Ultrasonographic Evaluation of a Patient With a Successful Digital Sympathectomy in Raynaud Phenomenon: A Case Report.
Selective periarterial sympathectomy in Raynaud phenomenon (RP) has not been adequately studied as there was no reliable method to evaluate outcomes. However, dynamic Doppler ultrasonography may have clinical value in the management and follow-up of patients with RP; but few reports describe using the device to assess surgical outcomes. Here, we report a case of successful digital sympathectomy in a single digit and the postoperative evaluation using ultrasonography. A 23-year-old patient with secondary RP underwent surgery targeting both common digital artery (ulnar side) and the proper digital artery (radial side). The procedure yielded immediate pain relief and the improvement of recurrent fingertip ulceration. The 1-year postoperative assessment with dynamic Doppler ultrasonography using a hockey-stick probe was performed with a cold provocation test and revealed peak systolic velocity improvement comparable to the nontreated ulnar side but prominent fibrosis on the radial aspect. We anticipate that Doppler ultrasonography may be an effective tool for the postoperative assessment of patients who underwent digital sympathectomy for treatment of RP.


Influenza Hemifusion Phenotype Depends on Membrane Context: Differences in Cell-Cell and Virus-Cell Fusion.
Influenza viral entry into the host cell cytoplasm is accomplished by a process of membrane fusion mediated by the viral hemagglutinin protein. Hemagglutinin acts in a pH-triggered fashion, inserting a short fusion peptide into the host membrane followed by refolding of a coiled-coil structure to draw the viral envelope and host membranes together. Mutations to this fusion peptide provide an important window into viral fusion mechanisms and protein-membrane interactions. Here, we show that a well-described fusion peptide mutant, G1S, has a phenotype that depends strongly on the viral membrane context. The G1S mutant is well known to cause a "hemifusion" phenotype based on experiments in transfected cells, where cells expressing G1S hemagglutinin can undergo lipid mixing in a pH-triggered fashion similar to virus but will not support fusion pores. We compare fusion by the G1S hemagglutinin mutant expressed either in cells or in influenza virions and show that this hemifusion phenotype occurs in transfected cells but that native virions are able to support full fusion, albeit at a slower rate and 10-100× reduced infectious titer. We explain this with a quantitative model where the G1S mutant, instead of causing an absolute block of fusion, alters the protein stoichiometry required for fusion. This change slightly slows fusion at high hemagglutinin density, as on the viral surface, but at lower hemagglutinin density produces a hemifusion phenotype. The quantitative model thus reproduces the observed virus-cell and cell-cell fusion phenotypes, yielding a unified explanation where membrane context can control the observed viral fusion phenotype.


Nutrition for the Next Generation: Older Children and Adolescents.
This paper reviews information on why the nutrition of older children (5-9 years) and adolescents (10-19 years) is important and the consequences that it can have over generations. Developing countries still face a high burden of undernutrition and anemia, while the burden of overweight and obesity is on the rise in both developing and developed countries. There are evidence-based interventions which can improve the nutritional status and these include interventions for a balanced and diverse diet and micronutrient supplementation, especially iron and multiple micronutrient supplementation where there is sufficient evidence to reduce anemia. There is mixed evidence for the effective strategies to prevent and control obesity and a dearth of evidence from developing countries. Adolescent pregnancy also poses greater challenges to the health of mother and child, and advocacy should be rampant to delay the age of marriage and pregnancy. Interventions targeted to improving the nutritional status among "pregnant adolescents" have shown improvement in birth weight and a reduction in low birth weight and preterm delivery. Traditional platforms including school-based and community-based approaches offer a mixed picture of effectiveness, but emerging avenues of mHealth and social media could also be channelized to reach this population. The population of this age group is on the rise globally, and failure to invest in improving the nutrition of older children and adolescents will further increase the number of dependents in coming generations and negatively influence the health of future generations and progress of nations.


Characterization of algal community composition and structure from the nearshore environment, Lake Tahoe (United States).
Periphyton assemblages from the nearshore environment of the west (California) side of Lake Tahoe, were analyzed to determine their taxonomic composition and community structure across habitats and seasons. Lake Tahoe is the second deepest lake in the US and an iconic oligotrophic subalpine lake with remarkable transparency. It has experienced offshore cultural eutrophication since the 1960s with observations of nuisance nearshore algal growth since the mid 2000s attributed to anthropogenic stressors. Samplings from November 2019-September 2020 provide useful snapshots against which older monitoring may be contextualized. A voucher flora, complete with descriptions, photo-documentation and referencing to species concepts employed, was created as a method of providing reproducible identification and enumeration of algal species, and more seamless reconciliation of detailed taxonomic data with future monitoring projects. The eulittoral zone (0-2 m) is seasonally dominated by elongate araphid (Synedra, Ulnaria) and stalked or entubed diatoms (Gomphonema, Cymbella, Encyonema). The sublittoral zone (>2 m) is dominated by a nitrogen-fixing Epithemia-cyanobacteria assemblage with less seasonal changes in dominance and composition that expanded to impinge on the 2 m depths of the eulittoral zone in the Fall. Sublittoral epipsammic samples, despite their proximity to rocks, had a very distinct diatom composition and high species dominance, similar to what was seen in the Fall eulittoral samples, with high numbers of Staurosirella chains and small biraphid diatoms. The deeper samples at 30 and 50 m contained high numbers of live Epithemia, and indicate a thriving sublittoral assemblage at these greater depths, but with less biomass. The 2019-20 data show many of the same diatom taxa observed in the 1970's and 1980's but with changes in species dominance. Notably, there was less of the green alga Mougeotia, when compared to the 1970's data, and a higher dominance by nitrogen fixing Epithemia in the sublittoral zone, persisting year-round. These new data show roughly double the algal species biodiversity that had been documented previously in the Lake Tahoe nearshore, and is largely attributed to the methods employed. Adopting these new methods in future monitoring efforts should improve harmonization of taxonomic data and help advance our knowledge of the contributions to nearshore cultural eutrophication.


RNA-Dependent Epigenetic Silencing Directs Transcriptional Downregulation Caused by Intronic Repeat Expansions.
Transcriptional downregulation caused by intronic triplet repeat expansions underlies diseases such as Friedreich's ataxia. This downregulation of gene expression is coupled with epigenetic changes, but the underlying mechanisms are unknown. Here, we show that an intronic GAA/TTC triplet expansion within the IIL1 gene of Arabidopsis thaliana results in accumulation of 24-nt short interfering RNAs (siRNAs) and repressive histone marks at the IIL1 locus, which in turn causes its transcriptional downregulation and an associated phenotype. Knocking down DICER LIKE-3 (DCL3), which produces 24-nt siRNAs, suppressed transcriptional downregulation of IIL1 and the triplet expansion-associated phenotype. Furthermore, knocking down additional components of the RNA-dependent DNA methylation (RdDM) pathway also suppressed both transcriptional downregulation of IIL1 and the repeat expansion-associated phenotype. Thus, our results show that triplet repeat expansions can lead to local siRNA biogenesis, which in turn downregulates transcription through an RdDM-dependent epigenetic modification.


Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells.
HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34(+) cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements.


A new treatment modality for fibromyalgia syndrome: hyperbaric oxygen therapy.
Fibromyalgia syndrome (FMS) is characterized by longstanding multifocal pain with generalized allodynia/hyperalgesia. There are several treatment methods but none has been specifically approved for this application. We conducted a randomized controlled study to evaluate the effect of hyperbaric oxygen (HBO) therapy in FMS (HBO group: n = 26; control group: n = 24). Tender points and pain threshold were assessed before, and after the first and fifteenth sessions of therapy. Pain was also scored on a visual analogue scale (VAS). There was a significant reduction in tender points and VAS scores and a significant increase in pain threshold of the HBO group after the first and fifteenth therapy sessions. There was also a significant difference between the HBO and control groups for all parameters except the VAS scores after the first session. We conclude that HBO therapy has an important role in managing FMS.


Apolipoprotein Proteomics for Residual Lipid-Related Risk in Coronary Heart Disease.
Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid panels to guide use of emerging treatments for the prevention of coronary heart disease (CHD). This report assessed the relevance of 13 apolipoproteins measured using a single mass-spectrometry assay for risk of CHD in the PROCARDIS case-control study of CHD (941 cases/975 controls). The associations of apolipoproteins with CHD were assessed after adjustment for established risk factors and correction for statin use. Apolipoproteins were grouped into 4 lipid-related classes [lipoprotein(a), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides] and their associations with CHD were adjusted for established CHD risk factors and conventional lipids. Analyses of these apolipoproteins in a subset of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) were used to assess their within-person variability and to estimate a correction for statin use. The findings in the PROCARDIS study were compared with those for incident cardiovascular disease in the Bruneck prospective study (n=688), including new measurements of Apo(a). Triglyceride-carrying apolipoproteins (ApoC1, ApoC3, and ApoE) were most strongly associated with the risk of CHD (2- to 3-fold higher odds ratios for top versus bottom quintile) independent of conventional lipid measures. Likewise, ApoB was independently associated with a 2-fold higher odds ratios of CHD. Lipoprotein(a) was measured using peptides from the Apo(a)-kringle repeat and Apo(a)-constant regions, but neither of these associations differed from the association with conventionally measured lipoprotein(a). Among HDL-related apolipoproteins, ApoA4 and ApoM were inversely related to CHD, independent of conventional lipid measures. The disease associations with all apolipoproteins were directionally consistent in the PROCARDIS and Bruneck studies, with the exception of ApoM. Apolipoproteins were associated with CHD independent of conventional risk factors and lipids, suggesting apolipoproteins could help to identify patients with residual lipid-related risk and guide personalized approaches to CHD risk reduction.


