Do all leaf photosynthesis parameters of rice acclimate to elevated CO2 , elevated temperature, and their combination, in FACE environments?
Leaf photosynthesis of crops acclimates to elevated CO2 and temperature, but studies quantifying responses of leaf photosynthetic parameters to combined CO2 and temperature increases under field conditions are scarce. We measured leaf photosynthesis of rice cultivars Changyou 5 and Nanjing 9108 grown in two free-air CO2 enrichment (FACE) systems, respectively, installed in paddy fields. Each FACE system had four combinations of two levels of CO2 (ambient and enriched) and two levels of canopy temperature (no warming and warmed by 1.0-2.0°C). Parameters of the C3 photosynthesis model of Farquhar, von Caemmerer and Berry (the FvCB model), and of a stomatal conductance (gs ) model were estimated for the four conditions. Most photosynthetic parameters acclimated to elevated CO2 , elevated temperature, and their combination. The combination of elevated CO2 and temperature changed the functional relationships between biochemical parameters and leaf nitrogen content for Changyou 5. The gs model significantly underestimated gs under the combination of elevated CO2 and temperature by 19% for Changyou 5 and by 10% for Nanjing 9108 if no acclimation was assumed. However, our further analysis applying the coupled gs -FvCB model to an independent, previously published FACE experiment showed that including such an acclimation response of gs hardly improved prediction of leaf photosynthesis under the four combinations of CO2 and temperature. Therefore, the typical procedure that crop models using the FvCB and gs models are parameterized from plants grown under current ambient conditions may not result in critical errors in projecting productivity of paddy rice under future global change.


Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch.
We investigated roles for substance P (SP), gastrin-releasing peptide (GRP), and glutamate in the spinal neurotransmission of histamine-dependent and -independent itch. In anesthetized mice, responses of single superficial dorsal horn neurons to intradermal (i.d.) injection of chloroquine were partially reduced by spinal application of the α-amino-3-hydroxy-5-methyl-4-isoxazole proprionate acid (AMPA)/kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Co-application of CNQX plus a neurokinin-1 (NK-1) antagonist produced stronger inhibition, while co-application of CNQX, NK-1, and GRP receptor (GRPR) antagonists completely inhibited firing. Nociceptive-specific and wide dynamic range-type neurons exhibited differential suppression by CNQX plus either the GRPR or NK-1 antagonist, respectively. Neuronal responses elicited by i.d. histamine were abolished by CNQX alone. In behavioral studies, individual intrathecal administration of a GRPR, NK-1, or AMPA antagonist each significantly attenuated chloroquine-evoked scratching behavior. Co-administration of the NK-1 and AMPA antagonists was more effective, and administration of all 3 antagonists abolished scratching. Intrathecal CNQX alone prevented histamine-evoked scratching behavior. We additionally employed a double-label strategy to investigate molecular markers of pruritogen-sensitive dorsal root ganglion (DRG) cells. DRG cells responsive to histamine and/or chloroquine, identified by calcium imaging, were then processed for co-expression of SP, GRP, or vesicular glutamate transporter type 2 (VGLUT2) immunofluorescence. Subpopulations of chloroquine- and/or histamine-sensitive DRG cells were immunopositive for SP and/or GRP, with >80% immunopositive for VGLUT2. These results indicate that SP, GRP, and glutamate each partially contribute to histamine-independent itch. Histamine-evoked itch is mediated primarily by glutamate, with GRP playing a lesser role. Co-application of NK-1, GRP, and AMPA receptor antagonists may prove beneficial in treating chronic itch.


Characterization of clone 13, a naturally attenuated avirulent isolate of Rift Valley fever virus, which is altered in the small segment.
The 74HB59 strain of Rift Valley fever (RVF) virus, isolated from a human case in the Central African Republic, was shown to be composed of a heterogeneous population of viruses when plaque-purified clones were analyzed for their reactivity with monoclonal antibodies (MAbs) directed against the nucleocapsid (N) protein or the nonstructural (NSs) protein. One of these clones, C13, was of particular interest in that it proved to be avirulent in mice and hamsters, and highly immunogenic. Although C13 showed normal reactivity with a large panel of MAbs directed at the glycoproteins, it failed to react with specific MAbs or polyclonal antibodies directed at the NSs protein and with a specific MAb recognizing the N protein of the Egyptian strains. Consequently, the small RNA segment, which encodes the N and NSs proteins in an ambisense strategy, was sequenced and compared with the existing sequence of the attenuated MP-12 RVF virus strain. We found that the NSs gene contained, in addition to two conservative coding changes, a large internal deletion of 549 nucleotides that removes 69% of the open reading frame but conserves in-frame the N and C termini of the predicted translation product. In addition, the sequence revealed that the N protein of C13 contained a single amino acid change. Clone C13 replicated normally in certain cell types in vitro and in Culex pipiens mosquitoes after intrathoracic inoculation, but established abortive infections in MRC-5 human fibroblasts.


The VicGeneration study--a birth cohort to examine the environmental, behavioural and biological predictors of early childhood caries: background, aims and methods.
Dental caries (decay) during childhood is largely preventable however it remains a significant and costly public health concern, identified as the most prevalent chronic disease of childhood. Caries in children aged less than five years (early childhood caries) is a rapid and progressive disease that can be painful and debilitating, and significantly increases the likelihood of poor child growth, development and social outcomes. Early childhood caries may also result in a substantial social burden on families and significant costs to the public health system. A disproportionate burden of disease is also experienced by disadvantaged populations. This study involves the establishment of a birth cohort in disadvantaged communities in Victoria, Australia. Children will be followed for at least 18 months and the data gathered will explore longitudinal relationships and generate new evidence on the natural history of early childhood caries, the prevalence of the disease and relative contributions of risk and protective biological, environmental and behavioural factors. Specifically, the study aims to:1. Describe the natural history of early childhood caries (at ages 1, 6, 12 and 18 months), tracking pathways from early bacterial colonisation, through non-cavitated enamel white spot lesions to cavitated lesions extending into dentine.2. Enumerate oral bacterial species in the saliva of infants and their primary care giver.3. Identify the strength of concurrent associations between early childhood caries and putative risk and protective factors, including biological (eg microbiota, saliva), environmental (fluoride exposure) and socio-behavioural factors (proximal factors such as: feeding practices and oral hygiene; and distal factors such as parental health behaviours, physical health, coping and broader socio-economic conditions).4. Quantify the longitudinal relationships between these factors and the development and progression of early childhood caries from age 1-18 months. There is currently a lack of research describing the natural history of early childhood caries in very young children, or exploring the interactions between risk and protective factors that extend to include contemporary measures of socio-behavioural factors. This study will generate knowledge about pathways, prevalence and preventive opportunities for early childhood caries, the most prevalent child health inequality.


Investigation of molecular alterations of AKT-3 in triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer (BC) deaths, owing to its intrinsic aggressiveness and a lack of treatment options, especially targeted therapies. Thus, there is an urgent need for the development of better targeted treatments for TNBC. Molecular alteration of AKT-3 was previously reported in oestrogen receptor (ER)-positive BC. AKT-3 has also been suggested to play a role in hormone-unresponsive BC. The aim of this study was to investigate molecular alterations of AKT-3 in TNBC, to perform associated survival analysis, and to compare these findings with the incidence of AKT-3 molecular alterations in ER-positive BC. Our study revealed AKT-3 amplification and deletions in 11% (9/82) and 13% (11/82) of TNBCs, respectively. In contrast, 1% (2/209) of ER-positive BCs were found to have AKT-3 amplifications and deletions. A higher prevalence of AKT-3 copy number gains was observed in TNBC [26% (21/82)] than in ER-positive BC [9% (19/209)]. AKT-3 amplification together with Akt-3 protein expression was negatively associated with recurrence-free survival in TNBC. Furthermore, a negative association between high AKT-3 copy number and recurrence-free survival was observed. AKT-3 amplification could represent a potentially relevant oncogenic event in a subset of TNBCs that may, in turn, select cells sensitive to Akt-3 inhibitors.


Cancer of the nongastric hollow organs of the gastrointestinal tract after gastric surgery.
To estimate the risk of esophageal, gallbladder, small-bowel, and colon cancers after gastric surgery for benign disease, all 337 residents of Olmsted County, Minnesota, who had surgical treatment of benign peptic ulcer disease during the years 1935 through 1959, were followed up. Patients were followed up for 6552 person-years of observation. No esophageal cancers developed (0.8 were expected). Members of the cohort developed one small-bowel malignant neoplasm (0.2 were expected), two gallbladder cancers (1.1 was expected), and four colon cancers (11.2 were expected), but these figures do not reflect a significant increase in the risk of these malignant neoplasms. In particular, the relative risk of developing colon cancer was only 0.4 when this analysis had 88% power to detect a relative risk of two or more. When the present investigation and two previous studies of this cohort were taken together, there was no strong evidence for an increased risk of any gastrointestinal cancer following gastric surgery.


