" scheme employed in AUL treatment. An AUL patient who was complicated by a NRAS mutation and del5q was admitted to our hospital. The "VA" scheme was administrated, and complete remission (CR) was achieved at the end of the first cycle. The patient then underwent HLA-identical sibling allogeneic hematopoietic stem cell transplantation. The "VA" scheme has been extensively used in AML treatment, but its application in AUL treatment has not yet been reported. This study is the first to report an AUL patient treated with the "VA" scheme and achieved CR. Our result preliminarily suggested the effectiveness and safety of the "VA" scheme in AUL treatment, but validation is required in more clinical samples. The "VA" scheme provides a new treatment option for AUL patients and deserves further clinical promotion.


Role of glycosylation in expression of functional diphtheria toxin receptors.
We have previously demonstrated, by using a detergent-solubilized system, the existence of specific diphtheria toxin-binding glycoproteins on the surface of toxin-sensitive cells. We have now tested the effect of tunicamycin treatment on the sensitivity of cells in culture to diphtheria toxin and have investigated the toxin sensitivity of mutant cells with known defects in glycosylation of asparagine-linked glycoproteins. Treatment of CHO-K1 cells with tunicamycin, which blocks the synthesis of both high-mannose-type and complex-type oligosaccharide chains of asparagine-linked glycoproteins, resulted in a 50- to 100-fold decrease in sensitivity to diphtheria toxin. In contrast, CHO-K1 mutants, defective in the synthesis of either high-mannose-type or complex-type oligosaccharides, showed no difference in toxin sensitivity compared with that of their parental cell lines. When we used an acid shock system, which is believed to result in receptor-dependent direct toxin penetration at the cell surface, the toxin sensitivity of tunicamycin-treated cells was not restored to that of untreated cells, suggesting that tunicamycin treatment results in a decrease in functional toxin receptors. Direct binding studies with 125I-labeled toxin demonstrated that this decrease in functional receptors is due to a decrease in the affinity of the receptors rather than to a change in the number of receptors. Taken together, these data are consistent with the interpretation that the diphtheria toxin receptor is a glycoprotein and suggest that the toxin binds neither to carbohydrate residues unique to the high-mannose-type oligosaccharides nor to those unique to the complex-type oligosaccharides. Furthermore, these data are consistent with the hypothesis that diphtheria toxin binds to the peptide backbone of the glycoprotein receptor.


Artificial intelligence in stone disease.
Artificial intelligence (AI) is the ability of a machine, or computer, to simulate intelligent behavior. In medicine, the use of large datasets enables a computer to learn how to perform cognitive tasks, thereby facilitating medical decision-making. This review aims to describe advancements in AI in stone disease to improve diagnostic accuracy in determining stone composition, to predict outcomes of surgical procedures or watchful waiting and ultimately to optimize treatment choices for patients. AI algorithms show high accuracy in different realms including stone detection and in the prediction of surgical outcomes. There are machine learning algorithms for outcomes after percutaneous nephrolithotomy, extracorporeal shockwave lithotripsy, and for ureteral stone passage. Some of these algorithms show better predictive capabilities compared to existing scoring systems and nomograms. The use of AI can facilitate the development of diagnostic and treatment algorithms in patients with stone disease. Although the generalizability and external validity of these algorithms remain uncertain, the development of highly accurate AI-based tools may enable the urologist to provide more customized patient care and superior outcomes.


Development of the just culture assessment tool: measuring the perceptions of health-care professionals in hospitals.
Given the growing support for establishing a just patient safety culture in health-care settings, a valid tool is needed to assess and improve just patient safety culture. The purpose of this study was to develop a measure of individual perceptions of just culture for a hospital setting. The 27-item survey was administered to 998 members of a health-care staff in a pediatric research hospital as part of the hospital's ongoing patient safety culture assessment process. Subscales included balancing a blame-free approach with accountability, feedback and communication, openness of communication, quality of the event reporting process, continuous improvement, and trust. The final sample of 404 participants (40% response rate) included nurses, physicians, pharmacists, and other hospital staff members involved in patient care. Confirmatory factor analysis was used to test the internal structure of the measure and reliability analyses were conducted on the subscales. Moderate support for the factor structure was established with confirmatory factor analysis. After modifications were made to improve statistical fit, the final version of the measure included 6 subscales loading onto one higher-order dimension. Additionally, Cronbach α reliability scores for the subscales were positive, with each dimension being above 0.7 with the exception of one. The instrument designed and tested in this study demonstrated adequate structure and reliability. Given the uniqueness of the current sample, further verification of the JCAT is needed from hospitals that serve broader populations. A validated tool could also be used to evaluate the relation between just culture and patient safety outcomes.


Spectral phase effects on nonlinear resonant photochemistry of 1,3-cyclohexadiene in solution.
We have investigated the ring opening of 1,3-cyclohexadiene to form 1,3,5-cis-hexatriene (Z-HT) using optical pulse shaping to enhance multiphoton excitation. A closed-loop learning algorithm was used to search for an optimal spectral phase function, with the effectiveness or fitness of each optical pulse assessed using the UV absorption spectrum. The learning algorithm was able to identify pulses that increased the formation of Z-HT by as much as a factor of 2 and to identify pulse shapes that decreased solvent fragmentation while leaving the formation of Z-HT essentially unaffected. The highest yields of Z-HT did not occur for the highest peak intensity laser pulses. Rather, negative quadratic phase was identified as an important control parameter in the formation of Z-HT.


The varying impact of type, timing and frequency of exposure to childhood adversity on its association with adult psychotic disorder.
Childhood adversity has been associated with onset of psychosis in adulthood but these studies have used only general definitions of this environmental risk indicator. Therefore, we sought to explore the prevalence of more specific adverse childhood experiences amongst those with and without psychotic disorders using detailed assessments in a large epidemiological case-control sample (AESOP). Data were collected on 182 first-presentation psychosis cases and 246 geographically matched controls in two UK centres. Information relating to the timing and frequency of exposure to different types of childhood adversity (neglect, antipathy, physical and sexual abuse, local authority care, disrupted living arrangements and lack of supportive figure) was obtained using the Childhood Experience of Care and Abuse Questionnaire. Psychosis cases were three times more likely to report severe physical abuse from the mother that commenced prior to 12 years of age, even after adjustment for other significant forms of adversity and demographic confounders. A non-significant trend was also evident for greater prevalence of reported severe maternal antipathy amongst those with psychosis. Associations with maternal neglect and childhood sexual abuse disappeared after adjusting for maternal physical abuse and antipathy. Paternal maltreatment and other forms of adversity were not associated with psychosis nor was there evidence of a dose-response effect. These findings suggest that only specific adverse childhood experiences are associated with psychotic disorders and only in a minority of cases. If replicated, this greater precision will ensure that research into the mechanisms underlying the pathway from childhood adversity to psychosis is more fruitful.