Hypnosis in breast cancer care: a systematic review of randomized controlled trials.
Many breast cancer patients and survivors experience pain and emotional stress related to their disease, its diagnostic procedures, or treatment. Hypnosis has long been used for the treatment of such symptoms. The aim of this review was to systematically assess the effectiveness of hypnosis in women with breast cancer, breast cancer survivors, and in women undergoing diagnostic breast biopsy. PubMed, Scopus, the Cochrane Library, PsycINFO, and CAMBASE were screened through February 2014 for randomized controlled trials (RCTs) of hypnosis in women with breast cancer or undergoing diagnostic breast biopsy. RCTs on postmenopausal women without a history of breast cancer were also eligible. Primary outcomes were pain, distress, fatigue, nausea/vomiting, and hot flashes. Safety was defined as secondary outcome measure. Risk of bias was assessed by 2 reviewers independently using the Cochrane Risk of Bias Tool. Thirteen RCTs with 1357 patients were included. In women undergoing diagnostic breast biopsy (3 RCTs), hypnosis positively influenced pain and distress; 1 RCT on breast cancer surgery found effects of hypnosis on pain, distress, fatigue, and nausea. For women undergoing radiotherapy (3 RCTs), hypnosis combined with cognitive-behavioral therapy improved distress and fatigue. In 3 RCTs on women with and without a history of breast cancer experiencing hot flashes, hypnosis improved hot flashes and distress. Three RCTs on women with metastatic breast cancer found effects on pain and distress. This systematic review found sparse but promising evidence for the effectiveness of hypnosis in breast cancer care. While more research is needed to underpin these results, hypnosis can be considered as an ancillary intervention in the management of breast cancer-related symptoms.


Arterial transfer functions and the reconstruction of central aortic waveforms: myths, controversies and misconceptions.
Continuing reports in the literature regarding the potential of central pulse wave analysis in clinical practice and a recent consensus statement demonstrate the increasing interest in the clinical application of arterial transfer functions. A number of misconceptions, however, persist regarding their use. In spite of ongoing controversy, there are considerable published data that would permit users to assess the validity and accuracy of the technique. We provide a comprehensive review of available data, all of which appear to be clear and consistent. The technique does not permit accurate reconstruction of central waveforms from entirely non-invasively acquired data. We should move on from the misconception that what is being studied is central aortic data when transfer functions are applied non-invasively, and accept that it is radial waveform data that have been passed through a single mathematical transformation. We have a readily applicable, non-invasive and reproducible technique for acquiring radial waveform data, with or without the application of a generalized arterial transfer function. We must explore the potential of this technique in an analytical manner, and without untenable preconceptions, if we are to learn the secrets that it may yet reveal.


The endoderm of the mouse embryo arises by dynamic widespread intercalation of embryonic and extraembryonic lineages.
The cell movements underlying the morphogenesis of the embryonic endoderm, the tissue that will give rise to the respiratory and digestive tracts, are complex and not well understood. Using live imaging combined with genetic labeling, we investigated the cell behaviors and fate of the visceral endoderm during gut endoderm formation in the mouse gastrula. Contrary to the prevailing view, our data reveal no mass displacement of visceral endoderm to extraembryonic regions concomitant with the emergence of epiblast-derived definitive endoderm. Instead, we observed dispersal of the visceral endoderm epithelium and extensive mixing between cells of visceral endoderm and epiblast origin. Visceral endoderm cells remained associated with the epiblast and were incorporated into the early gut tube. Our findings suggest that the segregation of extraembryonic and embryonic tissues within the mammalian embryo is not as strict as believed and that a lineage previously defined as exclusively extraembryonic contributes cells to the embryo.


Prevalence of thyroid autoimmunity in patients with pemphigus vulgaris.
Among bullous diseases, pemphigus vulgaris (PV) is a classical variety of this type of skin disorders. To establish the real prevalence of thyroid abnormalities in such a disease, a prospective study was developed. For this reason, thyroid evaluation was performed in 15 consecutive patients who attended the Dermatology Clinic for PV and in a group of 15 healthy volunteers (Control Group) matched by age and gender. Thyroid function was evaluated by measuring T3, T4 and TSH. The presence or absence of goiter was searched by palpation, while thyroid autoimmunity was investigated through the assay of thyroperoxidase antibodies (TPO-Ab). In each group there were 9 women and 6 men, aging 25-65 years (mean = 48.3 y) in the PV Group, and 25-69 years (mean = 45.4 y) in the Control Group. It was found that 7 patients (46.6%) of the PV Group and 1 subject (6.7%) of the Control Group (p < 0.015) disclosed thyroidal alterations. Positive titers of TPO-Ab were observed in 6 patients with PV and in one volunteer. Goiter and subclinical hypothyroidism were found in one PV patient with negative TPO-Ab. Out of the total 7 cases with positive TPO-Ab, only a PV patient had an overt Hashimoto's thyroiditis. All other cases had only the presence of thyroid auto-antibodies without clinical evidences of chronic thyroiditis. It is concluded that PV is highly associated with primary thyroid disorders, mainly with positive titers of TPO-Ab, although most patients do not present overt clinical thyroid disease.


Molecularly designed architectures--the metalloligand way.
Designed materials offer noteworthy applications which are often architecture dependent. Despite knowing such a fact, one of the major challenges faced by the scientific community is to find ways to predict and, if possible, control the resultant architecture of a network. If such an exercise is fruitful, it creates enormous opportunities to synthesize exotic materials with tailor-made applications. Any network is composed of individual molecules and the transition from a single molecule to a network can be achieved through several routes taking advantage of synthetic chemistry. There exists a molecular building block at the heart of such a transition which mediates such a process from a single molecule to a network. Although a large number of building blocks have created assorted materials, utilization of a well-defined coordination complex as the building block (i.e., metalloligand) is unique for the construction of a designed architecture. A coordination complex as the building block offers structural rigidity that places the auxiliary functional groups to a pre-organized conformation. Such auxiliary functional groups could then coordinate a secondary metal ion or be involved in the self-assembly via weak interactions, such as hydrogen bonds. This review focuses on the recent progress achieved through assorted molecular building blocks towards generating ordered networks. Broadly, two classes of metalloligands will be discussed: those offering hydrogen bond sensitive functional groups and those tendering coordination bond responsive groups. Nevertheless, the result is the construction of networks of a highly-ordered nature in both cases. The present review is expected to provide new strategies for constructing functional materials through metalloligands for challenging and practical applications.


Medicine adaptive pathways to patients (MAPPs): using regulatory innovation to defeat Eroom's law.
Eroom's Law is, literally, Moore's law in reverse. The pharmaceutical sector invests $50 billion annually in research for new medicines but, "the number of new drugs approved per billion US dollars spent has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms". Pharmaceutical companies have invested enormous sums in new molecular entities (NME) in the areas of unmet medical need identified by the World Health Organization (WHO), but the approval rates from phase I are only 7% for cardiovascular disease, dropping to 4% for Alzheimer's disease. The increasing cost of research & development (R&D) is not only a factor of research management quality, but also indicative of an industry trying to address therapeutic areas that have incredibly complex biological mechanisms with budget-crushing failure rates. Medicine adaptive pathways to patients (MAPPs) build on the stratification breakthroughs of personalized medicine to facilitate new types of clinical trials that adapt to a given patient's response. At their core, MAPPs will have a limited commercial marketing authorization for a patient group who has access to new therapeutic agents while validating additional clinical endpoints at the same time. This gives MAPPs a theoretical ability to run trials that fulfil both the efficacy requirements for authorization and the effectiveness needs of national health technology assessments (HTA) simultaneously, providing patients with needed therapies in the most efficient timescale and trial size possible. In order to move science forward and meet these daunting medical challenges for patients, new collaborative approaches to testing the efficacy and effectiveness of new improved medicines such as MAPPs should be embraced by regulators in close partnership with patients, payers, and practitioners. To not do so puts the entire healthcare value chain, and the future health of patients, at risk.


Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study.
Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative option for adult T-cell leukemia (ATL), an intractable mature T-cell neoplasm causally linked with human T-cell leukemia virus type I (HTLV-I). We compared outcomes of 386 patients with ATL who underwent allogeneic HSCT using different graft sources: 154 received human leukocyte antigen (HLA)-matched related marrow or peripheral blood; 43 received HLA-mismatched related marrow or peripheral blood; 99 received unrelated marrow; 90 received single unit unrelated cord blood. After a median follow-up of 41 months (range, 1.5-102), 3-year overall survival for entire cohort was 33% (95% confidence interval, 28%-38%). Multivariable analysis revealed 4 recipient factors significantly associated with lower survival rates: older age (> 50 years), male sex, status other than complete remission, and use of unrelated cord blood compared with use of HLA-matched related grafts. Treatment-related mortality rate was higher among patients given cord blood transplants; disease-associated mortality was higher among male recipients or those given transplants not in remission. Among patients who received related transplants, donor HTLV-I seropositivity adversely affected disease-associated mortality. In conclusion, allogeneic HSCT using currently available graft source is an effective treatment in selected patients with ATL, although greater effort is warranted to reduce treatment-related mortality.


