Oral erlotinib, but not rapamycin, causes modest acceleration of bladder and hindlimb recovery from spinal cord injury in rats.
Erlotinib and Rapamycin are both in clinical use and experimental inhibition of their respective molecular targets, EGFR and mTORC1, has improved recovery from spinal cord injury. Our aim was to determine if daily Erlotinib or Rapamycin treatment started directly after spinal contusion injury in rats improves locomotion function or recovery of bladder function. Stockholm, Sweden. Rats were subjected to contusion injuries and treated during the acute phase with either Erlotinib or Rapamycin. Recovery of bladder function was monitored by measuring residual urine volume and hindlimb locomotion assessed by open-field observations using the BBB rating scale as well as by automated registration of gait parameters. Body weights were monitored. To determine whether Erlotinib and Rapamycin inhibit the same signaling pathway, a cell culture system and western blots were used. Erlotinib accelerated locomotor recovery and slightly improved bladder recovery; however, we found no long-term improvements of locomotor function. Rapamycin did neither improved locomotor function nor bladder recovery. In vitro studies confirmed that Erlotinib and Rapamycin both inhibit the EGFR-mTORC1 signaling pathway. We conclude that none of these two drug regimes improved long-term functional outcome in our current model of spinal cord injury. Nevertheless, oral treatment with Erlotinib may offer modest temporary advantages, whereas treatment with Rapamycin does not.


Micropollutant dynamics in Vidy Bay--a coupled hydrodynamic-photolysis model to assess the spatial extent of ecotoxicological risk.
The direct discharge of effluent wastewater into Vidy Bay (Lake Geneva) results in the formation of an effluent plume with locally high concentrations of wastewater-derived micropollutants. The micropollutant hotspots above the wastewater outfall present a potential ecotoxicological risk, yet the spatial extent of the plume and the associated ecotoxicological risk zone remain unclear. This work combines the two main processes affecting the spreading of the plume, namely dilution of micropollutants due to mixing and degradation by photolysis, into a coupled hydrodynamic-photolysis model, with which we estimated the spatial extent of the risk zone in Vidy Bay. The concentration of micropollutants around the wastewater outfall was simulated for typical wind scenarios and seasons relevant to Vidy Bay, and the resulting ecotoxicological risk was evaluated. Specifically, we determined the direct and indirect photolysis rate constants for 24 wastewater-derived micropollutants and implemented these in a hydrodynamic particle tracking model, which tracked the movement of water parcels from the wastewater outfall. Simulations showed that owing to thermal stratification, the zone of ecotoxicological risk is largest in summer and extends horizontally over 300 m from the outfall. Photolysis processes contribute to reducing the plume extent mainly under unstratified conditions when the plume surfaces. Moreover, it was shown that only a few compounds, mainly antibiotics, dominate the total ecotoxicological risk.


Relationship between Meloidogyne arenaria and Aflatoxin Contamination in Peanut.
Damaged and developing kernels of peanut (Arachis hypogaea) are susceptible to colonization by fungi in the Aspergillus flavus group which, under certain conditions, produces aflatoxins prior to harvest. Our objective was to determine whether infection of peanut roots and pods by Meloidogyne arenaria increases aflatoxin contamination of the kernels when peanut is subjected to drought stress. The experiment was a completely randomized 2-x-2 factorial with 6 replicates/treatment. The treatment factors were nematodes (plus and minus M. arenaria) and fungus (plus and minus A. flavus inoculum). The experiment was conducted in 2001 and 2002 in microplots under an automatic rain-out shelter. In treatments where A. flavus inoculum was added, aflatoxin concentrations were high (> 1,000 ppb) and not affected by nematode infection; in treatments without added fungal inoculum, aflatoxin concentrations were greater (P </= 0.05) in kernels from nematode-infected plants (1,190 ppb) than in kernels from uninfected plants (79 ppb). There was also an increase in aflatoxin contamination of kernels with increasing pod galling (r(2) = 0.83 in 2001, r(2) = 0.43 in 2002; P </= 0.04). Colonization of kernels by A. flavus increased with increasing pod galling (r(2) = 0.18; P = 0.04) in 2001 but not in 2002. Root-knot nematodes may have a greater role in enhancing aflatoxin contamination of peanut when conditions are not optimal for growth and aflatoxin production by fungi in the A. flavus group.


Nanomanipulation and controlled self-assembly of metal nanoparticles and nanocrystals for plasmonics.
Localized surface plasmon resonances (LSPRs) associated with metallic nanostructures offer unique possibilities for light concentration beyond the diffraction limit, which can lead to strong field confinement and enhancement in deep subwavelength regions. In recent years, many transformative plasmonic applications have emerged, taking advantage of the spectral and spatial tunability of LSPRs enabled by near-field coupling between constituent metallic nanostructures in a variety of plasmonic metastructures (dimers, metamolecules, metasurfaces, metamaterials, etc.). For example, the "hot spot" formed at the interstitial site (gap) between two coupled metallic nanostructures in a plasmonic dimer can be spectrally tuned via the gap size. Capitalizing on these capabilities, there have been significant advances in plasmon enhanced or enabled applications in light-based science and technology, including ultrahigh-sensitivity spectroscopies, light energy harvesting, photocatalysis, biomedical imaging and theranostics, optical sensing, nonlinear optics, ultrahigh-density data storage, as well as plasmonic metamaterials and metasurfaces exhibiting unusual linear and nonlinear optical properties. In this review, we present two complementary approaches for fabricating plasmonic metastructures. We discuss how meta-atoms can be assembled into unique plasmonic metastructures using a variety of nanomanipulation methods based on single- or multiple-probes in an atomic force microscope (AFM) or a scanning electron microscope (SEM), optical tweezers, and focused electron-beam nanomanipulation. We also provide a few examples of nanoparticle metamolecules with designed properties realized in such well-controlled plasmonic metastructures. For the spatial controllability on the mesoscopic and macroscopic scales, we show that controlled self-assembly is the method of choice to realize scalable two-dimensional, and three-dimensional plasmonic metastructures. In the section of applications, we discuss some key examples of plasmonic applications based on individual hot spots or ensembles of hot spots with high uniformity and improved controllability.


Molecular evolution and recombination in gender-associated mitochondrial DNAs of the Manila clam Tapes philippinarum.
Doubly uniparental inheritance (DUI) provides an intriguing system for addressing aspects of molecular evolution and intermolecular recombination of mitochondrial DNA. For this reason, a large sequence analysis has been performed on Tapes philippinarum (Bivalvia, Veneridae), which has mitochondrial DNA heteroplasmy that is consistent with a DUI. The sequences of a 9.2-kb region (containing 29 genes) from 9 individuals and the sequences of a single gene from another 44 individuals are analyzed. Comparisons suggest that the two sex-related mitochondrial genomes do not experience a neutral pattern of divergence and that selection may act with varying strength on different genes. This pattern of evolution may be related to the long, separate history of M and F genomes within their tissue-specific "arenas." Moreover, our data suggest that recombinants, although occurring in soma, may seldom be transmitted to progeny in T. philippinarum.


Adsorption and desorption of methylene blue on porous carbon monoliths and nanocrystalline cellulose.
The dynamic batch adsorption of methylene blue (MB), a widely used and toxic dye, onto nanocrystalline cellulose (NCC) and crushed powder of carbon monolith (CM) was investigated using the pseudo-first- and -second-order kinetics. CM outperformed NCC with a maximum capacity of 127 mg/g compared to 101 mg/g for NCC. The Langmuir isotherm model was applicable for describing the binding data for MB on CM and NCC, indicating the homogeneous surface of these two materials. The Gibbs free energy of -15.22 kJ/mol estimated for CM unravelled the spontaneous nature of this adsorbent for MB, appreciably faster than the use of NCC (-4.47 kJ/mol). Both pH and temperature exhibited only a modest effect on the adsorption of MB onto CM. The desorption of MB from CM using acetonitrile was very effective with more than 94 % of MB desorbed from CM within 10 min to allow the reusability of this porous carbon material. In contrast, acetonitrile was less effective than ethanol in desorbing MB from NCC. The two solvents were incapable of completely desorbing MB on commercial granular coal-derived activated carbon.


Mueller matrix calculations for randomly oriented rotationally symmetric objects with low contrast.
Mueller matrices for micrometer-sized objects (2 </= kalpha </= 15) have been calculated for spherical and randomly oriented nonspherical and inhomogeneous bodies with relative refractive indices <1.3. These matrices were found to be highly different from the Rayleigh-Debye matrix as well as from the matrices observed for particles with higher contrast. Some general conclusions have been drawn for homogeneous spherical and nonspherical particles. Layered spheres and spheres with a small imaginary part of the refractive index show some unusual polarization behavior. It was not possible to deduce general features for layered spheres because of their complexity. We found almost invariant Mueller matrices for particles with small absorption in the investigated Mie region.


The Health Utilities Index (HUI) system for assessing health-related quality of life in clinical studies.
This paper reviews the Health Utilities Index (HUI) systems as means to describe health status and obtain utility scores reflecting health-related quality of life (HRQoL). The HUI Mark 2 (HUI2) and Mark 3 (HUI3) classification and scoring systems are described. The methods used to estimate multiattribute utility functions for HUI2 and HUI3 are reviewed. The use of HUI in clinical studies for a wide variety of conditions in a large number of countries is illustrated. HUI provides a comprehensive description of the health status of subjects in clinical studies. HUI has been shown to be a reliable, responsive and valid measure in a wide variety of clinical studies. Utility scores provide an overall assessment of the HRQoL of patients. Utility scores are also useful in cost-utility analyses and related studies. General population norm data are available. The widespread use of HUI facilitates the interpretation of results and permits comparisons. HUI is a useful tool for assessing health status and HRQoL in clinical studies.