Arterial structure and function in ambulatory adolescents with cerebral palsy are not different from healthy controls.
Physical inactivity in youth with cerebral palsy (CP) places them at increased risk of developing cardiovascular disease. The current study assessed indices of arterial health in adolescents with CP, classified as levels I-II of the Gross Motor Function Classification System (GMFCS) (n = 11, age 13.2 ± 2.1 yr), in comparison to age- and sex-matched controls (n = 11, age 12.4 ± 2.3 yr). Groups were similar in anthropometric measurements, resting blood pressures, and heart rates. There were no group differences in brachial flow-mediated dilation (11.1 ± 7.8 versus 6.1 ± 3.6), carotid intima-media thickness (0.42 ± 0.04 versus 0.41 ± 0.03 mm), and distensibility (0.008 ± 0.002 versus 0.008 ± 0.002 mmHg) or central (4.3 ± 0.6 versus 4.1 ± 0.9 m/s) and peripheral pulse wave velocity (7.1 ± 1.7 versus 7.6 ± 1.1 m/s); CP versus healthy controls, respectively. Vigorous intensity physical activity (PA) was lower in the CP group (CP: 38 ± 80 min versus controls: 196 ± 174 min); groups were similar in light and moderate intensity PA levels. Arterial health of ambulatory youth with CP is not different from a control group despite lower vigorous PA levels. Similar studies need to examine individuals with more pronounced mobility limitations (GMFCS level III-V).


herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells?
The human ether-a-go-go-related gene (herg) encodes a K+ current (IHERG) that plays a fundamental role in heart excitability by regulating the action potential repolarization (IKr); mutations of this gene are responsible for the chromosome 7-linked long QT syndrome (LQT2). In this report, we show that in a variety (n = 17) of tumor cell lines of different species (human and murine) and distinct histogenesis (neuroblastoma, rhabdomyosarcoma, adenocarcinoma, lung microcytoma, pituitary tumors, insulinoma beta-cells, and monoblastic leukemia), a novel K+ inward-rectifier current (IIR), which is biophysically and pharmacologically similar to IHERG, can be recorded with the patch-clamp technique. Northern blot experiments with a human herg cDNA probe revealed that both in human and murine clones the very high expression of herg transcripts can be quantified in at least three clearly identifiable bands, suggesting an alternative splicing of HERG mRNA. Moreover, we cloned a cDNA encoding for IIR from the SH-SY5Y human neuroblastoma. The sequence of this cDNA result was practically identical to that already reported for herg, indicating a high conservation of this gene in tumors. Consistently, the expression of this clone in Xenopus oocytes showed that the encoded K+ channel had substantially all of the biophysical and pharmacological properties of the native IIR described for tumor cells. In addition, in the tumor clones studied, IIR governs the resting potential, whereas it could not be detected either by the patch clamp or the Northern blot techniques in cells obtained from primary cell cultures of parental tissues (sensory neurons and myotubes), whose resting potential is controlled by the classical K+ anomalous rectifier current. This current substitution had a profound impact on the resting potential, which was markedly depolarized in tumors as compared with normal cells. These results suggest that IIR is normally only expressed during the early stages of cell differentiation frozen by neoplastic transformation, playing an important pathophysiological role in the regulatory mechanisms of neoplastic cell survival. In fact, because of its biophysical features, IIR, besides keeping the resting potential within the depolarized values required for unlimited tumor growth, could also appear suitable to afford a selective advantage in an ischemic environment.


Molecular typing of Treponema pallidum: a systematic review and meta-analysis.
Syphilis is resurgent in many regions of the world. Molecular typing is a robust tool for investigating strain diversity and epidemiology. This study aimed to review original research on molecular typing of Treponema pallidum (T. pallidum) with three objectives: (1) to determine specimen types most suitable for molecular typing; (2) to determine T. pallidum subtype distribution across geographic areas; and (3) to summarize available information on subtypes associated with neurosyphilis and macrolide resistance. Two researchers independently searched five databases from 1998 through 2010, assessed for eligibility and study quality, and extracted data. Search terms included "Treponema pallidum," or "syphilis," combined with the subject headings "molecular," "subtyping," "typing," "genotype," and "epidemiology." Sixteen eligible studies were included. Publication bias was not statistically significant by the Begg rank correlation test. Medians, inter-quartile ranges, and 95% confidence intervals were determined for DNA extraction and full typing efficiency. A random-effects model was used to perform subgroup analyses to reduce obvious between-study heterogeneity. Primary and secondary lesions and ear lobe blood specimens had an average higher yield of T. pallidum DNA (83.0% vs. 28.2%, χ(2) = 247.6, p<0.001) and an average higher efficiency of full molecular typing (80.9% vs. 43.1%, χ(2) = 102.3, p<0.001) compared to plasma, whole blood, and cerebrospinal fluid. A pooled analysis of subtype distribution based on country location showed that 14d was the most common subtype, and subtype distribution varied across geographic areas. Subtype data associated with macrolide resistance and neurosyphilis were limited. Primary lesion was a better specimen for obtaining T. pallidum DNA than blood. There was wide geographic variation in T. pallidum subtypes. More research is needed on the relationship between clinical presentation and subtype, and further validation of ear lobe blood for obtaining T. pallidum DNA would be useful for future molecular studies of syphilis.


Surface composition and contact angle relationships for differently prepared solid dispersions.
Solid dispersions are promising drug delivery forms which offer the possibility to disperse a hydrophobic drug in a hydrophilic matrix and thereby improve the dissolution behavior and the bioavailability of the drug. One important aspect and a prerequisite in understanding the drug dissolution mechanism from solid dispersions is a better analytical monitoring of the solid dispersion surface properties, such as powder surface composition and water adsorption properties. In this paper, we have considered chemical and structural surface analysis data for solid dispersions processed by spray drying or roto-evaporation and compared these data with information obtained by contact angle measurements. Firstly, we establish the usefulness and suitability of X-ray photoelectron spectroscopy (XPS) for determination of surface chemical composition and scanning electron microscopy (SEM) for determining the structure of solid dispersions composed of different types of carriers, drugs and drug concentrations. Secondly, we measure contact angles of solid dispersions to describe wettability, to finally establish a link between the surface chemical composition, the powder structure and the wetting behavior. These experimental methods offer a rapid screening tool for the selection of carrier, drug concentration and/or process in early development. In addition, they provide a useful tool for investigating structural aspects of solid dispersions which have intrinsic relevance for drug dissolution and stability.


Interventions in organizational and community context: a framework for building evidence on dissemination and implementation in health services research.
The effective dissemination and implementation of evidence-based health interventions within community settings is an important cornerstone to expanding the availability of quality health and mental health services. Yet it has proven a challenging task for both research and community stakeholders. This paper presents the current framework developed by the UCLA/RAND NIMH Center to address this research-to-practice gap by: (1) providing a theoretically-grounded understanding of the multi-layered nature of community and healthcare contexts and the mechanisms by which new practices and programs diffuse within these settings; (2) distinguishing among key components of the diffusion process-including contextual factors, adoption, implementation, and sustainment of interventions-showing how evaluation of each is necessary to explain the course of dissemination and outcomes for individual and organizational stakeholders; (3) facilitating the identification of new strategies for adapting, disseminating, and implementing relatively complex, evidence-based healthcare and improvement interventions, particularly using a community-based, participatory approach; and (4) enhancing the ability to meaningfully generalize findings across varied interventions and settings to build an evidence base on successful dissemination and implementation strategies.