Comparison of serological and real-time PCR assays to diagnose Bordetella pertussis infection in 2007.
Bacterial culture for diagnosing pertussis infection has high specificity but poor sensitivity and is slow. Highly sensitive real-time PCR assays and single-serum pertussis serology have been developed to overcome these limitations, but there are few data available on the relative sensitivities and specificities of such assays for pertussis diagnosis. Using data on 195 participants (>or=7 years old) from an epidemiological study, we assessed the sensitivity, specificity, and performance (Youden index) for pertussis diagnosis of the pertussis toxin enzyme-linked immunosorbent assay (using single and paired serology) and of real-time PCR assays (using the IS481 and ptxA-Pr targets). All available diagnostic information (clinical and laboratory) was pooled to serve as the gold standard. Single serology was the most efficient diagnostic test (Youden index, 0.57 to 0.58), with relatively high sensitivity (>64%) and high specificity (>90%), independent of the cutoff level. IS481 PCR performance was superior to that of ptxA-Pr PCR, and it was the second-most-efficient tool (Youden index, 0.30). Performing both ptxA-Pr and IS481 PCRs did not improve diagnostic performance. The greatest test efficiency (Youden index, 0.69 to 0.74) was achieved when single-serum serology was used in combination with IS481 or ptxA-Pr PCR or paired serology. Combining single serology with one PCR or paired serology increased the sensitivity with an associated limited decrease in specificity. The most specific tests for diagnosis of pertussis were single serology and ptxA-Pr PCR, and the most sensitive diagnostic tool was the combination of IS481 PCR with single serology.


A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis.
Alternative medicine is used extensively by patients with chronic pain due to e.g., osteoarthritis. Only few of these drugs have be tested in a controlled setting and the present study was undertaken to examine the effect of ginger extract, one of the most popular herbal medications. Ginger extract was compared to placebo and Ibuprofen in patients with osteoarthritis of the hip or knee in a controlled, double blind, double dummy, cross-over study with a wash-out period of one week followed by three treatment periods in a randomized sequence, each of three weeks duration. Acetaminophen was used as rescue medication throughout the study. The study was conducted in accordance with Good Clinical Practice (European Guideline for GCP). A ranking of efficacy of the three treatment periods: Ibuprofen>ginger extract>placebo was found for visual analogue scale of pain (Friedman test: 24.65, P< 0.00001) and the Lequesne-index (Friedman test: 20.76, P< 0.00005). In the cross-over study, no significant difference between placebo and ginger extract could be demonstrated (Siegel-Castellan test), while explorative tests of differences in the first treatment period showed a better effect of both Ibuprofen and ginger extract than placebo (Chi-square, P< 0.05). There were no serious adverse events reported during the periods with active medications. In the present study a statistically significant effect of ginger extract could only be demonstrated by explorative statistical methods in the first period of treatment before cross-over, while a significant difference was not observed in the study as a whole.


Phenolic compounds and antioxidant activities of selected species of seaweeds from Danish coast.
Water and ethanolic extracts of 16 species of seaweeds collected along the Danish coasts were screened for antioxidant activities using four in vitro antioxidant assays (2,2-diphenyl-1-picrylhydrazyl radical scavenging activity, reducing power, ferrous ion-chelating and liposome model system). Furthermore their effectiveness in retarding lipid peroxidation in fish oil was evaluated by an accelerated stability test. Significant differences were observed in total and individual phenolic content and the antioxidant activities of seaweed species evaluated. Ethanol was more efficient for polyphenol extraction than water. Polysiphonia fucoides and all the Fucus species tested showed highest radical scavenging activity, reducing power, inhibition of oxidation in liposome model system and in fish oil and were high in phenolic content. These seaweeds could be potential rich sources of natural antioxidants for protection of foods against oxidation. In general, the various antioxidative assays correlated well with the total phenolic content, indicating that algal polyphenols are active components in these extracts. However, in some of the antioxidative assays some species with low total phenolic content also showed good antioxidative effects indicating that some other co-extracted active compounds such as pigments and tocopherols in ethanolic extracts and sulphated polysaccharides, proteins or peptides in water extracts may also contribute to the overall antioxidant properties and this needs further investigation.


The spatial and seasonal distribution of Bulinus truncatus, Bulinus forskalii and Biomphalaria pfeifferi, the intermediate host snails of schistosomiasis, in N'Djamena, Chad.
There is a paucity of epidemiological and malacological data pertaining to schistosomiasis in Chad. In view of a recently articulated elimination agenda, a deeper understanding of the spatio-temporal distribution of schistosomiasis intermediate host snails is pivotal. We conducted cross-sectional malacological surveys during the dry season (April/May 2013) and after the short rainy season (October 2013) in N'Djamena, the capital of Chad. Snails were identified at the genus and species level using morphological keys and molecular DNA barcoding approaches. Those belonging to Bulinus and Biomphalaria were examined for cercarial shedding. Snail habitats were characterised and their predictive potential for the presence of schistosomiasis intermediate host snails explored. Seasonal patterns were studied using geographical information system and kriging in order to interpolate snail abundance data to make predictions at non-sampled locations across N'Djamena. Overall, 413 Bulinus truncatus, 369 Bulinus forskalii and 108 Biomphalaria pfeifferi snails were collected and subjected to cercarial shedding. During the dry season, one Bu. truncatus of 119 snails collected shed Schistosoma spp. cercariae (0.84%), while S. mansoni was shed by one of 108 Bi. pfeifferi snails (0.93%). None of the snails collected after the rainy season shed Schistosoma spp. cercariae. The abundance of Bu. truncatus and Bu. forskalii showed an inverse U-shape relationship with the square term of conductivity, i.e. low abundance at the lowest and highest levels of conductivity and high abundance at intermediate levels. Bi. pfeifferi showed a negative, linear association with pH in the dry seasons. It is planned to link these intermediate host snail data to infection data in human populations with the goal to draw a predictive risk map that can be utilised for control and elimination of schistosomiasis in N'Djamena.


Depression prevalence in disadvantaged young black women--African and Caribbean immigrants compared to US-born African Americans.
Research with Mexican Americans suggests that immigrants have lower rates of mental disorders than U. S.-born Mexican Americans. We examine the prevalence of depression, somatization, alcohol use and drug use among black American women, comparing rates of disorders among U. S.-born, Caribbean-born, and African-born subsamples. Women in Women, Infants and Children (WIC) programs, county-run Title X family planning clinics, and low-income pediatric clinics were interviewed using the PRIME-MD. In total, 9,151 black women were interviewed; 7,965 were born in the U. S., 913 were born in Africa, and 273 were born in the Caribbean. Controlling for other predictors, U.S.-born black women had odds of probable depression that were 2.94 times greater than the African-born women (p<0.0001, 95% CI: 2.07, 4.18) and 2.49 times greater than Caribbean-born women (p<0.0016, 95% CI: 1.41, 4.39). Likelihood of somatization did not differ among women who were U. S. born, African born, or Caribbean born. Rates of alcohol and drug problems were exceedingly low among all three groups, with less than 1% of the women reporting either alcohol or drug problems. These results mirror similar findings for Mexican immigrant as compared with American-born Mexican Americans. The findings suggest that living in the U. S. might increase depression among poor black women receiving services in county entitlement clinics. Further research with ethnically validated instruments is needed to identify protective and risk factors associated with depression in immigrant and U. S.-born poor black women.


Quantifying lives lost due to variability in emergency general surgery outcomes: Why we need a national emergency general surgery quality improvement program.
Nearly 4 million Americans present to hospitals with conditions requiring emergency general surgery (EGS) annually, facing significant morbidity and mortality. Unlike elective surgery and trauma, there is no dedicated national quality improvement program to improve EGS outcomes. Our objective was to estimate the number of excess deaths that could potentially be averted through EGS quality improvement in the United States. Adults with the American Association for the Surgery of Trauma-defined EGS diagnoses were identified in the Nationwide Emergency Department Sample 2006 to 2014. Hierarchical logistic regression was performed to benchmark treating hospitals into reliability adjusted mortality quintiles. Weighted generalized linear modeling was used to calculate the relative risk of mortality at each hospital quintile, relative to best-performing quintile. We then calculated the number of excess deaths at each hospital quintile versus the best-performing quintile using techniques previously used to quantify potentially preventable trauma deaths. Twenty-six million EGS patients were admitted, and 6.5 million (25%) underwent an operation. In-hospital mortality varied from 0.3% to 4.1% across the treating hospitals. Relative to the best-performing hospital quintile, an estimated 158,177 (153,509-162,736) excess EGS deaths occurred at lower-performing hospital quintiles. Overall, 47% of excess deaths occurred at the worst-performing hospitals, while 27% of all excess deaths occurred among the operative cohort. Nearly 200,000 excess EGS deaths occur across the United States each decade. A national initiative to enable structures and processes of care associated with optimal EGS outcomes is urgently needed to achieve "Zero Preventable Deaths after Emergency General Surgery." Care management, level IV.