Early and late signs that precede dying among older persons in nursing homes: the multidisciplinary team's perspective.
Nursing home residents in Sweden are old, frail and usually have multiple morbidities which often make dying a prolonged suffering. It has been found that older persons at nursing homes receive far less palliative care than younger persons, partly because it is difficult to identify when the final stage of life begins. The identification may help the staff to enable the older person and their families to participate in planning the care in accordance with their own preferences and values. With this in mind the aim was to explore the experiences of early and late signs preceding dying in older persons in nursing homes from the multidisciplinary team's perspective. The focus group method was used to interview 20 health-care professionals on the basis of semi-structured questions. Four focus groups were conducted at four nursing homes in two counties in southern Sweden. The groups included different professionals such as assistant nurses, registered nurses, occupational therapists, physiotherapists, social workers and unit managers. The analysis was conducted according to the focus group method developed by Kruger and Casey. The analysis revealed one major theme, from unawareness to obviousness, which illustrates that the participants experienced dying as a happening, not a process, and found it difficult to identify early signs. Even though it was a new way of thinking, several suggestions of early signs were presented. The main category "Going into a bubble" illustrates early signs, which meant that the older person showed signs of wanting to withdraw from the outside world. The main category "The body begins to shut down" illustrates late signs, which meant that the older person showed signs that indicate that the body starts to prepare for death. This study conveys new knowledge concerning the multidisciplinary team's collective experience of early and late signs that precede dying. This knowledge can increase the understanding of when a palliative care approach needs to be in place at nursing homes. The use of a palliative care approach in care planning requires consensus in the perception of the dying process of frail older persons.


Tri-party underground symbiosis between a weevil, bacteria and a desert plant.
Inhabitants of arid ecosystems face severe nitrogen and water limitations. Inventive adaptations by organisms occupying such habitats are essential for survival. This study describes a tri-party symbiotic interaction between a plant (Salsola inermis), a beetle (Conorhynchus pistor), and a bacterium (Klebsiella pneumonia). The weevil survives by living within a mud structure affixed to the plant roots, thus benefiting from increased carbon and water, and refuge from predators and parasites. Active nitrogen-fixing bacteria harbored within the weevil's gut mediate this interaction, by supplying nitrogen to the system, which eventually promotes seed development. We studied the correlation between the weevil's existence and (i) root carbon and nitrogen content, (ii) soil water content and (iii) seed weight. Roots hosting weevils contained more nitrogen, heavier seeds and less carbon. In addition, water content was higher around the roots than in open spaces a short distance from the plant stem. Bacterial studies and nitrogen-fixation analyses, including molecular and chemical assays, indicated atmospheric nitrogen fixation in the larval stage and identified the bacterium. The coexistence of weevil and bacterial behavior coinciding with the plant's life cycle was revealed here by a long period of field observations. Out of over 60,000 known weevils, this is the only report of a weevil living most of its life underground without harming plants. The unique tri-party interaction described herein shows the important ecological role of desert plant roots and provides an example of a sustainable consortium of living organisms coping with the challenging desert environment.


Bacterial secretion systems contribute to rapid tissue decay in button mushroom soft rot disease.
The soft rot pathogen Janthinobacterium agaricidamnosum causes devastating damage to button mushrooms (Agaricus bisporus), one of the most cultivated and commercially relevant mushrooms. We previously discovered that this pathogen releases the membrane-disrupting lipopeptide jagaricin. This bacterial toxin, however, could not solely explain the rapid decay of mushroom fruiting bodies, indicating that J. agaricidamnosum implements a more sophisticated infection strategy. In this study, we show that secretion systems play a crucial role in soft rot disease. By mining the genome of J. agaricidamnosum, we identified gene clusters encoding a type I (T1SS), a type II (T2SS), a type III (T3SS), and two type VI secretion systems (T6SSs). We targeted the T2SS and T3SS for gene inactivation studies, and subsequent bioassays implicated both in soft rot disease. Furthermore, through a combination of comparative secretome analysis and activity-guided fractionation, we identified a number of secreted lytic enzymes responsible for mushroom damage. Our findings regarding the contribution of secretion systems to the disease process expand the current knowledge of bacterial soft rot pathogens and represent a significant stride toward identifying targets for their disarmament with secretion system inhibitors. IMPORTANCE The button mushroom (Agaricus bisporus) is the most popular edible mushroom in the Western world. However, mushroom crops can fall victim to serious bacterial diseases that are a major threat to the mushroom industry, among them being soft rot disease caused by Janthinobacterium agaricidamnosum. Here, we show that the rapid dissolution of mushroom fruiting bodies after bacterial invasion is due to degradative enzymes and putative effector proteins secreted via the type II secretion system (T2SS) and the type III secretion system (T3SS), respectively. The ability to degrade mushroom tissue is significantly attenuated in secretion-deficient mutants, which establishes that secretion systems are key factors in mushroom soft rot disease. This insight is of both ecological and agricultural relevance by shedding light on the disease processes behind a pathogenic bacterial-fungal interaction which, in turn, serves as a starting point for the development of secretion system inhibitors to control disease progression.


Efficacy of long-term anticoagulant treatment in subgroups of patients after myocardial infarction.
To investigate the efficacy of long term oral anticoagulant treatment in subgroups of patients after myocardial infarction. Analysis of the effect of anticoagulant treatment in subgroups of hospital survivors of myocardial infarction based upon age, gender, history of hypertension, previous myocardial infarction, smoking habits, diabetes mellitus, Killip class, anterior location of infarction, thrombolytic therapy, and use of beta blockers. Participants of a multicentre, randomised, double blind, placebo controlled trial that assessed the effect of oral anticoagulant treatment on mortality as well as cerebrovascular and cardiovascular morbidity in 3404 hospital survivors of acute myocardial infarction. The effect of anticoagulant treatment on recurrent myocardial infarction, cerebrovascular events, and vascular events (the composite endpoint of reinfarction, cerebrovascular event, and vascular death). Long term anticoagulant treatment was associated with a reduction in mortality of 10% (95% confidence interval -11% to 27%), recurrent myocardial infarction of 53% (41% to 62%), cerebrovascular events of 40% (10% to 60%) and vascular events of 35% (24% to 45%). Treatment effect with respect to recurrent myocardial infarction was comparable among all subgroups of patients. Although treatment effect appeared to be somewhat smaller in females than in males (-11% v -45%), and in patients with diabetes compared to those without (-14% v -42%) with respect to vascular events, none of these differences reached statistical significance. In multivariate analysis, more advanced age, previous myocardial infarction, diabetes mellitus, and heart failure during admission were independently associated with increased incidence of cardiovascular complications. The relative benefit of long term anticoagulant therapy in survivors of myocardial infarction is not modified by known prognostic factors for cardiovascular disease.


Recombinant raccoon pox vaccine protects mice against lethal plague.
Using a raccoon poxvirus (RCN) expression system, we have developed new recombinant vaccines that can protect mice against lethal plague infection. We tested the effects of a translation enhancer (EMCV-IRES) in combination with a secretory (tPA) signal or secretory (tPA) and membrane anchoring (CHV-gG) signals on in vitro antigen expression of F1 antigen in tissue culture and the induction of antibody responses and protection against Yersinia pestis challenge in mice. The RCN vector successfully expressed the F1 protein of Y. pestis in vitro. In addition, the level of expression was increased by the insertion of the EMCV-IRES and combinations of this and the secretory signal or secretory and anchoring signals. These recombinant viruses generated protective immune responses that resulted in survival of 80% of vaccinated mice upon challenge with Y. pestis. Of the RCN-based vaccines we tested, the RCN-IRES-tPA-YpF1 recombinant construct was the most efficacious. Mice vaccinated with this construct withstood challenge with as many as 1.5 million colony forming units of Y. pestis (7.7 x 10(4)LD(50)). Interestingly, vaccination with F1 fused to the anchoring signal (RCN-IRES-tPA-YpF1-gG) elicited significant anti-F1 antibody titers, but failed to protect mice from plague challenge. Our studies demonstrate, in vitro and in vivo, the potential importance of the EMCV-IRES and secretory signals in vaccine design. These molecular tools provide a new approach for improving the efficacy of vaccines. In addition, these novel recombinant vaccines could have human, veterinary, and wildlife applications in the prevention of plague.


Versatile protection from mutagenic DNA lesions conferred by bipartite recognition in nucleotide excision repair.
Nucleotide excision repair is a cut-and-patch pathway that eliminates potentially mutagenic DNA lesions caused by ultraviolet light, electrophilic chemicals, oxygen radicals and many other genetic insults. Unlike antigen recognition by the immune system, which employs billions of immunoglobulins and T-cell receptors, the nucleotide excision repair complex relies on just a few generic factors to detect an extremely wide range of DNA adducts. This molecular versatility is achieved by a bipartite strategy initiated by the detection of abnormal strand fluctuations, followed by the localization of injured residues through an enzymatic scanning process coupled to DNA unwinding. The early recognition subunits are able to probe the thermodynamic properties of nucleic acid substrates but avoid direct contacts with chemically altered bases. Only downstream subunits of the bipartite recognition process interact more closely with damaged bases to delineate the sites of DNA incision. Thus, consecutive factors expand the spectrum of deleterious genetic lesions conveyed to DNA repair by detecting distinct molecular features of target substrates.


What rural doctors want: a qualitative study in Chhattisgarh state.
The importance of addressing concerns of rural health worker welfare in order to improve their performance and retention is widely acknowledged; yet there is little empirical research on the needs of rural health professionals. We report findings from a qualitative research study in rural Chhattisgarh, involving indepth interviews with 37 practitioners and data analysis using the "framework" approach. Participants' expressions of their needs encompassed a range of reforms and improvements, including better salaries and job security, more rational posting and promotion procedures, and facility improvements. Opportunities for need-based skills training and better housing also emerged as key needs, as did better schools, assurance of personal security, and recognition and appreciation of their services by the administration. Increased investment in rural infrastructure and training, graded packages of benefits for rural doctors, and governance reforms to improve the internal accountability of government health services emerge as recommendations from the study.