Antitumor activity of triterpenoid saponin-rich Adisia gigantifolia extract on human breast adenocarcinoma cells in vitro and in vivo.
The aim of this study was to explore whether the ethanolic extract of Ardisia gigantifolia rhizomes (AGB-5), a traditional herbal medicine from China, could affect the proliferation of human breast adenocarcinoma (MCF-7) cells in vitro and to explore the antitumor effects of AGB-5 in BALB/c mice engrafted with MCF-7 cells. The results showed that AGB-5 markedly inhibited the proliferation of MCF-7 cells with an IC50 value of 11.89±1.12 µg/mL, increased the S phase and decreased the G2/M phase without influence on G1 phase. MCF-7 cells treated with AGB-5 presented a dose-dependent increase of apoptosis compared with the control group. AGB-5 also significantly increased the activity of caspase-3 and -9 in a dose-dependent manner in MCF-7 cells. Furthermore, in an in vivo model, AGB-5 reduced tumor volume, brought back the red blood cell (RBC) and white blood cell (WBC) count near to normal value, enhanced superoxide dismutase and catalase level of MCF-7 bearing mice. This is the first study to verify the antitumor activity of A. gigantifolia in vivo. The results suggest that AGB-5 may have potential beneficial effects against human breast adenocarcinoma.


alpha-Melanocyte-stimulating-hormone precursors in the pig pituitary.
The occurrence of intermediates from the processing of ACTH-(1-39) [adrenocorticotropic hormone-(1-39)] to alpha-melanocyte-stimulating hormone was investigated in normal pig pituitaries by the use of sensitive and specific radioimmunoassays for ACTH-(1-13), ACTH-(1-14), ACTH-(1-13)-NH2 and ACTH-(1-39). Fractionation by reverse-phase h.p.l.c. revealed ACTH(1-17) and their acetylated analogues. The intermediate lobe contained NO-diacetyl-ACTH-(1-13)-NH2, N-acetyl-ACTH-(1-13)-NH2 and ACTH-(1-13)-NH2. In addition, the corresponding ACTH-(1-14) peptides (the glycine-extended precursor of the amidated peptides) were detected in lower amounts in both the intermediate lobe and the anterior lobe. ACTH-(1-17), ACTH-(1-13) and their acetylated analogues could not be detected in the anterior lobe or the intermediate lobe. The results suggest that an endopeptidase initially cleaves ACTH-(1-39) at the Lys-16-Arg-17 bond. ACTH-(1-16) is then processed by a pituitary carboxypeptidase to ACTH-(1-14) and ACTH-(17-39) by the aminopeptidase to ACTH-(18-39).


Extracellular nucleotide catabolism by the Group B Streptococcus ectonucleotidase NudP increases bacterial survival in blood.
Streptococcus agalactiae (Group B Streptococcus) is a commensal of the human intestine and vagina of adult women but is the leading cause of invasive infection in neonates. This Gram-positive bacterium displays a set of virulence-associated surface proteins involved in the interaction with the host, such as adhesion to host cells, invasion of tissues, or subversion of the immune system. In this study, we characterized a cell wall-localized protein as an ecto-5'-nucleoside diphosphate phosphohydrolase (NudP) involved in the degradation of extracellular nucleotides which are central mediators of the immune response. Biochemical characterization of recombinant NudP revealed a Mn(2+)-dependent ecto-5'-nucleotidase activity on ribo- and deoxyribonucleoside 5'-mono- and 5'-diphosphates with a substrate specificity different from that of known orthologous enzymes. Deletion of the gene coding the housekeeping enzyme sortase A led to the release of NudP into the culture supernatant, confirming that this enzyme is anchored to the cell wall by its non-canonical LPXTN motif. The NudP ecto-5'-nucleotidase activity is reminiscent of the reactions performed by the mammalian ectonucleotidases CD39 and CD73 involved in regulating the extracellular level of ATP and adenosine. We further demonstrated that the absence of NudP activity decreases bacterial survival in mouse blood, a process dependent on extracellular adenosine. In vivo assays in animal models of infection showed that NudP activity is critical for virulence. These results demonstrate that Group B Streptococcus expresses a specific ecto-5'-nucleotidase necessary for its pathogenicity and highlight the diversity of reactions performed by this enzyme family. These results suggest that bacterial pathogens have developed specialized strategies to subvert the mammalian immune response controlled by the extracellular nucleotide signaling pathways.


Characterization of an antibody directed against a surface component of normal and pleomorphic cells of Streptococcus sanguis.
Whole cells of Streptococcus sanguis were utilized as an immunoadsorbent to purify large quantities of an antibody (S1) directed against a cell surface component. The S-1 antibody was isolated from antisera to normal (N) and pleomorphic (O) cells by a similar adsorption-elution procedure. The S-1 antibody isolated from antisera to N cells reacted in gel diffusion in identify with the S-1 antibody to O cells, indicating that the antigen which binds S-1 antibody (Ag-1) may not be radically altered when cells become pleomorphic. The S-1 antibodies directed against both N and O cells had restricted heterogeneity, indicating that for both types of cell Ag-1 may have a simple repeating structure. However, N cells were agglutinated to a greater extent by S-1 antibody than O cells. In addition the distribution of the bound S-1 antibody became altered as the cells became pleomorphic. Utilizing the technique of indirect immunofluorescence we observed that the S-1 antibody was distributed evenly on the surface of N cells. As the cells became pleomorphic, the antibody appeared to bind preferentially at the cell poles (capping). Later, as the cells became more grossly deformed, additional bands of immunofluorescence appeared to bisect the cells. Electron microscopic analysis indicated that the bound antibody was not associated with septal notches. The results suggest that the arrangement rather than the immunological properties of Ag-1 became altered as cells became pleomorphic.


Increased anthropogenic disturbance and aridity reduce phylogenetic and functional diversity of ant communities in Caatinga dry forest.
Anthropogenic disturbance and climate change are major threats to biodiversity. The Brazilian Caatinga is the world's largest and most diverse type of seasonally dry tropical forest. It is also one of the most threatened, but remains poorly studied. Here, we analyzed the individual and combined effects of anthropogenic disturbance (three types: livestock grazing, wood extraction, and miscellaneous use of forest resources) and increasing aridity on taxonomic, phylogenetic and functional ant diversity in the Caatinga. We found no aridity and disturbance effects on taxonomic diversity. In spite of this, functional diversity, and to a lesser extent phylogenetic diversity, decreased with increased levels of disturbance and aridity. These effects depended on disturbance type: livestock grazing and miscellaneous resource use, but not wood extraction, deterministically filtered both components of diversity. Interestingly, disturbance and aridity interacted to shape biodiversity responses. While aridity sometimes intensified the negative effects of disturbance, the greatest declines in biodiversity were in the wettest areas. Our results imply that anthropogenic disturbance and aridity interact in complex ways to endanger biodiversity in seasonally dry tropical forests. Given global climate change, neotropical semi-arid areas are habitats of concern, and our findings suggest Caatinga conservation policies must prioritize protection of the wettest areas, where biodiversity loss stands to be the greatest. Given the major ecological relevance of ants, declines in both ant phylogenetic and functional diversity might have downstream effects on ecosystem processes, insect populations, and plant populations.


