Clinical impact of urinary CD11b and CD163 on the renal outcomes of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.
The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN. U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period. U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-related disease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy. Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.


α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy.
The antiepileptic drug ethosuximide has recently been shown to be neuroprotective in various Caenorhabditis elegans and rodent neurodegeneration models. It is therefore a promising repurposing candidate for the treatment of multiple neurodegenerative diseases. However, high concentrations of the drug are required for its protective effects in animal models, which may impact on its translational potential and impede the identification of its molecular mechanism of action. Therefore, we set out to develop more potent neuroprotective lead compounds based on ethosuximide as a starting scaffold. Chemoinformatic approaches were used to identify compounds with structural similarity to ethosuximide and to prioritise these based on good predicated blood-brain barrier permeability and C. elegans bioaccumulation properties. Selected compounds were initially screened for anti-convulsant activity in a C. elegans pentylenetetrazol-induced seizure assay, as a rapid primary readout of bioactivity; and then assessed for neuroprotective properties in a C. elegans TDP-43 proteinopathy model based on pan-neuronal expression of human A315T mutant TDP-43. The most potent compound screened, α-methyl-α-phenylsuccinimide (MPS), ameliorated the locomotion defects and extended the shortened lifespan of TDP-43 mutant worms. MPS also directly protected against neurodegeneration by reducing the number of neuronal breaks and cell body losses in GFP-labelled GABAergic motor neurons. Importantly, optimal neuroprotection was exhibited by external application of 50 μM MPS, compared to 8 mM for ethosuximide. This greater potency of MPS was not due to bioaccumulation to higher internal levels within the worm, based on 1H-nuclear magnetic resonance analysis. Like ethosuximide, the activity of MPS was abolished by mutation of the evolutionarily conserved FOXO transcription factor, daf-16, suggesting that both compounds act via the same neuroprotective pathway(s). In conclusion, we have revealed a novel neuroprotective activity of MPS that is >100-fold more potent than ethosuximide. This increased potency will facilitate future biochemical studies to identify the direct molecular target(s) of both compounds, as we have shown here that they share a common downstream DAF-16-dependent mechanism of action. Furthermore, MPS is the active metabolite of another approved antiepileptic drug, methsuximide. Therefore, methsuximide may have repurposing potential for treatment of TDP-43 proteinopathies and possibly other human neurodegenerative diseases.


A novel electric design for electromagnetic stimulation--the Slinky coil.
A novel coil design for inductive electromagnetic stimulation of neural cells has been simulated and experimentally tested. This coil improves the focal effect of a magnetic stimulator, and it reduces its inductance, hence the efficiency of the system is improved. The basic structure of the device is derived from the popular "Slinky" toy. The actual device is formed by winding different numbers of loops forming a helical coil on a half torus. The loops are bunched at the axis of the torus. The coil, due to its geometry, generates a unique distribution of eddy currents in nearby tissues which is favorable compared to a solenoid type stimulator. This renders the Slinky coil more selective than conventional coils used for magnetic stimulation. The distribution of eddy currents was analyzed using Matlab, following Faraday's Law of Induction. Improved focality permits the current through the coil to be reduced for the same effect. In addition, the reduced inductance of the Slinky coil decreases the power requirement; thus, the improved efficiency of the system may allow the generation of bursts of pulses, and expand the utilization of the system to possible functional activation of certain neuro-muscular structures when peripheral nerves are stimulated.


Inhibition of 5-lipoxygenase downregulates stemness and kills prostate cancer stem cells by triggering apoptosis via activation of c-Jun N-terminal kinase.
The cancer stem cell (CSC) concept suggests that neoplastic clones are maintained exclusively by a rare group of cells possessed with stem cell properties. CSCs are characterized by features that include self-renewal, pluripotency and tumorigenicity, and are thought to be solely responsible for tumor recurrence and metastasis. A hierarchically organized CSC model is becoming increasingly evident for various types of cancer, including prostate cancer. The CD44 (+), CD133 (+) cell subpopulations were isolated from human prostate tumors which exhibit stem-like properties showing therapeutic-resistance, capacity of self-renewal, and exact recapitulation of the original tumor in vivo. Thus, an important challenge is to find measures to eliminate these cancer stem cells, which will stop tumor growth and prevent disease-recurrence. However, knowledge about molecular features critical for the survival of prostate cancer stem cells (PCSC) is meager. Here we report that inhibition of 5-lipoxygenase (5-Lox) by shRNA or MK591 dramatically kills PCSC by inducing apoptosis, suggesting that 5-Lox plays an essential role in the survival of PCSC. Interestingly, MK591 treatment decreases protein levels and inhibits transcriptional activities of Nanog and c-Myc. Since Nanog and c-Myc play important roles as stemness factors, our findings indicate that the 5-Lox activity plays a causal role in maintaining prostate cancer stemness via regulation of Nanog and c-Myc, and suggest that further exploration of 5-Lox-mediated signaling in PCSC may lead to development of novel, target-based, durable strategies to effectively block development and growth of prostate tumors, and prevent prostate cancer recurrence.


Application of CRISPR/Cas9-Based Reverse Genetics in Leishmania braziliensis: Conserved Roles for HSP100 and HSP23.
The protozoan parasite Leishmania (Viannia) braziliensis (L. braziliensis) is the main cause of human tegumentary leishmaniasis in the New World, a disease affecting the skin and/or mucosal tissues. Despite its importance, the study of the unique biology of L. braziliensis through reverse genetics analyses has so far lagged behind in comparison with Old World Leishmania spp. In this study, we successfully applied a cloning-free, PCR-based CRISPR-Cas9 technology in L. braziliensis that was previously developed for Old World Leishmania major and New World L. mexicana species. As proof of principle, we demonstrate the targeted replacement of a transgene (eGFP) and two L. braziliensis single-copy genes (HSP23 and HSP100). We obtained homozygous Cas9-free HSP23- and HSP100-null mutants in L. braziliensis that matched the phenotypes reported previously for the respective L. donovani null mutants. The function of HSP23 is indeed conserved throughout the Trypanosomatida as L. majorHSP23 null mutants could be complemented phenotypically with transgenes from a range of trypanosomatids. In summary, the feasibility of genetic manipulation of L. braziliensis by CRISPR-Cas9-mediated gene editing sets the stage for testing the role of specific genes in that parasite's biology, including functional studies of virulence factors in relevant animal models to reveal novel therapeutic targets to combat American tegumentary leishmaniasis.


Natural selection and outbreeding depression suggest adaptive differentiation in the invasive range of a clonal plant.
Analyses of phenotypic selection and demography in field populations are powerful ways to establishing the potential role of natural selection in shaping evolution during biological invasions. Here we use experimental F2 crosses between native and introduced populations of Mimulus guttatus to estimate the pattern of natural selection in part of its introduced range, and to seek evidence of outbreeding depression of colonists. The F2s combined the genome of an introduced population with the genome of either native or introduced populations. We found that the introduced × introduced cross had the fastest population growth rate owing to increased winter survival, clonality and seed production. Our analysis also revealed that selection through sexual fitness favoured large floral displays, large vegetative and flower size, lateral spread and early flowering. Our results indicate a source-of-origin effect, consistent with outbreeding depression exposed by mating between introduced and native populations. Our findings suggest that well-established non-native populations may pay a high fitness cost during subsequent bouts of admixture with native populations, and reveal that processes such as local adaptation in the invasive range can mediate the fitness consequences of admixture.


The use of 3D surface fitting for robust polyp detection and classification in CT colonography.
In this paper we describe the development of a computationally efficient computer-aided detection (CAD) algorithm based on the evaluation of the surface morphology that is employed for the detection of colonic polyps in computed tomography (CT) colonography. Initial polyp candidate voxels were detected using the surface normal intersection values. These candidate voxels were clustered using the normal direction, convexity test, region growing and Gaussian distribution. The local colonic surface was classified as polyp or fold using a feature normalized nearest neighborhood classifier. The main merit of this paper is the methodology applied to select the robust features derived from the colon surface that have a high discriminative power for polyp/fold classification. The devised polyp detection scheme entails a low computational overhead (typically takes 2.20min per dataset) and shows 100% sensitivity for phantom polyps greater than 5mm. It also shows 100% sensitivity for real polyps larger than 10mm and 91.67% sensitivity for polyps between 5 to 10mm with an average of 4.5 false positives per dataset. The experimental data indicates that the proposed CAD polyp detection scheme outperforms other techniques that identify the polyps using features that sample the colon surface curvature especially when applied to low-dose datasets.


The microRNA-29 Family Dictates the Balance Between Homeostatic and Pathological Glucose Handling in Diabetes and Obesity.
The microRNA-29 (miR-29) family is among the most abundantly expressed microRNA in the pancreas and liver. Here, we investigated the function of miR-29 in glucose regulation using miR-29a/b-1 (miR-29a)-deficient mice and newly generated miR-29b-2/c (miR-29c)-deficient mice. We observed multiple independent functions of the miR-29 family, which can be segregated into a hierarchical physiologic regulation of glucose handling. miR-29a, and not miR-29c, was observed to be a positive regulator of insulin secretion in vivo, with dysregulation of the exocytotic machinery sensitizing β-cells to overt diabetes after unfolded protein stress. By contrast, in the liver both miR-29a and miR-29c were important negative regulators of insulin signaling via phosphatidylinositol 3-kinase regulation. Global or hepatic insufficiency of miR-29 potently inhibited obesity and prevented the onset of diet-induced insulin resistance. These results demonstrate strong regulatory functions for the miR-29 family in obesity and diabetes, culminating in a hierarchical and dose-dependent effect on premature lethality.


Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease.
Mutations in five PARK genes (SNCA, PARKIN, DJ-1, PINK1, and LRRK2) are well-established genetic causes of Parkinson disease (PD). Recently, G2385R substitution in LRRK2 has been determined as a susceptibility allele in Asian PD. The objective of this study is to determine the frequency of mutations in these PARK genes in a Korean early-onset Parkinson disease (EOPD) cohort. The authors sequenced 35 exons in SNCA, PARKIN, DJ-1, PINK1, and LRRK2 in 72 unrelated EOPD (age-at-onset <or=50) recruited from ten movement disorders clinics in South Korea. Gene dosage change of the aforementioned genes was studied using multiple ligation-dependent probe amplification. We found four patients with PARKIN mutations, which were homozygous deletion of exon 4, compound heterozygous deletion of exon 2 and exon 4, heterozygous deletion of exon 4, and heterozygous nonsense mutation (Q40X). Four patients had PINK1 mutations; a compound heterozygous mutation (N367S and K520RfsX522) and three heterozygous mutations (G32R, R279H, and F385L). A missense mutation of SNCA (A53T) was found in a familial PD with autosomal dominant inheritance. Nine patients (12.5%) had heterozygous G2385R polymorphism of LRRK2, whereas none had G2019S mutation. However, no mutations were detected in DJ-1 and UCHL1 in our series. We identified genetic variants in PARKIN, PINK1, LRRK2, and SNCA as a cause or genetic risk factors for PD in 25% of Korean EOPD, and mutation of PARKIN was the most common genetic cause.


Cognitively Challenging Agility Boot Camp Program for Freezing of Gait in Parkinson Disease.
Introduction. It is well documented that freezing of gait (FoG) episodes occur in situations that are mentally challenging, such as dual tasks, consistent with less automatic control of gait in people with Parkinson disease (PD) and FoG. However, most physical rehabilitation does not include such challenges. The purpose was to determine (1) feasibility of a cognitively challenging Agility Boot Camp-Cognitive (ABC-C) program and (2) effects of this intervention on FoG, dual-task cost, balance, executive function, and functional connectivity. Methods. A total of 46 people with PD and FoG enrolled in this randomized crossover trial. Each participant had 6 weeks of ABC-C and Education interventions. Outcome measures were the following: FoG, perceived and objective measures; dual-task cost on gait; balance; executive function; and right supplementary motor area (SMA)-pedunculopontine nucleus (PPN) functional connectivity. Effect sizes were calculated. Results. ABC-C had high compliance (90%), with a 24% dropout rate. Improvements after exercise, revealed by moderate and large effect sizes, were observed for subject perception of FoG after exercise, dual-task cost on gait speed, balance, cognition (Scales for Outcomes in Parkinson's disease-Cognition), and SMA-PPN connectivity. Conclusions. The ABC-C for people with PD and FoG is a feasible exercise program that has potential to improve FoG, balance, dual-task cost, executive function, and brain connectivity. The study provided effect sizes to help design future studies with more participants and longer duration to fully determine the potential to improve FoG.


The ecology of suburban juvenile European hedgehogs (Erinaceus europaeus) in Denmark.
European hedgehog (Erinaceus europaeus) populations are widespread across diverse habitats but are declining in Western Europe. Drastic declines have been described in the UK, with the most severe declines occurring in rural areas. Hedgehogs are widely distributed in Denmark, but their status remains unknown.Fieldwork on hedgehogs has tended to focus on rural areas, leaving their ecology in suburban habitats largely unexplored, with clear implications for conservation initiatives. Here, we study the ecology of 35 juvenile hedgehogs using radio tracking during their first year of life in the suburbs of western Copenhagen.We use radio-tracking data to estimate (a) home range sizes in autumn and spring/summer, (b) survival during their first year of life, (c) the body mass changes before, during, and after hibernation, and (d) the hibernation behavior of the juvenile hedgehogs.We show that males and females have small home ranges compared with previous studies. The 95% MCP home range sizes in autumn were 1.33 ha (95% CI = 0.88-2.00) for males and 1.40 ha (95% CI = 0.84-2.32) for females; for spring/summer they were 6.54 ha (95% CI = 3.76-11.38) for males and 1.51 ha (95% CI = 0.63-3.63) for females. The juvenile survival probabilities during the study period from September 2014 to July 2015 were .56 for females and .79 for males. All healthy individuals gained body mass during the autumn and survived hibernation with little body mass loss thus demonstrating that the juveniles in the study were capable of gaining sufficient weight in the wild to survive their first hibernation.The climate is changing, but there is a lack of knowledge on how this affects mammal ecology. The exceptionally mild autumn of 2014 caused the juvenile hedgehogs to delay hibernation for up to a month compared with previous studies in Denmark.


A novel photo-active Cd:1,4-benzene dicarboxylate metal organic framework templated using [Ru(ii)(2,2'-bipyridine)3]2+: synthesis and photophysics of RWLC-5.
The development of photoactive porous materials is of significant importance for applications ranging from sustainable energy to pharmaceutical development and catalysis. A particularly attractive class of photo-active materials is the metal-organic framework (MOF)-based platform in which the photo-active elements are components of the framework itself or photo-active guests encapsulated within the MOF cavities. It has now been demonstrated that the photo-active [Ru(2,2'-bipyridine)3]2+ (RuBpy) complex can template the formation of MOFs with varying three dimensional structures. Here we report the synthesis and structural and photo-physical characterization of a new RuBpy-templated MOF composed of Cd2+ ions with 1,4-benzenedicarboxylate ligands (RWLC-5) that contains crystallographically resolved RuBpy complexes. The new material displays a biphasic emission decay (130 ns and 1180 ns, T = 20 °C) and a bathochromically shifted emission maximum, relative to RuBpy in solution (603 nm for RuBpy in ethanol vs. 630 nm for RWLC-5). The emission lifetimes also do not display temperature-dependent decays which are characteristic of RuBpy type complexes as well as other RuBpy templated MOFs. The lack of temperature dependence is consistent with the complete deactivation of the 3LF state of the encapsulated RuBpy complex due to a constrained environment. The fast phase decay is attributed to a water molecule hydrogen bonded to a bipyridine ligand associated with ∼38% of the encapsulated RuBpy complexes resulting in the nonradiative deactivation of the 3MLCT state.


[Rhabdomyolisis caused by spinning in nine patients].
Rhabdomyolysis is a syndrome that results from the destruction of the skeletal muscle. The one produced by exercise is observed after an intense physical effort. A form of high-intensity exercise called spinning or indoor cycling that involves using a stationary bicycle, has been exceptionally reported as a generating factor of muscular damage in the medical literature. A retrospective study was performed to assess the clinical presentation and the complications shown by nine patients who experienced rhabdomyolysis caused by indoor cycling. The prevailing symptoms were myalgias, asthenia, myoglobinuria and functional impotence of the lower limbs. All the patients showed significant muscular enzyme increases and the values of creatinephosphokinase ranged from 1650 to 165 000 IU/l. Only one of the patients showed kidney failure and another patient showed hypocalcemia; both parameters standardized with treatment. No relationship has been found between the increase of muscular enzymes and the development of complications. The aim of this study is to present a series of cases of rhabdomyolysis caused by indoor cycling and to warn about the risks that this activity may involve.


Myeloid neddylation targets IRF7 and promotes host innate immunity against RNA viruses.
Neddylation, an important type of post-translational modification, has been implicated in innate and adapted immunity. But the role of neddylation in innate immune response against RNA viruses remains elusive. Here we report that neddylation promotes RNA virus-induced type I IFN production, especially IFN-α. More importantly, myeloid deficiency of UBA3 or NEDD8 renders mice less resistant to RNA virus infection. Neddylation is essential for RNA virus-triggered activation of Ifna gene promoters. Further exploration has revealed that mammalian IRF7undergoes neddylation, which is enhanced after RNA virus infection. Even though neddylation blockade does not hinder RNA virus-triggered IRF7 expression, IRF7 mutant defective in neddylation exhibits reduced ability to activate Ifna gene promoters. Neddylation blockade impedes RNA virus-induced IRF7 nuclear translocation without hindering its phosphorylation and dimerization with IRF3. By contrast, IRF7 mutant defective in neddylation shows enhanced dimerization with IRF5, an Ifna repressor when interacting with IRF7. In conclusion, our data demonstrate that myeloid neddylation contributes to host anti-viral innate immunity through targeting IRF7 and promoting its transcriptional activity.


Bias of averages in life-cycle footprinting of infrastructure: truck and bus case studies.
The life-cycle output (e.g., level of service) of infrastructure systems heavily influences their normalized environmental footprint. Many studies and tools calculate emission factors based on average productivity; however, the performance of these systems varies over time and space. We evaluate the appropriate use of emission factors based on average levels of service by comparing them to those reflecting a distribution of system outputs. For the provision of truck and bus services where fuel economy is assumed constant over levels of service, emission factor estimation biases, described by Jensen's inequality, always result in larger-than-expected environmental impacts (3%-400%) and depend strongly on the variability and skew of truck payloads and bus ridership. Well-to-wheel greenhouse gas emission factors for diesel trucks in California range from 87 to 1,500 g of CO2 equivalents per ton-km, depending on the size and type of trucks and the services performed. Along a bus route in San Francisco, well-to-wheel emission factors ranged between 53 and 940 g of CO2 equivalents per passenger-km. The use of biased emission factors can have profound effects on various policy decisions. If average emission rates must be used, reflecting a distribution of productivity can reduce emission factor biases.


Revealing Cues for Fungal Interplay in the Plant-Air Interface in Vineyards.
Plant-associated microorganisms play a crucial role in plant health and productivity. Belowground microbial diversity is widely reported as a major factor in determining the composition of the plant microbiome. In contrast, much less is known about the role of the atmosphere in relation to the plant microbiome. The current study examined the hypothesis that the atmospheric microbiome influences the composition of fungal communities of the aboveground organs (flowers, fruit, and leaves) of table grape and vice versa. The atmosphere surrounding grape plantings exhibited a significantly higher level of fungal diversity relative to the nearby plant organs and shared a higher number of phylotypes (5,536 OTUs, 40.3%) with the plant than between organs of the same plant. Using a Bayesian source tracking approach, plant organs were determined to be the major source of the atmospheric fungal community (92%). In contrast, airborne microbiota had only a minor contribution to the grape microbiome, representing the source of 15, 4, and 35% of the fungal communities of leaves, flowers, and fruits, respectively. Moreover, data indicate that plant organs and the surrounding atmosphere shared a fraction of each other's fungal communities, and this shared pool of fungal taxa serves as a two-way reservoir of microorganisms. Microbial association analysis highlighted more positive than negative interactions between fungal phylotypes. Positive interactions were more common within the same environment, while negative interactions appeared to occur more frequently between different environments, i.e., atmosphere, leaf, flower, and fruit. The current study revealed the interplay between the fungal communities of the grape phyllosphere with the surrounding air. Plants were identified as a major source of recruitment for the atmospheric microbiome, while the surrounding atmosphere contributed only a small fraction of the plant fungal community. The results of the study suggested that the plant-air interface modulates the plant recruitment of atmospheric fungi, taking a step forward in understanding the plant holobiont assembly and how the atmosphere surrounding plants plays a role in this process. The impact of plants on the atmospheric microbiota has several biological and epidemiological implications for plants and humans.