Acute retinal ischemia inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production.
Because retinal vascular disease is associated with ischemia and increased oxidative stress, the vasodilator function of retinal arterioles was examined after retinal ischemia induced by elevated intraocular pressure (IOP). The role of superoxide anions in the development of vascular dysfunction was assessed. IOP was increased and maintained at 80 to 90 mm Hg for 30, 60, or 90 minutes by infusing saline into the anterior chamber of a porcine eye. The fellow eye with normal IOP (10-20 mm Hg) served as control. In some pigs, superoxide dismutase mimetic TEMPOL (1 mM) or vehicle (saline) was injected intravitreally before IOP elevation. After enucleation, retinal arterioles were isolated and pressurized without flow for functional analysis by recording diameter changes using videomicroscopic techniques. Dihydroethidium (DHE) was used to detect superoxide production in isolated retinal arterioles. Isolated retinal arterioles developed stable basal tone and the vasodilations to endothelium-dependent nitric oxide (NO)-mediated agonists bradykinin and L-lactate were significantly reduced only by 90 minutes of ischemia. However, vasodilation to endothelium-independent NO donor sodium nitroprusside was unaffected after all time periods of ischemia. DHE staining showed that 90 minutes of ischemia significantly increased superoxide levels in retinal arterioles. Intravitreal injection of membrane-permeable radical scavenger but not vehicle before ischemia prevented elevation of vascular superoxide and preserved bradykinin-induced dilation. Endothelium-dependent NO-mediated dilation of retinal arterioles is impaired by 90 minutes of ischemia induced by elevated IOP. The inhibitory effect appears to be mediated by the alteration of NO signaling via vascular superoxide.


Potential Involvement of Type I Interferon Signaling in Immunotherapy in Seasonal Allergic Rhinitis.
Specific immunotherapy (SIT) reverses the symptoms of seasonal allergic rhinitis (SAR) in most patients. Recent studies report type I interferons shifting the balance between type I T helper cell (Th1) and type II T helper cells (Th2) towards Th2 dominance by inhibiting the differentiation of naive T cells into Th1 cells. As SIT is thought to cause a shift towards Th1 dominance, we hypothesized that SIT would alter interferon type I signaling. To test this, allergen and diluent challenged CD4+ T cells from healthy controls and patients from different time points were analyzed. The initial experiments focused on signature genes of the pathway and found complex changes following immunotherapy, which were consistent with our hypothesis. As interferon signaling involves multiple genes, expression profiling studies were performed, showing altered expression of the pathway. These findings require validation in a larger group of patients in further studies.


Informing species conservation at multiple scales using data collected for marine mammal stock assessments.
Conservation planning and the design of marine protected areas (MPAs) requires spatially explicit information on the distribution of ecological features. Most species of marine mammals range over large areas and across multiple planning regions. The spatial distributions of marine mammals are difficult to predict using habitat modelling at ecological scales because of insufficient understanding of their habitat needs, however, relevant information may be available from surveys conducted to inform mandatory stock assessments. We use a 20-year time series of systematic aerial surveys of dugong (Dugong dugong) abundance to create spatially-explicit models of dugong distribution and relative density at the scale of the coastal waters of northeast Australia (∼136,000 km(2)). We interpolated the corrected data at the scale of 2 km * 2 km planning units using geostatistics. Planning units were classified as low, medium, high and very high dugong density on the basis of the relative density of dugongs estimated from the models and a frequency analysis. Torres Strait was identified as the most significant dugong habitat in northeast Australia and the most globally significant habitat known for any member of the Order Sirenia. The models are used by local, State and Federal agencies to inform management decisions related to the Indigenous harvest of dugongs, gill-net fisheries and Australia's National Representative System of Marine Protected Areas. In this paper we demonstrate that spatially-explicit population models add value to data collected for stock assessments, provide a robust alternative to predictive habitat distribution models, and inform species conservation at multiple scales.


Potato consumption is not associated with elevated cardiometabolic risk in adolescent girls.
We examined the association between potato consumption in two different age periods during adolescence and risk of obesity and cardiometabolic dysfunction in White and Black girls. We used data from the biracial prospective National Growth and Health Study. Average potato consumption was derived from multiple 3-d food records in two age periods, 9-11 and 9-17 years, and included white and sweet potatoes from all sources. Multivariable logistic regression models were used to estimate OR for becoming overweight, developing prehypertension, elevated TAG levels or impaired fasting glucose (IFG) at 18-20 years of age according to the category of daily potato intake. We also stratified by cooking method (fried/non-fried) and race. ANCOVA was also used to estimate adjusted mean levels of BMI, systolic blood pressure, diastolic blood pressure, log-transformed TAG, the TAG:HDL ratio and fasting glucose levels associated with potato intake category. Higher potato consumption was associated with higher fruit and non-starchy vegetable intakes and higher Healthy Eating Index scores in Black girls. There were no statistically significant associations overall between moderate or higher (v. lower) intakes of potatoes and risks of overweight, prehypertension, elevated fasting TAG, high TAG:HDL ratio or IFG. Also, no adverse associations were found between fried or non-fried potato intake and cardiometabolic outcomes. Potato consumption has been the subject of much controversy in recent years. This study adds evidence that potato consumption among healthy girls during the critical period of adolescence was not associated with cardiometabolic risk.


Ecological immunology: costly parasite defences and trade-offs in evolutionary ecology.
In the face of continuous threats from parasites, hosts have evolved an elaborate series of preventative and controlling measures - the immune system - in order to reduce the fitness costs of parasitism. However, these measures do have associated costs. Viewing an individual's immune response to parasites as being subject to optimization in the face of other demands offers potential insights into mechanisms of life history trade-offs, sexual selection, parasite-mediated selection and population dynamics. We discuss some recent results that have been obtained by practitioners of this approach in natural and semi-natural populations, and suggest some ways in which this field may progress in the near future.


Synergism of obesity genes with hepatic steroid sulfotransferases to mediate diabetes in mice.
Sulfotransferases controlling the intrahepatic ratio of active androgens to estrogens represent key determinants of whether an obesity mutation will be diabetogenic in C57BL/KsJ female mice. Three unlinked genes (diabetes [db], obese [ob], and fat [fat]) all produced comparable obesity in C57BL/KsJ females, but only the fat mutation was not diabetogenic. The fat gene was incapable of eliciting virilizing changes in hepatic sulfotransferase activity, whereas both db and ob accelerated estrogen and suppressed androgen sulfation. Northern-blot analysis confirmed anomalous suppression of hepatic androgen sulfotransferase transcription in db and ob but not fat females. These findings suggest the utility of obesity genes in analyzing the interaction between hyperandrogenism, hyperinsulinemia, and diabetes.


Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.
Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype.


Effect of fullerenol nanoparticles on oxidative stress induced by paraquat in honey bees.
The enormous progress in nanomaterials development and their use, followed by their inevitable environmental print, has arisen the emerging questions concerning their influence to the living systems. Honey bees are considered to be quite a suitable model system for the risk assessment and prediction of various external influences. To the best of our knowledge, this is the first study dealing with the influence of fullerenol nanoparticles (FNP), a biodegradable carbon nanomaterials' representative, to honey bees. This investigation was conducted with an aim to merge two different open-ended questions: the potential toxic effect of FNP to the bees on the one hand and antioxidative effect of FNP on the other hand. Since FNP antioxidative properties were proved in a number of in vivo models, we hypothesized the similar outcomes, and according to this assumption, we opted for paraquat as a well-known oxidative stress inducer. FNP did not have toxic effect in none of investigated concentrations. The results also confirmed the potential of FNP to reduce oxidative stress through the gene expression of antioxidative enzymes and the change in the redox state of the cells. Additional experiments are needed for a better understanding of the exact mechanism and complex patterns of FNP's activity.


Quantum dots: from fluorescence to chemiluminescence, bioluminescence, electrochemiluminescence, and electrochemistry.
During the past decade, nanotechnology has become one of the major forces driving basic and applied research. As a novel class of inorganic fluorochromes, research into quantum dots (QDs) has become one of the fastest growing fields of nanotechnology today. QDs are made of a semiconductor material with tunable physical dimensions as well as unique optoelectronic properties, and have attracted multidisciplinary research efforts to further their potential bioanalytical applications. Recently, numerous optical properties of QDs, such as narrow emission band peaks, broad absorption spectra, intense signals, and remarkable resistance to photobleaching, have made them biocompatible and sensitive for biological assays. In this review, we give an overview of these exciting materials and describe their potential, especially in biomolecules analysis, including fluorescence detection, chemiluminescence detection, bioluminescence detection, electrochemiluminescence detection, and electrochemical detection. Finally, conclusions are made, including highlighting some critical challenges remaining and a perspective of how this field can be expected to develop in the future.


Variability in the vacuum-ultraviolet transmittance of magnesium fluoride windows.
In the course of the development of a domed magnesium fluoride detector window for the Space Telescope Imaging Spectrograph, slated to be a second-generation instrument aboard the Hubble Space Telescope, sample window materials from various commercial sources displayed a wide variability in vacuum ultraviolet transmittance. As a result a test program was undertaken in cooperation with the supplier of a prototype domed window to maximize transmittance. Results of the program have provided clues to the causes of the variations experienced, and they point to careful selection of raw materials and strict process control to achieve optimization.


Asplenia and spleen hypofunction.
Asplenia (the congenital or acquired absence of the spleen) and hyposplenism (defective spleen function) are common causes of morbidity and mortality. The spleen is a secondary lymphoid organ that is responsible for the regulation of immune responses and blood filtration. Hence, asplenia or hyposplenism increases susceptibility to severe and invasive infections, especially those sustained by encapsulated bacteria (namely, Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type b). Asplenia is predominantly due to splenectomy for either traumatic events or oncohaematological conditions. Hyposplenism can be caused by several conditions, including haematological, infectious, autoimmune and gastrointestinal disorders. Anatomical disruption of the spleen and depletion of immune cells, especially IgM memory B cells, seem to be predominantly responsible for the clinical manifestations. Early recognition of hyposplenism and proper management of asplenia are warranted to prevent overwhelming post-splenectomy infections through vaccination and antibiotic prophylaxis. Although recommendations are available, the implementation of vaccination strategies, including more effective and immunogenic vaccines, is needed. Additionally, screening programmes for early detection of hyposplenism in high-risk patients and improvement of patient education are warranted.