Splicing factor 2-associated protein p32 participates in ribosome biogenesis by regulating the binding of Nop52 and fibrillarin to preribosome particles.
Ribosome biogenesis starts with transcription of the large ribosomal RNA precursor (47S pre-rRNA), which soon combines with numerous factors to form the 90S pre-ribosome in the nucleolus. Although the subsequent separation of the pre-90S particle into pre-40S and pre-60S particles is critical for the production process of mature small and large ribosomal subunits, its molecular mechanisms remain undetermined. Here, we present evidence that p32, fibrillarin (FBL), and Nop52 play key roles in this separation step. Mass-based analyses combined with immunoblotting showed that p32 associated with 155 proteins including 31 rRNA-processing factors (of which nine were components of small subunit processome, and six were those of RIX1 complex), 13 chromatin remodeling components, and six general transcription factors required for RNA polymerase III-mediated transcription. Of these, a late rRNA-processing factor Nop52 interacted directly with p32. Immunocytochemical analyses demonstrated that p32 colocalized with an early rRNA-processing factor FBL or Nop52 in the nucleolus and Cajal bodies, but was excluded from the nucleolus after actinomycin D treatment. p32 was present in the pre-ribosomal fractions prepared by cell fractionation or separated by ultracentrifugation of the nuclear extract. p32 also associated with pre-rRNAs including 47S/45S and 32S pre-rRNAs. Furthermore, knockdown of p32 with a small interfering RNA slowed the early processing from 47S/45S pre-rRNAs to 18S rRNA and 32S pre-rRNA. Finally, Nop52 was found to compete with FBL for binding to p32 probably in the nucleolus. Given the fact that FBL and Nop52 are associated with pre-ribosome particles distinctly different from each other, we suggest that p32 is a new rRNA maturation factor involved in the remodeling from pre-90S particles to pre-40S and pre-60S particles that requires the exchange of FBL for Nop52.


The nuclear debate: clashes in congress and california.
Federal and state governments may be headed toward a collision over a key aspect in the development of nuclear power. Antinuclear groups in California are pressing for a law that would ban nuclear power plants unless Congress removes the present legal limitations on the damages payable in the event of a nuclear accident. But Congress, far from repealing the limitation (mandated by the Price-Anderson nuclear insurance law), recently voted to extend it. The skirmish on Capitol Hill over the Price-Anderson law is analyzed in the first of the following articles; the events that have made the California proposition possible are discussed in the second.


A First-in-Human Dose Finding Study of Camrelizumab in Patients with Advanced or Metastatic Cancer in Australia.
Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population. Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks. Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3-28.9). Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia. ClinicalTrials.gov Identifier: NCT02492789.


Low Band Gap Coplanar Conjugated Molecules Featuring Dynamic Intramolecular Lewis Acid-Base Coordination.
Ladder-type conjugated molecules with a low band gap and low LUMO level were synthesized through an N-directed borylation reaction of pyrazine-derived donor-acceptor-donor precursors. The intramolecular boron-nitrogen coordination bonds played a key role in rendering the rigid and coplanar conformation of these molecules and their corresponding electronic structures. Experimental investigation and theoretical simulation revealed the dynamic nature of such coordination, which allowed for active manipulation of the optical properties of these molecules by using competing Lewis basic solvents.


Epilepsy surgery of focal cortical dysplasia-associated tumors.
The goal of the present study was to evaluate the clinical characteristics and postoperative seizure outcome of epileptogenic tumors associated with focal cortical dysplasias (FCDs) compared to both solitary FCD type I and solitary tumors. Particular attention is given to FCD type IIIb (tumors associated with FCD type I), which have been recently classified as a separate entity. We retrospectively reviewed the clinical charts of 1,109 patients who were operated on for drug-resistant focal epilepsy, including 492 patients with a histologic diagnosis of solitary FCD I and II (83 and 157 cases, respectively), solitary tumors (179 cases), and FCD-associated tumors (73 cases, 58 of which met the criteria of FCD IIIb of the new International League Against Epilepsy [ILAE] classification). The different subgroups were evaluated for clinical characteristics and postoperative surgical outcome. Clinical variables and postoperative seizure outcome of patients with coexisting tumor and FCDs (FCD IIIb and tumor associated FCD II) were similar to those of patients with a solitary tumor and differed significantly from patients with solitary FCDs. Nevertheless, tumors associated with FCDs are characterized by a striking male predominance and a higher seizure frequency as compared to solitary tumors. Patients with drug-resistant focal epilepsy secondary to a solitary tumor or with a tumor-associated FCD have similar basic clinical presentation and postoperative seizure outcome. Nevertheless, the epileptogenic contribution of the associated FCDs can be crucial, and it needs to be adequately assessed. The impact of FCD on tumor-related epilepsy deserves future research in order to optimize the surgical strategies aimed at seizure relief.


An examination of the relationship between hotspots and recombination associated with chromosome 21 nondisjunction.
Trisomy 21, resulting in Down Syndrome (DS), is the most common autosomal trisomy among live-born infants and is caused mainly by nondisjunction of chromosome 21 within oocytes. Risk factors for nondisjunction depend on the parental origin and type of meiotic error. For errors in the oocyte, increased maternal age and altered patterns of recombination are highly associated with nondisjunction. Studies of normal meiotic events in humans have shown that recombination clusters in regions referred to as hotspots. In addition, GC content, CpG fraction, Poly(A)/Poly(T) fraction and gene density have been found to be significant predictors of the placement of sex-averaged recombination in the human genome. These observations led us to ask whether the altered patterns of recombination associated with maternal nondisjunction of chromosome 21 could be explained by differences in the relationship between recombination placement and recombination-related genomic features (i.e., GC content, CpG fraction, Poly(A)/Poly(T) fraction or gene density) on 21q or differential hot-spot usage along the nondisjoined chromosome 21. We found several significant associations between our genomic features of interest and recombination, interestingly, these results were not consistent among recombination types (single and double proximal or distal events). We also found statistically significant relationships between the frequency of hotspots and the distribution of recombination along nondisjoined chromosomes. Collectively, these findings suggest that factors that affect the accessibility of a specific chromosome region to recombination may be altered in at least a proportion of oocytes with MI and MII errors.