Test-retest reliability of a self-administered Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in primary care patients.
The time required to conduct drug and alcohol screening has been a major barrier to its implementation in mainstream healthcare settings. Because patient self-administered tools are potentially more efficient, we translated the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) into an audio guided computer assisted self interview (ACASI) format. This study reports on the test-retest reliability of the ACASI ASSIST in an adult primary care population. Adult primary care patients completed the ACASI ASSIST, in English or Spanish, twice within a 1-4 week period. Among the 101 participants, there were no significant differences between test administrations in detecting moderate to high risk use for tobacco, alcohol, or any other drug class. Substance risk scores from the two administrations had excellent concordance (90-98%) and high correlation (ICC 0.90-0.97) for tobacco, alcohol, and drugs. The ACASI ASSIST has good test-retest reliability, and warrants additional study to evaluate its validity for detecting unhealthy substance use.


High-throughput sequencing reveals key genes and immune homeostatic pathways activated in myeloid dendritic cells by Porphyromonas gingivalis 381 and its fimbrial mutants.
The human microbiome consists of highly diverse microbial communities that colonize our skin and mucosal surfaces, aiding in maintenance of immune homeostasis. The keystone pathogen Porphyromonas gingivalis induces a dysbiosis and disrupts immune homeostasis through as yet unclear mechanisms. The fimbrial adhesins of P. gingivalis facilitate biofilm formation, invasion of and dissemination by blood dendritic cells; hence, fimbriae may be key factors in disruption of immune homeostasis. In this study we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) in human monocyte-derived dendritic cells (MoDCs) in response to in vitro infection/exposure by Pg381 or its isogenic mutant strains that solely express minor-Mfa1 fimbriae (DPG3), major-FimA fimbriae (MFI) or are deficient in both fimbriae (MFB) relative to uninfected control. Our results yielded a total of 479 DEGs that were at least two-fold upregulated and downregulated in MoDCs significantly (P ≤ 0.05) by all four strains and certain DEGs that were strain-specific. Interestingly, the gene ontology biological and functional analysis shows that the upregulated genes in DPG3-induced MoDCs were more significant than other strains and associated with inflammation, immune response, anti-apoptosis, cell proliferation, and other homeostatic functions. Both transcriptome and quantitative polymerase chain reaction results show that DPG3, which solely expresses Mfa1, increased ZNF366, CD209, LOX1, IDO1, IL-10, CCL2, SOCS3, STAT3 and FOXO1 gene expression. In conclusion, we have identified key DC-mediated immune homeostatic pathways that could contribute to dysbiosis in periodontal infection with P. gingivalis.


The recombinant 65-kD heat shock protein of Mycobacterium bovis Bacillus Calmette-Guerin/M. tuberculosis is a target molecule for CD4+ cytotoxic T lymphocytes that lyse human monocytes.
Since little is known about Tc cells in the human immune response to intracellular parasites, we have studied the role of Tc cells in response to M. bovis Bacillus Calmette-Guerin (BCG). Donors whose PBMC responded to BCG, purified protein derivative (PPD), and the recombinant 65-kD heat shock protein (HSP) of BCG generated BCG/PPD-specific CD4+ effector T lymphocytes that lysed PPD as well as recombinant 65-kD-pulsed monocytes. Nonpulsed or irrelevant antigen-pulsed target cells were lysed to a much lower but still significant extent. PPD-stimulated effector lymphocytes of a recombinant 65-kD nonresponder lysed PPD but not recombinant 65-kD-pulsed monocytes. Recombinant 65-kD-educated effector lymphocytes lysed both recombinant 65-kD- and PPD-pulsed monocytes. In addition, these effector cells efficiently lysed nonpulsed target cells. These results demonstrate that in recombinant 65-kD responders, the recombinant 65-kD HSP of BCG is an immunodominant target as well as a triggering molecule for BCG/PPD-specific CD4+ cytotoxic T cells that lyse autologous monocytes. The implications of these findings with respect to the role of the 65-kD HSP in autoimmunity are discussed.


Synthesis, crystal structures, linear and nonlinear optical properties, and theoretical studies of (p-R-phenyl)-, (p-R-phenylethynyl)-, and (E)-[2-(p-R-phenyl)ethenyl]dimesitylboranes and related compounds.
The (p-R-phenyl)dimesitylboranes (R=Me(2)N, MeO, MeS, Br, I), (p-R-phenylethynyl)dimesitylboranes (R=Me(2)N, MeO, MeS, H), (E)-[2-(p-R-phenyl)ethenyl]dimesitylboranes (R=Me(2)N, H(2)N, MeO, MeS, H, CN, NO(2)), (E)-[2-(2-thienyl)ethenyl]dimesitylborane, and (E)-[2-(o-carboranyl)ethenyl]dimesitylborane have been prepared through the reaction of the appropriate p-R-phenyl- and p-R-phenylethynyllithium reagents with dimesitylboron fluoride and by hydroboration of the appropriate p-R-phenylacetylene, 2-ethynylthiophene, and o-ethynylcarborane with dimesitylborane. Their UV/Vis absorption and emission spectra have been recorded in a range of solvents with the fluorescence maxima of the donor-substituted compounds in particular exhibiting large bathochromic shifts in highly polar solvents, indicative of charge transfer leading to large dipole moments in the excited state. The molecular structures of the (p-R-phenyl)dimesitylboranes (R=Me(2)N, MeO, MeS, Br, I), the (E)-[2-(p-R-phenyl)ethenyl]dimesitylboranes (R=Me(2)N, H(2)N MeO, MeS, H), (p-R-phenylethynyl)dimesitylborane (R=Me(2)N), and (E)-[2-(2-thienyl)ethenyl]dimesitylborane, which have been determined from single-crystal X-ray diffraction measurements, offer evidence of increased conjugation in the ground state with increased donor strength of the R substituent. Their first- and second-order molecular hyperpolarizabilities have been obtained from EFISH and THG measurements, the first-order hyperpolarizabilities being largest for the strongest R-substituent donors. AM1 calculations have been performed on these compounds, showing reasonable agreement with the experimentally obtained bond lengths and hyperpolarizabilities, as well as on several related hypothetical compounds containing multiple C==C bonds, most of which are proposed to have even larger hyperpolarizabilities.


Comparison of biomarkers of oxidative stress and cardiovascular disease in humans and chimpanzees (Pan troglodytes).
In the oxidative stress hypothesis of aging, the aging process is the result of cumulative damage by reactive oxygen species. Humans and chimpanzees are remarkably similar; but humans live twice as long as chimpanzees and therefore are believed to age at a slower rate. The purpose of this study was to compare biomarkers for cardiovascular disease, oxidative stress, and aging between male chimpanzees and humans. Compared with men, male chimpanzees were at increased risk for cardiovascular disease because of their significantly higher levels of fibrinogen, IGF1, insulin, lipoprotein a, and large high-density lipoproteins. Chimpanzees showed increased oxidative stress, measured as significantly higher levels of 5-hydroxymethyl-2-deoxyuridine and 8-iso-prostaglandin F(2alpha), a higher peroxidizability index, and higher levels of the prooxidants ceruloplasmin and copper. In addition, chimpanzees had decreased levels of antioxidants, including alpha- and beta-carotene, beta-cryptoxanthin, lycopene, and tocopherols, as well as decreased levels of the cardiovascular protection factors albumin and bilirubin. As predicted by the oxidative stress hypothesis of aging, male chimpanzees exhibit higher levels of oxidative stress and a much higher risk for cardiovascular disease, particularly cardiomyopathy, compared with men of equivalent age. Given these results, we hypothesize that the longer lifespan of humans is at least in part the result of greater antioxidant capacity and lower risk of cardiovascular disease associated with lower oxidative stress.


Antibiotic-resistant E. coli in surface water and groundwater in dairy operations in Northern California.
Generic Escherichia coli was isolated from surface water and groundwater samples from two dairies in Northern California and tested for susceptibility to antibiotics. Surface samples were collected from flush water, lagoon water, and manure solids, and groundwater samples were collected from monitoring wells. Although E. coli was ubiquitous in surface samples with concentrations ranging from several hundred thousand to over a million colony-forming units per 100 mL of surface water or per gram of surface solids, groundwater under the influence of these high surface microbial loadings had substantially fewer bacteria (3- to 7-log10 reduction). Among 80 isolates of E. coli tested, 34 (42.5%) were resistant to one or more antibiotics and 22 (27.5%) were multi-antibiotic resistant (resistant to ≥3 antibiotics), with resistance to tetracycline, cefoxitin, amoxicillin/clavulanic acid, and ampicillin being the most common. E. coli isolates from the calf hutch area exhibited the highest levels of multi-antibiotic resistance, much higher than isolates in surface soil solids from heifer and cow pens, flush alleys, manure storage lagoons, and irrigated fields. Among E. coli isolates from four groundwater samples, only one sample exhibited resistance to ceftriaxone, chloramphenicol, and tetracycline, indicating the potential of groundwater contamination with antibiotic-resistant bacteria from dairy operations.