How much is too much? A case report of nutritional supplement use of a high-performance athlete.
Although dietary nutrient intake is often adequate, nutritional supplement use is common among elite athletes. However, high-dose supplements or the use of multiple supplements may exceed the recommended daily allowance (RDA) of particular nutrients or even result in a daily intake above tolerable upper limits (UL). The present case report presents nutritional intake data and supplement use of a highly trained male swimmer competing at international level. Habitual energy and micronutrient intake were analysed by 3 d dietary reports. Supplement use and dosage were assessed, and total amount of nutrient supply was calculated. Micronutrient intake was evaluated based on RDA and UL as presented by the European Scientific Committee on Food, and maximum permitted levels in supplements (MPL) are given. The athlete's diet provided adequate micronutrient content well above RDA except for vitamin D. Simultaneous use of ten different supplements was reported, resulting in excess intake above tolerable UL for folate, vitamin E and Zn. Additionally, daily supplement dosage was considerably above MPL for nine micronutrients consumed as artificial products. Risks and possible side effects of exceeding UL by the athlete are discussed. Athletes with high energy intake may be at risk of exceeding UL of particular nutrients if multiple supplements are added. Therefore, dietary counselling of athletes should include assessment of habitual diet and nutritional supplement intake. Educating athletes to balance their diets instead of taking supplements might be prudent to prevent health risks that may occur with long-term excess nutrient intake.


Neuroimaging auditory verbal hallucinations in schizophrenia patient and healthy populations.
Auditory verbal hallucinations (AVH) are a cardinal feature of schizophrenia, but they can also appear in otherwise healthy individuals. Imaging studies implicate language networks in the generation of AVH; however, it remains unclear if alterations reflect biologic substrates of AVH, irrespective of diagnostic status, age, or illness-related factors. We applied multimodal imaging to identify AVH-specific pathology, evidenced by overlapping gray or white matter deficits between schizophrenia patients and healthy voice-hearers. Diffusion-weighted and T1-weighted magnetic resonance images were acquired in 35 schizophrenia patients with AVH (SCZ-AVH), 32 healthy voice-hearers (H-AVH), and 40 age- and sex-matched controls without AVH. White matter fractional anisotropy (FA) and gray matter thickness (GMT) were computed for each region comprising ICBM-DTI and Desikan-Killiany atlases, respectively. Regions were tested for significant alterations affecting both SCZ-AVH and H-AVH groups, relative to controls. Compared with controls, the SCZ-AVH showed widespread FA and GMT reductions; but no significant differences emerged between H-AVH and control groups. While no overlapping pathology appeared in the overall study groups, younger (<40 years) H-AVH and SCZ-AVH subjects displayed overlapping FA deficits across four regions (p < 0.05): the genu and splenium of the corpus callosum, as well as the anterior limbs of the internal capsule. Analyzing these regions with free-water imaging ascribed overlapping FA abnormalities to tissue-specific anisotropy changes. We identified white matter pathology associated with the presence of AVH, independent of diagnostic status. However, commonalities were constrained to younger and more homogenous groups, after reducing pathologic variance associated with advancing age and chronicity effects.


Research in clinical laboratory science: professionals' involvement.
To describe current qualitative and quantitative aspects of research engagement and other scholarly activities conducted by clinical laboratory science (CLS) professionals across a range of employment settings. A link to a 3-part online survey was sent by electronic mail to 7,572 members of the American Society for Clinical Laboratory Science and 500 program directors. email message, on-line survey all ASCLS members and all directors of accredited clinical laboratory educational programs Quantitative and qualitative measures of professionals' engagement in research and other scholarly activities 556 of 7572 (7.3%) persons completed the survey. Thirty-two percent of survey respondents reported spending between 1 to > 40 work hours per week conducting research with 68% of respondents not participating in research activities. Conducting research is an employment requirement for 18% of survey participants. Twenty-nine percent of respondents have published at least one research article, and 47% of respondents who conduct research have published studies in the journal Clinical Laboratory Science. More than 57% of respondents participate in non-research scholarly activities as part of their employment. CLS professionals who conduct research are more likely to do applied, clinical, or educational research than other types of research. Fifty-seven percent of respondents who conduct research lack external funding for their work. Ninety-three percent of total research dollars is obtained by respondents who hold the Ph.D. degree. The perception of the importance of conducting research varies by employment position. Barriers to participation in research include lack of inclusion of research in the job description, time constraints, inadequate research funding, limited opportunity, and lack of space and equipment. CLS professionals participate in research in limited numbers, and are more likely to engage in non-research types of scholarly activities. Numerous barriers are identified which impose limits to conducting research. Over half of CLS's research efforts lack external funding. Although there was broad representation among participants across educational levels, employment settings, and job positions, the number of survey respondents was limited. Possible directions for future research include conducting this survey using members of additional professional organizations.


Can text messages increase safer sex behaviours in young people? Intervention development and pilot randomised controlled trial.
Younger people bear the heaviest burden of sexually transmitted infections (STIs). Partner notification, condom use and STI testing can reduce infection but many young people lack the knowledge, skills and confidence needed to carry out these behaviours. Text messages can provide effective behavioural support. The acceptability and feasibility of a randomised controlled trial of safer sex support delivered by text message are not known. To assess the acceptability and feasibility of a randomised controlled trial of a safer sex intervention delivered by text message for young people aged 16-24 years. (1) Intervention development; (2) follow-up procedure development; (3) a pilot, parallel-arm randomised controlled trial with allocation via remote automated randomisation (ratio of 1 : 1) (participants were unmasked, whereas researchers analysing samples and data were masked); and (4) qualitative interviews. Participants were recruited from sexual health services in the UK. Young people aged 16-24 years diagnosed with chlamydia or reporting unprotected sex with more than one partner in the last year. A theory- and evidence-based safer sex intervention designed, with young people's input, to reduce the incidence of STIs by increasing the correct treatment of STIs, partner notification, condom use and STI testing before unprotected sex with a new partner. The intervention was delivered via automated mobile phone messaging over 12 months. The comparator was a monthly text message checking contact details. (1) Development of the intervention based on theory, evidence and expert and user views; (2) follow-up procedures; (3) pilot trial primary outcomes: full recruitment within 3 months and follow-up rate for the proposed primary outcomes for the main trial; and (4) participants' views and experiences regarding the acceptability of the intervention. In total, 200 participants were randomised in the pilot trial, of whom 99 were allocated to the intervention and 101 were allocated to the control. We fully recruited early and achieved an 81% follow-up rate for our proposed primary outcome of the cumulative incidence of chlamydia at 12 months. There was no differential follow-up between groups. In total, 97% of messages sent were successfully delivered to participants' mobile phones. Recipients reported that the tone, language, content and frequency of messages were appropriate. Messages reportedly increased knowledge of and confidence in how to use condoms and negotiate condom use and reduced stigma about STIs, enabling participants to tell a partner about a STI. Our research shows that the intervention is acceptable and feasible to deliver. Our pilot trial demonstrated that a main trial is feasible. It remains unclear which behaviour change techniques and elements of the intervention or follow-up procedures are associated with effectiveness. A further limitation is that in the trial one person entering data and the participants were unmasked. A randomised controlled trial to establish the effects of the intervention on STIs at 12 months is needed. Current Controlled Trials ISRCTN02304709. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 57. See the NIHR Journals Library website for further project information.


NMR-Based Metabolomics Separates the Distinct Stages of Disease in a Chronic Relapsing Model of Multiple Sclerosis.
Relapsing experimental allergic encephalomyelitis (Cr-EAE) is commonly used to explore the pathogenesis and efficacy of new therapies for MS, but it is unclear whether the metabolome of Cr-EAE is comparable to human multiple sclerosis (MS). For MS, the diagnosis and staging can be achieved by metabolomics on blood using a combination of magnetic resonance spectroscopy and partial least squares discriminant analysis (PLS-DA). Here, we sought to discover whether this approach could be used to differentiate between sequential disease states in Cr-EAE and whether the same metabolites would be discriminatory. Urine and plasma samples were obtained at different time-points from a clinically relevant model of MS. Using PLS-DA modelling for the urine samples furnished some predictive models, but could not discriminate between all disease states. However, PLS-DA modelling of the plasma samples was able to distinguish between animals with clinically silent disease (day 10, 28) and animals with active disease (day 14, 38). We were also able to distinguish Cr-EAE mice from naive mice at all-time points and control mice, treated with complete Freund's adjuvant alone, at day 14 and 38. Key metabolites that underpin these models included fatty acids, glucose and taurine. Two of these metabolites, fatty acids and glucose, were also key metabolites in separating relapsing-remitting MS from secondary-progressive MS in the human study. These results demonstrate the sensitivity of this metabolomics approach for distinguishing between different disease states. Furthermore, some, but not all, of the changes in metabolites were conserved in humans and the mouse model, which could be useful for future drug development.