Improvements in health status after Massachusetts health care reform.
Massachusetts enacted health care reform in 2006 to expand insurance coverage and improve access to health care. The objective of our study was to compare trends in health status and the use of ambulatory health services before and after the implementation of health reform in Massachusetts relative to that in other New England states. We used a quasi-experimental design with data from the Behavioral Risk Factor Surveillance System from 2001 to 2011 to compare trends associated with health reform in Massachusetts relative to that in other New England states. We compared self-reported health and the use of preventive services using multivariate logistic regression with difference-in-differences analysis to account for temporal trends. We estimated predicted probabilities and changes in these probabilities to gauge the differential effects between Massachusetts and other New England states. Finally, we conducted subgroup analysis to assess the differential changes by income and race/ethnicity. The sample included 345,211 adults aged eighteen to sixty-four. In comparing the periods before and after health care reform relative to those in other New England states, we found that Massachusetts residents reported greater improvements in general health (1.7%), physical health (1.3%), and mental health (1.5%). Massachusetts residents also reported significant relative increases in rates of Pap screening (2.3%), colonoscopy (5.5%), and cholesterol testing (1.4%). Adults in Massachusetts households that earned up to 300% of the federal poverty level gained more in health status than did those above that level, with differential changes ranging from 0.2% to 1.3%. Relative gains in health status were comparable among white, black, and Hispanic residents in Massachusetts. Health care reform in Massachusetts was associated with improved health status and the greater use of some preventive services relative to those in other New England states, particularly among low-income households. These findings may stem from expanded insurance coverage as well as innovations in health care delivery that accelerated after health reform.


Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions.
To present nationally representative data on 12-month and lifetime prevalence, correlates, and comorbidity of DSM-IV major depressive disorder (MDD) among adults in the United States. DESIGN/SETTING/ PARTICIPANTS: Face-to-face survey of more than 43 000 adults aged 18 years and older residing in households and group quarters in the United States. Prevalence and associations of MDD with sociodemographic correlates and Axis I and II disorders. The prevalence of 12-month and lifetime DSM-IV MDD was 5.28% (95% confidence interval, 4.98-5.57) and 13.23% (95% confidence interval, 12.64-13.81), respectively. Being female; Native American; middle-aged; widowed, separated, or divorced; and low income increased risk, and being Asian, Hispanic, or black decreased risk (P<.05). Women were significantly more likely to receive treatment than men. Both current and lifetime MDD were significantly associated with other specific psychiatric disorders, notably substance dependence, panic and generalized anxiety disorder, and several personality disorders. This large survey suggests a higher prevalence of MDD in the US population than large-sample estimates from the 1980s and 1990s. The shift in highest lifetime risk from young to middle-aged adults is an important transformation in the distribution of MDD in the United States and specificity in risk for an age-period cohort. Associations between MDD and Axis I and II disorders were strong and significant, with variation within broad categories by specific diagnoses signaling the need for attention to the genetic and environmental reasons for such variation, as well as the implications for treatment response.


Effect of recent historical events on migration and isonymic stratification among the Rama Amerindians from Nicaragua.
The Rama Amerindians from southern Nicaragua are one of few indigenous populations inhabiting the east coast and lowlands of southern Central America. Early-eighteenth-century ethnohistorical accounts depicted the Rama as a mobile hunter-gatherer and horticulturalist group dispersed in household units along southern Nicaraguan rivers. However, during the nineteenth and twentieth centuries, Rama settlement patterns changed to aggregated communities because of increased competition for local resources resulting from nonindigenous immigration. The objective of this study was to discern the degree of relatedness between and within subdivisions of seven of these communities based on patterns of surname variation and genealogical data. We applied surname analyses (n = 592) to evaluate inter- and intrapopulation variation, consanguinity and substructure estimates, and isolation by distance and used a genealogically based marital migration matrix obtained during fieldwork in 2007 and 2009 to better understand internal migration. Our evaluation indicates a pattern of geographic distribution linking kinships in major subpopulations to nearby family-based villages. Mantel tests provide a correlation (r = 0.4; p < 0.05) between distance matrices derived from surname and geography among Rama communities. Genealogical analysis reveals a pattern of kin networks within both peripheral and central populations, consistent with previous genetic investigations, where the Amerindian mitochondrial DNA haplogroup B2 is commonly found among peripheral communities and A2 is frequent in central subpopulations. Marital migration and genealogies provide additional information regarding the influx of non-Ramas to communities near populated villages. These results indicate that the disruption of the Rama's traditional way of life has had significant consequences on their population structure consistent with population fissions and aggregations since the eighteenth century.


Scales for rating motor impairment in Parkinson's disease: studies of reliability and convergent validity.
Study 1 examined the reliability of the ratings assigned to the performance of five sign-and-symptom items drawn from tests of motor impairment in Parkinson's disease. Patients with Parkinson's disease of varying severity performed gait, rising from chair, and hand function items. Video recordings of these performances were rated by a large sample of experienced and inexperienced neurologists and by psychology undergraduates, using a four point scale. Inter-rater reliability was moderately high, being higher for gait than hand function items. Clinical experience proved to have no systematic effect on ratings or their reliability. The idiosyncrasy of particular performances was a major source of unreliable ratings. Study 2 examined the intercorrelation of several standard rating scales, comprised of sign-and-symptom items as well as activities of daily living. The correlation between scales was high, ranging from 0.70 to 0.83, despite considerable differences in item composition. Inter-item correlations showed that the internal cohesion of the tests was high, especially for the self-care scale. Regression analysis showed that the relationship between the scales could be efficiently captured by a small selection of test items, allowing the construction of a much briefer test.


Extracellular signal-regulated kinase mitogen-activated protein kinase-dependent SOCS-3 gene induction requires c-Jun, signal transducer and activator of transcription 3, and specificity protein 3 transcription factors.
SOCS-3 gene induction by cAMP-elevating agents or the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), in primary HUVECs was found to require PKCη- and PKCε-dependent extracellular signal-regulated kinase (ERK) activation. The minimal, ERK-responsive element of the SOCS-3 promoter was localized to a region spanning nucleotides -107 to the transcription start site and contains conserved binding sites for AP-1 and SP1/SP3 transcription factors, as well as proximal and distal signal transducer and activator of transcription (pSTAT and dSTAT) binding elements. All three classes of transcription factor were activated in response to ERK activation. Moreover, representative protein components of each of these transcription factor binding sites, namely c-Jun, STAT3, and SP3, were found to undergo ERK-dependent phosphorylation within their respective transactivation domains. Mutational analysis demonstrated an absolute requirement for the SP1/SP3 binding element in controlling basal transcriptional activity of the minimal SOCS-3 promoter. In addition AP-1, pSTAT, and SP1/SP3 binding sites were required for ERK-dependent, PMA-stimulated SOCS-3 gene activation. The dSTAT site seems to be important for supporting activity of the AP-1 site, because combined deletion of both sites completely blocks transcriptional activation of SOCS-3 by PMA. Together these results describe novel, ERK-dependent regulation of transcriptional activity that requires codependent activation of multiple transcription factors within the same region of the SOCS-3 gene promoter.


Evaluation of the illumigene Mycoplasma Direct DNA Amplification Assay.
Mycoplasma pneumoniae is a common cause of community-acquired pneumonia. The illumigene Mycoplasma Direct (iMD) DNA amplification assay is a qualitative in vitro test utilizing loop-mediated isothermal amplification (LAMP) technology for the direct detection of M. pneumoniae DNA in respiratory specimens. The iMD assay does not require the preextraction of nucleic acids from specimens, which is a prerequisite step for the previously approved illumigene Mycoplasma (iM) assay. The aim of this prospective multicenter study was to evaluate the performance characteristics of the newly developed iMD assay, compared with the iM assay. Subjects with symptoms of upper respiratory illnesses suggesting M. pneumoniae infection were enrolled at three sites in the United States. Respiratory specimens were obtained using dual throat swabs. One swab was tested with the iMD assay at each enrollment site. Reference testing with the iM assay was performed by the manufacturer. Among 456 specimens tested, the iM reference method detected M. pneumoniae in 25 specimens (5.5%), while the iMD assay identified 34 specimens (7.5%) as M. pneumoniae positive. There were 10 false-positive results and 1 false-negative result with the iMD assay. The overall positive and negative agreement rates were 96.0% (95% confidence interval [CI], 80.5 to 99.3%) and 97.7% (95% CI, 95.8 to 98.7%), respectively. The overall agreement rate was determined to be 97.6% (95% CI, 95.7 to 98.6%). We conclude that the iMD test results were comparable to the iM assay results. The removal of the DNA extraction step for the iMD assay simplifies testing, saves time, and reduces the costs of detecting M. pneumoniae from throat swabs, compared to the iM assay.


Surgical treatment for isolated atrial fibrillation: minimally invasive vs. classic cut and sew maze.
We sought to compare outcomes after two surgical approaches for the treatment of atrial fibrillation (AF): a minimally invasive, staged hybrid approach combining surgery with catheter ablation, [Hybrid Maze (HM)] and the classic cut and sew Maze (CM). From April 2004 to March 2010, 63 stand-alone AF procedures were performed by two surgeons at a single center and followed up for ≥6 months. CM was offered to all patients. After July 2007, patients were also prospectively offered a two-stage HM: stage 1 = a beating heart bipolar radiofrequency pulmonary vein isolation and left atrial appendage ligation; stage 2 = transvenous catheter ablation connecting the pulmonary veins to each other and the mitral annulus when AF was present after stage 1. Outcomes were compared between 25 HM and 38 CM using χ or Fisher exact test analysis. Postoperatively, there was no difference in 30-day mortality (0%), complications (4% HM vs. 18% CM), or median length of stay (5 days). At last follow-up, 88% of HM and 95% of CM were free from AF; 80% of HM and 90% of CM were free from AF and antiarrhythmic medication (P ≥ 0.3). Twenty-nine percent of HM required a subsequent catheter ablation (stage 2) when compared with 8% of the CM patients (P = 0.04). Freedom from AF and antiarrhythmic medication at 1 year was 52% for the HM and 87.5% for the CM (P = 0.004). In AF patients reluctant to undergo a CM but willing to undergo subsequent catheter ablation, a minimally invasive approach is a reasonable strategy. Because pulmonary vein isolation alone may be sufficient in two-thirds of patients and delayed reconnection is common, an interval two-stage hybrid approach may prove preferable over a one-stage combined hybrid approach; however, successful sinus restoration may take longer with this approach.