Comparison of the performance of younger and older adults on three versions of a puzzle reproduction task.
Because constructional ability is a crucial perceptual-motor skill that relates to daily functioning, it should be accurately assessed in clients with neurological dysfunction. This study examined three versions of the Puzzle Reproduction task (a constructional ability task) of the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) in order to determine whether a reduced-detail version of the task would be easier (i.e., require less time to complete) than the original version and whether a subplacement version would be more difficult to perform (i.e., require more time to complete) than the original version. In addition, the study examined whether older adult subjects would perform more slowly than younger adult subjects. Seventy-two right-handed adults with no disabilities were divided into two age groups: 18 to 30 years old (n = 36) and 58 to 70 years old (n = 36). Each subject was tested on one of three versions of the LOTCA Puzzle Reproduction task (i.e., original subplacement, simplified). For the older subjects, the simplified version of the task required significantly less time than the original version, although there was not a significant time difference between the original and subplacement versions. For the younger subjects, the subplacement versions. required significantly more time than the original version, but there was no significant time difference between the original and simplified versions. Results also indicated that older subjects took significantly longer to perform all three versions of the task than did the younger subjects. The findings support the use of the simplified version of the LOTCA Puzzle Reproduction task with older adults or with persons with major cognitive-perceptual difficulties. Further studies of the level of difficulty of the subplacement version are needed to examine whether this version is more sensitive to constructional deficits in a sample of person with neurological impairments because even mild constructional deficits have been shown to relate to disabilities in daily functioning.


Health promotion in the workplace: the perspective of unskilled workers in a hospital setting.
It is important to explore the potential for health promotion from the perspective of participants in a particular situation. This study focuses on experiences of well-being and the potential for health promotion among unskilled workers in the kitchen and laundry room in an acute care hospital in Iceland. These experiences are analysed in light of the material and structural factors that shape working conditions. The research method used was grounded theory. The data were formal and informal interviews, and participant observation. The findings revealed considerable differences between the two work groups. At both sites strain on the body, caused by excessive noise, heavy lifting and uncomfortable working arrangements, were identified. Similarly, the work was often experienced as monotonous and demanding. Human relations were identified as a key factor in ameliorating the conditions that led to experiences of strain by the workers at both work sites. This was however where the two work places differed. In the laundry room, the workers felt respected and acknowledged by their coworkers and managers. Belonging to the work group was important and they felt listened to by the supervisor. Very little cohesiveness was observed among the workers in the kitchen. The managers seemed to be absent from the floor, workers were divided into work groups that sometimes showed antagonism towards each other and few channels were available for complaints and suggestions for improvement. The workers in the laundry room, on the other hand, related positive experiences of work. They felt that steps were taken by managers to improve working conditions to the extent possible and participated in those attempts by bringing up suggestions, implementing change and developing their own ways of coping with the work. This study gives important directions for health promotion in the workplace, emphasizing human relations at work, rather than individual health behaviour away from the work setting.


Clinical development of experimental therapies for malignant glioma.
Advances in medical and surgical treatments in the last two to three decades have resulted in quantum leaps in the overall survival of patients with many types of non-central nervous system (CNS) malignant disease, while survival of patients with malignant gliomas (WHO grades 3 and 4) has only moderately improved. Surgical resection, external fractionated radiotherapy and oral chemotherapy, during and after irradiation, remain the pillars of malignant glioma therapy and have shown significant benefits. However, numerous clinical trials with adjuvant agents, most of them administered systemically and causing serious complications and side effects, have not achieved a noteworthy extension of survival, or only with considerable deterioration in patients' quality of life. Significant attention was focussed in the last decades on the cell biology and molecular genetics of gliomas. Improved understanding of the fundamental features of tumour cells has resulted in the introduction and increasing clinical use of local therapies, which employ spatially defined delivery methods and tumour-selective agents specifically designed to be used in the environment of a glioma-invaded brain. This review summarises the key findings of some of the most recent and important clinical studies of locally administered novel treatments for malignant glioma. Several such therapies have shown considerable anti-tumour activity and a favourable profile of local and systemic side effects. These include biodegradable polymers for interstitial chemotherapy, targeted toxins administered by convection enhanced delivery, and intra- and peritumourally injected genetically modified viruses conferring glioma-selective toxicity. Areas of possible improvement of these therapies and essential future developments are also outlined.


Crystal structure of the radical SAM enzyme catalyzing tricyclic modified base formation in tRNA.
Wyosine and its derivatives, such as wybutosine, found in eukaryotic and archaeal tRNAs, are tricyclic hypermodified nucleosides. In eukaryotes, wybutosine exists exclusively in position 37, 3'-adjacent to the anticodon, of tRNA(Phe), where it ensures correct translation by stabilizing the codon-anticodon base-pairing during the ribosomal decoding process. Recent studies revealed that the wyosine biosynthetic pathway consists of multistep enzymatic reactions starting from a guanosine residue. Among these steps, TYW1 catalyzes the second step to form the tricyclic ring structure, by cyclizing N(1)-methylguanosine. In this study, we solved the crystal structure of TYW1 from Methanocaldococcus jannaschii at 2.4 A resolution. TYW1 assumes an incomplete TIM barrel with (alpha/beta)(6) topology, which closely resembles the reported structures of radical SAM enzymes. Hence, TYW1 was considered to catalyze the cyclization reaction by utilizing the radical intermediate. Comparison with other radical SAM enzymes allowed us to build a model structure complexed with S-adenosylmethionine and two [4Fe-4S] clusters. Mutational analyses in yeast supported the validity of this complex model structure, which provides a structural insight into the radical reaction involving two [4Fe-4S] clusters to create a complex tricyclic base.


Recent Updates on the Phytochemistry, Pharmacological, and Toxicological Activities of Zingiber zerumbet (L.) Roscoe ex Sm.
Zingiber zerumbet (L.) Roscoe ex Sm. (family, Zingiberaceae) is a potent medicinal herb widely known as shampoo ginger and its rhizome is used in numerous ethnomedicinal applications including antipyretic, anti-inflammatory, antibacterial, anti-diarrheal, antidiabetics, carminative, and diuretic. The aim of this review was to bring together all the scientific updates on the phytochemistry and pharmacological activities of this herb, including their toxicological studies, and critically analyzed the outcomes to provide directions for future research on the herb as potential source of bioactive metabolites for pharmaceutical and nutraceutical applications. A structured electronic search on worldwide accepted scientific databases (Web of Science, PubMed, Google Scholar, Science Direct, SciFinder, Wiley Online Library) was carried out to compile the relevant information. Some information was obtained from books and database on medicinal plants used in various countries. About 60 metabolites, mainly polyphenols, and terpenoids have been isolated and identified. However, most of the reported pharmacological studies were based on crude extracts, and only a few of those isolated metabolites, particularly zerumbone have been investigated for biological and pharmacological activities. Many of the mechanistic studies to understand the pharmacological effects of the plant are limited by many considerations with regard to design, experimentation and interpretation. The bioactive metabolites should be further investigated on their safety and more elaborate preclinical studies before clinical trials can be undertaken.


Plasticity of hippocampal circuitry in Alzheimer's disease.
Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.


Development of a quantitative methodology to assess the impacts of urban transport interventions and related noise on well-being.
Well-being impact assessments of urban interventions are a difficult challenge, as there is no agreed methodology and scarce evidence on the relationship between environmental conditions and well-being. The European Union (EU) project "Urban Reduction of Greenhouse Gas Emissions in China and Europe" (URGENCHE) explored a methodological approach to assess traffic noise-related well-being impacts of transport interventions in three European cities (Basel, Rotterdam and Thessaloniki) linking modeled traffic noise reduction effects with survey data indicating noise-well-being associations. Local noise models showed a reduction of high traffic noise levels in all cities as a result of different urban interventions. Survey data indicated that perception of high noise levels was associated with lower probability of well-being. Connecting the local noise exposure profiles with the noise-well-being associations suggests that the urban transport interventions may have a marginal but positive effect on population well-being. This paper also provides insight into the methodological challenges of well-being assessments and highlights the range of limitations arising from the current lack of reliable evidence on environmental conditions and well-being. Due to these limitations, the results should be interpreted with caution.


Characterization of Pseudoalteromonas citrea and P. nigrifaciens isolated from different ecological habitats based on REP-PCR genomic fingerprints.
DNA primers corresponding to conserved repetitive interspersed genomic motifs and PCR were used to show that REP, ERIC and BOX-like DNA sequences are present in marine, oxidative, gram-negative Pseudoalteromonas strains. REP, ERIC and BOX-PCR were used for rapid molecular characterization of both the type species of the genus and environmental strains isolated from samples collected in different geographical areas. PCR-generated genomic fingerprint patterns were found to be both complex and strain specific. Analysis of the genotypic structure of phenotypically diverse P. citrea revealed a geographic clustering of Far Eastern brown-pigmented, agar-digesting strains of this species. Marine isolates of P. nigrifaciens with 67-70% DNA relatedness generated genomic patterns different from those of the type strain and formed a separate cluster. It is concluded that REP, ERIC and BOX-PCR are effective in generating strain specific patterns that can be used to elucidate geographic distribution, with these genomic patterns providing a valuable biogeographic criterion.


PARP inhibitors for cancer therapy.
Poly(ADP-ribose) polymerase 1 (PARP-1) is a zinc-finger DNA-binding enzyme that is activated by binding to DNA breaks. Poly(ADP-ribosyl)ation of nuclear proteins by PARP-1 converts DNA damage into intracellular signals that activate either DNA repair by the base-excision pathway or cell death. A family of 18 PARPs has been identified, but only the most abundant, PARP-1 and PARP-2, which are both nuclear enzymes, are activated by DNA damage. PARP inhibitors of ever-increasing potency have been developed in the 40 years since the discovery of PARP-1, both as tools for the investigation of PARP-1 function and as potential modulators of DNA-repair-mediated resistance to cytotoxic therapy. Owing to the high level of homology between the catalytic domains of PARP-1 and PARP-2, the inhibitors probably affect both enzymes. Convincing biochemical evidence, which has been corroborated by genetic manipulation of PARP-1 activity, shows that PARP inhibition is associated with increased sensitivity to DNA-alkylating agents, topoisomerase I poisons and ionising radiation. Novel PARP inhibitors of sufficient potency and suitable pharmacokinetic properties to allow evaluation in animal models have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation; indeed, the combination with temozolomide resulted in complete tumour regression in two independent studies. The combination of a PARP inhibitor and temozolomide is currently undergoing clinical evaluation for the first time.