Single-molecule visualization of Saccharomyces cerevisiae leading-strand synthesis reveals dynamic interaction between MTC and the replisome.
The replisome, the multiprotein system responsible for genome duplication, is a highly dynamic complex displaying a large number of different enzyme activities. Recently, the Saccharomyces cerevisiae minimal replication reaction has been successfully reconstituted in vitro. This provided an opportunity to uncover the enzymatic activities of many of the components in a eukaryotic system. Their dynamic behavior and interactions in the context of the replisome, however, remain unclear. We use a tethered-bead assay to provide real-time visualization of leading-strand synthesis by the S. cerevisiae replisome at the single-molecule level. The minimal reconstituted leading-strand replisome requires 24 proteins, forming the CMG helicase, the Pol ε DNA polymerase, the RFC clamp loader, the PCNA sliding clamp, and the RPA single-stranded DNA binding protein. We observe rates and product lengths similar to those obtained from ensemble biochemical experiments. At the single-molecule level, we probe the behavior of two components of the replication progression complex and characterize their interaction with active leading-strand replisomes. The Minichromosome maintenance protein 10 (Mcm10), an important player in CMG activation, increases the number of productive replication events in our assay. Furthermore, we show that the fork protection complex Mrc1-Tof1-Csm3 (MTC) enhances the rate of the leading-strand replisome threefold. The introduction of periods of fast replication by MTC leads to an average rate enhancement of a factor of 2, similar to observations in cellular studies. We observe that the MTC complex acts in a dynamic fashion with the moving replisome, leading to alternating phases of slow and fast replication.


Does bioelectrochemical cell configuration and anode potential affect biofilm response?
Electrochemical gradients are the backbone of basic cellular functions, including chemo-osmotic transport and ATP synthesis. Microbial growth, terminal respiratory proteins and external electron transfer are major pathways competing for electrons. In BESs (bioelectrochemical systems), such as MFCs (microbial fuel cells), the electron flow can be via soluble inorganic/organic molecules or to a solid surface. The flow of electrons towards a solid surface can be via outer-membrane cytochromes or electron-shuttle molecules, mediated by conductive protein nanowires or extracellular matrices. In MECs (microbial electrolysis cells), the anode potential can vary over a wide range, which alters the thermodynamic energy available for bacteria capable of donating electrons to the electrode [termed EAB (electroactive bacteria)]. Thus the anode potential is an important electrochemical parameter determining the growth, electron distribution/transfer and electrical activity of films of these bacteria on electrodes. Different optimal applied potentials to anodes have been suggested in the literature, for selection for microbial growth, diversity and performance in biofilms on electrodes. In the present paper, we review the effects of anode potentials on electron-transfer properties of such biofilms, and report on the effect that electrochemical cell configuration may have on performance.


Electrophysiological correlates of improved short-term memory for emotional faces.
Long-term memory (LTM) is enhanced for emotional information, but the influence of stimulus emotionality on short-term memory (STM) is less clear. We examined the electrophysiological correlates of improved visual STM for emotional face identity, focusing on the P1, N170, P3b and N250r event-related potential (ERP) components. These correlates are taken to indicate which memory processing stages and cognitive processes contribute to the improved STM for emotional face identity. In the encoding phase, one or three angry, happy or neutral faces were presented for 2s, resulting in a memory load of one or three. The subsequent 1-s retention phase was followed by a 2-s retrieval phase, in which participants indicated whether a probe face had been present or not during encoding. Memory performance was superior for angry and happy faces over neutral faces at load three. None of the ERP components during encoding were affected by facial expression. During retrieval, the early P3b was decreased for emotional compared to neutral faces, which presumably reflects greater resource allocation to the maintenance of the emotional faces. Furthermore, the N250r during retrieval was increased for emotional compared to neutral faces, reflecting an enhanced repetition effect for emotional faces. These findings suggest that enhanced visual STM for emotional faces arises from improved maintenance and from improved detection of face repetition at retrieval.


Wiener reconstruction of undersampled imagery.
We derive a Fourier-domain Wiener filter for the reconstruction of undersampled imagery. The filter differs from previous implementations in that it permits adjustment of the trade-offs between sharpness of the reconstruction, noise amplification, and aliasing artifact suppression. Additionally, a net transfer function that characterizes the combined effects of the imaging system and the reconstruction process is derived. This net transfer function is valid for both unaliased and aliased spatial frequencies. The expression for the net transfer function is applicable to more general linear image sharpening algorithms.


The influence of intravascular volume expansion on cerebral blood flow and blood volume in normal rats.
Intravascular volume expansion can increase cerebral blood flow (CBF) in patients with cerebral ischemia. However, the changes in CBF produced by volume expansion in the normal brain remain the subject of debate, and the changes on cerebral blood volume (CBV; one determinant of intracranial pressure) have not been described. The effects of acute nondilutional volume expansion on cardiac output (CO), CBF, and CBV in normal rats were examined. Normocarbic, normothermic halothane/N2O-anesthetized rats were given 0, 6, 12, 24, or 36 ml of a blood-hetastarch mixture (n = 6 for each group). When volume loading was completed, 3H-nicotine was used to measure CBF, while 99mTc-labeled red cells and 14C-dextran were used to measure cerebral red cell and plasma volumes. Animals were killed by microwave irradiation (8KW x 770 msec). In different animals, cardiac output (CO) was measured by thermodilution during the infusion of 36 ml of blood-hetastarch. Central venous pressure (CVP) increased from 3.9 +/- 0.7 mmHg (mean +/- SD) in control animals to 13.0 +/- 2.0 mmHg in rats given 36 ml of blood. Cardiac output increased to 138 +/- 11% of control. There were no changes in arterial Hct or mean arterial pressure. There were no significant changes in CBF (which varied from 127 +/- 22 ml.100 g-1.min-1 in controls to 102 +/- 14 after the infusion of 36 ml). However, CBV increased in a linear fashion with increasing CVP, from 2.96 +/- 0.57 ml/100 g in control conditions to 4.47 +/- 0.83 ml/100 g after the infusion of 36 ml of blood/hetastarch. In normal brain, CBF does not change during volume expansion, in spite of an increase in CO. This contradicts earlier studies, the results of which indicate an independent role for cardiac output in CBF control. Cerebral blood volume increased in proportion to CVP, suggesting simple passive venous distention. Whether this could increase ICP and compromise cerebral perfusion remains unclear.


Epoxyeicosatrienoic intervention improves NAFLD in leptin receptor deficient mice by an increase in PGC1α-HO-1-PGC1α-mitochondrial signaling.
Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is considered to be an inflammatory disorder characterized by fatty acid accumulation, oxidative stress, and lipotoxicity. We have previously reported that epoxyeicosatrienoic acid-agonist (EET-A) has multiple beneficial effects on cardiac, renal and adipose tissue function while exhibiting both anti-inflammatory and anti-oxidant activities. We hypothesized that EET-A intervention would play a central role in attenuation of obesity-induced steatosis and hepatic fibrosis that leads to NAFLD. We studied the effect of EET-A on fatty liver using db/db mice as a model of obesity. Mice were fed a high fat diet (HFD) for 16 weeks and administered EET-A twice weekly for the final 8 weeks. db/db mice fed HFD significantly increased hepatic lipid accumulation as manifested by increases in NAS scores, hepatic fibrosis, insulin resistance, and inflammation, and decreases in mitochondrial mitofusin proteins (Mfn 1/2) and anti-obesity genes Fibroblast growth factor 21 (FGF21) and Cellular Repressor of E1A-Stimulated Genes 1 (CREG1). EET-A administration reversed the decrease in these genes and reduced liver fibrosis. Knockout of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in EET-A treated mice resulted in a reversal of the beneficial effects of EET-A administration. EET-A intervention diminishes fatty acid accumulation, fibrosis, and NFALD associated with an increase in HO-1-PGC1α and increased insulin receptor phosphorylation. A pharmacological strategy involving EETs may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NAFLD.


Resistance to cutaneous graft-vs.-host disease is not induced in T cell receptor delta gene-mutant mice.
The function of murine dendritic epidermal cells (dEC) remains largely speculative, probably because of the lack of a suitable in vivo model, although previous studies suggest that gamma/delta+ dEC may have originally evolved to serve as a self-protection mechanism(s). Our previous study demonstrated that the epidermis of mice that had spontaneously recovered from cutaneous graft-vs-host disease (GVHD) induced by local injection of CD4+ autoreactive T cells contained unexpectedly large numbers of dEC and became resistant to subsequent attempts to induce GVHD in a site-restricted manner, suggesting that the resistance is mediated by dEC. However, because alpha/beta+ dEC as well as gamma/delta+ dEC were greatly increased in number in the epidermis, it was unclear whether gamma/delta+ dEC are indeed responsible for this protection. The availability of this murine model and mice selectively lacking gamma/delta T cells as a result of disruption of the T cell receptor C delta gene segment allowed us to investigate the role of gamma/delta+ dEC. In the epidermis of gamma/delta T cell-deficient mice (delta-/-), a congenital lack of gamma/delta+ dEC was substituted for by alpha/beta+ dEC of either a CD4-8+ or a CD4-8- phenotype. After intradermal injection of the autoreactive T cells, delta-/- mice developed significantly enhanced delayed-type hypersensitivity responses and cutaneous GVHD, which persisted longer than in heterozygous littermate controls (delta+/-). Surprisingly, resistance to the cutaneous GVHD was not induced in the epidermis of delta-/- mice after spontaneous recovery from the GVHD, whereas the "susceptible" epidermis of delta-/+ mice contained large numbers of alpha/beta dEC comparable to those in "resistant" epidermis of delta+/- mice. Injection of day 16 fetal thymocytes from wild-type mice into delta-/- mice resulted in the appearance of donor-type gamma/delta+ dEC in the epidermis, and reconstitution with gamma/delta+ dEC restored the protective immune response of the epidermis against the GVHD to nearly normal levels. These results indicate that gamma/delta+ dEC are responsible for the site-restricted protection against cutaneous GVHD.