Ipsilateral femoral autograft reconstruction after resection of a pelvic tumor.
Reconstruction of bone after the resection of a pelvic tumor is challenging. The purpose of the present study was to evaluate the use of the ipsilateral femur as the graft material for reconstruction. We performed a retrospective review of thirteen patients with a malignant pelvic lesion who underwent resection followed by reconstruction with an ipsilateral femoral autograft and insertion of a total hip replacement. The study group included nine men and four women with a median age of fifty-one years at the time of the reconstruction. The diagnosis was chondrosarcoma in eight patients, metastasis in three, and myeloma and radiation-induced malignant disease in one each. The surviving patients were assessed functionally and radiographically; the cumulative probability of revision was estimated while taking into account competing risks. The median duration of follow-up was forty-nine months. At the time of the latest follow-up, seven patients were alive and disease-free and six had died from metastatic disease. Four patients had had revision of the reconstruction, two for the treatment of mechanical complications and two for the treatment of infection. Three other patients had mechanical complications but had not had a revision. The cumulative probability of revision of the reconstruction for mechanical failure was 8% (95% confidence interval, 0% to 23%), 8% (95% confidence interval, 0% to 23%), and 16% (95% confidence interval, 0% to 39%) at one, two, and four years, respectively. Although it has attendant complications consistent with pelvic tumor surgery, an ipsilateral femoral autograft reconstruction may be an option for reconstruction of pelvic discontinuity in a subgroup of patients following tumor resection. This innovative procedure requires longer-term follow-up studies.


Improving the phenotype risk score as a scalable approach to identifying patients with Mendelian disease.
The Phenotype Risk Score (PheRS) is a method to detect Mendelian disease patterns using phenotypes from the electronic health record (EHR). We compared the performance of different approaches mapping EHR phenotypes to Mendelian disease features. PheRS utilizes Mendelian diseases descriptions annotated with Human Phenotype Ontology (HPO) terms. In previous work, we presented a map linking phecodes (based on International Classification of Diseases [ICD]-Ninth Revision) to HPO terms. For this study, we integrated ICD-Tenth Revision codes and lab data. We also created a new map between HPO terms using customized groupings of ICD codes. We compared the performance with cases and controls for 16 Mendelian diseases using 2.5 million de-identified medical records. PheRS effectively distinguished cases from controls for all 15 positive controls and all approaches tested (P < 4 × 1016). Adding lab data led to a statistically significant improvement for 4 of 14 diseases. The custom ICD groupings improved specificity, leading to an average 8% increase for precision at 100 (-2% to 22%). Eight of 10 adults with cystic fibrosis tested had PheRS in the 95th percentile prio to diagnosis. Both phecodes and custom ICD groupings were able to detect differences between affected cases and controls at the population level. The ICD map showed better precision for the highest scoring individuals. Adding lab data improved performance at detecting population-level differences. PheRS is a scalable method to study Mendelian disease at the population level using electronic health record data and can potentially be used to find patients with undiagnosed Mendelian disease.


Beyond the competition-colonization trade-off: linking multiple trait response to disturbance characteristics.
Disturbances' role in shaping communities is well documented but highly disputed. We suggest replacing the overused two-trait trade-off approach with a functional group scheme, constructed from combinations of four key traits that represent four classes of species' responses to disturbances. Using model results and field observations from sites affected by two highly different disturbances, we demonstrated that popular dichotomous trade-offs are not sufficient to explain community dynamics, even if some emerge under certain conditions. Without disturbances, competition was only sufficient to predict species survival but not relative success, which required some escape mechanism (e.g., long-term dormancy). With highly predictable and large-scale disturbances, successful species showed a combination of high individual tolerance to disturbance and, more surprisingly, high competitive ability. When disturbances were less predictable, high individual tolerance and long-term seed dormancy were favored, due to higher environmental uncertainty. Our study demonstrates that theories relying on a small number of predefined trade-offs among traits (e.g., competition-colonization trade-off) may lead to unrealistic results. We suggest that the understanding of disturbance-community relationships can be significantly improved by employing sets of relevant trait assemblies instead of the currently common approach in which trade-offs are assumed in advance.


Interaction Between the μ-Opioid Receptor Gene and the Number of Heavy-Drinking Peers on Alcohol Use.
The presence of heavy-drinking peers may trigger genetic vulnerabilities to alcohol use. Limited correlational findings, albeit mixed as a function of age, suggest that carriers of a μ-opioid receptor (OPRM1) G allele may be more vulnerable than noncarriers to alcohol-promoting perceived peer environments. However, research has not yet examined such genetic susceptibility to actual (rather than perceived) peer environments through an experimental, ad libitum alcohol administration design. This study examined whether OPRM1 modulates the effects of heavy-drinking group size on alcohol consumption and explored potential mediators of such OPRM1-based differences. Caucasian young adult moderate to heavy drinkers (N = 116; mean age = 22 years [SD = 2.21], 49% female) were randomly assigned to consume alcohol in the presence of none, 1, or 3 heavy-drinking peer confederates. Results showed no significant moderating effects of OPRM1 in the relationship between the number (or presence) of heavy-drinking peers and voluntary alcohol consumption (partial η2 = 0.01). This result remained the same after controlling for sex, age, and typical drinking quantity as well as their 2-way interactions with OPRM1 and social drinking condition. In addition, OPRM1 did not moderate the peer influence on any proposed mediating variables, including craving for alcohol and subjective responses to alcohol. Findings suggest no OPRM1-based susceptibility to the number of heavy-drinking peers, adding to the existing mixed findings from correlational studies. Future research on OPRM1-related susceptibility to alcohol-promoting peer environments through meta-analytic synthesis and both experimental and prospective, multiwave designs is needed to resolve these mixed findings.


Atomistic and electronic structure of bimetallic cobalt/rhenium clusters from density functional theory calculations.
We have carried out computational density functional investigations of Co I Re J (J=0,1,2; I+J=14) metal atom clusters. Through thorough optimization of geometry, spin polarization, and electronic configuration, the most stable structures for each cluster have been identified. While the global minima are found to be well defined and energetically well separated from other local minima, the study reveals a plethora of different structures and symmetries only moderately higher in energy. A key point of interest is the effect of doping the cobalt clusters with rhenium. Aside from significant structural reorganizations, rhenium is found to stabilize the clusters and couple down the spin. Furthermore, the most stable clusters comprise highly coordinated rhenium and, in the case of Co 12 Re 2, Re-Re bonding. Our results are compared to earlier experimental and computational data.


Identification and Characterization of Novel Compounds Blocking Shiga Toxin Expression in Escherichia coli O157:H7.
Infections caused by Shiga toxin (Stx)-producing E. coli strains constitute a health problem, as they are problematic to treat. Stx production is a key virulence factor associated with the pathogenicity of enterohaemorrhagic E. coli (EHEC) and can result in the development of haemolytic uremic syndrome in infected patients. The genes encoding Stx are located on temperate lysogenic phages integrated into the bacterial chromosome and expression of the toxin is generally coupled to phage induction through the SOS response. We aimed to find new compounds capable of blocking expression of Stx type 2 (Stx2) as this subtype of Stx is more strongly associated with human disease. High-throughput screening of a small-molecule library identified a lead compound that reduced Stx2 expression in a dose-dependent manner. We show that the optimized compound interferes with the SOS response by directly affecting the activity and oligomerization of RecA, thus limiting phage activation and Stx2 expression. Our work suggests that RecA is highly susceptible to inhibition and that targeting this protein is a viable approach to limiting production of Stx2 by EHEC. This type of approach has the potential to limit production and transfer of other phage induced and transduced determinants.


HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication.
HIV-1 has at its disposal numerous proteins encoded by its genome which provide the required arsenal to establish and maintain infection in its host for a considerable number of years. One of the most important and enigmatic of these proteins is Nef. The Nef protein of HIV-1 plays a fundamental role in the virus life cycle. This small protein of approximately 27 kDa is required for maximal virus replication and disease progression. The mechanisms by which it is able to act as a positive factor during virus replication is an area of intense research and although some controversy surrounds Nef much has been gauged as to how it functions. Its ability to modulate the expression of key cellular receptors important for cell activation and control signal transduction elements and events by interacting with numerous cellular kinases and signalling molecules, including members of the Src family kinases, leading to an effect on host cell function is likely to explain at least in part its role during infection and represents a finely tuned mechanism where this protein assists HIV-1 to control its host.


The impact of previous cesarean section on the success of future fetal programming pattern.
The purpose of this study is to examine whether cesarean section in the first pregnancy is associated with the success or failure of programmed fetal growth phenotypes or patterns in the subsequent pregnancy. We analyzed data from a population-based retrospective cohort of singleton deliveries that occurred in the state of Missouri from 1978 to 2005 (n = 1,224,133). The main outcome was neonatal mortality, which was used as an index of the success of fetal programming. Cox proportional hazard and logistic regression models were used to generate point estimates and 95% confidence intervals. Mothers delivering by cesarean section in the first pregnancy were less likely to deliver subsequent appropriate-for-gestational-age (AGA) neonates (OR 0.91, 95% CI 0.89-0.92) when compared with mothers delivering vaginally. Of the 1,457 neonatal deaths in the second pregnancy, 383 early neonatal and 95 late neonatal deaths were to mothers with cesarean section deliveries in the first pregnancy. When compared with women with a previous vaginal delivery, AGA neonates of women with a primary cesarean section had 20% increased risk of both neonatal (OR 1.20, 95% CI 1.05-1.37) and early neonatal (OR 1.23, 95% CI 1.05-1.43) death. Our study suggests that previous cesarean section is a risk factor for neonatal mortality among AGA infants of subsequent pregnancy. Future prospective studies are needed to confirm these findings.