Pros and cons of gastric bypass surgery in individuals with obesity and type 2 diabetes: nationwide, matched, observational cohort study.
Long-term effects of gastric bypass (GBP) surgery have been presented in observational and randomised studies, but there are only limited data for persons with obesity and type 2 diabetes mellitus (T2DM) regarding postoperative complications. This is a nationwide observational study based on two quality registers in Sweden (National Diabetes Register, NDR and Scandinavian Obesity Surgery Register, SOReg) and other national databases. After merging the data, we matched individuals with T2DM who had undergone GBP with those not surgically treated for obesity on propensity score, based on sex, age, body mass index (BMI) and calendar time. The risks of postoperative outcomes (rehospitalisations) were assessed using Cox regression models. We identified 5321 patients with T2DM in the SOReg and 5321 matched controls in the NDR, aged 18-65 years, with BMI >27.5 kg/m² and followed for up to 9 years. We assessed risks for all-cause mortality and hospitalisations for cardiovascular disease, severe kidney disease, along with surgical and other medical conditions. The results agree with the previously suggested lower risks of all-cause mortality (49%) and cardiovascular disease (34%), and we also found positive effects for severe kidney disease but significantly increased risks (twofold to ninefold) of several short-term complications after GBP, such as abdominal pain and gastrointestinal conditions, frequently requiring surgical procedures, apart from reconstructive plastic surgery. Long-term, the risk of anaemia was 92% higher, malnutrition developed approximately three times as often, psychiatric diagnoses were 33% more frequent and alcohol abuse was three times as great as in the control group. This nationwide study confirms the benefits and describes the panorama of adverse events after bariatric surgery in persons with obesity and T2DM. Long-term postoperative monitoring and support, as better selection of patients by appropriate specialists in interdisciplinary settings, should be provided to optimise the outcomes.


Differences in the functional neuroanatomy of inhibitory control across the adult life span.
Inhibitory control, the ability to suppress irrelevant or interfering stimuli, is a fundamental cognitive function that deteriorates during aging, but little is understood about the bases of decline. Thus, we used event-related functional magnetic resonance imaging (fMRI) to study inhibitory control in healthy adults aged 18 to 78. Activation during "successful inhibition" occurred predominantly in right prefrontal and parietal regions and was more extensive, bilaterally and prefrontally, in the older groups. Presupplementary motor area was also more active in poorer inhibitory performers. Therefore, older adults activate areas that are comparable to those activated by young adults during inhibition, as well as additional regions. The results are consistent with a compensatory interpretation and extend the aging neuroimaging literature into the cognitive domain of inhibition.


British rubber and cable industry cohort: 49-year mortality follow-up.
The International Agency for Research on Cancer (IARC) has determined there is sufficient evidence that working in the rubber manufacturing industry increases the risk of cancers of the stomach, lung, bladder and leukaemia and lymphoma. To examine mortality patterns of a prospective cohort of men from the rubber and cable manufacturing industries in Great Britain. SMRs were calculated for males aged 35+ years at start of follow-up in 1967-2015 using the population of England and Wales as the external comparator. Tests for homogeneity and trends in SMRs were also completed. For all causes, all malignant neoplasms, non-malignant respiratory diseases and circulatory diseases, SMRs were significantly elevated, and also particularly for cancers of the stomach (SMR=1.26,95% CI 1.18 to 1.36), lung (1.25,95% CI 1.21 to 1.29) and bladder (1.16,95% CI 1.05 to 1.28). However, the observed deaths for leukaemia, non-Hodgkin's lymphoma (NHL) and multiple myeloma were as expected. Bladder cancer risks were elevated only in workers exposed to antioxidants containing 1-naphthylamine and 2-naphthylamine. This study provides evidence of excess risks in the rubber industry for some non-cancer diseases and supports IARC's conclusions in relation to risks for cancers of the bladder, lung and stomach, but not for leukaemia, NHL or multiple myeloma.


Vocal Imitations of Non-Vocal Sounds.
Imitative behaviors are widespread in humans, in particular whenever two persons communicate and interact. Several tokens of spoken languages (onomatopoeias, ideophones, and phonesthemes) also display different degrees of iconicity between the sound of a word and what it refers to. Thus, it probably comes at no surprise that human speakers use a lot of imitative vocalizations and gestures when they communicate about sounds, as sounds are notably difficult to describe. What is more surprising is that vocal imitations of non-vocal everyday sounds (e.g. the sound of a car passing by) are in practice very effective: listeners identify sounds better with vocal imitations than with verbal descriptions, despite the fact that vocal imitations are inaccurate reproductions of a sound created by a particular mechanical system (e.g. a car driving by) through a different system (the voice apparatus). The present study investigated the semantic representations evoked by vocal imitations of sounds by experimentally quantifying how well listeners could match sounds to category labels. The experiment used three different types of sounds: recordings of easily identifiable sounds (sounds of human actions and manufactured products), human vocal imitations, and computational "auditory sketches" (created by algorithmic computations). The results show that performance with the best vocal imitations was similar to the best auditory sketches for most categories of sounds, and even to the referent sounds themselves in some cases. More detailed analyses showed that the acoustic distance between a vocal imitation and a referent sound is not sufficient to account for such performance. Analyses suggested that instead of trying to reproduce the referent sound as accurately as vocally possible, vocal imitations focus on a few important features, which depend on each particular sound category. These results offer perspectives for understanding how human listeners store and access long-term sound representations, and sets the stage for the development of human-computer interfaces based on vocalizations.


Linking genomic responses of gonads with reproductive impairment in marine medaka (Oryzias melastigma) exposed chronically to the chemopreventive and antifouling agent, 3,3'-diindolylmethane (DIM).
3,3'-Diindolylmethane (DIM) has been promoted as an effective chemopreventive and antifouling additive. However, the concurrent risks or side effects of DIM are not fully understood, especially on tissues responsive to estrogen. Therefore, this study employed marine medaka (Oryzias melastigma) as a test model to evaluate relative safety and explore mechanisms of toxic action of DIM on development and function of gonad after chronic (28days) aqueous exposure to relatively low doses (0μg/L or 8.5μg/L). Integration of comprehensive toxicogenomic analysis at the transcriptome and proteome levels with apical endpoints, such as production of eggs and swimming performance of larvae, elucidated the molecular linkage in gonad from bottom up along the reproductive adverse outcome pathway. A series of sequential changes at the transcript and protein levels were linked to lesser fecundity and viability of larvae exposed to DIM. Anomalous production of vitellogenin (VTG) and eggshell proteins in testis confirmed the estrogenic potency of DIM. In the ovary, although storage of VTG was greater, lesser expressions of cathepsin enzymes blocked cleavage and incorporation of VTG into oocytes as yolk, which acted together with lower eggshell proteins to inhibit maturation of primary oocyte and thus contributed to impairment of fecundity. Overall, this study demonstrated that exposure to DIM impaired reproductive fitness. Diverse molecular initiating changes in gonads were linked to apical endpoints that could be used in assessment of risks posed by DIM on gametogenesis. In combination with chemical stability and potent endocrine disruption, the results of this study can inform decisions about the use of DIM either as chemopreventive or antifouling agent.


Perceptual consciousness overflows cognitive access.
One of the most important issues concerning the foundations of conscious perception centers on the question of whether perceptual consciousness is rich or sparse. The overflow argument uses a form of 'iconic memory' to argue that perceptual consciousness is richer (i.e., has a higher capacity) than cognitive access: when observing a complex scene we are conscious of more than we can report or think about. Recently, the overflow argument has been challenged both empirically and conceptually. This paper reviews the controversy, arguing that proponents of sparse perception are committed to the postulation of (i) a peculiar kind of generic conscious representation that has no independent rationale and (ii) an unmotivated form of unconscious representation that in some cases conflicts with what we know about unconscious representation.


Evaluation of an immunochromatographic assay for rapid detection of Salmonella enterica serovars Typhimurium and Enteritidis.
An immunochromatographic assay was developed to detect Salmonella enterica serovars Typhimurium and Enteritidis in a single strip. The assay was constructed in the form of a sandwich, using 2 specific anti-S. Typhimurium and anti-S. Enteritidis antibodies immobilized on a nitrocellulose membrane at separated test lines, while the other specific antibody to Salmonella spp. was conjugated with gold nanoparticles. The test strips can immediately detect S. Typhimurium and S. Enteritidis specifically in a culture medium at levels as low as 10(4) and 10(6) cfu/ml, respectively. The contamination of S. Typhimurium and S. Enteritidis at 1 cfu/ml or greater can be detected by the test strips after 6-24 hr incubation. The specificities of the test strips to detect S. Typhimurium and S. Enteritidis, in spiked samples, were obtained at 100%; the sensitivities were at 98.89% (89/90) and 87.50% (70/80), respectively, compared with the conventional method. The newly developed multiplex immunochromatographic assay is the first report on the efficient detection of both S. Typhimurium and S. Enteritidis simultaneously in single strip. This test strip also provides advantages of simplicity and very rapid detection of these specific bacterial contaminants in chicken and can be useful for mass detection on chicken farms and in other veterinary products.


Healthcare workers' perceptions of lean: a context-sensitive, mixed methods study in three Swedish hospitals.
As the application of lean in healthcare expands, further research is needed in at least two areas: first, on the role of context in shaping lean and its consequences and second, on how healthcare workers perceive lean. Accordingly, this context-sensitive, mixed methods study addressed how hospital workers' perceptions of lean varied across contexts in three Swedish hospitals. Registered nurses and physicians at the hospitals and across units differing in acuity completed standardized surveys (N = 236, 57% response rate) about their perceptions of hospital-wide lean implementation. Perceptions varied by: hospital context, with one hospital's employees reporting the least favorable perceptions; unit acuity, with higher-acuity units reporting more favorable perceptions; and professional role, with nurses reporting more favorable perceptions than physicians. Individual interviews, group interviews, and observations provided insight about these dissimilar contexts and possible explanations for context-specific variability. Findings are discussed with respect to strategies for implementing lean in healthcare; the importance of attending to levels, context, and worker consequences of lean; and directions for future research.