Gingival Retraction Methods: A Systematic Review.
The aim of this systematic review was to assess the gingival retraction methods in terms of the amount of gingival retraction achieved and changes observed in various clinical parameters: gingival index (GI), plaque index (PI), probing depth (PD), and attachment loss (AL). Data sources included three major databases, PubMed, CINAHL plus (Ebsco), and Cochrane, along with hand search. Search was made using the key terms in different permutations of gingival retraction* AND displacement method* OR technique* OR agents OR material* OR medicament*. The initial search results yielded 145 articles which were narrowed down to 10 articles using a strict eligibility criteria of including clinical trials or experimental studies on gingival retraction methods with the amount of tooth structure gained and assessment of clinical parameters as the outcomes conducted on human permanent teeth only. Gingival retraction was measured in 6/10 studies whereas the clinical parameters were assessed in 5/10 studies. The total number of teeth assessed in the 10 included studies was 400. The most common method used for gingival retraction was chemomechanical. The results were heterogeneous with regards to the outcome variables. No method seemed to be significantly superior to the other in terms of gingival retraction achieved. Clinical parameters were not significantly affected by the gingival retraction method.


Differential effects of low and high doses of Taxol in anaplastic thyroid cancer cells: possible implication of the Pin1 prolyl isomerase.
To study the molecular mechanisms of dose-dependent effects of an anticancer drug, Taxol, on the cell cycle machinery and apoptosis-related proteins in thyroid anaplastic cancer cell lines ARO and KTC-2. Western blot analysis was used for the detection of various proteins and of their phosphorylated forms. Low dose of Taxol that cause apoptosis (25 nM) enhanced Rb protein phosphorylation, decreased the expression of cyclin-dependent kinase inhibitors p27(KIP1) and p21(WAF1) , and potentiated the accumulation of phosphorylated p53 and of the prolyl isomerase Pin1. High Taxol doses (100 and 1000 nM) that cause necrosis-like cell death drastically decreased Pin1 level in both cell lines. Low doses of Taxol promoted G(1)/S transition, thus exhibiting mitogen-like effect. Drug-induced Pin1 accumulation could probably facilitate this transition and in parallel contribute to apoptosis via the p53/p73-dependent mechanism. At higher doses of Taxol, there was a dramatic decrease of Pin1 levels which may be a reason for G(2)/M cell cycle arrest.


Polycystic ovary syndrome in men: Stein-Leventhal syndrome revisited.
Polycystic ovary syndrome (PCOS), also referred to as Stein-Leventhal syndrome, is one of the most common endocrinopathies. It is characterized by hyperandrogenism, hyperinsulinemia, central obesity, polycystic ovaries, and anovulation. However, some of these manifestations, including the polycystic ovaries, are neither specific for the disorder, nor found in all affected individuals. PCOS appears to be due to one or more primary defects in the upstream gonadotropin/androgen and/or insulin pathway, with the polycystic ovaries being one of many downstream manifestations. Yet, the pathophysiology of PCOS is not completely elucidated. Since the primary defect underlying PCOS may be an upstream endocrine and/or metabolic disturbance, rather than a defect in the ovaries themselves, we hypothesize that this aberration can also arise in men and that the absence of polycystic ovaries in men with other stigmata of the disorder should not eliminate the diagnosis. Our hypothesis is supported by the observation that a genetic susceptibility to PCOS exists, and that PCOS-type manifestations are not limited to women. Indeed, male relatives may suffer from insulin resistance, obesity, diabetes mellitus, and cardiovascular disease. Therefore, recognition of this syndrome in men is important, since pharmacologic treatments identified for women with PCOS may alleviate metabolic problems related to insulin resistance and its sequelae in men with a similar underlying defect. We suggest that first-degree relatives of patients with PCOS should be examined not only for phenotypic features characteristic of PCOS but also for biochemical evidence of hyperinsulinemia and hyperandrogenism. In addition to examining these individuals for obesity, the women should be evaluated for hirsutism and the men should be screened for early-onset male-pattern alopecia and excess hairiness. Serologic evaluation should included the ratio of fasting levels of glucose to insulin, a glucose tolerance test, the free testosterone level and the sex hormone-binding globulin level. Finally, both male and female first-degree relatives of patients with PCOS should be tested for the underlying molecular defect(s) of this condition, once it is identified. As new treatments for PCOS emerge, e.g. insulin-sensitizing drugs, it will be important to determine if these treatments have beneficial effects on the metabolic symptoms and complications in all afflicted patients, regardless of gender.


The Impact of Biologics and Tofacitinib on Cardiovascular Risk Factors and Outcomes in Patients with Rheumatic Disease: A Systematic Literature Review.
Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients. A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events. Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated. Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients.


Absence of Association of Metabolic Syndrome with PPARGC1A, PPARG and UCP1 Gene Polymorphisms in Asian Indians.
The objective of this study was to evaluate the association of PPARG coactivator1 alpha (PPARGC1A), peroxisome proliferator activated receptor gamma (PPARG), and uncoupling protein1 (UCP1) gene polymorphisms with the metabolic syndrome (MS) in an Asian Indian population. Nine common polymorphisms were genotyped via polymerase chain reaction restriction fragment length polymorphism and direct sequencing in 950 normal glucose-tolerant subjects and 550 type 2 diabetic subjects, chosen randomly from the Chennai Urban Rural Epidemiological Study, an ongoing population based study in Southern India. Among the 9 polymorphisms examined, only the Thr394Thr variant of the PPARGC1A gene was significantly associated with diabetes and obesity. The genotype frequency of GA of Thr394Thr variant was 16% (138/887) in the nonMS group and 22% (136/613) in the MS group, and this genotype frequency was significantly higher with MS both in males (p = 0.01) and females (p = 0.05), compared to the without-MS group. Logistic regression analysis revealed that the odds ratio for MS for the susceptible genotype GA of Thr394Thr was 1.411 [95% CI: 1.03-1.84, p = 0.012]. In the multiple logistic regression analysis, however, there was no association of this polymorphism as an independent factor with MS. Hence, the study shows that the polymorphisms in the PPARGC1A, PPARG and UCP1 genes are not associated with MS in Asian Indians.


Impact of ceftiofur injection on gut microbiota and Escherichia coli resistance in pigs.
Resistance to extended-spectrum cephalosporins (ESCs) is an important health concern. Here, we studied the impact of the administration of a long-acting form of ceftiofur on the pig gut microbiota and ESC resistance in Escherichia coli. Pigs were orally inoculated with an ESC-resistant E. coli M63 strain harboring a conjugative plasmid carrying a gene conferring resistance, bla CTX-M-1. On the same day, they were given or not a unique injection of ceftiofur. Fecal microbiota were studied using quantitative PCR analysis of the main bacterial groups and quantification of short-chain fatty acids. E. coli and ESC-resistant E. coli were determined by culture methods, and the ESC-resistant E. coli isolates were characterized. The copies of the bla CTX-M-1 gene were quantified. After ceftiofur injection, the main change in gut microbiota was the significant but transitory decrease in the E. coli population. Acetate and butyrate levels were significantly lower in the treated group. In all inoculated groups, E. coli M63 persisted in most pigs, and the bla CTX-M-1 gene was transferred to other E. coli. Culture and PCR results showed that the ceftiofur-treated group shed significantly more resistant strains 1 and 3 days after ESC injection. Thereafter, on most dates, there were no differences between the groups, but notably, one pig in the nontreated group regularly excreted very high numbers of ESC-resistant E. coli, probably leading to a higher contamination level in its pen. In conclusion, the use of ESCs, and also the presence of high-shedding animals, are important features in the spread of ESC resistance.


Coptis chinensis inhibits hepatocellular carcinoma cell growth through nonsteroidal anti-inflammatory drug-activated gene activation.
Conventional chemotherapy of liver cancer fails to provide satisfactory remission and may cause serious side effects, thus it is crucial to derive alternative treatments that effectively inhibit cancer cell growth with known mechanisms of action. In the present study, we investigated the anti-carcinogenic effects of Coptis chinensis and its major constituent, berberine, in HepG2 hepatocellular carcinoma (HCC) cells and attempted to elucidate the underlying mechanism, including involvement of the nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1). Inhibition of cell proliferation, induction of apoptosis and cell cycle arrest at the G2/M phase were observed in HepG2 cells treated with Coptis chinensis or berberine. The pro-apoptotic effects were associated with corresponding down-regulation of Bcl-2, activation of procaspase-3 and -9 as well as cleavage of poly (ADP-ribose) polymerase. We further demonstrated the involvement of NAG-1 in the pro-apoptotic events following prior activation of its upstream transcriptional factor early growth response gene (Egr-1). This was confirmed by increased NAG-1 promoter activity preceded by the elevation of Egr-1/ DNA binding activity. Our results suggest that both Coptis chinensis and berberine are potential anti-carcinogenic agents in treating HCC by inducing cell cycle arrest and promotion of apoptosis, while NAG-1 is a molecular target during the drug-induced pro-apoptotic action in HepG2 cells.