Corrosion in stainless-steel and nickel-titanium files.
This study evaluated and compared the corrosion susceptibility of stainless-steel and nickel-titanium (NiTi) endodontic files immersed in sodium hypochlorite. For each of the stainless-steel files (Kerr K-Flex, Caulk Flex-O, and Union Broach Flex-R) plus the NiTi files (Union Broach NiTi and Tulsa NiTi), the cutting flutes of 24 ISO size 20 files were immersed into 5.25% sodium hypochlorite. Their open circuit potential (OCP) was recorded for 1 h on a strip chart with high impedance. The strip chart recording for each file was classified into a stability score: (i) stable, (ii) unstable, or (iii) erratic. The OCP was measured by a potentiostat and a standard calomel electrode reference. The OCP classification of unstable and erratic for the files evaluated were as follows: K-Flex (16%), Flex-R (12%), Flex-O (75%), Union Broach NiTi (62%), and Tulsa NiTi (0%). After OCP testing, each of the 120 files was inspected by light microscopy at x 25. The frequencies of visually observed corrosion were detected as follows: K-Flex (2/24), Flex-R (1/24), Flex-O (6/24), Union Broach NiTi (2/24), and Tulsa NiTi (0/24). There was a significant difference in corrosion frequency between brands when evaluated by OCP and light microscopy; however, there was no significant difference between stainless steel and NiTi.


The asymmetry in idiotype-isotype expression in the response to phosphocholine is due to divergence in the expressed repertoires of Lyb-5+ and Lyb-5- B cells.
The X-linked CBA/N immune defect was used to investigate the roles of Lyb-5- and Lyb-5+ B cells in the memory response to PC-KLH (phosphocholine-conjugated keyhole limpet hemocyanin). (CBA/N X BALB/c)F1 (CB) male mice express the xid mutation and thereby lack the Lyb-5+ B cell subset, whereas their female littermates are normal and express both Lyb-5+ and Lyb-5- B cells. After priming with PC-conjugated hemocyanin (PC-Hy) in complete Freund's adjuvant, female B cells produce three phenotypic sets of PC-KLH-specific antibody. The first set (group I) is dominated by T15+, IgM, IgA, and IgG3, PC-specific antibodies. The second subset (group II) is specific for phenylphosphocholine (PPC), and is dominated by T15-, IgG1, and IgG2 antibodies. The third set (group III) recognizes an epitope(s) composed of both the PPC hapten and carrier determinants. PC-Hy-primed B cells from immune defective CB male mice produce the same number of IgG1 and IgG2 plaque-forming cells (PFC) as do PC-Hy-primed normal female cells, and these PFC are also predominantly T15- and PPC specific (group II). In addition, a significant amount of group III IgG1 and IgG2 antibody is observed in the immune defective male response. In contrast to female B cells, immune defective male B cells produce a low IgM, IgA, and IgG3 memory response that is not composed of PC-specific (group I) antibodies; in fact, most of these antibodies arise from group III precursors and are not inhibited by either PC or PPC. PC-specific antibodies usually represent less than 25% of the anti-PC-KLH response in immune defective mice; however, these PC-specific antibodies are predominantly T15-. These data suggest that the Lyb-5-B cells in both normal and immune defective mice produce the T15-, IgG1, and IgG2 antibodies that dominate the secondary immune response to PC-KLH, and that the Lyb-5+ B cells produce the T15+, IgM, IgA, and IgG3 portion of the secondary response in normal mice. This hypothesis was confirmed by priming normal mice with the R36a strain of Streptococcus pneumoniae or with PC-Hy in saline. These forms of PC-antigen prime only the Lyb-5+ B cell subset. The adoptive transfer of these two B cell sources results in an anti-PC-KLH response that is T15 dominant and totally PC inhibitable.(ABSTRACT TRUNCATED AT 400 WORDS)


Affirming the Value of the Resident Assessment Instrument: Minimum Data Set Version 2.0 for Nursing Home Decision-Making and Quality Improvement.
We examined the agreement over time of the physical functioning domains of the Resident Assessment Instrument: Minimum Data Set Version 2.0 (RAI-MDS) and the Functional Independence Measure (FIM) in nursing home residents with dementia. We completed a secondary analysis of data from a longitudinal quasi-experimental study of residents who could transfer independently or with the assistance of one person. FIM assessments were completed at up to three time points by researchers using interviews. RAI-MDS assessments, completed by nursing home staff, were matched to the FIM assessment by nearest time. FIM and RAI-MDS assessments were correlated based on time between assessments using Pearson's correlation. Items for activities of daily living (ADL) from the RAI-MDS were rescaled using two previously published crosswalks. Motor and ADL subscales were also used, containing eight and six items, respectively. A total of 362 paired interviews and assessments were collected from 130 residents. The mean scores and standard deviations were as follows: FIM: 19.64 (7.60); William's RAI-MDS crosswalk: 18.04 (5.25); and Velozo's RAI-MDS crosswalk: 18.09 (6.50). Using both crosswalks, most items showed medium (r > 0.3) or large (r > 0.5) correlations, even at greater than 41 days between assessments. Subscales showed large correlations for all time intervals for both crosswalks. The RAI-MDS remains stable when data are collected greater than 41 days from the FIM assessment. These findings should add confidence in the RAI-MDS data and its clinical utility.


Molecular characterization and expression of DERL1 in bovine ovarian follicles and corpora lutea.
The endoplasmic reticulum (ER) is a major site of protein synthesis and facilitates the folding and assembly of newly synthesized proteins. Misfolded proteins are retrotranslocated across the ER membrane and destroyed at the proteasome. DERL1 is an important protein involved in the retrotranslocation and degradation of a subset of misfolded proteins from the ER. We characterized a 2617 bp cDNA from bovine granulosa cells that corresponded to bovine DERL1. Two transcripts of 3 and 2.6 kb were detected by Northern blot analysis, and showed variations in expression among tissues. During follicular development, DERL1 expression was greater in day 5 dominant follicles compared to small follicles, ovulatory follicles, or corpus luteum (CL). Within the CL, DERL1 mRNA expression was intermediate in midcycle, and lowest in late cycle as compared to early in the estrous cycle. Western blot analyses demonstrated the presence of DERL1 in the bovine CL at days 5, 11, and 18 of the estrous cycle. Co-immunoprecipitation using luteal tissues showed that DERL1 interacts with class I MHC but not with VIMP or p97 ATPase. The interaction between DERL1 and MHC I suggests that, in the CL, DERL1 may regulate the integrity of MHC I molecules that are transported to the ER membrane. Furthermore, the greater expression of DERL1 mRNA is associated with the active follicular development and early luteal stages, suggesting a role of DERL1 in tissue remodeling events and maintenance of function in reproductive tissues.


Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections.
The number of transcatheter aortic valve implantation (TAVI) procedures is rapidly increasing. This has a major impact on health care resource planning. However, the annual numbers of TAVI candidates per country are unknown. The aim of this study was to estimate current and future number of annual TAVI candidates in 27 European countries, the USA and Canada. Systematic literature searches and meta-analyses were performed on aortic stenosis (AS) epidemiology and decision-making in severe symptomatic AS. The incidence rate of severe AS was determined. Findings were combined with population statistics and integrated into a model employing Monte Carlo simulations to predict the annual number of TAVI candidates. Various future scenarios and sensitivity analyses were explored. Data from 37 studies (n = 26 402) informed the model. The calculated incidence rate of severe AS was 4.4‰/year [95% confidence interval (95% CI) 3.0-6.1‰] in patients ≥65 years. AS-related symptoms were present in 68.3% (95% CI 60.8-75.9%) of patients with severe AS. Despite having severe symptomatic AS, 41.6% (95% CI 36.9-46.3%) did not undergo surgical aortic valve replacement. Of the non-operated patients, 61.7% (95% CI 42.0-81.7%) received TAVI. The model predicted 114 757 (95% CI 69 380-172 799) European and 58 556 (95% CI 35 631-87 738) Northern-American TAVI candidates annually. Currently, approximately 180 000 patients can be considered potential TAVI candidates in the European Union and in Northern-America annually. This number might increase up to 270 000 if indications for TAVI expand to low-risk patients. These findings have major implications for health care resource planning in the 29 individual countries.


From scientific article to press release to media coverage: advocating alcohol abstinence and democratising risk in a story about alcohol and pregnancy.
In this article, we follow the approach taken by Riesch and Spiegalhalter in "Careless pork costs lives': Risk stories from science to press release to media' published in this journal, and offer an assessment of one example of a 'risk story'. Using content and thematic qualitative analysis, we consider how the findings of an article 'Fetal Alcohol Exposure and IQ at Age 8: Evidence from a Population-Based Birth-Cohort Study' were framed in the article itself, the associated press release, and the subsequent extensive media coverage. We contextualise this consideration of a risk story by discussing a body of work that critically engages with the development and global proliferation of efforts to advocate for alcohol abstinence to pregnant (and pre-pregnant) women. This work considers the 'democratisation' of risk, a term used to draw attention to the expansion of the definition of the problem of drinking in pregnancy to include any drinking and all women. We show here how this risk story contributed a new dimension to the democratisation of risk through claims that were made about uncertainty and certainty. A central argument we make concerns the contribution of the researchers themselves (not just lobby groups or journalists) to this outcome. We conclude that the democratisation of risk was advanced in this case not simply through journalists exaggerating and misrepresenting research findings, but that communication to the press and the initial interpretation of findings played their part. We suggest that this risk story raises concerns about the accuracy of reporting of research findings, and about the communication of unwarrantedly worrying messages to pregnant women about drinking alcohol.


Isolation of eukaryotic DNA fragments containing structural genes and the adjacent sequences.
In Drosophila melanogaster structural genes are located close to moderately reiterated sequences. One of the clones obtained contains the DNA related to intercalary heterochromatin of D. melanogaster. These are individual differences in the distribution of genetic material in polytenic chromosomes of different stocks of D. melanogaster. The techniques that allow isolation of DNA fragments containing structural genes at the beginning, in the middle, or the end of the coding strand have been elaborated.