The detection and management of intracranial hypertension after initial suture release and decompression for craniofacial dysostosis syndromes.
We performed a retrospective study of 107 consecutive patients with syndromic forms of craniosynostosis (craniofacial dysostosis) seen by the craniofacial team at the Hospital for Sick Children between 1986 and 1992. There were 51 patients with Crouzon's syndrome, 33 with Apert's syndrome, 8 with Pfeiffer syndrome, 11 with Saethre-Chotzen syndrome, and 4 with kleeblättschadel anomaly. Six patients developed raised intracranial pressure (ICP) after initial suture release and decompression (Apert's syndrome, three patients; Pfeiffer syndrome, one patient; Saethre-Chotzen syndrome, two patients). Raised ICP was considered in those children who returned with a bulging fontanelle, progressive frontal bone protrusion, intermittent headaches, irritability, and vomiting. The diagnosis of raised ICP was based on papilledema (four patients), progressive macrocephaly (one patient), and ICP monitoring (one patient). No child in this group had hydrocephalus requiring cerebrospinal fluid diversion. Once raised ICP was detected in these children, a second operation was immediately performed to reduce the ICP with the intention of expanding the volume of the cranial cavity. The second procedures included: anterior cranial vault and upper orbital reshaping (four patients), posterior cranial vault reshaping (one patient), and total cranial vault reshaping (one patient). There were no perioperative complications in these patients, although one patient showed subsequent recurrence of raised ICP requiring further cranial vault re-expansion. At follow-up, ranging from 3 to 7 years, all six patients were asymptomatic without evidence of raised ICP. In our series, raised ICP occurred in 6% of the children with a craniofacial dysostosis syndrome after initial suture release and decompression.(ABSTRACT TRUNCATED AT 250 WORDS)


Rubella antibody levels in school-aged children in Newfoundland: Implications for a two-dose rubella vaccination strategy.
To determine the prevailing levels of rubella immunity among school-aged children who received a single dose of measles-mumps-rubella (MMR) vaccine at one year of age. Cross-sectional study with a two stage cluster sampling of randomly picked schools across the province of Newfoundland. A total of 1053, five to 17-year-old children were enrolled; vaccination history was verified through official records; and a sample of blood was taken. Rubella immunity was determined by enzyme immunoassay based on a serum antibody protective cut-off titre of more than 10 IU. A total of 145 (13.8%) were found to be nonimmune. The rate of susceptibility ranged from 3.2% to 25.9% for different age groups. The proportion susceptible was significantly higher at 16.5% in the age group eight to 17 years old versus 3.9% for the age group five to eight years old (χ(2)=24.08; df=1, P<0.001). There was a significant regression of logarithm titre values on the age of children with an average decline in titre values of 8.1% per annum. A substantial number of those who were given a single dose of MMR II vaccine may not have protective immunity against rubella as they reach prime reproductive age. There is a definite need to consider a two-dose rubella vaccination strategy in Canada, and these data suggest the second dose given after eight years of age will be most beneficial. In the move towards a routine two-dose measles vaccination strategy in Canada, the MMR II vaccine is being used for the second dose and given either at 18 months of age or at school entry. While this approach will have an overall beneficial effect, the impact of the above timing of the second dose on long term rubella immunity cannot be predicted at this time. These data also underscore the continuing need for prenatal rubella screening program.


Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease.
Hashimoto's thyroiditis (HT) and Graves' disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production and antibodies to the receptor for the thyroid-stimulating hormone, are characteristic of HT and GD, respectively. It is presently accepted that genetic susceptibility, environmental factors, including nutritional factors and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin (Tg) is more immunogenic. The recent introduction of universal salt iodisation can have a similar, although transient, effect. Iron: iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/l ameliorated symptoms. Selenium: selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of Tg to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.


Sea urchin eggs in the acid reign.
Sea urchin eggs have been an indispensable model system for studying egg activation and ionic signalling for at least a century. Instrumental in the discovery of two Ca(2+)-mobilizing second messengers, cyclic ADP-ribose and NAADP, the sea urchin has revolutionized cell biology for all phyla. This review attempts to summarize what we currently know about egg acidic vesicles in the context of Ca(2+) signalling. The dynamics of Ca(2+) storage, Ca(2+) mobilization, proton fluxes and two-pore channels will be discussed.


Trajectories of depression and their relationship with health status and social service use.
This longitudinal study was conducted between 1994 and 2004 in a cohort of Southern Taiwan community-living elderly residents. The study aims to explore the trajectories of depression and how these patterns differed between respondents who survived and those who died during data collection phases; this study also investigated how health status change and health/social service use predicted the different trajectories of depression. Eight hundred and ten participants had completed all six waves of the survey or were followed-up at each wave until death in the prospective study in Kaohsiung City. Depressive symptoms were evaluated by the Short Psychiatric Evaluation Schedule (SPES). Changes in levels of depression during the ageing process were identified. Different trajectories clearly reflected heterogeneity within depression and the association with mortality. The study highlighted that diabetes, gastrointestinal problems, heart disease and disability, whether at baseline or as new occurrences, were predictors of health decline. High uses of health/social services were also predictive of increased depression. These findings identified depression as a highly dynamic process, characterized by different trajectories of depression between states of no, mild and severe depression. Greater awareness of these various trajectories should potentially improve the prevention and/or management strategies of depression.


Design and results of the pretest of the IDEFICS study.
During the preparatory phase of the baseline survey of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study, standardised survey procedures including instruments, examinations, methods, biological sampling and software tools were developed and pretested for their feasibility, robustness and acceptability. A pretest was conducted of full survey procedures in 119 children aged 2-9 years in nine European survey centres (N(per centre)=4-27, mean 13.22). Novel techniques such as ultrasound measurements to assess subcutaneous fat and bone health, heart rate monitors combined with accelerometers and sensory taste perception tests were used. Biological sampling, physical examinations, sensory taste perception tests, parental questionnaire and medical interview required only minor amendments, whereas physical fitness tests required major adaptations. Callipers for skinfold measurements were favoured over ultrasonography, as the latter showed only a low-to-modest agreement with calliper measurements (correlation coefficients of r=-0.22 and r=0.67 for all children). The combination of accelerometers with heart rate monitors was feasible in school children only. Implementation of the computer-based 24-h dietary recall required a complex and intensive developmental stage. It was combined with the assessment of school meals, which was changed after the pretest from portion weighing to the more feasible observation of the consumed portion size per child. The inclusion of heel ultrasonometry as an indicator of bone stiffness was the most important amendment after the pretest. Feasibility and acceptability of all procedures had to be balanced against their scientific value. Extensive pretesting, training and subsequent refinement of the methods were necessary to assess the feasibility of all instruments and procedures in routine fieldwork and to exchange or modify procedures that would otherwise give invalid or misleading results.


Influence of surface chemistry and structure of activated carbon on adsorption of fulvic acids from water solution.
The adsorption of fulvic acids (FA) from aqueous solutions on activated carbon (AC) with different characteristics of surface chemical state has been investigated. To characterize the adsorbability of FA with complex fractional composition, a method of estimation of modified Freundlich equation constants was employed, and "conventional component" was used to evaluate the change in Gibbs free adsorption energy. It has been shown that change in activated carbon surface energy in-homogeneity due to oxidation leads mainly to a decrease in the adsorption energy of fulvic acids and to an increase of the concentration range of the conventional portion of the low adsorbable fraction. Decrease in the adsorption energy of organic substrate may result in higher degree of spontaneous bioregeneration of activated carbon and hence in its longer life in the processes of FA solutions filtration.


PRS-Net: Planar Reflective Symmetry Detection Net for 3D Models.
In geometry processing, symmetry is a universal type of high-level structural information of 3D models and benefits many geometry processing tasks including shape segmentation, alignment, matching, and completion. Thus it is an important problem to analyze various symmetry forms of 3D shapes. Planar reflective symmetry is the most fundamental one. Traditional methods based on spatial sampling can be time-consuming and may not be able to identify all the symmetry planes. In this article, we present a novel learning framework to automatically discover global planar reflective symmetry of a 3D shape. Our framework trains an unsupervised 3D convolutional neural network to extract global model features and then outputs possible global symmetry parameters, where input shapes are represented using voxels. We introduce a dedicated symmetry distance loss along with a regularization loss to avoid generating duplicated symmetry planes. Our network can also identify generalized cylinders by predicting their rotation axes. We further provide a method to remove invalid and duplicated planes and axes. We demonstrate that our method is able to produce reliable and accurate results. Our neural network based method is hundreds of times faster than the state-of-the-art methods, which are based on sampling. Our method is also robust even with noisy or incomplete input surfaces.


Detection of Desulfotomaculum in an Italian rice paddy soil by 16S ribosomal nucleic acid analyses.
Two specific primers were developed for the amplification of 16S rRNA genes of Desulfotomaculum lineage 1 to detect members of the genus Desulfotomaculum in rice field soil. The combination of both primers in PCR allowed the specific amplification and cloning of ten 16S rDNA sequences of this group from rice paddy soil DNA extracts. The phylogenetic analysis showed that these sequences formed a deeply branching cluster within Desulfotomaculum lineage 1, together with two sequences from the database and two sequences from a hydrocarbon-contaminated aquifer. Dissimilarity values to validly described species, including recently isolated strains of Desulfotomaculum from rice paddy microcosms, were higher than 12%. Within the new cluster the cloned sequences formed three separate groups which were each represented by at least two sequences with identities of >/=99% while one sequence represented an additional group. The sequences should represent sulfate-reducing organisms because they clearly fell into the physiologically coherent group of Gram-positive sulfate reducers. The relative abundance of bacteria of the Desulfotomaculum lineage 1 in rice paddy soil and root samples was estimated with rRNA dot blot hybridizations of extracted RNA. The relative RNA content of Desulfotomaculum lineage 1 was 0.55% in the bulk soil and 1% in the rice root samples, respectively, of the total 16S rRNA content (probe Eub338). Hybridization of rRNA with a probe targeting the new cluster represented by the cloned sequences confirmed the high abundance of 16S rRNA sequences from this cluster in the rice paddy field samples. Another hybridization probe detecting Desulfotomaculum acetoxidans and two closely related Desulfotomaculum isolates from rice paddy soil indicated that these bacteria were less abundant.