Effect of one-HLA-haplotype-matched and HLA-mismatched blood transfusions on recipient T lymphocyte allorepertoires.
Pretransplant blood transfusion has a well-known beneficial effect on posttransplant graft survival. Recently, it has been proposed that the clinical benefit of transfusion is due to HLA-DR antigen sharing between the blood donor(s) and the recipient. Immunological studies have suggested that this might result from a functional deletion of donor-reactive cytotoxic T lymphocytes. We investigated frequencies of alloreactive lymphocyte precursors with cytotoxic or interleukin-2-producing helper function by limiting dilution analysis in 10 renal dialysis patients before and after transfusion with fresh, allogeneic whole blood. Five patients received blood transfusions from donors matched for one HLA haplotype (or one HLA-B-DR antigen) and the other five patients received blood from fully HLA-mismatched donors. Contrary to some previous reports, frequency analysis of cytotoxic T lymphocyte precursors revealed no significant differences between the two treatment groups in terms of development of blood donor-specific hyporesponsiveness after transfusion. Split-well analysis of cytotoxic T lymphocyte precursors reactive with single-mismatched HLA antigens demonstrated that the effects of transfusion on alloreactive specificity are complex and may vary depending on the particular antigens mismatched between the recipient and blood donor. Analysis of donor-specific helper T lymphocyte precursor frequencies revealed a significant decrease of interleukin-2-producing cells 3 months after transfusion in the total patient population. This effect was most prominent in the recipients of HLA-mismatched blood, but it also exhibited some degree of nonspecificity, as frequencies of third-party reactive helper T lymphocyte precursors were also significantly reduced. Our overall results suggest that the degree of HLA matching between blood donor and recipient does not greatly influence the effect of blood transfusion on the T lymphocyte allorepertoire. The apparent induced down-regulation of helper T lymphocyte activity may play a role in the reported immunosuppressive effects of allogeneic blood transfusion.


Masking of the CBF1/RBPJ kappa transcriptional repression domain by Epstein-Barr virus EBNA2.
Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) is a transcriptional activator that is essential for EBV-driven B cell immortalization. EBNA2 is targeted to responsive promoters through interaction with a cellular DNA binding protein, C promoter binding factor 1 (CBF1). A transcriptional repression domain has been identified within CBF1. This domain also interacts with EBNA2, and repression is masked by EBNA2 binding. Thus, EBNA2 acts by countering transcriptional repression. Mutation at amino acid 233 of CBF1 abolishes repression and correlates with a loss-of-function mutation in the Drosophila homolog Su(H).


GASTRIC CANCER WITH POSITIVE EXPRESSION OF ESTROGEN RECEPTOR ALPHA: A CASE SERIES FROM A SINGLE WESTERN CENTER.
Despite advances in therapies, the prognosis of patients with advanced gastric cancer (GC) remains poor. Several studies have demonstrated the expression of estrogen receptor alpha (ERa); however, its significance in GC remains controversial. The present study aims to report a case series of GC with ERa-positive expression and describe their clinicopathological characteristics and prognosis. We retrospectively evaluated patients with GC who underwent gastrectomy with curative intent between 2009 and 2019. ERa expression was assessed by immunohistochemistry through tissue microarray construction. Patients with ERa-negative gastric adenocarcinoma served as a comparison group. During the selected period, 6 (1.8%) ERa-positive GC were identified among the 345 GC patients analyzed. All ERa-positive patients were men, aged 34-78 years, and had Lauren diffuse GC and pN+ status. Compared with ERa-negative patients, ERa-positive patients had larger tumor size (p=0.031), total gastrectomy (p=0.012), diffuse/mixed Lauren type (p=0.012), presence of perineural invasion (p=0.030), and lymph node metastasis (p=0.215). The final stage was IIA in one case, IIIA in three cases, and IIIB in two cases. Among the six ERa-positive patients, three had disease recurrence (peritoneal) and died. There was no significant difference in survival between ERa-positive and ERa-negative groups. ERa expression is less common in GC, is associated with diffuse histology and presence of lymph node metastasis, and may be a marker related to tumor progression and worse prognosis. Also, a high rate of peritoneal recurrence was observed in ERa-positive patients.


Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer.
Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.


Internal conversion and intersystem crossing pathways in UV excited, isolated uracils and their implications in prebiotic chemistry.
The photodynamic properties of molecules determine their ability to survive in harsh radiation environments. As such, the photostability of heterocyclic aromatic compounds to electromagnetic radiation is expected to have been one of the selection pressures influencing the prebiotic chemistry on early Earth. In the present study, the gas-phase photodynamics of uracil, 5-methyluracil (thymine) and 2-thiouracil-three heterocyclic compounds thought to be present during this era-are assessed in the context of their recently proposed intersystem crossing pathways that compete with internal conversion to the ground state. Specifically, time-resolved photoelectron spectroscopy measurements evidence femtosecond to picosecond timescales for relaxation of the singlet (1)ππ* and (1)nπ* states as well as for intersystem crossing to the triplet manifold. Trapping in the excited triplet state and intersystem crossing back to the ground state are investigated as potential factors contributing to the susceptibility of these molecules to ultraviolet photodamage.


Human kallikrein-related peptidase 12: antibody generation and immunohistochemical localization in prostatic tissues.
Human tissue kallikrein-related peptidases (genes, KLKs; proteins, KLKs) are a subgroup of serine proteases present in a variety of tissues and biological fluids. A number of human tissue KLKs are established or candidate serologic biomarkers for prostate cancer. Human kallikrein-related peptidase 12 (KLK12, KLK12), recently identified in our laboratory, is a novel member of the KLK gene family. Here, we report generation of antibodies against the full-length recombinant KLK12 (classical form) and the immunohistological localization of this KLK in normal and malignant prostate tissues. The mature form of KLK12 cDNA was amplified using PCR and cloned into a plasmid vector for protein production in E. coli. Following identification by mass spectroscopy, recombinant KLK12 was purified and used as immunogen in rabbits. Anti- KLK12 antibody was used for immunostaining of paraffin-embedded sections of human prostate tissue. Immunoexpression of KLK12 in benign and malignant prostate tissue was evaluated using a prostate cancer tissue array. Anti-KLK12 antibody showed a predominantly apical and membranous staining of the luminal cells of the normal prostate in contrast with the predominantly diffuse cytoplasmic staining observed in both prostatic intra-epithelial neoplasia and adenocarcinomas. This was occasionally associated with an intense granular supranuclear staining. More than 95% of the prostate cancers on the tissue microarray were KLK12 positive. Higher levels of KLK12 in malignant prostatic glands, and the shift in subcellular localization of KLK12 in prostate cancer observed in this study point to the potential role of this kallikrein during prostate carcinogenesis.


Differentiation-dependent alterations in histone methylation and chromatin architecture at the inducible chicken lysozyme gene.
It is now well established that locus-wide chromatin remodeling and dynamic alterations of histone modifications are required for the developmentally regulated activation of tissue-specific genes. However, little is known about the dynamics of these events during cell differentiation and how chromatin of an entire gene locus responds to signal transduction processes. To address this issue we investigated chromatin accessibility, linker histone distribution, and the histone methylation status at the macrophage-specific chicken lysozyme locus and the ubiquitously expressed gas41 locus in multipotent precursor cell lines and BM2 monoblast cells. The latter can be induced to go through macrophage maturation by treatment with phorbol-12-myristate acetate and can be further stimulated with bacterial lipopolysaccharide. We show that expression of the lysozyme gene in undifferentiated monoblasts is low and that a high level of gene expression requires both cell differentiation and lipopolysaccharide stimulation. However, depletion of the linker histone H1 is observed already in lysozyme non-expressing multipotent precursor cells. In undifferentiated monoblasts, the lysozyme regulatory regions are marked by the presence of monomethylated histone H3 lysine 4, which becomes increasingly converted into trimethylated H3 lysine K4 during cell differentiation. We also present evidence for extensive, differentiation-dependent alterations in nuclease accessibility at the lysozyme promoter without alterations of nucleosome and transcription factor occupancy.


Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.
The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.


Herpes simplex virus immediate early infected-cell polypeptide 4 binds to DNA and promotes transcription.
In herpes simplex virus (HSV)-infected cells, there is a sequential expression of viral genes. In vivo experiments have implicated the Mr 175,000 immediate early protein ICP4 (infected-cell polypeptide 4) in the regulation of viral RNA synthesis, but the mechanism whereby ICP4 regulates transcription of viral genes is at present unknown. In this report we describe experiments with an in vitro transcription system and a purified preparation of ICP4 (estimated 5% of total protein). Using DNA from the HSV glycoprotein D gene (gD) as the template, we have observed that specific binding occurs between ICP4 and DNA sequences adjacent to the gD gene promoter and ICP4 stimulates initiation of transcription from the gD gene. The degree of stimulation depends on the amount of ICP4 present in the incubation. The kinetics of RNA synthesis demonstrate that the protein acts at the initiation step of transcription. These results identify ICP4 as a viral transcription factor whose presence on DNA facilitates the formation of transcription complexes.