5-Hydroxytryptamine and histamine as mediators of the vascular injury produced by agents which damage mast cells in rats.
Each of the four agents, ovomucoid, dextran, 48/80, and testis extract, when injected beneath the skin of the dorsa of the paws of rats produces a local vascular injury characterized by a protein-rich edema. Each agent also produces damage to mast cells. Either 5-hydroxytryptamine or histamine produces a response similar in the gross to that elicited by the agents which damage mast cells; however, neither of these two agents produces mast cell damage. On a weight basis 5-hydroxytryptamine is a much more potent edema-producing agent than histamine. The edema-producing action of 5-hydroxytryptamine can be differentiated from the similar action of histamine by the use of specific antagonists; dibenamine is a 5-hydroxytryptamine antagonist and pyrilamine a histamine antagonist. The edema produced by the mast cell-damaging agents is partially inhibited by dibenamine but is not diminished by pyrilamine. It is completely inhibited by treatment of rats with both drugs. The drugs which inhibit edema do not prevent mast cell damage by ovomucoid, dextran, 48/80, or testis extract. The observations are consistent with the hypothesis that agents which damage mast cells, "release" both 5-hydroxytryptamine and histamine and that in the rat the edema associated with mast cell damage is mediated largely by 5-hydroxytryptamine.


Collection and review of updated scientific epidemiological data on porcine epidemic diarrhoea.
Porcine epidemic diarrhoea (PED) is a non-zoonotic viral disease of pigs caused by a coronavirus and characterised by watery diarrhoea and weight loss. PED is not notifiable to the EU or World Organisation for Animal Health listed but it is notifiable at the national level in Finland, France, Ireland and Sweden. PED case reports from seven countries and PED surveillance and monitoring activities in thirteen countries were reported. This information was combined with an extensive literature review to provide an update on global PED occurrence, circulating strains and impact in 2014-2015. PED confirmed cases have been reported in North America, South America, Asia and Europe. PED virus (PEDV) sequences originating from EU pig herds indicate that the strains currently in circulation share nearly 100% sequence identity and have greater than 99% sequence identity with the reference INDEL (insertion/deletion) strain USA/OH851/2014. In 2014-2015, greater genetic variability has been reported in strains circulating in Asia compared with EU Member States and a non-INDEL strain has been detected in the Ukraine in 2014. Data on impact confirms that mortality is higher in suckling piglets and diarrhoea is observed in all age groups. The reported impact is in agreement with that reported in EFSA AHAW Panel (2014) indicating that the impact of recently reported PED outbreaks in Asia and the USA seems to be more severe than that described in EU countries, although the impact of different PEDV strains is difficult to compare between one country and another, as impact is dependent not only on pathogenicity but also on factors such as biosecurity, herd size, farm management, sanitary status or herd immune status.


Calcium-dependent oligomerization of CAR proteins at cell membrane modulates ABA signaling.
Regulation of ion transport in plants is essential for cell function. Abiotic stress unbalances cell ion homeostasis, and plants tend to readjust it, regulating membrane transporters and channels. The plant hormone abscisic acid (ABA) and the second messenger Ca(2+) are central in such processes, as they are involved in the regulation of protein kinases and phosphatases that control ion transport activity in response to environmental stimuli. The identification and characterization of the molecular mechanisms underlying the effect of ABA and Ca(2+) signaling pathways on membrane function are central and could provide opportunities for crop improvement. The C2-domain ABA-related (CAR) family of small proteins is involved in the Ca(2+)-dependent recruitment of the pyrabactin resistance 1/PYR1-like (PYR/PYL) ABA receptors to the membrane. However, to fully understand CAR function, it is necessary to define a molecular mechanism that integrates Ca(2+) sensing, membrane interaction, and the recognition of the PYR/PYL interacting partners. We present structural and biochemical data showing that CARs are peripheral membrane proteins that functionally cluster on the membrane and generate strong positive membrane curvature in a Ca(2+)-dependent manner. These features represent a mechanism for the generation, stabilization, and/or specific recognition of membrane discontinuities. Such structures may act as signaling platforms involved in the recruitment of PYR/PYL receptors and other signaling components involved in cell responses to stress.


Effects of 7 wk of endurance training on human skeletal muscle metabolism during submaximal exercise.
This is the first study to examine the effects of endurance training on the activation state of glycogen phosphorylase (Phos) and pyruvate dehydrogenase (PDH) in human skeletal muscle during exercise. We hypothesized that 7 wk of endurance training (Tr) would result in a posttransformationally regulated decrease in flux through Phos and an attenuated activation of PDH during exercise due to alterations in key allosteric modulators of these important enzymes. Eight healthy men (22 +/- 1 yr) cycled to exhaustion at the same absolute workload (206 +/- 5 W; approximately 80% of initial maximal oxygen uptake) before and after Tr. Muscle biopsies (vastus lateralis) were obtained at rest and after 5 and 15 min of exercise. Fifteen minutes of exercise post-Tr resulted in an attenuated activation of PDH (pre-Tr: 3.75 +/- 0.48 vs. post-Tr: 2.65 +/- 0.38 mmol.min(-1).kg wet wt(-1)), possibly due in part to lower pyruvate content (pre-Tr: 0.94 +/- 0.14 vs. post-Tr: 0.46 +/- 0.03 mmol/kg dry wt). The decreased pyruvate availability during exercise post-Tr may be due to a decreased muscle glycogenolytic rate (pre-Tr: 13.22 +/- 1.01 vs. post-Tr: 7.36 +/- 1.26 mmol.min(-1).kg dry wt(-1)). Decreased glycogenolysis was likely mediated, in part, by posttransformational regulation of Phos, as evidenced by smaller net increases in calculated muscle free ADP (pre-Tr: 111 +/- 16 vs. post-Tr: 84 +/- 10 micromol/kg dry wt) and P(i) (pre-Tr: 57.1 +/- 7.9 vs. post-Tr: 28.6 +/- 5.6 mmol/kg dry wt). We have demonstrated for the first time that several signals act to coordinately regulate Phos and PDH, and thus carbohydrate metabolism, in human skeletal muscle after 7 wk of endurance training.


Mining Electronic Health Records to Extract Patient-Centered Outcomes Following Prostate Cancer Treatment.
The clinical, granular data in electronic health record (EHR) systems provide opportunities to improve patient care using informatics retrieval methods. However, it is well known that many methodological obstacles exist in accessing data within EHRs. In particular, clinical notes routinely stored in EHR are composed from narrative, highly unstructured and heterogeneous biomedical text. This inherent complexity hinders the ability to perform automated large-scale medical knowledge extraction tasks without the use of computational linguistics methods. The aim of this work was to develop and validate a Natural Language Processing (NLP) pipeline to detect important patient-centered outcomes (PCOs) as interpreted and documented by clinicians in their dictated notes for male patients receiving treatment for localized prostate cancer at an academic medical center.