Interactions between nonpolar surfaces coated with the nonionic surfactant hexaoxyethylene dodecyl ether C12E6 and the origin of surface charges at the air/water interface.
The interactions between nonpolar surfaces coated with the nonionic surfactant hexaoxyethylene dodecyl ether C12E6 were investigated using two techniques and three different types of surfaces. As nonpolar surfaces, the air/water interface, silanated negatively charged glass, and thiolated uncharged gold surfaces were chosen. The interactions between the air/water interfaces were measured with a thin film pressure balance in terms of disjoining pressure as a function of film thickness. The interactions between the solid/liquid interfaces were determined using a bimorph surface force apparatus. The influence of the nature of the surface on the interaction forces was investigated at surfactant concentrations below and above the cmc. The adsorption of the nonionic surfactant on the uncharged thiolated surface does not, as expected, lead to any buildup of a surface charge. On the other hand, adsorption of C12E6 on the charged silanated glass and the charged air/water interface results in a lowering of the surface charge density. The reduction of the surface charge density on the silanated glass surfaces is rationalized by changes in the dielectric permittivity around the charged silanol groups. The reason for the surface charge observed at the air/water interface as well as its decrease with increasing surfactant concentration is discussed and a new mechanism for generation of OH- ions at this particular interface is proposed.


Recovery from hematopoietic injury by modulating prostaglandin E(2) signaling post-irradiation.
While high dose total body irradiation (TBI) is used therapeutically, the proliferation of nuclear weapons, increasing use of nuclear power, and worldwide radical terrorism underscore the need to develop countermeasures to a radiological mass casualty event. The hematopoietic syndrome of the acute radiation syndrome (HS-ARS) results from severe compromise to the hematopoietic system, including lymphocytopenia, neutropenia, thrombocytopenia, and possible death from infection and/or hemorrhage. Given adequate time to recover, expand, and appropriately differentiate, bone marrow hematopoietic stem cells (HSC) and progenitor cells (HPC) may overcome HS-ARS and restore homeostasis of the hematopoietic system. Prostaglandin E(2) (PGE(2)) has been shown to have pleiotropic effects on hematopoiesis, acting to inhibit apoptosis and promote self-renewal of HSC, while inhibiting HPC proliferation. We assessed the radio-mitigating potential of modulating PGE(2) signaling in a mouse model of HS-ARS. Treatment with the PGE(2) analog 16,16 dimethyl PGE(2) (dmPGE(2)) 6h post-irradiation or inhibition of PGE(2) synthesis via delayed administration of the non-steroidal anti-inflammatory drug (NSAID) Meloxicam resulted in increased survival of lethally irradiated mice. Both early dmPGE(2) and delayed Meloxicam treatment were associated with increased HPC activity 35days following irradiation, demonstrating enhanced recovery of hematopoiesis. Our results define two different treatment modalities that are highly effective and safe to administer, and can be readily available.


Controlled evaluation of a transition clinic for Dutch young people with cystic fibrosis.
Transition clinics (TCs) are advocated as best practice to support young people with cystic fibrosis (CF) during transition to adulthood and adult care. We aimed to research the functioning of a TC for young people with CF compared with direct hand-over care and to evaluate whether those treated at the TC have better transfer experiences and outcomes compared with the control group. Mixed-methods retrospective controlled design, including interviews with professionals, observations of clinics, chart reviews (at four measurement moments), and patient surveys. Qualitative data analysis focused on organization and daily routines, and barriers and facilitators experienced. Young people's transfer experiences, self-management, health care use, and clinical outcomes were assessed quantitatively. The most notable feature distinguishing the TC and direct hand-over care comprised joint consultations between pediatric and adult care professionals in the former. A transition coordinator was considered essential for the success of the TC. The main barriers were lack of time, planning, and reimbursement issues. Young people treated at the TC tended to have better transfer experiences and were more satisfied. They reported significantly more trust in their adult care professionals. Their self-management-related outcomes were less favorable. The TC had several perceived benefits and showed positive trends in transfer experiences and satisfaction, but no differences in health-related outcomes. Structured preparation of young people, joint consultations with pediatric and adult care professionals, and better coordination were perceived as facilitating elements. Further improvement demands solutions for organizational and financial barriers, and better embedding of self-management interventions in CF care.


A Switch in Microtubule Orientation during C. elegans Meiosis.
In oocytes of many organisms, meiotic spindles form in the absence of centrosomes [1-5]. Such female meiotic spindles have a pointed appearance in metaphase with microtubules focused at acentrosomal spindle poles. At anaphase, the microtubules of acentrosomal spindles then transition to an inter-chromosomal array, while the spindle poles disappear. This transition is currently not understood. Previous studies have focused on this inter-chromosomal microtubule array and proposed a pushing model to drive chromosome segregation [6, 7]. This model includes an end-on orientation of microtubules with chromosomes. Alternatively, chromosomes were thought to associate along bundles of microtubules [8, 9]. Starting with metaphase, this second model proposed a pure lateral chromosome-to-microtubule association up to the final meiotic stages of anaphase. Here, we applied large-scale electron tomography [10] of staged C. elegans oocytes in meiosis to analyze the orientation of microtubules in respect to chromosomes. We show that microtubules at metaphase I are primarily oriented laterally to the chromosomes and that microtubules switch to an end-on orientation during progression through anaphase. We further show that this switch in microtubule orientation involves a kinesin-13 microtubule depolymerase, KLP-7, which removes laterally associated microtubules around chromosomes. From this, we conclude that both lateral and end-on modes of microtubule-to-chromosome orientations are successively used in C. elegans oocytes to segregate meiotic chromosomes.


Topoisomerase II from Chlorella virus PBCV-1 has an exceptionally high DNA cleavage activity.
Chlorella virus PBCV-1 topoisomerase II is the only functional type II enzyme known to be encoded by a virus that infects eukaryotic cells. However, it has not been established whether the protein is expressed following viral infection or whether the enzyme has any catalytic features that distinguish it from cellular type II topoisomerases. Therefore, the present study characterized the physiological expression of PBCV-1 topoisomerase II and individual reaction steps catalyzed by the enzyme. Results indicate that the topoisomerase II gene is widely distributed among Chlorella viruses and that the protein is expressed 60-90 min after viral infection of algal cells. Furthermore, the enzyme has an extremely high DNA cleavage activity that sets it apart from all known eukaryotic type II topoisomerases. Levels of DNA scission generated by the viral enzyme are approximately 30 times greater than those observed with human topoisomerase IIalpha. The high levels of cleavage are not due to inordinately tight enzyme-DNA binding or to impaired DNA religation. Thus, they most likely reflect an elevated forward rate of scission. The robust DNA cleavage activity of PBCV-1 topoisomerase II provides a unique tool for studying the catalytic functions of type II topoisomerases.


Phenotypic and genetic diversity of chlorine-resistant Methylobacterium strains isolated from various environments.
Strains of pink-pigmented facultative methylotrophs which were isolated previously from various environments and assigned tentatively to the genus Methylobacterium were characterized in comparison with authentic strains of previously known species of this genus. Most of the isolates derived from chlorinated water supplies exhibited resistance to chlorine, whereas 29 to 40% of the isolates from air, natural aquatic environments, and clinical materials were chlorine resistant. None of the tested authentic strains of Methylobacterium species obtained from culture collections exhibited chlorine resistance. Numerical analysis of phenotypic profiles showed that the test organisms tested were separated from each other except M. organophilum and M. rhodesianum. The chlorine-resistant isolates were randomly distributed among all clusters. The 16S ribosomal DNA (rDNA) sequence-based phylogenetic analyses showed that representatives of the isolates together with known Methylobacterium species formed a line of descent distinct from that of members of related genera in the alpha-2 subclass of the Proteobacteria and were divided into three subclusters within the Methylobacterium group. These results demonstrate that there is phenotypic and genetic diversity among chlorine-resistant Methylobacterium strains within the genus.


Spatial non-uniformity in exfoliated WS2 single layers.
Monolayers of transition metal dichalcogenides (TMDs) are atomically thin two-dimensional crystals with attractive optoelectronic properties, which are promising for emerging applications in nanophotonics. Here, we report on the extraordinary spatial non-uniformity of the photoluminescence (PL) and strain properties of exfoliated WS2 monolayers. Specifically, it is shown that the edges of such monolayers exhibit remarkably enhanced PL intensity compared to their respective central area. A comprehensive analysis of the recombination channels involved in the PL process demonstrates a spatial non-uniformity across the monolayer's surface and reflects on the non-uniformity of the intrinsic electron density across the monolayer. Auger electron imaging and spectroscopy studies complemented with PL measurements in different environments indicate that oxygen chemisorption and physisorption are the two fundamental mechanisms responsible for the observed non-uniformity. At the same time Raman spectroscopy analysis shows remarkable strain variations among the different locations of an individual monolayer, however such variations cannot be strictly correlated with the non-uniform PL emission. Our results shed light on the role of the chemical bonding in the competition between exciton complexes in monolayer WS2, providing a method of engineering new nanophotonic functions using WS2 monolayers. It is therefore envisaged that our findings could find diverse applications towards the development of TMD-based optoelectronic devices.


Humanization reveals pervasive incompatibility of yeast and human kinetochore components.
Kinetochores assemble on centromeres to drive chromosome segregation in eukaryotic cells. Humans and budding yeast share most of the structural subunits of the kinetochore, whereas protein sequences have diverged considerably. The conserved centromeric histone-H3 variant, CenH3 (CENP-A in humans and Cse4 in budding yeast) marks the site for kinetochore assembly in most species. A previous effort to complement Cse4 in yeast with human CENP-A was unsuccessful, however co-complementation with the human core nucleosome was not attempted. Previously, our lab successfully humanized the core nucleosome in yeast, however this severely affected cellular growth. We hypothesized that yeast Cse4 is incompatible with humanized nucleosomes and that the kinetochore represented a limiting factor for efficient histone humanization. Thus, we argued that including the human CENP-A or a Cse4-CENP-A chimera might improve histone humanization and facilitate kinetochore function in humanized yeast. The opposite was true: CENP-A expression reduced histone humanization efficiency, was toxic to yeast, and disrupted cell-cycle progression and kinetochore function in wild-type cells. Suppressors of CENP-A toxicity included gene deletions of subunits of three conserved chromatin-remodeling complexes, highlighting their role in CenH3 chromatin positioning. Finally, we attempted to complement the subunits of the NDC80 kinetochore complex, individually and in combination, without success, in contrast to a previous study indicating complementation by the human NDC80/HEC1 gene. Our results suggest that limited protein sequence similarity between yeast and human components in this very complex structure leads to failure of complementation.


Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases.
In the mammalian central nervous system, receptors for excitatory amino acid neurotransmitters such as the alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA)-kainate receptor mediate a large fraction of excitatory transmission. Currents induced by activation of the AMPA-kainate receptor were potentiated by agents that specifically stimulate adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A (PKA) activity or were supported by intracellular application of the catalytic subunit of PKA by itself or in combination with cAMP. Furthermore, depression of these currents by a competitive inhibitor of PKA indicates that AMPA-kainate receptors are regulated by endogenous PKA. Endogenous protein phosphatases also regulate these receptors because an inhibitor of cellular phosphates enhanced kainate currents. Modulation of PKA and phosphatases may regulate the function of these receptors and thus contribute to synaptic plasticity in hippocampal neurons.


Dynamic excitatory and inhibitory gain modulation can produce flexible, robust and optimal decision-making.
Behavioural and neurophysiological studies in primates have increasingly shown the involvement of urgency signals during the temporal integration of sensory evidence in perceptual decision-making. Neuronal correlates of such signals have been found in the parietal cortex, and in separate studies, demonstrated attention-induced gain modulation of both excitatory and inhibitory neurons. Although previous computational models of decision-making have incorporated gain modulation, their abstract forms do not permit an understanding of the contribution of inhibitory gain modulation. Thus, the effects of co-modulating both excitatory and inhibitory neuronal gains on decision-making dynamics and behavioural performance remain unclear. In this work, we incorporate time-dependent co-modulation of the gains of both excitatory and inhibitory neurons into our previous biologically based decision circuit model. We base our computational study in the context of two classic motion-discrimination tasks performed in animals. Our model shows that by simultaneously increasing the gains of both excitatory and inhibitory neurons, a variety of the observed dynamic neuronal firing activities can be replicated. In particular, the model can exhibit winner-take-all decision-making behaviour with higher firing rates and within a significantly more robust model parameter range. It also exhibits short-tailed reaction time distributions even when operating near a dynamical bifurcation point. The model further shows that neuronal gain modulation can compensate for weaker recurrent excitation in a decision neural circuit, and support decision formation and storage. Higher neuronal gain is also suggested in the more cognitively demanding reaction time than in the fixed delay version of the task. Using the exact temporal delays from the animal experiments, fast recruitment of gain co-modulation is shown to maximize reward rate, with a timescale that is surprisingly near the experimentally fitted value. Our work provides insights into the simultaneous and rapid modulation of excitatory and inhibitory neuronal gains, which enables flexible, robust, and optimal decision-making.


Improving return-to-work after childbirth: design of the Mom@Work study, a randomised controlled trial and cohort study.
Many women suffer from health problems after giving birth, which can lead to sick leave. About 30% of Dutch workers are on sick leave after maternity leave. Structural contact of supervisors with employees on maternity leave, supported by early medical advice of occupational physicians, may increase the chances of return-to-work after maternity leave. In addition, to understand the process of sick leave and return-to-work after childbirth it is important to gain insight into which factors hinder return-to-work after childbirth, as well, as which prognostic factors lead to the development of postpartum health complaints. In this paper, the design of the Mom@Work study is described. The Mom@Work study is simultaneously a randomised controlled trial and a cohort study. Pregnant women working for at least 12 hours a week at one of the 15 participating companies are eligible to participate. The supervisors of these pregnant employees are randomised at 35 weeks pregnancy into the intervention group or control group. During maternity leave, supervisors in the intervention group contact their employee six weeks after delivery using a structured interview. When employees do not expect to return to their jobs at the end of their scheduled maternity leave due to health problems, the supervisor offers early support of the occupational physician. Supervisors in the control group have no structural contact with their employees during maternity leave. Measurements take place at 30 weeks pregnancy and at 6, 12, 24 and 52 weeks postpartum. In addition, cost data are collected. For the RCT, primary outcome measures are sick leave and return-to-work, and secondary outcome measures are costs, health, satisfaction with intervention and global feelings of recovery. Outcome measures for the cohort are pregnancy-related pelvic girdle pain, fatigue and depression. Finally, a number of prognostic factors for return-to-work and for the development of complaints will be measured. The Mom@Work study will provide important information about return-to-work of employees after giving birth. Results will give insight in prognosis of postpartum sick leave and complaints. Also, the role of supervisors and occupational physicians in successful return-to-work after childbirth will be clarified.


Evidence for Accelerated Decline of Functional Brain Network Efficiency in Schizophrenia.
Previous work suggests that individuals with schizophrenia display accelerated aging of white matter integrity, however, it is still unknown whether functional brain networks also decline at an elevated rate in schizophrenia. Given the known degradation of functional connectivity and the normal decline in cognitive functioning throughout healthy aging, we aimed to test the hypothesis that efficiency of large-scale functional brain networks supporting overall cognition, as well as integrity of hub nodes within those networks, show evidence of accelerated aging in schizophrenia. Using pseudo-resting state data in 54 healthy controls and 46 schizophrenia patients, in which task-dependent signal from 3 tasks was regressed out to approximate resting-state data, we observed a significant diagnosis by age interaction in the prediction of both global and local efficiency of the cingulo-opercular network, and of the local efficiency of the fronto-parietal network, but no interaction when predicting both default mode network and whole brain efficiency. We also observed a significant diagnosis by age interaction for the node degree of the right anterior insula, left dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex. All interactions were driven by stronger negative associations between age and network metrics in the schizophrenia group than the healthy controls. These data provide evidence that is consistent with accelerated aging of large-scale functional brain networks in schizophrenia that support higher-order cognitive ability.


A Case Study of Performance Degradation Attributable to Run-Time Bounds Checks on C++ Vector Access.
Programmers routinely omit run-time safety checks from applications because they assume that these safety checks would degrade performance. The simplest example is the use of arrays or array-like data structures that do not enforce the constraint that indices must be within bounds. This report documents an attempt to measure the performance penalty incurred by two different implementations of bounds-checking in C and C++ using a simple benchmark and a desktop PC with a modern superscalar CPU. The benchmark consisted of a loop that wrote to array elements in sequential order. With this configuration, relative to the best performance observed for any access method in C or C++, mean degradation of only (0.881 ± 0.009) % was measured for a standard bounds-checking access method in C++. This case study showed the need for further work to develop and refine measurement methods and to perform more comparisons of this type. Comparisons across different use cases, configurations, programming languages, and environments are needed to determine under what circumstances (if any) the performance advantage of unchecked access is actually sufficient to outweigh the negative consequences for security and software quality.


Plasmon resonant coupling in metallic nanowires.
We investigate the plasmon resonances of interacting silver nanowires with a 50 nm diameter. Both non-touching and intersecting configurations are investigated. While individual cylinders exhibit a single plasmon resonance, we observe much more complex spectra of resonances for interacting structures. The number and magnitude of the different resonances depend on the illumination direction and on the distance between the particles. For very small separations, we observe a dramatic field enhancement between the particles, where the electric field amplitude reaches a hundredfold of the illumination. A similar enhancement is observed in the grooves created in slightly intersecting particles. The topology of these different resonances is related to the induced polarization charges. The implication of these results to surface enhanced Raman scattering (SERS) are discussed.


Diagnostic significance of 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy in urinary tract infection.
A total of 106 children with symptomatic urinary tract infection (73 girls and 33 boys, 0-15.9 years of age) were studied by means of a dimercaptosuccinic acid (DMSA) scan, renal ultrasound, and a desmopressin test during infection and at follow up approximately two months later. At follow up they were also investigated by means of intravenous urography (IVU) and micturition cystourethrography (MCU). During infection 23 children had a normal DMSA scan while 83 children had an abnormal one. The median C reactive protein and SD score for renal concentration capacity in the former group were 15 (range < 10-178) mg/l and -1.0 SD score (range -2.4 to 1.8), respectively, and in the latter group 98 (range < 10-320) mg/l and -3.1 SD score (range -5.7 to 1.1), respectively. In the former group there was no significant finding in any child on ultrasound or IVU and only one had significant vesicoureteric reflux (VUR) (grade 3). At follow up 51 children had a normal DMSA scan while 55 children showed persistent changes. The median SD score for renal concentration capacity in the former group was -0.9 SD score (range -3.2 to 1.4) and in the latter group -1.6 SD score (range -4.6 to 2.5). No significant changes were found in the former group on ultrasound or IVU and only two children had significant VUR (grade 3). In the latter group 20 children showed changes on ultrasound, 15 showed changes on IVU, and 23 had VUR. These results suggest that a normal DMSA scan during or approximately two months after urinary tract infection in children indicates a low risk of finding significant pathology of the urinary tract.


A 3D bioprinting system to produce human-scale tissue constructs with structural integrity.
A challenge for tissue engineering is producing three-dimensional (3D), vascularized cellular constructs of clinically relevant size, shape and structural integrity. We present an integrated tissue-organ printer (ITOP) that can fabricate stable, human-scale tissue constructs of any shape. Mechanical stability is achieved by printing cell-laden hydrogels together with biodegradable polymers in integrated patterns and anchored on sacrificial hydrogels. The correct shape of the tissue construct is achieved by representing clinical imaging data as a computer model of the anatomical defect and translating the model into a program that controls the motions of the printer nozzles, which dispense cells to discrete locations. The incorporation of microchannels into the tissue constructs facilitates diffusion of nutrients to printed cells, thereby overcoming the diffusion limit of 100-200 μm for cell survival in engineered tissues. We demonstrate capabilities of the ITOP by fabricating mandible and calvarial bone, cartilage and skeletal muscle. Future development of the ITOP is being directed to the production of tissues for human applications and to the building of more complex tissues and solid organs.