Diabetes mellitus, fasting glucose, and risk of cause-specific death.
The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).


Antidepressant fluoxetine induces multiple antibiotics resistance in Escherichia coli via ROS-mediated mutagenesis.
Antibiotic resistance poses a great threat to global public health. Overuse of antibiotics is generally considered as the major factor contributing to it. However, little is known about whether non-antibiotic drugs could play potential roles in the emergence of antibiotic resistance. We aimed to investigate whether antidepressant fluoxetine induces multiple antibiotic resistances and reveal underlying mechanisms. Escherichia coli K12 was exposed to different concentrations of fluoxetine (0, 0.5, 5, 50 and 100 mg/L) and the resistant strains were isolated by plating on antibiotic containing plates. Resistant strains were randomly selected to determine the increase of minimum inhibition concentration (MIC) of multiple antibiotics. Genome-wide DNA sequencing was performed on cells cultured in lysogeny broth (LB) without any fluoxetine or antibiotics exposure. RNA sequencing and proteomic profiling of isolated mutants grown in LB with 100 mg/L fluoxetine were analyzed to reveal the underlying mechanisms. Exposure of Escherichia coli to fluoxetine at 5-100 mg/L after repeated subculture in LB for 30 days promoted its mutation frequency resulting in increased resistance against the antibiotics chloramphenicol, amoxicillin and tetracycline. This increase was up to 5.0 × 107 fold in a dose-time pattern. Isolated mutants with resistance to one of these antibiotics also exhibited multiple resistances against fluoroquinolone, aminoglycoside, β-lactams, tetracycline and chloramphenicol. According to global transcriptional and proteomic analyses, the AcrAB-TolC pump together with the YadG/YadH transporter, a Tsx channel and the MdtEF-TolC pump have been triggered to export the antibiotics to the exterior of the cell. Whole-genome DNA analysis of the mutants further revealed that ROS-mediated mutagenesis (e.g., deletion, insertion, and substitution) of DNA-binding transcriptional regulators (e.g., marR, rob, sdiA, cytR and crp) to up-regulate the expression of efflux pumps, may further enhance the antibiotic efflux. Our findings for the first time demonstrated that the exposure to antidepressant fluoxetine induces multiple antibiotic resistance in E. coli via the ROS-mediated mutagenesis.


Hyperfluidization-coupled membrane microdomain reorganization is linked to activation of the heat shock response in a murine melanoma cell line.
Targeting of the Hsp function in tumor cells is currently being assessed as potential anticancer therapy. An improved understanding of the molecular signals that trigger or attenuate the stress protein response is essential for advances to be made in this field. The present study provides evidence that the membrane fluidizer benzyl alcohol (BA), a documented nondenaturant, acts as a chaperone inducer in B16(F10) melanoma cells. It is demonstrated that this effect relies basically on heat shock transcription factor 1 (HSF1) activation. Under the conditions tested, the BA-induced Hsp response involves the up-regulation of a subset of hsp genes. It is shown that the same level of membrane fluidization (estimated in the core membrane region) attained with the closely analogous phenethyl alcohol (PhA) does not generate a stress protein signal. BA, at a concentration that activates heat shock genes, exerts a profound effect on the melting of raft-like cholesterol-sphingomyelin domains in vitro, whereas PhA, at a concentration equipotent with BA in membrane fluidization, has no such effect. Furthermore, through the in vivo labeling of melanoma cells with a fluorescein labeled probe that inserts into the cholesterol-rich membrane domains [fluorescein ester of polyethylene glycol-derivatized cholesterol (fPEG-Chol)], we found that, similarly to heat stress per se, BA, but not PhA, initiates profound alterations in the plasma membrane microdomain structure. We suggest that, apart from membrane hyperfluidization in the deep hydrophobic region, a distinct reorganization of cholesterol-rich microdomains may also be required for the generation and transmission of stress signals to activate hsp genes.


Fabry-perot spectrometer adjustment for the compensation of Doppler shift from rapidly rotating and rapidly flowing sources.
The Doppler shift of light from a rapidly rotating or rapidly flowing source limits the spectroscopic resolution with which it can be studied using Fabry-Perot spectrometers that have the usual axial fringe adjustment. Because of the angular dependence of the wavenumber transmitted by the Fabry-Perot, the entrance aperture can be positioned off-axis at an angle chosen such that the wavenumber shift across the entrance aperture matches the shift presented by the source, thereby compensating for the Doppler effect. The principle can be extended to the Michelson interferometer for Fourier transform spectroscopy when the Michelson is used without field compensation. High resolution spectra obtained with a PEPSIOS spectrometer using the entire disk of Jupiter, a rapidly rotating planet, are presented as an example.


A role for autophagy in β-cell life and death.
Autophagy is a vacuolar, self-digesting mechanism responsible for the removal of organelles and defined regions of the cytoplams. This process has, in general, a beneficial role for the cell, since it regulates the turnover of aged proteins and eliminates damaged structures. However, cells that undergo altered autophagy may be triggered to die in a non-apoptotic manner. As a matter of fact, in recent years it has become clear that dysregulated autophagy may be implicated in several disorders, such as cancer, neurodegenerative diseases and hepatic encephalopathy. We have recently shown that β-cells of type 2 diabetic subjects show signs of autophagy associated death, which may contribute to the overall loss of β-cell mass in type 2 diabetes. In addition, studies with cell lines and rodent models have demonstrated the importance of autophagy in β-cell function and survival. Altogether, the available evidence supports the view that autophagy is implicated in β-cell pathophysiology, and suggests that addressing the molecular mechanisms involved in autophagic regulation might provide clues for preventing or treating β-cell damage in diabetes.


L30A Mutation of Phospholemman Mimics Effects of Cardiac Glycosides in Isolated Cardiomyocytes.
To determine if mutations introduced into phospholemman (PLM) could increase the level of PLM-Na,K-ATPase (NKA) binding, we performed scanning mutagenesis of the transmembrane domain of PLM and measured Förster resonance energy transfer (FRET) between each mutant and NKA. We observed an increased level of binding to NKA for several PLM mutants compared to that of the wild type (WT), including L27A, L30A, and I32A. In isolated cardiomyocytes, overexpression of WT PLM increased the amplitude of the Ca2+ transient compared to the GFP control. The Ca2+ transient amplitude was further increased by L30A PLM overexpression. The L30A mutation also delayed Ca2+ extrusion and increased the duration of cardiomyocyte contraction. This mimics aspects of the effect of cardiac glycosides, which are known to increase contractility through inhibition of NKA. No significant differences between WT and L30A PLM-expressing myocytes were observed after treatment with isoproterenol, suggesting that the superinhibitory effects of L30A are reversible with β-adrenergic stimulation. We also observed a decrease in the extent of PLM tetramerization with L30A compared to WT using FRET, suggesting that L30 is an important residue for mediating PLM-PLM binding. Molecular dynamics simulations revealed that the potential energy of the L30A tetramer is greater than that of the WT, and that the transmembrane α helix is distorted by the mutation. The results identify PLM residue L30 as an important determinant of PLM tetramerization and of functional inhibition of NKA by PLM.


Changes in bone mineral density in response to 24 weeks of resistance training in college-age men and women.
Osteoporosis is a chronic disease of major public health concern. Characterized by low bone mass and increasing risk for fracture, osteoporosis occurs to a greater extent in women. Resistance training is a mode of exercise that can be used to build peak bone mass during youth, thereby preventing osteoporosis later in life. Our aim was to evaluate the effectiveness of a resistance training protocol designed to apply loads to the hip and spine in men and women. We recruited recreationally active men (n = 12) and women (n = 12), ages of 18-23. An additional 10 participants (5 men, 5 women) served as controls. Volunteers completed questionnaires to assess health history, physical activity, dietary intake, and menstrual history. The training program was performed for 24 weeks, on 3 nonconsecutive days per week, including exercises for the upper, lower, and core musculature, marked by an undulating periodization varying between 67 and 95% of 1 repetition maximum (1RM) on the multijoint exercises of bench press, squats, and deadlifts. Dual energy X-ray absorptiometry (Hologic Explorer, Waltham, MA, USA) was used to assess bone mineral density (BMD, g · cm(-2)). A 2-tailed analysis of covariance, controlling for body mass index, revealed that in comparison to women, men had significantly greater increases in BMD at the lateral spine and femoral neck. Male exercisers were found to increase BMD by 2.7-7.7%, whereas percent change in women ranged from -0.8 to 1.5%, depending on the bone site. Both male and female controls demonstrated about 1% change at any bone site. Results indicate that 24 weeks of resistance training, including squat and deadlift exercises, is effective in increasing BMD in young healthy men. Similar benefits were not derived by women who followed the same protocol.