Women Remain at Risk of Iodine Deficiency during Pregnancy: The Importance of Iodine Supplementation before Conception and Throughout Gestation.
In Australia, pregnant women are advised to take an iodine supplement (I-supp) (150 µg/day) to reduce risks to the foetus associated with iodine deficiency (ID). To examine the impact of this recommendation on iodine status, and to identify factors that contribute to adequacy during gestation, supplement use and Urinary Iodine Concentration (UIC) was measured in 255 pregnant women (gestation range 6 to 41 weeks) in Tasmania. The median UIC (MUIC) of 133 µg/L (Inter-quartile range 82⁻233) was indicative of ID, being below the 150⁻249 µg/L range for adequacy during pregnancy. Women taking an iodine-containing-supplement (I-supp) had a significantly higher MUIC (155 µg/L) (n = 171) compared to the combined MUIC (112.5 µg/L) (n = 84) of those who had never (120 µg/L) (n = 61) or were no longer taking an I-supp (90 µg/L) (n = 23) (p = 0.017). Among women reporting I-supp use, the MUIC of those commencing the recommended 150 µg/day prior to conception was significantly higher than those starting supplementation following pregnancy confirmation: 196 (98⁻315) µg/L (n = 45) versus 137.5 (82.5⁻233.5) µg/L (n = 124), p = 0.032. Despite recommendations for iodine supplementation pregnant Tasmanian women remain at risk of ID. Commencing an I-supp of 150 µg/day prior to conception and continuing throughout pregnancy is required to ensure adequacy. Timely advice regarding the importance of adequate iodine nutrition, including supplementation is needed to reduce the risk of irreversible in utero neurocognitive damage to the foetus.


A Methylome-Wide Association Study of Trajectories of Oppositional Defiant Behaviors and Biological Overlap With Attention Deficit Hyperactivity Disorder.
In 671 mother-child (49% male) pairs from an epidemiological birth cohort, we investigated (a) prospective associations between DNA methylation (at birth) and trajectories (ages 7-13) of oppositional defiant disorder (ODD), and the ODD subdimensions of irritable and headstrong; (b) common biological pathways, indexed by DNA methylation, between ODD trajectories and attention deficit hyperactivity disorder (ADHD); (c) genetic influence on DNA methylation; and (d) prenatal risk exposure associations. Methylome-wide significant associations were identified for the ODD and headstrong, but not for irritable. Overlap analysis indicated biological correlates between ODD, headstrong, and ADHD. DNA methylation in ODD and headstrong was (to a degree) genetically influenced. DNA methylation associated with prenatal risk exposures of maternal anxiety (headstrong) and cigarette smoking (ODD and headstrong).


[Circulating Haemophilus influenzae in Cuba. Characterization of strains isolated from meningitis].
Haemophilus influenzae B(Hib) is often associated with serious systemic infections in children under 5 years of age. Since 1993, it is the most frequent agent isolated in meningoencephalitis. All the strains isolated in the country have been characterized in the National Reference Laboratory at the "Pedro Kourí" Tropical Medicine Institute. Results revealed that 97% of strains isolated from bacterial meningoencephalitis in Cuba during the period 1993-1995 corresponded to serotype B, 0.6% to serotype A and 2.4 not belong to any serotype. The classification of serotype B-strains into biotypes proved that 76% was biotype I and 21% biotype II, 8 to biotype III and 1.2% was biotype V. This study found the following resistance to ampicillin 40%, to chloranphenicol 43.3%, sulpha metoxazol 36%, trimetroprim 37.3% and tetracycline 31%.


Cross-editing by a tRNA synthetase allows vertebrates to abundantly express mischargeable tRNA without causing mistranslation.
The accuracy in pairing tRNAs with correct amino acids by aminoacyl-tRNA synthetases (aaRSs) dictates the fidelity of translation. To ensure fidelity, multiple aaRSs developed editing functions that remove a wrong amino acid from tRNA before it reaches the ribosome. However, no specific mechanism within an aaRS is known to handle the scenario where a cognate amino acid is mischarged onto a wrong tRNA, as exemplified by AlaRS mischarging alanine to G4:U69-containing tRNAThr. Here, we report that the mischargeable G4:U69-containing tRNAThr are strictly conserved in vertebrates and are ubiquitously and abundantly expressed in mammalian cells and tissues. Although these tRNAs are efficiently mischarged, no corresponding Thr-to-Ala mistranslation is detectable. Mistranslation is prevented by a robust proofreading activity of ThrRS towards Ala-tRNAThr. Therefore, while wrong amino acids are corrected within an aaRS, a wrong tRNA is handled in trans by an aaRS cognate to the mischarged tRNA species. Interestingly, although Ala-tRNAThr mischarging is not known to occur in bacteria, Escherichia coli ThrRS also possesses robust cross-editing ability. We propose that the cross-editing activity of ThrRS is evolutionarily conserved and that this intrinsic activity allows G4:U69-containing tRNAThr to emerge and be preserved in vertebrates to have alternative functions without compromising translational fidelity.


Mandibular intraosseous schwannoma in a child: Report of a rare case.
Intraosseous schwannomas is a very rare neoplasm, and less than 50 cases have been reported in the medical literature. In this article, the clinical, radiographic and histopathologic appearances of a rare case of intraosseous schwannomas are presented. The importance of this case is that other benign central lesions such as odontogenic tumors and cysts might be included in differential diagnosis. This case was recognized in a 9-year-old child, which is a very rare occurrence. The diagnosis was confirmed by immunohistochemical staining with S100 protein.


RNA vaccines: A transformational advance.
Vaccines have stemmed many infectious diseases, but when SARS-CoV-2 emerged, traditional vaccine development would not have been fast enough. This year's Nobel Prize in Physiology or Medicine recognizes work that enabled the rapid development of mRNA vaccines, which halted the COVID-19 pandemic. The feat was a product of basic biological insights coupled with technological innovations, which have transformed vaccine design.


Cisplatin induces p53-dependent FLICE-like inhibitory protein ubiquitination in ovarian cancer cells.
Understanding the mechanism of cisplatin (CDDP) action may improve therapeutic strategy for ovarian cancer. Although p53 and FLICE-like inhibitory protein (FLIP) are determinants of CDDP sensitivity in ovarian cancer, the interaction between p53 and FLIP remains poorly understood. Here, using two chemosensitive ovarian cancer cell lines and various molecular and cellular approaches, we show that CDDP induces p53-dependent FLIP ubiquitination and degradation, and apoptosis in vitro. Moreover, we showed that Itch (an E3 ligase) forms a complex with FLIP and p53 upon CDDP treatment. These results suggest that p53 facilitates FLIP down-regulation by CDDP-induced FLIP ubiquitination and proteasomal degradation.


Axillary lymph node metastases in adenoid cystic carcinoma of the breast. A rare finding.
Adenoid cystic carcinoma (ACC) of the breast is a rare malignant salivary-type neoplasm that has a good prognosis and represents less than 1% of all breast cancers. It is a triple negative carcinoma that presents as a painful mass. The mean age at the time of diagnosis is 50-60 years old. The solid variant of this type of tumour with basaloid features and presence of nodal metastases is very rare and considered to have a more aggressive clinical course. We present a case with presence of axillary lymph node metastases that was successfully treated with no evidence of recurrence one year after the diagnosis and review the literature.