Breast Imaging in Women Previously Irradiated for Hodgkin Lymphoma.
Women treated with mantle irradiation for Hodgkin lymphoma (HL) are at an increased risk of developing breast cancer (BC). Current guidelines recommend screening breast magnetic resonance imaging (MRI) as an adjunct to mammography (M) in these patients. There are limited data, however, as to the impact of breast MRI on cancer detection rates. The aim of the current study is to evaluate the use of breast MRI in survivors of HL treated and followed at a single institution. We retrospectively reviewed 980 female patients treated with mantle irradiation for HL between 1961 and 2008. Records were reviewed to determine age at radiotherapy treatment, radiotherapy dose, breast imaging (including M and breast MRI), biopsy results if applicable, and incidence of BC. A total of 118 patients had breast imaging performed at our institution. Median age at HL diagnosis was 28 years (range, 10 to 69 y). Median radiotherapy dose was 36 Gy (range, 20 to 45 Gy). Seventy-nine patients (67%) underwent M screening only, 1 (1%) breast MRI only, and 38 (32%) both M and breast MRI. Of these 38, 19 (50%) underwent 54 screening MRI studies (range per patient=1 to 8), 13 (34%) underwent preoperative MRI for workup of BC, and 6 (16%) initiated screening MRI of the contralateral breast only after diagnosed with BC. Fifty-nine biopsies were performed: 47 were prompted by suspicious M findings only, 10 by palpable findings on physical examination (PE), and 2 by suspicious breast MRI findings. Of the 47 biopsies prompted by M, 24 revealed malignant disease, whereas 23 proved to be benign. All 10 biopsies performed by palpation were malignant. Both biopsies prompted by MRI findings were benign. With M, there were 34 true-positive findings in 32 patients, 23 false-positive findings, and 1 false-negative finding. With screening MRI, there were 2 false-positive findings, 1 false-negative finding, and no true-positive findings. The role of screening breast MRI in women previously irradiated for HL is evolving. Further education of patients and physicians is important to increase awareness of more sensitive BC screening modalities in this high-risk population. Future studies are necessary to determine the appropriate integration of screening breast MRI into the ongoing follow-up of these women.


Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma.
Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase 1 study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added on progression during treatment. Sixty-six patients were enrolled (30, dose-escalation cohorts; 36, safety expansion). Patients received a median of 5 prior therapies (range, 1-15); 61% were bortezomib and lenalidomide double refractory, and 46% had t(11;14). Venetoclax was generally well tolerated. Most common adverse events included mild gastrointestinal symptoms (nausea [47%], diarrhea [36%], vomiting [21%]). Cytopenias were the most common grade 3/4 events, with thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%) reported. The overall response rate (ORR) was 21% (14/66), and 15% achieved very good partial response or better (≥VGPR). Most responses (12/14 [86%]) were reported in patients with t(11;14). In this group, ORR was 40%, with 27% of patients achieving ≥VGPR. Biomarker analysis confirmed that response to venetoclax correlated with higher BCL2:BCL2L1 and BCL2:MCL1 mRNA expression ratios. Venetoclax monotherapy at a daily dose up to 1200 mg has an acceptable safety profile and evidence of single-agent antimyeloma activity in patients with relapsed/refractory MM, predominantly in patients with t(11;14) abnormality and those with a favorable BCL2 family profile. Registered at www.clinicaltrials.gov: #NCT01794520.


Regulatory changes in pterin and carotenoid genes underlie balanced color polymorphisms in the wall lizard.
Reptiles use pterin and carotenoid pigments to produce yellow, orange, and red colors. These conspicuous colors serve a diversity of signaling functions, but their molecular basis remains unresolved. Here, we show that the genomes of sympatric color morphs of the European common wall lizard (Podarcis muralis), which differ in orange and yellow pigmentation and in their ecology and behavior, are virtually undifferentiated. Genetic differences are restricted to two small regulatory regions near genes associated with pterin [sepiapterin reductase (SPR)] and carotenoid [beta-carotene oxygenase 2 (BCO2)] metabolism, demonstrating that a core gene in the housekeeping pathway of pterin biosynthesis has been coopted for bright coloration in reptiles and indicating that these loci exert pleiotropic effects on other aspects of physiology. Pigmentation differences are explained by extremely divergent alleles, and haplotype analysis revealed abundant transspecific allele sharing with other lacertids exhibiting color polymorphisms. The evolution of these conspicuous color ornaments is the result of ancient genetic variation and cross-species hybridization.


More capture, more suppression: Distractor suppression due to statistical regularities is determined by the magnitude of attentional capture.
Salient yet irrelevant objects often interfere with daily tasks by capturing attention against our best interests and intentions. Recent research has shown that through implicit learning, distraction by a salient object can be reduced by suppressing the location where this distractor is likely to appear. Here, we investigated whether suppression of such high-probability distractor locations is an all-or-none phenomenon or specifically tuned to the degree of interference caused by the distractor. In two experiments, we varied the salience of two task-irrelevant singleton distractors each of which was more likely to appear in one specific location in the visual field. We show that the magnitude of interference by a distractor determines the magnitude of suppression for its high-probability location: The more salient a distractor, the more it becomes suppressed when appearing in its high-probability location. We conclude that distractor suppression emerges as a consequence of the spatial regularities regarding the location of a distractor as well as its potency to interfere with attentional selection.


Individual and family characteristics associated with health indicators at entry into multidisciplinary pediatric weight management: findings from the CANadian Pediatric Weight management Registry (CANPWR).
(1) To explore individual and family characteristics related to anthropometric and cardiometabolic health indicators and (2) examine whether characteristics that correlate with cardiometabolic health indicators differ across severity of obesity at time of entry to Canadian pediatric weight management clinics. We conducted a cross-sectional analysis of 2-17 year olds with overweight or obesity who registered in the CANadian Pediatric Weight Management Registry (CANPWR) between May 2013 and October 2017 prior to their first clinic visit. Individual modifiable health behaviors included dietary intake, physical activity, screen time, and sleep. Family characteristics included parental BMI, family medical history, socioeconomic status and family structure. Linear mixed effects stepwise regression analysis was performed to determine which characteristics were related to each health indicator: BMI z-score; waist circumference; waist to height ratio; blood pressure; glycemia; HDL cholesterol; non-HDL cholesterol; triglycerides. This study included 1296 children (mean age ± standard deviation: 12.1 ± 3.5 years; BMI z-score: 3.55 ± 1.29; 95.3% with obesity). Hours spent sleeping (estimated β = -0.10; 95% CI [-0.15, -0.05], p = 0.0001), hours per week of organized physical activity (estimated β = -0.32; 95% CI [-0.53, -0.11], p = 0.0026), daily sugared drink intake (estimated β = 0.06; 95% CI [0.01, 0.10], p = 0.0136) and maternal BMI (estimated β = 0.03; 95% CI [0.02, 0.04], p < 0.0001) were associated with BMI z-score (adj. R2 = 0.2084), independent of other individual and family characteristics. Physical activity, total sugared drink intake and sleep duration were associated with glycemia and non-HDL cholesterol, independent of child BMI z-score. However, irrespective of obesity severity, little of the variance (0.86-11.1%) in cardiometabolic health indicators was explained by individual modifiable health behaviors. Physical activity, total sugared drink intake and hours spent sleeping were related to anthropometric and some cardiometabolic health indicators in children entering pediatric weight management programs. This highlights the importance of these modifiable health behaviors on multiple health indicators in children with obesity.


Pneumonia in a Captive Central Bearded Dragon With Concurrent Detection of Helodermatid Adenovirus 2 and a Novel Mycoplasma Species.
A 4-year-old captive male central bearded dragon ( Pogona vitticeps) was presented for recurrent episodic dyspnea and anorexia with occasional expulsion of oral mucoid discharge. Despite empirical antimicrobial therapy and supportive care, the animal died and was submitted for autopsy. Defining histologic features included heterophilic and lymphocytic interstitial pneumonia, with occasional amphophilic intranuclear inclusions and prominent type II pneumocyte hyperplasia. Transmission electron microscopy revealed intranuclear 80-nm, nonenveloped, hexagonal viral particles within pneumocytes. Helodermatid adenovirus 2 (HeAdV2) was determined as the etiologic agent through pan-adenoviral consensus polymerase (PCR) chain reaction and sequencing. Nucleic acid from a novel Mycoplasma sp. (provisionally called Mycoplasma pogonae) was identified by pan-generic PCR targeting the mycoplasma 16S ribosomal RNA gene with sequencing and phylogenetic analysis. As bacteria morphologically consistent with Mycoplasma sp. were not observed by special stains and transmission electron microscopy, the detection of M. pogonae nucleic acid is of indeterminate significance; however, M. pogonae and HeAdV2 coinfection may have exacerbated disease.


Intraoperative, full-rotation, three-dimensional image (O-arm)-based navigation system for cervical pedicle screw insertion.
The aim of this study was to retrospectively evaluate the reliability and accuracy of cervical pedicle screw (CPS) placement using an intraoperative, full-rotation, 3D image (O-arm)-based navigation system and to assess the advantages and disadvantages of the system. The study involved 21 consecutive patients undergoing posterior stabilization surgery of the cervical spine between April and December 2009. The patients, in whom 108 CPSs had been inserted, underwent screw placement based on intraoperative 3D imaging and navigation using the O-arm system. Cervical pedicle screw positions were classified into 4 grades, according to pedicle-wall perforations, by using postoperative CT. Of the 108 CPSs, 96 (88.9%) were classified as Grade 0 (no perforation), 9 (8.3%) as Grade 1 (perforations < 2 mm, CPS exposed, and < 50% of screw diameter outside the pedicle), and 3 (2.8%) as Grade 2 (perforations between ≥ 2 and < 4 mm, CPS breached the pedicle wall, and > 50% of screw diameter outside the pedicle). No screw was classified as Grade 3 (perforation > 4 mm, complete perforation). No neurovascular complications occurred because of CPS placement. The O-arm offers high-resolution 2D or 3D images, facilitates accurate and safe CPS insertion with high-quality navigation, and provides other substantial benefits for cervical spinal instrumentation. Even with current optimized technology, however, CPS perforation cannot be completely prevented, with 8.3% instances of minor violations, which do not cause significant complications, and 2.8% instances of major pedicle violations, which may cause catastrophic complications. Therefore, a combination of intraoperative 3D image-based navigation with other techniques may result in more accurate CPS placement.