Impact of gender on response to highly active antiretroviral therapy in HIV-1 infected patients: a nationwide population-based cohort study.
Impact of gender on time to initiation, response to and risk of modification of highly active antiretroviral therapy (HAART) in HIV-1 infected individuals is still controversial. From a nationwide cohort of Danish HIV infected individuals we identified all heterosexually infected women (N=587) and heterosexually infected men (N=583) with no record of Hepatitis C infection diagnosed with HIV after 1 January 1997. Among these subjects, 473 women (81%) and 435 men (75%) initiated HAART from 1 January 1997 to 31 December 2009. We used Cox regression to calculate hazard ratio (HR) for time to initiation of HAART, Poisson regression to assess incidence rate ratios (IRR) of risk of treatment modification the first year, logistic regression to estimate differences in the proportion with an undetectable viral load, and linear regression to detect differences in CD4 count at year 1, 3 and 6 after start of HAART. At initiation of HAART, women were younger, predominantly of Black ethnicity and had a higher CD4 count (adjusted p=0.026) and lower viral load (adjusted p=0.0003). When repeating the analysis excluding pregnant women no difference was seen in CD4 counts (adjusted p=0.21). We observed no delay in time to initiation of HAART in women compared to men (HR 0.91, 95% CI 0.79-1.06). There were no gender differences in risk of treatment modification of the original HAART regimen during the first year of therapy for either toxicity (IRR 0.97 95% CI 0.66-1.44) or other/unknown reasons (IRR 1.18 95% CI 0.76-1.82). Finally, CD4 counts and the risk of having a detectable viral load at 1, 3 and 6 years did not differ between genders. In a setting with free access to healthcare and HAART, gender does neither affect time from eligibility to HAART, modification of therapy nor virological and immunological response to HAART. Differences observed between genders are mainly attributable to initiation of HAART in pregnant women.


THAM Administration to Pediatric Trauma Patients in a Combat Zone.
Pediatric casualties made up a significant proportion of patients during the recent military conflicts in Iraq and Afghanistan. Damage control resuscitation strategies used by military physicians included rapid reversal of metabolic acidosis to mitigate its pathophysiologic consequences, primarily through hemorrhage control and volume restoration. Alkalizing agents, including tris(hydroxymethyl)aminomethane (THAM), are potential therapeutic adjuncts to treat significant acidosis. There is, however, limited published data on THAM administration in the pediatric trauma population. We compared demographics and outcomes among pediatric trauma patients in Afghanistan and Iraq receiving THAM versus those not receiving THAM. We queried the Department of Defense Trauma Registry for all of the pediatric patients admitted to US and Coalition fixed-facility hospitals in Afghanistan and Iraq from January 2007 to January 2016. We retrieved data on age, sex, location, mechanism of injury, Injury Severity Scores, ventilator days, days in the intensive care unit, days of total hospitalization, and survival to hospital discharge. We excluded subjects if they were dead on arrival to the emergency department. From January 2007 to January 2016, there were 3386 pediatric subjects that met our inclusion criteria. Of these, 15 received THAM. The youngest subject receiving THAM was a 2-month-old burn victim. Subjects receiving THAM were more likely to be injured by submersion or burn (P < 0.001), had higher composite Injury Severity Scores (17 vs 10; P < 0.001) and Abbreviated Injury Scores for the thorax and abdomen (P = 0.004 and P = 0.019, respectively), and longer ventilator days/intensive care unit stays/hospital lengths of stay (P < 0.001/P < 0.001/P = 0.013). In addition, subjects receiving THAM had a lower survival rate than subjects not receiving THAM (73.3% vs 91.7%; P = 0.011). THAM was administered rarely to pediatric trauma casualties during the conflicts in Afghanistan and Iraq. Subjects receiving THAM were more critically injured than the baseline population.


Nef alleles from all major HIV-1 clades activate Src-family kinases and enhance HIV-1 replication in an inhibitor-sensitive manner.
The HIV-1 accessory factor Nef is essential for high-titer viral replication and AIDS progression. Nef function requires interaction with many host cell proteins, including specific members of the Src kinase family. Here we explored whether Src-family kinase activation is a conserved property of Nef alleles from a wide range of primary HIV-1 isolates and their sensitivity to selective pharmacological inhibitors. Representative Nef proteins from the major HIV-1 subtypes A1, A2, B, C, F1, F2, G, H, J and K strongly activated Hck and Lyn as well as c-Src to a lesser extent, demonstrating for the first time that Src-family kinase activation is a highly conserved property of primary M-group HIV-1 Nef isolates. Recently, we identified 4-amino substituted diphenylfuropyrimidines (DFPs) that selectively inhibit Nef-dependent activation of Src-family kinases as well as HIV replication. To determine whether DFP compounds exhibit broad-spectrum Nef-dependent antiretroviral activity against HIV-1, we first constructed chimeric forms of the HIV-1 strain NL4-3 expressing each of the primary Nef alleles. The infectivity and replication of these Nef chimeras was indistinguishable from that of wild-type virus in two distinct cell lines (U87MG astroglial cells and CEM-T4 lymphoblasts). Importantly, the 4-aminopropanol and 4-aminobutanol derivatives of DFP potently inhibited the replication of all chimeric forms of HIV-1 in both U87MG and CEM-T4 cells in a Nef-dependent manner. The antiretroviral effects of these compounds correlated with inhibition of Nef-dependent activation of endogenous Src-family kinases in the HIV-infected cells. Our results demonstrate that the activation of Hck, Lyn and c-Src by Nef is highly conserved among all major clades of HIV-1 and that selective targeting of this pathway uniformly inhibits HIV-1 replication.


Effects of locally administered rhBMP-2 and bisphosphonate on bone regeneration in the rat fibula.
To evaluate the ability of xenogenic bone and absorbable collagen sponge to function as an rhBMP-2 carrier and the osteoinductivity of bisphosphonate by comparison with recombinant human bone morphogenetic protein-2 (rhBMP-2). Thirty-two Sprague-Dawley male rats were divided into four groups. Segmental ostectomy of both fibulae was performed, and the defect area was then treated with Rapiderm Pad (absorbable collagen sponge; COL_BMP) or CollaOss (xenogenic bone; XENO_BMP) with application of rhBMP-2. Alternatively, both fibulae were grafted with xenogenic bone with different bisphosphonate concentrations (XENO_Low BP, XENO_High BP). After 4 or 8 weeks, animals were sacrificed, and radiographic, histological, histomorphometric, and immunohistochemical analyses were performed. Recombinant human bone morphogenetic protein-2 promoted bone formation, regardless of the carrier, and exhibited continuity between the graft material and defect area. Moreover, the results showed that higher concentrations of bisphosphonate were associated with greater bone formation than lower concentrations of bisphosphonate. Absorbable collagen sponges with rhBMP-2 were advantageous in that there was no remaining graft material and that the bone was remodeled to resemble the existing fibula. The local application of bisphosphonate promoted new bone formation, particularly when used at high concentrations. High-concentration bisphosphonate induced new bone formation comparable to rhBMP-2 with lesser remaining bone material.


Enhancement of lithium-ion hopping on halogen-doped χ3 borophene.
Borophenes, which are two-dimensional boron counterparts made of the three synthetic polymorphs T, β12 and χ3, have been considered as potential anode materials in Li-ion batteries with extremely high capacities. However, Li hopping on β12 and χ3 borophenes is quite slow with high energy barriers (around 0.6 eV), thus preventing the application of these borophenes in the fast charging realm. Here, we have used halogen functionalization in an attempt to boost the sluggish Li-ion diffusion dynamics in the prototype χ3 borophene system. Halogens bind strongly to χ3 borophene with substantial electron transfer from the latter to the former, thereby leading to local electron deficiency in the χ3 borophene. The synergy of electron extraction from χ3 borophene and the electrostatic attraction between halogens and Li results in an enhanced affinity between χ3 borophene and Li as well as a reduction in the Li-ion hopping barrier. Iodine is the preferred dopant, for which most diffusion paths exhibit energy barriers typically smaller than 0.2 eV. Our results suggest that halogen incorporation could facilitate intercalation and de-intercalation of Li-ions in borophene-based anode materials.


Spontaneous growth in German children and adolescents with genetically confirmed Prader-Willi syndrome.
Height and weight in children with Prader-Willi syndrome, diagnosed by standard clinical criteria, follow a specific developmental pattern resulting in early childhood obesity, absent pubertal growth spurt and adolescent short stature. New molecular techniques (methylation analysis, fluorescence in situ hybridization) now allow the unequivocal diagnosis of Prader-Willi syndrome (PWS). We investigated the possibility of a bias in syndrome-specific growth standards based on clinically diagnosed patients by comparing these standards with new standards derived from 100 German patients with molecularly confirmed PWS, none of whom had received a growth-promoting therapy. Height centile curves of the German patients fall in the tall range of standards derived from American patients. This is mainly due to an elevation of the lower centile ranges in both sexes. When the height standards derived from German patients are compared to those of a large multinational cohort of patients, 78% of whom were not confirmed by genetic testing, only minor differences in the height centiles become apparent. The population background therefore does not appear to play a major role for the observed differences. In a marked proportion of patients a decreased sitting height/height ratio is found. This was usually associated with scoliosis. Weight standards from our study group show that after 14 y of age German girls with PWS are heavier than their American counterparts. Standards for the body mass index of German patients of both sexes are increased over normal reference standards (p < 0.0001) and do increase with age (boys: p = 0.0038; girls: p = 0.0004). PWS genotypes or sex had no apparent influence on SDS for height, weight and body mass index. Because of the observed differences to other growth standards, use of the newly constructed centile curves is advocated in German patients with molecularly confirmed PWS to avoid delay in the diagnosis of additional growth-compromising conditions.


Crystal structures of poly(ADP-ribose) polymerase-1 (PARP-1) zinc fingers bound to DNA: structural and functional insights into DNA-dependent PARP-1 activity.
Poly(ADP-ribose) polymerase-1 (PARP-1) has two homologous zinc finger domains, Zn1 and Zn2, that bind to a variety of DNA structures to stimulate poly(ADP-ribose) synthesis activity and to mediate PARP-1 interaction with chromatin. The structural basis for interaction with DNA is unknown, which limits our understanding of PARP-1 regulation and involvement in DNA repair and transcription. Here, we have determined crystal structures for the individual Zn1 and Zn2 domains in complex with a DNA double strand break, providing the first views of PARP-1 zinc fingers bound to DNA. The Zn1-DNA and Zn2-DNA structures establish a novel, bipartite mode of sequence-independent DNA interaction that engages a continuous region of the phosphodiester backbone and the hydrophobic faces of exposed nucleotide bases. Biochemical and cell biological analysis indicate that the Zn1 and Zn2 domains perform distinct functions. The Zn2 domain exhibits high binding affinity to DNA compared with the Zn1 domain. However, the Zn1 domain is essential for DNA-dependent PARP-1 activity in vitro and in vivo, whereas the Zn2 domain is not strictly required. Structural differences between the Zn1-DNA and Zn2-DNA complexes, combined with mutational and structural analysis, indicate that a specialized region of the Zn1 domain is re-configured through the hydrophobic interaction with exposed nucleotide bases to initiate PARP-1 activation.