The Need for Collective Awareness of Attempted Suicide Rates in a Warming Climate.
Background: Climate factors may offer a stronger explanation of the variations in suicide rates compared with economic variables, even in the case of patients admitted involuntarily. Aims: We assessed the role of temperature as a determinant of the increased prevalence of suicide attempts (SA). Method: The sample comprised all cases of hospitalization for SA at the Psychiatric Clinic of the IRCCS Ospedale Policlinico San Martino between August 2013 and July 2018. For ambient temperature, data were provided by the Meteorological Observatory of the University of Genoa. Results: We noted a peak in suicides that was typically found in late spring and early summer due to global warming. Limitations: Other environmental/psychological factors contributing to the onset of an acute clinical event were not considered. The cross-sectional design of the study is another limitation. Conclusion: Further studies are needed to clarify the impact of climatic factors on suicide behavior and implement early intervention and preventive strategies for mental health.


Improved cardiac function and dietary fatty acid metabolism after modest weight loss in subjects with impaired glucose tolerance.
Using a novel positron emission tomography (PET) method with oral administration of 14(R,S)-[¹⁸F]-fluoro-6-thia-heptadecanoic acid (¹⁸FTHA), we recently demonstrated that subjects with impaired glucose tolerance (IGT) display an impairment in cardiac function associated with increased myocardial uptake of dietary fatty acids. Here, we determined whether modest weight loss induced by lifestyle changes might improve these cardiac metabolic and functional abnormalities. Nine participants with IGT, enrolled in a one-year lifestyle intervention trial, were invited to undergo determination of organ-specific postprandial dietary fatty acids partition using the oral ¹⁸FTHA method, and cardiac function and oxidative metabolic index using PET [¹¹C]acetate kinetics with ECG-gated PET ventriculography before and after the intervention. The intervention resulted in significant weight loss and reduction of waist circumference, with reduced postprandial plasma glucose, insulin, and triglycerides excursion. We observed a significant increase in stroke volume, cardiac output, and left ventricular ejection fraction associated with reduced myocardial oxidative metabolic index and fractional dietary fatty acid uptake. Modest weight loss corrects the exaggerated myocardial channeling of dietary fatty acids and improves myocardial energy substrate metabolism and function in IGT subjects.


Perianal Crohn's disease: a review.
Perianal involvement in Crohn's disease (CD), which encompasses fistulas, ulcers, abscesses, strictures and cancer, can lead to significant impairment in quality of life. The objective of this article is to review the major perianal complications of CD and the current medical and surgical modalities used to treat them. Antibiotics are commonly used despite a lack of controlled trials to validate their use and should be used as a bridge to maintenance therapy. The anti-metabolites azathioprine and 6-MP have shown a positive response in terms of fistula closure, although these data are mostly from trials looking at this as a secondary endpoint. Infliximab is an effective agent for induction and maintenance of treatment of fistulizing CD. Further studies to evaluate the use of subcutaneous anti-tumor necrosis factors are needed to convincingly prove their efficacy for perianal fistulizing disease. In CD, clinicians should avoid surgery as a first-line approach for skin tags, hemorrhoids or fissures in the setting of proctitis. Surgery, particularly lateral internal sphincterotomy, in combination with medical therapy is associated with higher fissure healing rates in the absence of proctitis. Fistulotomy is curative for most simple low perianal fistulae, but complex fistulas often require sphincter-sparing surgical procedures. Less invasive approaches such as a chemical sphincterotomy should be used first, with therapy escalated only if this fails.


Detrimental impact of sulfide on the seagrass Zostera marina in dark hypoxia.
Sulfide poisoning, hypoxia events, and reduced light availability pose threats to marine ecosystems such as seagrass meadows. These threats are projected to intensify globally, largely due to accelerating eutrophication of estuaries and coastal environments. Despite the urgency, our current comprehension of the metabolic pathways that underlie the deleterious effects of sulfide toxicity and hypoxia on seagrasses remains inadequate. To address this knowledge gap, I conducted metabolomic analyses to investigate the impact of sulfide poisoning under dark-hypoxia in vitro conditions on Zostera marina, a vital habitat-forming marine plant. During the initial 45 minutes of dark-hypoxia exposure, I detected an acclimation phase characterized by the activation of anaerobic metabolic pathways and specific biochemical routes that mitigated hypoxia and sulfide toxicity. These pathways served to offset energy imbalances, cytosolic acidosis, and sulfide toxicity. Notably, one such route facilitated the transformation of toxic sulfide into non-toxic organic sulfur compounds, including cysteine and glutathione. However, this sulfide tolerance mechanism exhibited exhaustion post the initial 45-minute acclimation phase. Consequently, after 60 minutes of continuous sulfide exposure, the sulfide toxicity began to inhibit the hypoxia-mitigating pathways, culminating in leaf senescence and tissue degradation. Utilizing metabolomic approaches, I elucidated the intricate metabolic responses of seagrasses to sulfide toxicity under in vitro dark-hypoxic conditions. My findings suggest that future increases in coastal eutrophication will compromise the resilience of seagrass ecosystems to hypoxia, primarily due to the exacerbating influence of sulfide.


NAD+-dependent glyceraldehyde-3-phosphate dehydrogenase from Thermoproteus tenax. The first identified archaeal member of the aldehyde dehydrogenase superfamily is a glycolytic enzyme with unusual regulatory properties.
The hyperthermophilic archaeum Thermoproteus tenax possesses two glyceraldehyde-3-phosphate dehydrogenases differing in cosubstrate specificity and phosphate dependence of the catalyzed reaction. NAD+-dependent glyceraldehyde-3-phosphate dehydrogenase catalyzes the phosphate-independent irreversible oxidation of D-glyceraldehyde 3-phosphate to 3-phosphoglycerate. The coding gene was cloned, sequenced, and expressed in Escherichia coli. Sequence comparisons showed no similarity to phosphorylating glyceraldehyde-3-phosphate dehydrogenases but revealed a relationship to aldehyde dehydrogenases, with the highest similarity to the subgroup of nonphosphorylating glyceraldehyde-3-phosphate dehydrogenases. The activity of the enzyme is affected by a series of metabolites. All effectors tested influence the affinity of the enzyme for its cosubstrate NAD+. Whereas NADP(H), NADH, and ATP reduce the affinity for the cosubstrate, AMP, ADP, glucose 1-phosphate, and fructose 6-phosphate increase the affinity for NAD+. Additionally, most of the effectors investigated induce cooperativity of NAD+ binding. The irreversible catabolic oxidation of glyceraldehyde 3-phosphate, the control of the enzyme by energy charge of the cell, and the regulation by intermediates of glycolysis and glucan degradation identify the NAD+-dependent glyceraldehyde-3-phosphate dehydrogenase as an integral constituent of glycolysis in T. tenax. Its regulatory properties substitute for those lacking in the reversible nonregulated pyrophosphate-dependent phosphofructokinase in this variant of the Embden-Meyerhof-Parnas pathway.