NifH-Harboring Bacterial Community Composition across an Alaskan Permafrost Thaw Gradient.
Since nitrogen (N) is often limiting in permafrost soils, we investigated the N2-fixing genetic potential and the inferred taxa harboring those genes by sequencing nifH gene fragments in samples taken along a permafrost thaw gradient in an Alaskan boreal soil. Samples from minimally, moderately and extensively thawed sites were taken to a depth of 79 cm to encompass zones above and below the depth of the water table. NifH reads were translated with frameshift correction and 112,476 sequences were clustered at 5% amino acid dissimilarity resulting in 1,631 OTUs. Sample depth in relation to water table depth was correlated to differences in the NifH sequence classes with those most closely related to group I nifH-harboring Alpha- and Beta-Proteobacteria in higher abundance above water table depth while those related to group III nifH-harboring Delta Proteobacteria more abundant below. The most dominant below water table depth NifH sequences, comprising 1/3 of the total, were distantly related to Verrucomicrobia-Opitutaceae. Overall, these results suggest that permafrost thaw alters the class-level composition of N2-fixing communities in the thawed soil layers and that this distinction corresponds to the depth of the water table. These nifH data were also compared to nifH sequences obtained from a study at an Alaskan taiga site, and to those of other geographically distant, non-permafrost sites. The two Alaska sites were differentiated largely by changes in relative abundances of the same OTUs, whereas the non-Alaska sites were differentiated by the lack of many Alaskan OTUs, and the presence of unique halophilic, sulfate- and iron-reducing taxa in the Alaska sites.


Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice.
Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1-/- mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1-/- mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes.


Activation of inflammasomes by tumor cell death mediated by gold nanoshells.
Gold nanoshell-enabled photothermal therapy (NEPTT) utilizes the efficient thermal conversion of near infrared (NIR) light for the ablation of cancer cells. Cancer therapies that combine cell killing with the induction of a strong immune response against the dying tumor cells have been shown to increase therapeutic efficacy in the clearance and regression of cancers. In this study, we assessed the ability of dying cells generated by in vitro NEPTT to activate inflammasome complexes. We quantified levels of major danger-associated molecular patterns (DAMPs), including adenosine triphosphate (ATP), adenosine diphosphate (ADP), and uric acid, released from tumor cells treated by NEPTT. The amount of DAMPs released was dependent on the dose of nanoshells internalized by cells. However, under all the employed conditions, the levels of generated DAMPs were insufficient to activate inflammasome complexes and to induce the production of pro-inflammatory cytokines (i.e. IL-1β). The results from this study provide insights into the development of nanoplasmonics for combining both photothermal therapy and immunotherapy to eradicate cancers.


Carbon:Nitrogen:Phosphorus Stoichiometry in Fungi: A Meta-Analysis.
Surveys of carbon:nitrogen:phosphorus ratios are available now for major groups of biota and for various aquatic and terrestrial biomes. However, while fungi play an important role in nutrient cycling in ecosystems, relatively little is known about their C:N:P stoichiometry and how it varies across taxonomic groups, functional guilds, and environmental conditions. Here we present the first systematic compilation of C:N:P data for fungi including four phyla (Ascomycota, Basidiomycota, Glomeromycota, and Zygomycota). The C, N, and P contents (percent of dry mass) of fungal biomass varied from 38 to 57%, 0.23 to 15%, and 0.040 to 5.5%, respectively. Median C:N:P stoichiometry for fungi was 250:16:1 (molar), remarkably similar to the canonical Redfield values. However, we found extremely broad variation in fungal C:N:P ratios around the central tendencies in C:N:P ratios. Lower C:P and N:P ratios were found in Ascomycota fungi than in Basidiomycota fungi while significantly lower C:N ratios (p < 0.05) and higher N:P ratios (p < 0.01) were found in ectomycorrhizal fungi than in saprotrophs. Furthermore, several fungal stoichiometric ratios were strongly correlated with geographic and abiotic environmental factors, especially latitude, precipitation, and temperature. The results have implications for understanding the roles that fungi play in function in symbioses and in soil nutrient cycling. Further work is needed on the effects of actual in situ growth conditions of fungal growth on stoichiometry in the mycelium.


Temporal Patterns of In-Hospital Falls of Elderly Patients.
A potentially important factor yet to receive adequate study is the time when hospital falls occur. A prior study conducted before the system-wide introduction of preventive measures revealed a biphasic 24-hour pattern of hospital falls with major peak in the morning. The purpose was to identify the temporal patterning of falls among elderly patients in hospitals with comprehensive fall prevention programs in place. A 4-year observational study was conducted by the local health authority in the five nonteaching public hospitals located in the province of Ferrara, Italy. Fall records involving patients of ages ≥65 years hospitalized in the general medical departments were used. Single- and multiple-component cosinor (time series) analyses were used to explore 24-hour, weekly, and annual patterns of falls. A total of 763 falls were experienced by 709 different elderly hospitalized patients. Falls typically took place in the patient's hospital room (72%) and bathroom (23%). Major causes were patient instability (32%) and accident (13%), and most occurred when not wearing footwear (45%) or wearing inappropriate sling-back open-toe shoes (39%). Falls happened while standing (39%), while seated (21%), and while getting into, out of, or laying in bed (32%)-either with the bed rails raised or lowered. Fall outcome usually involved no injury (58%) or slight injury (35%), but some (7%) were disabling. Fall occurrence was higher during the night (46%) compared to either the morning (30%) or afternoon (24%) shift. Patterns across 24 hours were characterized by a single major and one or more minor peaks that seemed to be associated with a variety of scheduled patient, hospital, and nursing activities. Multiple-component cosinor analysis identified significant (p < .05) prominent day-night patterns according to fall location, patient position, cause, injury severity, and type of footwear. Falls were more frequent, but not significantly so, on Fridays, Sundays, and Mondays compared with Tuesdays, and were more frequent in winter and spring (p = .003). Documentation by cause and circumstance of these moderate- to high-amplitude temporal patterns in hospital falls of elderly patients advances the knowledge of fall epidemiology by identifying the times of day, week, and year and nursing shifts of elevated risk that is of critical importance to improving hospital patient safety programs.


An electronic health record driven algorithm to identify incident antidepressant medication users.
We validated an algorithm designed to identify new or prevalent users of antidepressant medications via population-based drug prescription records. We obtained population-based drug prescription records for the entire Olmsted County, Minnesota, population from 2011 to 2012 (N=149,629) using the existing electronic medical records linkage infrastructure of the Rochester Epidemiology Project (REP). We selected electronically a random sample of 200 new antidepressant users stratified by age and sex. The algorithm required the exclusion of antidepressant use in the 6 months preceding the date of the first qualifying antidepressant prescription (index date). Medical records were manually reviewed and adjudicated to calculate the positive predictive value (PPV). We also manually reviewed the records of a random sample of 200 antihistamine users who did not meet the case definition of new antidepressant user to estimate the negative predictive value (NPV). 161 of the 198 subjects electronically identified as new antidepressant users were confirmed by manual record review (PPV 81.3%). Restricting the definition of new users to subjects who were prescribed typical starting doses of each agent for treating major depression in non-geriatric adults resulted in an increase in the PPV (90.9%). Extending the time windows with no antidepressant use preceding the index date resulted in only modest increases in PPV. The manual abstraction of medical records of 200 antihistamine users yielded an NPV of 98.5%. Our study confirms that REP prescription records can be used to identify prevalent and incident users of antidepressants in the Olmsted County, Minnesota, population.


The correlation structure of epidemic models.
For a general Markov SIS epidemic model, the fates of individuals at different times are shown to be positively correlated. When the population is subjected to two diseases, a certain condition, here called positive interference, results in positive correlations between individuals with respect to either disease, while another condition, called competition, gives negative correlation between diseases and positive correlation within each disease. The results generalize to two classes of disease, with positive interference within each class and competition between classes. A general (non-Markov) SIR model (which includes the general epidemic and generalized Reed-Frost models) exhibits positive correlation. The results for SIS models rely heavily on monotonicity properties and in some cases on a careful choice of partial order. For the SIR models a graphical construction of the models is used.


Brachial plexus injury: An unusual devastating complication during hospitalization in intensive care unit.
Brachial plexus injury due to prolonged immobilization of the arms in a hyper-abducted position during intensive care unit (ICU) follow-up is uncommon. In this article, we present an unusual case of a 20-year-old male drug addict who sustained unattended brachial plexus injury in left upper extremity after being bound over the axilla tightly during ICU follow-up. He had progressive numbness and near-total immobility of the left upper extremity. Atrophy, loss of muscle strength, and absence of deep tendon reflexes were observed in left upper extremity. Electrodiagnostic studies showed lower trunk partial axonal involvement. After aggressive physical therapy, patient's muscle function improved, showing full strength in all muscles innervated by median, ulnar, musculocutaneous, axillary and radial nerves. During follow-up of unconscious patients in ICU, clinicians and other staff should be more careful about restraining such patients by considering complications such as nerve injuries.