Bortezomib as a therapeutic candidate for neuroblastoma.
Outcomes remain poor in neuroblastoma despite intensive treatment. Agents with potential efficacy can be drawn from anti-neoplastic drugs introduced for other malignancies. Bortezomib, a proteasome inhibitor, modulates cell-signaling molecules leading to apoptosis. Bortezomib, alone and in combination with other agents, was tested across an in vitro panel of neuroblastic, stromal, and chemo-resistant neuroblastoma cell types to determine its effect on cell viability and to assess for interactions between bortezomib and other chemotherapeutic agents that either limit or increase overall response. Each subtype of neuroblastoma was sensitive to bortezomib and killing occurred with EC50 values of approximately 50 nM. When bortezomib was combined with other agents (doxorubicin, etoposide, SN-38, carboplatin, or cisplatin), no antagonism was observed. The bortezomib-doxorubicin combination was especially effective, demonstrating synergy on isobolographic analysis and resulting in a decrease in EC50 from 50 ng/mL with doxorubicin alone to 5 ng/mL with 25 nM bortezomib. Interestingly, the different cell types exhibited varying response patterns to treatment with bortezomib alone and in combination with other drugs suggesting different mechanisms may be engaged. A decision analysis, incorporating these results showing efficacy in all cell types, the synergy obtained in combination, and the available toxicity data, supports a phase II clinical trial of bortezomib in neuroblastoma.


Covalently linked HslU hexamers support a probabilistic mechanism that links ATP hydrolysis to protein unfolding and translocation.
The HslUV proteolytic machine consists of HslV, a double-ring self-compartmentalized peptidase, and one or two AAA+ HslU ring hexamers that hydrolyze ATP to power the unfolding of protein substrates and their translocation into the proteolytic chamber of HslV. Here, we use genetic tethering and disulfide bonding strategies to construct HslU pseudohexamers containing mixtures of ATPase active and inactive subunits at defined positions in the hexameric ring. Genetic tethering impairs HslV binding and degradation, even for pseudohexamers with six active subunits, but disulfide-linked pseudohexamers do not have these defects, indicating that the peptide tether interferes with HslV interactions. Importantly, pseudohexamers containing different patterns of hydrolytically active and inactive subunits retain the ability to unfold protein substrates and/or collaborate with HslV in their degradation, supporting a model in which ATP hydrolysis and linked mechanical function in the HslU ring operate by a probabilistic mechanism.


Embedding covalency into metal catalysts for efficient electrochemical conversion of CO2.
CO2 conversion is an essential technology to develop a sustainable carbon economy for the present and the future. Many studies have focused extensively on the electrochemical conversion of CO2 into various useful chemicals. However, there is not yet a solution of sufficiently high enough efficiency and stability to demonstrate practical applicability. In this work, we use first-principles-based high-throughput screening to propose silver-based catalysts for efficient electrochemical reduction of CO2 to CO while decreasing the overpotential by 0.4-0.5 V. We discovered the covalency-aided electrochemical reaction (CAER) mechanism in which p-block dopants have a major effect on the modulating reaction energetics by imposing partial covalency into the metal catalysts, thereby enhancing their catalytic activity well beyond modulations arising from d-block dopants. In particular, sulfur or arsenic doping can effectively minimize the overpotential with good structural and electrochemical stability. We expect this work to provide useful insights to guide the development of a feasible strategy to overcome the limitations of current technology for electrochemical CO2 conversion.


MRI-based attenuation correction for whole-body PET/MRI: quantitative evaluation of segmentation- and atlas-based methods.
PET/MRI is an emerging dual-modality imaging technology that requires new approaches to PET attenuation correction (AC). We assessed 2 algorithms for whole-body MRI-based AC (MRAC): a basic MR image segmentation algorithm and a method based on atlas registration and pattern recognition (AT&PR). Eleven patients each underwent a whole-body PET/CT study and a separate multibed whole-body MRI study. The MR image segmentation algorithm uses a combination of image thresholds, Dixon fat-water segmentation, and component analysis to detect the lungs. MR images are segmented into 5 tissue classes (not including bone), and each class is assigned a default linear attenuation value. The AT&PR algorithm uses a database of previously aligned pairs of MRI/CT image volumes. For each patient, these pairs are registered to the patient MRI volume, and machine-learning techniques are used to predict attenuation values on a continuous scale. MRAC methods are compared via the quantitative analysis of AC PET images using volumes of interest in normal organs and on lesions. We assume the PET/CT values after CT-based AC to be the reference standard. In regions of normal physiologic uptake, the average error of the mean standardized uptake value was 14.1% ± 10.2% and 7.7% ± 8.4% for the segmentation and the AT&PR methods, respectively. Lesion-based errors were 7.5% ± 7.9% for the segmentation method and 5.7% ± 4.7% for the AT&PR method. The MRAC method using AT&PR provided better overall PET quantification accuracy than the basic MR image segmentation approach. This better quantification was due to the significantly reduced volume of errors made regarding volumes of interest within or near bones and the slightly reduced volume of errors made regarding areas outside the lungs.


Characterisation of Peste Des Petits Ruminants Disease in Pastoralist Flocks in Ngorongoro District of Northern Tanzania and Bluetongue Virus Co-Infection.
Peste des petits ruminants (PPR) disease was first confirmed in Tanzania in 2008 in sheep and goats in Ngorongoro District, northern Tanzania, and is now endemic in this area. This study aimed to characterise PPR disease in pastoralist small ruminant flocks in Ngorongoro District. During June 2015, 33 PPR-like disease reports were investigated in different parts of the district, using semi-structured interviews, clinical examinations, PPR virus rapid detection test (PPRV-RDT), and laboratory analysis. Ten flocks were confirmed as PPRV infected by PPRV-RDT and/or real-time reverse transcription-polymerase chain reaction (RT-qPCR), and two flocks were co-infected with bluetongue virus (BTV), confirmed by RT-qPCR. Phylogenetic analysis of six partial N gene sequences showed that the PPR viruses clustered with recent lineage III Tanzanian viruses, and grouped with Ugandan, Kenyan and Democratic Republic of Congo isolates. No PPR-like disease was reported in wildlife. There was considerable variation in clinical syndromes between flocks: some showed a full range of PPR signs, while others were predominantly respiratory, diarrhoea, or oro-nasal syndromes, which were associated with different local disease names (olodua-a term for rinderpest, olkipiei-lung disease, oloirobi-fever, enkorotik-diarrhoea). BTV co-infection was associated with severe oro-nasal lesions. This clinical variability makes the field diagnosis of PPR challenging, highlighting the importance of access to pen-side antigen tests and multiplex assays to support improved surveillance and targeting of control activities for PPR eradication.


The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord.
Cutaneous sensory neurons that detect noxious stimuli project to the dorsal horn of the spinal cord, while those innervating muscle stretch receptors project to the ventral horn. DRG11, a paired homeodomain transcription factor, is expressed in both the developing dorsal horn and in sensory neurons, but not in the ventral spinal cord. Mouse embryos deficient in DRG11 display abnormalities in the spatio-temporal patterning of cutaneous sensory afferent fiber projections to the dorsal, but not the ventral spinal cord, as well as defects in dorsal horn morphogenesis. These early developmental abnormalities lead, in adults, to significantly attenuated sensitivity to noxious stimuli. In contrast, locomotion and sensori-motor functions appear normal. Drg11 is thus required for the formation of spatio-temporally appropriate projections from nociceptive sensory neurons to their central targets in the dorsal horn of the spinal cord.


Abnormal task driven neural oscillations in multiple sclerosis: A visuomotor MEG study.
Multiple sclerosis (MS) is a debilitating disease commonly attributed to degradation of white matter myelin. Symptoms include fatigue, as well as problems associated with vision and movement. Although areas of demyelination in white matter are observed routinely in patients undergoing MRI scans, such measures are often a poor predictor of disease severity. For this reason, it is instructive to measure associated changes in brain function. Widespread white-matter demyelination may lead to delays of propagation of neuronal activity, and with its excellent temporal resolution, magnetoencephalography can be used to probe such delays in controlled conditions (e.g., during a task). In healthy subjects, responses to visuomotor tasks are well documented: in motor cortex, movement elicits a localised decrease in the power of beta band oscillations (event-related beta desynchronisation) followed by an increase above baseline on movement cessation (post-movement beta rebound (PMBR)). In visual cortex, visual stimulation generates increased gamma oscillations. In this study, we use a visuomotor paradigm to measure these responses in MS patients and compare them to age- and gender-matched healthy controls. We show a significant increase in the time-to-peak of the PMBR in patients which correlates significantly with the symbol digit modalities test: a measure of information processing speed. A significant decrease in the amplitude of visual gamma oscillations in patients is also seen. These findings highlight the potential value of electrophysiological imaging in generating a new understanding of visual disturbances and abnormal motor control in MS patients. Hum Brain Mapp 38:2441-2453, 2017. © 2017 Wiley Periodicals, Inc.