Multimarker reverse transcriptase-polymerase chain reaction assay in lymphatic drainage and sentinel node tumor burden.
We assessed molecular (presence of melanoma cells markers in lymph fluid [LY]) and pathological features (sentinel lymph node [SN] tumor burden according to Rotterdam criteria, metastases microanatomic location) and correlated them with survival and melanoma prognostic factors in a group of patients with positive SN biopsy. We analyzed 368 consecutive SN-positive patients after completion lymph node dissection (CLND). In 321 patients we obtained data on SLN microanatomic location/tumor burden (only 7 cases had metastases <0.1 mm); in 137 we additionally analyzed 24-hour collected LY after CLND (multimarker reverse transcriptase-polymerase chain reaction [MM-RT-PCR] with primers for tyrosinase, MART1 (MelanA), and uMAGE mRNA (27.7% positive samples)]. Median follow-up time was 41 months. According to univariate analysis, the following factors had a negative impact on overall survival (OS): higher Breslow thickness (P = .0001), ulceration (P < .0001), higher Clark level (P = .008), male gender (P = .0001), metastatic lymph nodes >1 (P < .0001), nodal metastases extracapsular extension (P < .0001), metastases to additional non-SNs (P = .0004), micrometastases size ≥ 0.1 mm (P = .0006), and positive LY MM-RT-PCR (P = .0007). SN tumor burden showed linear correlation with increasing Breslow thickness (P = .01). The 5-year OS rates for SLN tumor burden <0.1 mm, 1-1.0 mm, and >1.0 mm were 84%/66%/44%, respectively, and for positive and negative LY MM-RT-PCR 47%/0%, respectively. The independent factors for shorter OS (multivariate analysis): male gender, primary tumor ulceration, number of involved nodes ≥ 4, micrometastases size >1.0 mm, and, in additional model including molecular analysis-positive MM-RT-PCR results (hazard ratio [HR] 3.2), micrometastases size >1.0 mm (HR 1.13), and primary tumor ulceration (HR 2.17). Similar results were demonstrated for disease-free survival (DFS) data. SN tumor burden categories according to Rotterdam criteria and the positive result of LY MM-RT-PCR assay demonstrated additional, independent prognostic value in SN-positive melanoma patients, showing significant correlation with shorter DFS and OS.


The histological distribution of blood group substances A and B in man.
The mapping out of the histologic distribution of blood group antigens A and B in human tissues was performed by means of the fluorescent antibody technique. Human hyperimmune sera were conjugated with fluorescein isocyanate and applied to frozen sections of human material obtained at autopsy or after surgical removal. The material examined encompassed A, B, and AB subjects. In the latter the anti-A and the anti-B conjugate elicited the same picture. Group O tissues were used for controls and were uniformly negative. The secretor status of subjects was determined from the saliva or by the Lewis typing of erythrocytes. The results fall into the following main divisions: Endothelia of Vessels.-Widespread localization was demonstrated in the cell walls of endothelium of capillaries, veins, arteries, and of sinusoidal cells of spleen. Stratified Epithelia.-These showed good outlining of cells of the Malpighian (and the granular, when present) layers. In transitional epithelia, cells of the basal and contiguous layers gave specific staining. Mucus-Secreting Apparatus.-Positive staining was obtained in glands, goblet cells, and secreting surface epithelia. In non-secretors there was no identifiable antigen with the important exception of the deeper parts of gastric foveolae, deeper parts of crypts of Lieberkühn of bowel mucosa and Brunner's glands of the duodenum. Various Organs of Secretion and Excretion.-The pancreas (exocrine portion) and the sweat glands were found to produce the antigen irrespectively of secretor status. Breast, prostate, and endometrial glands on the other hand apparently secrete the antigen in conformity with the subject's secretor:non-secretor make-up. Thus the secretor:non-secretor status governs principally the antigens associated with mucous secretions and this in most but not all locations. The possible nature of this control is briefly discussed.


Evidence for multiple independent origins of trans-splicing in Metazoa.
In contrast to conventional splicing, which joins exons from a single primary transcript, trans-splicing links stretches of RNA from separate transcripts, derived from distinct regions of the genome. Spliced leader (SL) trans-splicing is particularly well known in trypanosomes, nematodes, and flatworms, where it provides messenger RNAs with a leader sequence and cap that allow them to be translated efficiently. One of the largest puzzles regarding SL trans-splicing is its evolutionary origin. Until now SL trans-splicing has been found in a small and disparate set of organisms (including trypanosomes, dinoflagellates, cnidarians, rotifers, nematodes, flatworms, and urochordates) but not in most other eukaryotic lineages, including well-studied groups such as fungi, plants, arthropods, and vertebrates. This patchy distribution could either suggest that trans-splicing was present in early eukaryotes/metazoans and subsequently lost in multiple lineages or that it evolved several times independently. Starting from the serendipitous discovery of SL trans-splicing in an arthropod, we undertook a comprehensive survey of this process in the animal kingdom. By surveying expressed sequence tag data from more than 70 metazoan species, we show that SL trans-splicing also occurs in at least two groups of arthropods (amphipod and copepod crustaceans), in ctenophores, and in hexactinellid sponges. However, we find no evidence for SL trans-splicing in other groups of arthropods and sponges or in 15 other phyla that we have surveyed. Although the presence of SL trans-splicing in hydrozoan cnidarians, hexactinellid sponges, and ctenophores might suggest that it was present at the base of the Metazoa, the patchy distribution that is evident at higher resolution suggests that SL trans-splicing has evolved repeatedly among metazoan lineages. In agreement with this scenario, we discuss evidence that SL precursor RNAs can readily evolve from ubiquitous small nuclear RNAs that are used for conventional splicing.


N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) and Risk of Hypertension in the Atherosclerosis Risk in Communities (ARIC) Study.
Brain natriuretic peptide (BNP) is released by the heart in response to ventricular and auricular wall stress. Release of BNP is traditionally considered part of the body's protective mechanism against pressure overload by inducing vasodilatation and diuresis. More recent evidence demonstrates that BNP also promotes vessel wall stress and preliminary studies suggest that chronic increased levels may increase risk of hypertension. This study aimed to evaluate the prospective association of N-terminal BNP (NT-proBNP), a cleavage product of BNP, with risk of hypertension in the Atherosclerosis Risk in Communities cohort study. We conducted a prospective analysis of 3,798 middle-aged participants in the ARIC study without hypertension at baseline (1996-1998). Using Cox proportional hazards models, we characterized the association between NT-proBNP at baseline and newly diagnosed hypertension for a maximum of 14 years of follow-up (median = 9 years). We observed 2,113 new hypertension cases over the follow-up period. Higher baseline NT-proBNP was independently associated with an increased risk of hypertension. Adjusted hazard ratios for incident hypertension in the highest quartile compared to the lowest quartile of NT-proBNP at baseline was 1.24 (95% CI: 1.08-1.42). Each log-unit increase in NT-proBNP was associated with an 8% increased risk of hypertension (95% CI: 1.03-1.13). Persons with elevated NT-proBNP, even with normal blood pressure at baseline, were at increased risk of developing hypertension. Our results suggest that elevated circulating BNP might contribute to the development of hypertension in previously normotensive individuals.