Conjugated fatty acid-rich oil from Gynostrmma pentaphyllum seed can ameliorate lipid and glucose metabolism in type 2 diabetes mellitus mice.
Gynostrmma pentaphyllum seed oil (GPSO), extracted from G. pentaphyllum seeds, is rich in conjugated linolenic acid, which is a special fatty acid consisting of cis-9, trans-11, trans-13 isomers. Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia resulting from insulin resistance, and is usually accompanied by hypertension, hyperlipidemia, atherosclerosis (i.e., the metabolic syndrome, or syndrome X), and polycystic ovarian disease. This study aimed to investigate the effect of GPSO on T2DM hepatic lipid metabolism and the underlying mechanism involving level of protein expression. In the experiment, the model of T2DM was established. Kunming male mice were fed with a high-fat diet and injected with streptozocin, in which the exploration of detailed mechanism in the therapy of T2DM was targeted. The results showed that the ability of oral glucose tolerance was improved in the GPSO group. Biochemical indices also revealed that GPSO had a positive effect on hypoglycemic activity, suggesting that GPSO could promote the expression of glucose transporter 4 in liver and skeletal muscle.


A muscle cell variant defective in glycosaminoglycan biosynthesis forms nerve-induced but not spontaneous clusters of the acetylcholine receptor and the 43 kDa protein.
Myotubes of the C2 mouse muscle cell line form clusters of ACh receptors (AChRs) at apparently random sites along their length when cultured alone, and near sites of nerve-muscle contact when cocultured with neurons. We find in aneural cultures that myotubes of a C2 variant, S27, which is defective in glycosaminoglycan synthesis, express the AChR on their surface, but do not form clusters. S27 cells in aneural cultures also express the 43 kDa protein but do not cluster it. The altered distribution of laminin and collagen IV on the surface of S27 myotubes suggests that the basal lamina is abnormal. Neither the addition of exogenous proteoglycans or conditioned medium from wild-type C2 cells, nor the growth of S27 cells on substrates rich in basal lamina elements caused clusters to appear on S27 myotubes in aneural cultures. When cultured with primary neurons, however, S27 myotubes formed large clusters of the AChR near sites of neurite contact. The clusters were coincident with patches of the 43 kDa protein. Prelabeling experiments indicate that at least some AChRs in the clusters arise through aggregation. Although Torpedo agrin induces AChR clusters on C2 myotubes, it does not do so on S27 cells. Our experiments suggest that the spontaneous formation of clusters of AChRs and the 43 kDa protein in aneural cultures of myotubes depends upon the normal synthesis of muscle proteoglycans, and that nerve-induced clustering does not. Thus, there appear to be multiple mechanisms for the formation of AChR clusters.


Sire attractiveness influences offspring performance in guppies.
According to the good-genes hypothesis, females choose among males to ensure the inheritance of superior paternal genes by their offspring. Despite increasing support for this prediction, in some cases differential (non-genetic) maternal effects may obscure or amplify the relationship between paternal attractiveness and offspring quality. Artificial insemination controls such effects because it uncouples mate choice from copulation, therefore denying females the opportunity of assessing male attractiveness. We adopted this technique in the live-bearing fish Poecilia reticulata and examined whether paternal coloration was associated with the behavioural performance of newborn offspring. Sexually receptive virgin females were inseminated with sperm taken individually from donor males that exhibited high variation in the area of orange pigmentation, a trait known to influence female choice in the study population. Our analysis of offspring performance focused on the anti-predator behaviour of newborn fish, including schooling by sibling pairs, the response (swimming speed) of these fishes to a simulated avian predator, and the time taken for a naive investigator to capture the offspring. Although we found no significant effect of sire coloration on either schooling or swimming speed, our analysis revealed a significant positive association between sire coloration and the ability of newborn offspring to evade capture. This finding supports the view that at least one aspect of anti-predator behaviour in newborn offspring is influenced by sire genotype, which in turn is revealed by the expression of secondary sexual traits.


Family-based associations in measures of psychological distress and quality of life in a cardiac screening clinic for inheritable cardiac diseases: a cross-sectional study.
Family-based cardiac screening programmes for persons at risk for genetic cardiac diseases are now recommended. However, the psychological wellbeing and health related quality of life (QoL) of such screened patients is poorly understood, especially in younger patients. We sought to examine wellbeing and QoL in a representative group of adults aged 16 and over in a dedicated family cardiac screening clinic. Prospective survey of consecutive consenting patients attending a cardiac screening clinic, over a 12 month period. Data were collected using two health measurement tools: the Short Form 12 (version 2) and the Hospital Anxiety and Depression Scale (HADS), along with baseline demographic and screening visit-related data. The HADS and SF-12v.2 outcomes were compared by age group. Associations with a higher HADS score were examined using logistic regression, with multi-level modelling used to account for the family-based structure of the data. There was a study response rate of 86.6%, with n=334 patients providing valid HADS data (valid response rate 79.5%), and data on n=316 retained for analysis. One-fifth of patients were aged under 25 (n=61). Younger patients were less likely than older to describe significant depression on their HADS scale (p<0.0001), although there were overall no difference between the prevalence of a significant HADS score between the younger and older age groups (18.0% vs 20.0%, p=0.73). Significant positive associates of a higher HADS score were having lower educational attainment, being single or separated, and being closely related to the family proband. Between-family variance in anxiety and depression scores was greater than within-family variance. High levels of anxiety were seen amongst patients attending a family-based cardiac screening clinic.Younger patients also had high rates of clinically significant anxiety. Higher levels of anxiety and depression tends to run in families, and this has implications for family screening and intervention programmes.


Chlorpropamide alcohol flushing: a normal response?
The relationship between chlorpropamide alcohol flushing and non-insulin dependent diabetes remains uncertain. It is known, however, that the frequency of facial flushing with alcohol and the temperature response depend upon both the plasma level of chlorpropamide and the starting facial temperature [10]. We tested 23 young adult non-diabetic subjects with 8 g of ethanol after a dose of chlorpropamide 250 mg twice daily for 2 days or a placebo, in a double blind, cross-over manner. Previously, nine other subjects had participated in a pilot study to assess the safety of the chlorpropamide dose and to ensure that adequate plasma chlorpropamide levels were achieved. No subject was negative for chlorpropamide alcohol flushing, as defined by the following criteria: facial temperature rise of 35% or more of maximum possible rise, observer assessment or subject assessment. In 26 of the total 32 subjects, all three criteria were fulfilled. Thus, among young, healthy non-diabetic adults chlorpropamide alcohol flushing would appear to be a normal phenomenon.


Oxidative damage in synovial tissue is associated with in vivo hypoxic status in the arthritic joint.
To assess levels of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanine; 8-oxo-dG) and lipid peroxidation (4-hydroxy-2-nonenal; 4-HNE) in serum, synovial fluid and tissue of patients with inflammatory arthritis in relation to in vivo hypoxia levels, disease activity and angiogenic markers. Oxygen levels in synovial tissue were assessed using an oxygen/temperature probe. Nuclear and cytoplasmic 8-oxo-dG and 4-HNE levels were assessed in synovial tissue from 23 patients by immunohistochemistry. 8-Oxo-dG and 4-HNE levels in serum and synovial fluid were determined using 8-oxo-dG and hexanoyl-Lys (HEL) adduct ELISAs, respectively. Serum vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) levels were also measured by ELISA. The median oxygen tension in synovial tissue was profoundly hypoxic at 19.35 mm Hg (2.5%). Nuclear 8-oxo-dG levels were significantly higher than nuclear 4-HNE levels in the lining and sublining layers (all p<0.001). In contrast, cytoplasmic 4-HNE levels were higher than cytoplasmic 8-oxo-dG levels in both cell layers (all p<0.001). Reduced in vivo oxygen tension correlated with high lipid peroxidation in synovial fluid (p=0.027; r=0.54) and tissue (p=0.004; r=0.58). Serum VEGF levels were positively correlated with cytoplasmic 4-HNE expression (p=0.05; r=0.43) and intensity (p=0.006; r=0.59) in the lining layer. Serum Ang2 levels were positively correlated with nuclear 4-HNE expression and intensity in both cell layers (all p < or = 0.05). DAS28-C-reactive protein was correlated with nuclear 4-HNE expression in the sublining layer (p=0.02; r=0.48) and DAS28-erythrocyte sedimentation rate was correlated with nuclear 4-HNE expression in both cell layers (p < or = 0.03). Lipid peroxidation is associated with low oxygen tension in vivo, disease activity and angiogenic marker expression in inflammatory arthritis.


Non-suicidal self-injury, attempted suicide, and suicidal intent among psychiatric inpatients.
Although attempted suicide and non-suicidal self-injury (NSSI) differ in several important ways, a significant number of individuals report histories of both behaviors. The current study further examined the relations between NSSI and attempted suicide among psychiatric inpatients. Self-report questionnaires were administered to 117 psychiatric inpatients at a general hospital (M=39.45 years old, S.D.=12.84 years, range=17-73 years). We found that presence and number of NSSI episodes were significantly related to presence and number of suicide attempts. Supporting the importance of NSSI assessment, patients' history of NSSI (presence and frequency) was more strongly associated with history of suicide attempts than were patients' depressive symptoms, hopelessness, and symptoms of borderline personality disorder, and as strongly associated with suicide attempt history as current levels of suicidal ideation. Finally, among patients with a history of suicide attempts, those with an NSSI history reported significantly greater lethal intent for their most severe attempt, and patients' number of prior NSSI episodes was positively correlated with the level of lethal intent associated with their most severe suicide attempt.