Infrastructure adaptation and emergence of loops in network routing with time-dependent loads.
Network routing approaches are widely used to study the evolution in time of self-adapting systems. However, few advances have been made for problems where adaptation is governed by time-dependent inputs. In this work we study a dynamical systems where the edge conductivities of a network are regulated by time-varying mass loads injected on nodes. Motivated by empirical observations, we assume that conductivities adapt slowly with respect to the characteristic time of the loads. Furthermore, assuming the loads to be periodic, we derive a dynamics where the evolution of the system is controlled by a matrix obtained with the Fourier coefficients of the input loads. Remarkably, we find a sufficient condition on these coefficients that determines when the resulting network topologies are trees. We show an example of this on the Bordeaux bus network where we tune the input loads to interpolate between loopy and tree topologies. We validate our model on several synthetic networks and provide an expression for long-time solutions of the original conductivities.


Eradication of Biofilm-Like Microcolony Structures of Borrelia burgdorferi by Daunomycin and Daptomycin but not Mitomycin C in Combination with Doxycycline and Cefuroxime.
Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne disease in the United States and Europe. While the majority of Lyme disease patients can resolve their symptoms if treated promptly, 10-20% of patients suffer from prolonged symptoms called post-treatment Lyme disease syndrome (PTLDS). Although the cause for PTLDS is unclear, one possibility is the presence of bacterial persisters not effectively cleared by the current Lyme antibiotics. Recent studies identified several drug candidates including daptomycin, daunomycin, doxorubicin, and mitomycin C that had good activity against B. burgdorferi persisters. However, their relative activities against B. burgdorferi persisters have not been evaluated under the same conditions. In this study, we tested the anti-persister activities of these drugs against both 7-day and 15-day old stationary phase cultures of B. burgdorferi individually as well as in combination with Lyme antibiotics doxycycline and cefuroxime (Ceftin). Our findings demonstrate daunomycin and daptomycin were more active than mitomycin C in single drug comparison at 10 and 20 μM, as well as in drug combinations with doxycycline and cefuroxime. In addition, daunomycin was more active than doxorubicin which correlated with their ability to stain and accumulate in B. burgdorferi. The two drug combination of doxycycline and cefuroxime was unable to eradicate biofilm-like microcolonies of B. burgdorferi persisters. However, the addition of either daunomycin or daptomycin to the doxycycline + cefuroxime combination completely eradicated the biofilm-like structures and produced no visible bacterial regrowth after 7 and 21 days, while the addition of doxorubicin was unable to prevent regrowth at either 7 or 21 day subculture. Mitomycin C in combination with doxycycline and cefuroxime caused no regrowth at 7 days but visible spirochetal regrowth occurred after 21 day subculture. Furthermore, we found that cefuroxime (Ceftin), the third commonly used and most active antibiotic to treat Lyme disease, could replace cefoperazone (a drug no longer available in the US) in the daptomycin + doxycycline combination with complete eradication of the biofilm-like structures as shown by lack of any regrowth in subcultures. Our findings may have implications for improved treatment of Lyme disease.


Single-scattering solutions to radiative transfer in infinite turbid media.
An instantaneous point source generating a light field in an infinite turbid medium with anisotropic individual scatterers is considered. Single-scattering solutions are sought as the first term of a series expansion of the solution of the radiative transfer equation in successive scattering orders. A simple formula for a single-scattering solution in media with an arbitrary axially symmetric phase function is derived. Applications of this formula are shown for the Henyey-Greenstein phase function, an ellipsoidal phase function, and a linear phase function. In addition, the single-scattering term of the RTE solution derived by Kholin [Zh. Vych. Mat. i Mat. Fys.4, 1126 (1964)] for media with a phase function represented by a finite series in Legendre polynomials is considered in more detail.


Contact-free measurement of cardiac pulse based on the analysis of thermal imagery.
We have developed a novel method to measure human cardiac pulse at a distance. It is based on the information contained in the thermal signal emitted from major superficial vessels. This signal is acquired through a highly sensitive thermal imaging system. Temperature on the vessel is modulated by pulsative blood flow. To compute the frequency of modulation (pulse), we extract a line-based region along the vessel. Then, we apply fast Fourier transform (FFT) to individual points along this line of interest to capitalize on the pulse's thermal propagation effect. Finally, we use an adaptive estimation function on the average FFT outcome to quantify the pulse. We have carried out experiments on a data set of 34 subjects and compared the pulse computed from our thermal signal analysis method to concomitant ground-truth measurements obtained through a standard contact sensor (piezo-electric transducer). The performance of the new method ranges from 88.52% to 90.33% depending on the clarity of the vessel's thermal imprint. To the best of our knowledge, it is the first time that cardiac pulse has been measured several feet away from a subject with passive means.


Prospecting for Energy-Rich Renewable Raw Materials: Agave Leaf Case Study.
Plant biomass from different species is heterogeneous, and this diversity in composition can be mined to identify materials of value to fuel and chemical industries. Agave produces high yields of energy-rich biomass, and the sugar-rich stem tissue has traditionally been used to make alcoholic beverages. Here, the compositions of Agave americana and Agave tequilana leaves are determined, particularly in the context of bioethanol production. Agave leaf cell wall polysaccharide content was characterized by linkage analysis, non-cellulosic polysaccharides such as pectins were observed by immuno-microscopy, and leaf juice composition was determined by liquid chromatography. Agave leaves are fruit-like--rich in moisture, soluble sugars and pectin. The dry leaf fiber was composed of crystalline cellulose (47-50% w/w) and non-cellulosic polysaccharides (16-22% w/w), and whole leaves were low in lignin (9-13% w/w). Of the dry mass of whole Agave leaves, 85-95% consisted of soluble sugars, cellulose, non-cellulosic polysaccharides, lignin, acetate, protein and minerals. Juice pressed from the Agave leaves accounted for 69% of the fresh weight and was rich in glucose and fructose. Hydrolysis of the fructan oligosaccharides doubled the amount of fermentable fructose in A. tequilana leaf juice samples and the concentration of fermentable hexose sugars was 41-48 g/L. In agricultural production systems such as the tequila making, Agave leaves are discarded as waste. Theoretically, up to 4000 L/ha/yr of bioethanol could be produced from juice extracted from waste Agave leaves. Using standard Saccharomyces cerevisiae strains to ferment Agave juice, we observed ethanol yields that were 66% of the theoretical yields. These data indicate that Agave could rival currently used bioethanol feedstocks, particularly if the fermentation organisms and conditions were adapted to suit Agave leaf composition.


A biomarker approach to syndrome-based treatment of severe childhood illness in malaria-endemic areas.
This opinion article deals with the diagnostic clinical challenges faced by clinicians or health care workers in malaria-endemic areas when a severely sick child presents to the clinic with fever, coma or respiratory distress. Indeed, the coexistence of malaria with other severe infections like meningitis, invasive bacterial infection or pneumonia makes appropriate treatment allocation a matter of life and death. The use of biomarkers has been proposed as a potential solution to this problem. The arrival of high-throughput technologies allowed thousands of molecules (transcripts, proteins and metabolites) to be been screened in clinical samples from large cohorts of well/characterised patients. The major aim of these studies was to identify biomarkers that inform important decisions: should this child be referred to hospital? Should antibiotics, anti-malarials, or both, be administered? There is a large discrepancy between the number of biomarker discovery studies published and the number of biomarkers that have been clinically validated, let alone implemented. This article reflects on the many opportunities and obstacles encountered in biomarker research in malaria-endemic areas.


Water-oxidation catalysis by synthetic manganese oxides--systematic variations of the calcium birnessite theme.
Layered manganese oxides from the birnessite mineral family have been identified as promising heterogeneous compounds for water-oxidation catalysis (WOC), a key reaction for the conversion of renewable energy into storable fuels. High catalytic rates were especially observed for birnessites which contain calcium as part of their structures. With the aim to systematically improve the catalytic performance of such oxide materials, we used a flexible synthetic route to prepare three series of calcium birnessites, where we varied the calcium concentrations, the ripening times of the original precipitates and the temperature of the heat treatment following the initial synthetic steps (tempering) during the preparation process. The products were carefully analysed by a number of analytical techniques and then probed for WOC activity using the Ce(4+)-system. We find that our set of twenty closely related manganese oxides shows large, but somewhat systematic alterations in catalytic rates, indicating the importance of synthesis parameters for maximum catalytic performance. The catalyst of the series for which the highest water-oxidation rate was found is a birnessite of medium calcium content (Ca : Mn ratio 0.2 : 1) that had been subjected to a tempering temperature of 400 °C. On the basis of the detailed analysis of the results, a WOC reaction scheme for birnessites is proposed to explain the observed trends in reactivity.


Antimicrobial peptide evolution in the Asiatic honey bee Apis cerana.
The Asiatic honeybee, Apis cerana Fabricius, is an important honeybee species in Asian countries. It is still found in the wild, but is also one of the few bee species that can be domesticated. It has acquired some genetic advantages and significantly different biological characteristics compared with other Apis species. However, it has been less studied, and over the past two decades, has become a threatened species in China. We designed primers for the sequences of the four antimicrobial peptide cDNA gene families (abaecin, defensin, apidaecin, and hymenoptaecin) of the Western honeybee, Apis mellifera L. and identified all the antimicrobial peptide cDNA genes in the Asiatic honeybee for the first time. All the sequences were amplified by reverse transcriptase-polymerase chain reaction (RT-PCR). In all, 29 different defensin cDNA genes coding 7 different defensin peptides, 11 different abaecin cDNA genes coding 2 different abaecin peptides, 13 different apidaecin cDNA genes coding 4 apidaecin peptides and 34 different hymenoptaecin cDNA genes coding 13 different hymenoptaecin peptides were cloned and identified from the Asiatic honeybee adult workers. Detailed comparison of these four antimicrobial peptide gene families with those of the Western honeybee revealed that there are many similarities in the quantity and amino acid components of peptides in the abaecin, defensin and apidaecin families, while many more hymenoptaecin peptides are found in the Asiatic honeybee than those in the Western honeybee (13 versus 1). The results indicated that the Asiatic honeybee adult generated more variable antimicrobial peptides, especially hymenoptaecin peptides than the Western honeybee when stimulated by pathogens or injury. This suggests that, compared to the Western honeybee that has a longer history of domestication, selection on the Asiatic honeybee has favored the generation of more variable antimicrobial peptides as protection against pathogens.