Grain dust and endotoxin inhalation challenges produce similar inflammatory responses in normal subjects.
To compare the physiologic and inflammatory response following inhalation of corn dust extract (CDE) and lipopolysaccharide (LPS) solutions in normal subjects. Randomized, double-blind crossover design. Fourteen healthy, nonatopic, nonasthmatic, never-smoking volunteers. On separate visits, subjects underwent a series of four inhalation challenges to LPS or CDE, each containing either a high (6 micrograms/mL) or low (0.9 microgram/mL) endotoxin concentration, and administered at equal Xolumes. Chest tightness, cough, dyspnea, and sputum production were experienced following both LPS and CDE exposures and with similar frequency at both high and low endotoxin concentrations. LPS and CDE inhalations caused acute declines in FEV1, and the changes in FEV1 from baseline following exposure to both inhalants were not significantly different at both high and low endotoxin concentrations. Following exposure to the high-endotoxin LPS and CDE, no consistent differences in total cell and cytokine (tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta [IL-1 beta], IL-6, IL-8) concentrations were seen between exposures, although the neutrophil concentration was greater following the LPS exposure (p = 0.01). BAL cellularity and cytokine concentrations following the low-endotoxin LPS and CDE exposure revealed no differences, except for IL-1 beta, which was greater following LPS exposure (p = 0.05). The high-endotoxin LPS and CDE exposures resulted in greater increases in BAL neutrophils and cytokines in comparison to its respective low-endotoxin exposure. At exposure levels of endotoxin, LPS and CDE result in similar symptoms, changes in airflow, and increases in BAL inflammatory cells and mediators. Moreover, the physiologic and inflammatory response to LPS and CDE appears to be related to the exposure level of endotoxin.


Rapid whole-genome sequencing for surveillance of Salmonella enterica serovar enteritidis.
For Salmonella enterica serovar Enteritidis, 85% of isolates can be classified into 5 pulsed-field gel electrophoresis (PFGE) types. However, PFGE has limited discriminatory power for outbreak detection. Although whole-genome sequencing has been found to improve discrimination of outbreak clusters, whether this procedure can be used in real-time in a public health laboratory is not known. Therefore, we conducted a retrospective and prospective analysis. The retrospective study investigated isolates from 1 confirmed outbreak. Additional cases could be attributed to the outbreak strain on the basis of whole-genome data. The prospective study included 58 isolates obtained in 2012, including isolates from 1 epidemiologically defined outbreak. Whole-genome sequencing identified additional isolates that could be attributed to the outbreak, but which differed from the outbreak-associated PFGE type. Additional putative outbreak clusters were detected in the retrospective and prospective analyses. This study demonstrates the practicality of implementing this approach for outbreak surveillance in a state public health laboratory.


Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts.
Marfan syndrome (MFS) is an autosomal dominant genetic disease caused by abnormal formation of the extracellular matrix with an incidence of 1 in 3, 000 to 5, 000. Patients with Marfan syndrome experience poor quality of life caused by skeletal disorders such as scoliosis, and they are at high risk of sudden death from cardiovascular impairment. Suitable animal models of MFS are essential for conquering this intractable disease. In particular, studies employing pig models will likely provide valuable information that can be extrapolated to humans because of the physiological and anatomical similarities between the two species. Here we describe the generation of heterozygous fibrillin-1 (FBN1) mutant cloned pigs (+/Glu433AsnfsX98) using genome editing and somatic cell nuclear transfer technologies. The FBN1 mutant pigs exhibited phenotypes resembling those of humans with MFS, such as scoliosis, pectus excavatum, delayed mineralization of the epiphysis and disrupted structure of elastic fibres of the aortic medial tissue. These findings indicate the value of FBN1 mutant pigs as a model for understanding the pathogenesis of MFS and for developing treatments.


Resilience, Emotional Intelligence, and Occupational Performance in Family Members Who Are the Caretakers of Patients with Dementia in Spain: A Cross-Sectional, Analytical, and Descriptive Study.
The concern in the scientific community for the study of people with dementia and their families is comprehensible, especially the importance of knowing the effects that caring for the patient has on their family dynamic, paying special attention to the main caregiver. The objective of this study was to analyze the relationship of resilience and emotional intelligence with functional performance in the main caregivers of people with dementia in Spain according to the phase of the disease. A cross-sectional, descriptive, and analytical study was carried out. A total of 144 primary family caregivers of patients with dementia in Spain were included in the study. The following variables were measured: sociodemographic, psychosocial, and occupational, as well as resilience and emotional intelligence. The caregivers obtained a low moderate resilience (mean = 64.01 ± 14.5), an emotional intelligence bordering between moderate and high (mean = 78.48 ± 14.82), and a 61.8% self-care categorized as somewhat and quite a bit. The presence of higher levels of resilience in family caregivers of people with dementia were positively related to the time spent on self-care (r = 0.227; p = 0.033) and leisure (r = 0.262; p = 0.014), especially in the moderate phase of the disease, while in the severe phase, this relationship appeared with productivity (r = 0.355; p = 0.034). The higher levels of emotional intelligence were positively related to a greater time dedicated to self-care (r = 0.233, p = 0.005), as well as the data observed in the moderate and severe phase (r = 0.214; p = 0.046 and r = 0.398; p = 0.016 respectively). The primary caregivers of relatives with dementia who have higher levels of resilience and emotional intelligence spend more time on self-care and leisure activities, especially in the moderate phase of the disease.


Inositol 1,4,5-trisphosphate receptor 1 mutation perturbs glucose homeostasis and enhances susceptibility to diet-induced diabetes.
The inositol 1,4,5-trisphosphate receptors (IP3Rs) as ligand-gated Ca(2)(+) channels are key modulators of cellular processes. Despite advances in understanding their critical role in regulating neuronal function and cell death, how this family of proteins impact cell metabolism is just emerging. Unexpectedly, a transgenic mouse line (D2D) exhibited progressive glucose intolerance as a result of transgene insertion. Inverse PCR was used to identify the gene disruption in the D2D mice. This led to the discovery that Itpr1 is among the ten loci disrupted in chromosome 6. Itpr1 encodes for IP3R1, the most abundant IP3R isoform in mouse brain and also highly expressed in pancreatic β-cells. To study IP3R1 function in glucose metabolism, we used the Itpr1 heterozygous mutant mice, opt/+. Glucose homeostasis in male mice cohorts was examined by multiple approaches of metabolic phenotyping. Under regular diet, the opt/+ mice developed glucose intolerance but no insulin resistance. Decrease in second-phase glucose-stimulated blood insulin level was observed in opt/+ mice, accompanied by reduced β-cell mass and insulin content. Strikingly, when fed with high-fat diet, the opt/+ mice were more susceptible to the development of hyperglycemia, glucose intolerance, and insulin resistance. Collectively, our studies identify the gene Itpr1 being interrupted in the D2D mice and uncover a novel role of IP3R1 in regulation of in vivo glucose homeostasis and development of diet-induced diabetes.


A formation mechanism for catalytically grown helix-shaped graphite nanotubes.
The concept of a spatial-velocity hodograph is introduced to describe quantitatively the extrusion of a carbon tubule from a catalytic particle. The conditions under which a continuous tubular surface can be generated are discussed in terms of this hodograph, the shape of which determines the geometry of the initial nanotube. The model is consistent with all observed tubular shapes and explains why the formation process induces stresses that may lead to "spontaneous" plastic deformation of the tubule. This result is due to the violation of the continuity condition, that is, to the mismatch between the extrusion velocity by the catalytic particle, required to generate a continuous tubular surface, and the rate of carbon deposition.


Integration of linear, heterologous DNA molecules into the Bacillus subtilis chromosome: mechanism and use in induction of predictable rearrangements.
Linear DNA molecules composed of a central region nonhomologous with the Bacillus subtilis chromosome and two flanking regions homologous with the chromosome can integrate into the chromosome, provided that the homologous regions have the same relative orientation. The resulting chromosome can be maintained in a haploid or in a merodiploid cell together with a parental chromosome. This can most easily be explained by supposing that the integration occurs by crossing over at each homologous region and that a part of the chromosome between these regions is deleted and replaced by the central nonhomologous region of the integrating molecule. If no essential genes were replaced during that process a haploid cell would be obtained; if essential genes were replaced a merodiploid cell would be obtained. The use of appropriate linear molecules therefore should allow the induction of deletions, extending from a given chromosomal site in a predetermined direction, and defined duplications in the B. subtilis chromosome.


Influence of Institutional Guidelines on Oral Hygiene Practices in Intensive Care Units.
Maintaining oral hygiene is a key component of preventing ventilator-associated pneumonia; however, practices are inconsistent. To explore how characteristics of institutional guidelines for oral hygiene influence nurses' oral hygiene practices and perceptions of that practice. Oral hygiene section of a larger survey study on prevention of ventilator-associated pneumonia. Critical care nurses at 8 hospitals in Northern California that had more than 1000 ventilator days in 2009 were recruited to participate in the survey. Twenty-one questions addressed oral hygiene practices and practice perceptions. Descriptive statistics, analysis of variance, and Spearman correlations were used for analyses. A total of 576 critical care nurses (45% response rate) responded to the survey. Three types of institutional oral hygiene guidelines existed: nursing policy, order set, and information bulletin. Nursing policy provided the most detail about the oral hygiene care; however, adherence, awareness, and priority level were higher with order sets (P < .05). The content and method of disseminating these guidelines varied, and nursing practices were affected by these differences. Nurses assessed the oral cavity and used oral swabs more often when those practices were included in institutional guidelines. The content and dissemination method of institutional guidelines on oral hygiene do influence the oral hygiene practices of critical care nurses. Future studies examining how institutional guidelines could best be incorporated into routine workflow are needed.


Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022.
To compare the safety of nelfinavir and nevirapine-based antiretroviral treatment in HIV-1-infected pregnant women. In Pediatric AIDS Clinical Trials Group Protocol 1022, 38 antiretroviral-naive pregnant women at 10-30 weeks' gestation were randomized to nelfinavir or nevirapine with zidovudine plus lamivudine. The study was suspended because of greater than expected toxicity and changes in nevirapine prescribing information. The incidence of treatment-limiting hepatic or cutaneous toxicity was compared between groups for all subjects and for the subset with CD4 cell counts greater than 250 cells/microL at study entry. Toxicity was seen in 1 (5%) of 21 subjects randomized to nelfinavir and 5 (29%) of 17 subjects randomized to nevirapine (P = 0.07). Within the nevirapine group, 1 subject developed fulminant hepatic failure and died, and another developed Stevens-Johnson syndrome. The one adverse event associated with nelfinavir occurred in a subject with a CD4 cell count less than 250 cells/microL. All 5 events among subjects with a CD4 cell count greater than 250 cells/microL were associated with nevirapine (P = 0.04). Continuous nevirapine may be associated with increased toxicity among HIV-1-infected pregnant women with CD4 cell counts greater than 250 cells/microL, as has been observed in non-pregnant women.


Serum hemoglobin concentration and risk of renal function decline in early stages of diabetic kidney disease: a nationwide, biopsy-based cohort study.
Prognosticating disease progression in patients with diabetic kidney disease (DKD) is challenging, especially in the early stages of kidney disease. Anemia can occur in the early stages of kidney disease in diabetes. We therefore postulated that serum hemoglobin (Hb) concentration, as a reflection of incipient renal tubulointerstitial impairment, can be used as a marker to predict DKD progression. Drawing on nationally representative data of patients with biopsy-proven DKD, 246 patients who had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 at renal biopsy were identified: age 56 (45-63) years; 62.6% men; Hb 13.3 (12.0-14.5) g/dL; eGFR 76.2 (66.6-88.6) mL/min/1.73 m2; urine albumin-to-creatinine ratio 534 (100-1480) mg/g Crea. Serum Hb concentration was divided into quartiles: ≤12, 12.1-13.3, 13.4-14.5 and ≥14.6 g/dL. The association between serum Hb concentration and the severity of renal pathological lesions was explored. A multivariable Cox regression model was used to estimate the risk of DKD progression (new onset of end-stage kidney disease, 50% reduction of eGFR or doubling of serum creatinine). The incremental prognostic value of DKD progression by adding serum Hb concentration to the known risk factors of DKD was assessed. Serum Hb levels negatively correlated with all renal pathological features, especially with the severity of interstitial fibrosis (ρ = -0.52; P < 0.001). During a median follow-up of 4.1 years, 95 developed DKD progression. Adjusting for known risk factors of DKD progression, the hazard ratio in the first, second and third quartile (the fourth quartile was reference) were 2.74 [95% confidence interval (CI) 1.26-5.97], 2.33 (95% CI 1.07-5.75) and 1.46 (95% CI 0.71-3.64), respectively. Addition of the serum Hb concentration to the known risk factors of DKD progression improved the prognostic value of DKD progression (the global Chi-statistics increased from 55.1 to 60.8; P < 0.001). Serum Hb concentration, which reflects incipient renal fibrosis, can be useful for predicting DKD progression in the early stages of kidney disease.


Microbial sulfur transformations in sediments from Subglacial Lake Whillans.
Diverse microbial assemblages inhabit subglacial aquatic environments. While few of these environments have been sampled, data reveal that subglacial organisms gain energy for growth from reduced minerals containing nitrogen, iron, and sulfur. Here we investigate the role of microbially mediated sulfur transformations in sediments from Subglacial Lake Whillans (SLW), Antarctica, by examining key genes involved in dissimilatory sulfur oxidation and reduction. The presence of sulfur transformation genes throughout the top 34 cm of SLW sediments changes with depth. SLW surficial sediments were dominated by genes related to known sulfur-oxidizing chemoautotrophs. Sequences encoding the adenosine-5'-phosphosulfate (APS) reductase gene, involved in both dissimilatory sulfate reduction and sulfur oxidation, were present in all samples and clustered into 16 distinct operational taxonomic units. The majority of APS reductase sequences (74%) clustered with known sulfur oxidizers including those within the "Sideroxydans" and Thiobacillus genera. Reverse-acting dissimilatory sulfite reductase (rDSR) and 16S rRNA gene sequences further support dominance of "Sideroxydans" and Thiobacillus phylotypes in the top 2 cm of SLW sediments. The SLW microbial community has the genetic potential for sulfate reduction which is supported by experimentally measured low rates (1.4 pmol cm(-3)d(-1)) of biologically mediated sulfate reduction and the presence of APS reductase and DSR gene sequences related to Desulfobacteraceae and Desulfotomaculum. Our results also infer the presence of sulfur oxidation, which can be a significant energetic pathway for chemosynthetic biosynthesis in SLW sediments. The water in SLW ultimately flows into the Ross Sea where intermediates from subglacial sulfur transformations can influence the flux of solutes to the Southern Ocean.


Coloring genetically modified soybean grains with anthocyanins by suppression of the proanthocyanidin genes ANR1 and ANR2.
Detection and quantification of the levels of adventitious presence of genetically modified (GM) soybeans in non-GM grain shipments currently requires sophisticated tests that can have issues with their reproducibility. We show here that pigment biosynthesis in the soybean seed coat can be manipulated to provide a distinct color that would enable the simple visible detection of the GM soybean grain. We observed that a distinct red-brown grain color could be engineered by the simultaneous suppression of two proanthocyanidin (PA) genes, ANTHOCYANIDIN REDUCTASE1 (ANR1) and ANR2. Multiple reaction monitoring by liquid chromatography tandem mass spectrometry was used to quantify differentially accumulated seed coat metabolites, and revealed the redirection of metabolic flux into the anthocyanin pigment pathway and unexpectedly the flavonol-3-O-glucoside pathway. The upregulations of anthocyanin isogenes (DFR1 and GST26) and the anthocyanin/flavonol-3-O-glycosyltransferase (UGT78K2) were identified by quantitative RT-PCR to be endogenous feedback and feedforward responses to overaccumulation of upstream flavonoid intermediates resulting from ANR1 and ANR2 suppressions. These results suggested the transcription of flavonoid genes to be a key component of the mechanism responsible for the redirection of metabolite flux. This report identifies the suppression of PA genes to be a novel approach for engineering pigmentation in soybean grains.


Comparing the effects of HIV self-testing to standard HIV testing for key populations: a systematic review and meta-analysis.
We update a previous systematic review to inform new World Health Organization HIV self-testing (HIVST) recommendations. We compared the effects of HIVST to standard HIV testing services to understand which service delivery models are effective for key populations. We did a systematic review of randomised controlled trials (RCTs) which compared HIVST to standard HIV testing in key populations, published from 1 January 2006 to 4 June 2019 in PubMed, Embase, Global Index Medicus, Social Policy and Practice, PsycINFO, Health Management Information Consortium, EBSCO CINAHL Plus, Cochrane Library and Web of Science. We extracted study characteristic and outcome data and conducted risk of bias assessments using the Cochrane ROB tool version 1. Random effects meta-analyses were conducted, and pooled effect estimates were assessed along with other evidence characteristics to determine the overall strength of the evidence using GRADE methodology. After screening 5909 titles and abstracts, we identified 10 RCTs which reported on testing outcomes. These included 9679 participants, of whom 5486 were men who have sex with men (MSM), 72 were trans people and 4121 were female sex workers. Service delivery models included facility-based, online/mail and peer distribution. Support components were highly diverse and ranged from helplines to training and supervision. HIVST increased testing uptake by 1.45 times (RR=1.45 95% CI 1.20, 1.75). For MSM and small numbers of trans people, HIVST increased the mean number of HIV tests by 2.56 over follow-up (mean difference = 2.56; 95% CI 1.24, 3.88). There was no difference between HIVST and SoC in regard to positivity among tested overall (RR = 0.91; 95% CI 0.73, 1.15); in sensitivity analysis of positivity among randomised HIVST identified significantly more HIV infections among MSM and trans people (RR = 2.21; 95% CI 1.20, 4.08) and in online/mail distribution systems (RR = 2.21; 95% CI 1.14, 4.32). Yield of positive results in FSW was not significantly different between HIVST and SoC. HIVST reduced linkage to care by 17% compared to SoC overall (RR = 0.83; 95% CI 0.74, 0.92). Impacts on STI testing were mixed; two RCTs showed no decreases in STI testing while one showed significantly lower STI testing in the intervention arm. There were no negative impacts on condom use (RR = 0.95; 95% CI 0.83, 1.08), and social harm was very rare. HIVST is safe and increases testing uptake and frequency as well as yield of positive results for MSM and trans people without negative effects on linkage to HIV care, STI testing, condom use or social harm. Testing uptake was increased for FSW, yield of positive results were not and linkage to HIV care was worse. Strategies to improve linkage to care outcomes for both groups are crucial for effective roll-out.


Representation of molecular structures with persistent homology for machine learning applications in chemistry.
Machine learning and high-throughput computational screening have been valuable tools in accelerated first-principles screening for the discovery of the next generation of functionalized molecules and materials. The application of machine learning for chemical applications requires the conversion of molecular structures to a machine-readable format known as a molecular representation. The choice of such representations impacts the performance and outcomes of chemical machine learning methods. Herein, we present a new concise molecular representation derived from persistent homology, an applied branch of mathematics. We have demonstrated its applicability in a high-throughput computational screening of a large molecular database (GDB-9) with more than 133,000 organic molecules. Our target is to identify novel molecules that selectively interact with CO2. The methodology and performance of the novel molecular fingerprinting method is presented and the new chemically-driven persistence image representation is used to screen the GDB-9 database to suggest molecules and/or functional groups with enhanced properties.