Technological innovations in the recreational fishing sector: implications for fisheries management and policy.
Technology that is developed for or adopted by the recreational fisheries sector (e.g., anglers and the recreational fishing industry) has led to rapid and dramatic changes in how recreational anglers interact with fisheries resources. From improvements in finding and catching fish to emulating their natural prey and accessing previously inaccessible waters, to anglers sharing their exploits with others, technology is completely changing all aspects of recreational fishing. These innovations would superficially be viewed as positive from the perspective of the angler (aside from the financial cost of purchasing some technologies), yet for the fisheries manager and policy maker, technology may create unintended challenges that lead to reactionary or even ill-defined approaches as they attempt to keep up with these changes. The goal of this paper is to consider how innovations in recreational fishing are changing the way that anglers interact with fish, and thus how recreational fisheries management is undertaken. We use a combination of structured reviews and expert analyses combined with descriptive case studies to highlight the many ways that technology is influencing recreational fishing practice, and, relatedly, what it means for changing how fisheries and/or these technologies need to be managed-from changes in fish capture, to fish handling, to how anglers share information with each other and with managers. Given that technology is continually evolving, we hope that the examples provided here lead to more and better monitoring of technological innovations and engagement by the management and policy authorities with the recreational fishing sector. Doing so will ensure that management actions related to emerging and evolving recreational fishing technology are more proactive than reactive.


The involvement of primary motor cortex in mental rotation revealed by transcranial magnetic stimulation.
We used single-pulse transcranial magnetic stimulation of the left primary hand motor cortex and motor evoked potentials of the contralateral right abductor pollicis brevis to probe motor cortex excitability during a standard mental rotation task. Based on previous findings we tested the following hypotheses. (i) Is the hand motor cortex activated more strongly during mental rotation than during reading aloud or reading silently? The latter tasks have been shown to increase motor cortex excitability substantially in recent studies. (ii) Is the recruitment of the motor cortex for mental rotation specific for the judgement of rotated but not for nonrotated Shepard & Metzler figures? Surprisingly, motor cortex activation was higher during mental rotation than during verbal tasks. Moreover, we found strong motor cortex excitability during the mental rotation task but significantly weaker excitability during judgements of nonrotated figures. Hence, this study shows that the primary hand motor area is generally involved in mental rotation processes. These findings are discussed in the context of current theories of mental rotation, and a likely mechanism for the global excitability increase in the primary motor cortex during mental rotation is proposed.


Prevalence of hydrogen peroxide-producing Lactobacillus species in normal women and women with bacterial vaginosis.
A predominance of Lactobacillus species in the vaginal flora is considered normal. In women with bacterial vaginosis, the prevalence and concentrations of intravaginal Gardnerella vaginalis and anaerobes are increased, whereas the prevalence of intravaginal Lactobacillus species is decreased. Because some lactobacilli are known to produce hydrogen peroxide (H2O2), which can be toxic to organisms that produce little or no H2O2-scavenging enzymes (e.g., catalase), we postulated that an absence of H2O2-producing Lactobacillus species could allow an overgrowth of catalase-negative organisms, such as those found among women with bacterial vaginosis. In this study, H2O2-producing facultative Lactobacillus species were found in the vaginas of 27 (96%) of 28 normal women and 4 (6%) of 67 women with bacterial vaginosis (P less than 0.001). Anaerobic Lactobacillus species (which do not produce hydrogen peroxide) were isolated from 24 (36%) of 67 women with bacterial vaginosis and 1 (4%) of 28 normal women (P less than 0.001). The production of H2O2 by Lactobacillus species may represent a nonspecific antimicrobial defense mechanism of the normal vaginal ecosystem.


Synthesis, structure, and magnetic properties of the fullerene-based ferromagnets Eu3C70 and Eu9C70.
Intercalation of C(70) with europium affords two kinds of magnetic compounds, a canted antiferromagnet Eu(x)C(70) (x approximately 3) and a ferromagnet Eu(x)C(70) (x approximately 9) with transition temperatures (T(C)) of 5 and 38 K, respectively. The Curie constants in the paramagnetic phase and the saturation moment in the ferromagnetic phase are both understood by the full moment of Eu(2+) for both systems. The structure of Eu(3)(-)(delta)C(70) (delta approximately 0.27) is pseudo-monoclinic, derived by a simple deformation of the parent face-centered cubic (fcc) structure. Eu(9)(-)(delta)C(70) (delta approximately 0.2) forms an fcc structure, in which cuboctahedral clustering of Eu(2+) ions is observed in the enhanced size octahedral holes. The observed T(C) of the Eu(9)(-)(delta)C(70) ferromagnet is comparable to or larger than those of simple binary Eu-based ferromagnets, such as Eu chalcogenides or carbides, despite the low atomic ratio of Eu in the chemical formulas. This can be understood by the short Eu(2+)-Eu(2+) distances and high coordination numbers permitted by the multiple occupation by Eu(2+) ions of the expanded octahedral interstitial sites in higher fullerene-based solids.


FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors.
Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies.


Effects of NEFAs during IVM on pig embryos from granulosa cell-cocultured oocytes.
Circulating levels of nonesterified fatty acids (NEFAs) are elevated in some females, which can impair oocyte maturation and embryo development, and may alter the phenotype of the progeny. However, the effects of NEFAs on human embryo development are not clear due to ethical limitations. Thus, we used pig as the model to investigate the impacts of NEFAs on oocyte and embryo due to their similar reproductive and metabolic physiologies to humans. In this study, porcine cumulus-oocyte complexes were in vitro maturated under a pathologically high concentration of NEFAs (468 μM palmitic acid, 194 μM stearic acid, and 534 μM oleic acid) with the presence of granulosa cell monolayer, in contrast to control without NEFAs. The mature oocytes were fertilized to produce embryos for further analysis of the transcriptome and DNA methylation patterns. The elevated level of NEFAs decreased the blastocyst rate and delayed the blastocyst development. Ingenuity pathway analysis showed that the most affected gene pathways were related mainly to cell activities, metabolism, and inflammation. These findings indicated that oocytes exposed to the exogenous high level of NEFAs during in vitro maturation resulted in altered gene expression and DNA methylation of early embryos, which have detrimental impacts on blastocyst quality.


Sustained Effects of Acupuncture Stimulation Investigated with Centrality Mapping Analysis.
Acupuncture can have instant and sustained effects, however, its mechanisms of action are still unclear. Here, we investigated the sustained effect of acupuncture by evaluating centrality changes in resting-state functional magnetic resonance imaging after manually stimulating the acupuncture point ST36 at the lower leg or two control point locations (CP1 same dermatome, CP2 different dermatome). Data from a previously published experiment evaluating instant BOLD effects and S2-seed-based resting state connectivity was re-analyzed using eigenvector centrality mapping and degree centrality mapping. These data-driven methods might add new insights into sustained acupuncture effects on both global and local inter-region connectivity (centrality) by evaluating the summary of connections of every voxel. We found higher centrality in parahippocampal gyrus and middle temporal gyrus after ST36 stimulation in comparison to the two control points. These regions are positively correlated to major hubs of the default mode network, which might be the primary network affected by chronic pain. The stronger integration of both regions within the whole-brain connectome after stimulation of ST36 might be a potential contributor to pain modulation by acupuncture. These findings highlight centrality mapping as a valuable analysis for future imaging studies investigating clinically relevant outcomes associated with physiological response to acupuncture stimulation. NCT01079689, ClinicalTrials.gov.


Serum soluble interleukin-2 receptor level is a predictive marker for EBUS-TBNA-based diagnosis of sarcoidosis.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a widely available diagnostic tool for suspected stage I/II sarcoidosis. Combination of EBUS-TBNA and transbronchial lung biopsy (TBLB) has been proposed as diagnostic procedure in clinical settings. The aim of this study was to assess the diagnostic yield of combined EBUS-TBNA and TBLB and identify the markers correlated with a high diagnostic rate. We retrospectively analyzed the data of 37 patients with suspected stage I/II sarcoidosis with enlarged hilar or mediastinal lymph nodes on computed tomography (CT) images. These patients had been scheduled to undergo EBUS-TBNA and TBLB. Serum levels of sarcoidosis markers (angiotensin-converting enzyme [ACE], soluble interleukin-2 receptor [sIL-2R], and lysozyme), CT findings, and examination techniques were evaluated as predictive markers for diagnosis. Of the 37 patients, 32 had undergone both EBUS-TBNA and TBLB, while the remaining 5 patients had only undergone EBUS-TBNA. The diagnosis was confirmed by TBLB in 16 of the 32 patients (50.0%), EBUS-TBNA in 31 of the 37 patients (83.8%), and combined TBLB and EBUS-TBNA in all patients (100.0%). The serum level of sIL-2R, but not that of ACE or lysozyme, was correlated with successful diagnosis by EBUS-TBNA. In patients with stage I/II sarcoidosis, the serum level of sIL-2R is a promising and useful marker for predicting the diagnosis by EBUS-TBNA and reducing the burden of additional TBLB and its possible complications. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 8-16).