Evolution of proteomes: fundamental signatures and global trends in amino acid compositions.
The evolutionary characterization of species and lifestyles at global levels is nowadays a subject of considerable interest, particularly with the availability of many complete genomes. Are there specific properties associated with lifestyles and phylogenies? What are the underlying evolutionary trends? One of the simplest analyses to address such questions concerns characterization of proteomes at the amino acids composition level. In this work, amino acid compositions of a large set of 208 proteomes, with significant number of representatives from the three phylogenetic domains and different lifestyles are analyzed, resorting to an appropriate multidimensional method: Correspondence analysis. The analysis reveals striking discrimination between eukaryotes, prokaryotic mesophiles and hyperthemophiles-themophiles, following amino acid usage. In sharp contrast, no similar discrimination is observed for psychrophiles. The observed distributional properties are compared with various inferred chronologies for the recruitment of amino acids into the genetic code. Such comparisons reveal correlations between the observed segregations of species following amino acid usage, and the separation of amino acids following early or late recruitment. A simple description of proteomes according to amino acid compositions reveals striking signatures, with sharp segregations or on the contrary non-discriminations following phylogenies and lifestyles. The distribution of species, following amino acid usage, exhibits a discrimination between [high GC]-[high optimal growth temperatures] and [low GC]-[moderate temperatures] characteristics. This discrimination appears to coincide closely with the separation of amino acids following their inferred early or late recruitment into the genetic code. Taken together the various results provide a consistent picture for the evolution of proteomes, in terms of amino acid usage.


Optoacoustic Imaging of Human Vasculature: Feasibility by Using a Handheld Probe.
Purpose To investigate whether multispectral optoacoustic tomography (MSOT) developed for deep-tissue imaging in humans could enable the clinical assessment of major blood vessels and microvasculature. Materials and Methods The study was approved by the Institutional Review Board of the University Medical Center Groningen (CCMO-NL-43587) and registered in the Dutch National Trial Registry (NTR4125). The authors designed a real-time handheld optoacoustic scanner for human use, based on a concave 8-MHz transducer array, attaining 135° angular coverage. They applied a single-pulse-frame (SPF) sequence, which enabled motion insensitive optoacoustic imaging during handheld operation. SPF optoacoustic imaging was applied to imaging arteries and microvascular landmarks in the lower extremities of 10 healthy volunteers. The diameters selected microvessels were determined by measuring the full width at half maximum through the vessels in the MSOT images. Duplex ultrasonography was performed on the same landmarks in seven of the 10 volunteers for subjective comparison to the corresponding optoacoustic images. Results Optoacoustic imaging resolved blood vessels as small as 100 µm in diameter and within 1 cm depth. Additionally, MSOT provided images reflecting hemoglobin oxygen saturation in blood vessels, clearly identifying arteries and veins, and was able to identify pulsation in arteries during imaging. Larger blood vessels, specifically the tibialis posterior and the dorsalis pedis arteries, were also visualized with MSOT. Conclusion Handheld MSOT was found to be capable of clinical vascular imaging, providing visualization of major blood vessels and microvasculature and providing images of hemoglobin oxygen saturation and pulsation. (©) RSNA, 2016.


Implementation of a cardiac PET stress program: comparison of outcomes to the preceding SPECT era.
Cardiac positron emission testing (PET) is more accurate than single photon emission computed tomography (SPECT) at identifying coronary artery disease (CAD); however, the 2 modalities have not been thoroughly compared in a real-world setting. We conducted a retrospective analysis of 60-day catheterization outcomes and 1-year major adverse cardiovascular events (MACE) after the transition from a SPECT- to a PET-based myocardial perfusion imaging (MPI) program. MPI patients at Intermountain Medical Center from January 2011-December 2012 (the SPECT era, n = 6,777) and January 2014-December 2015 (the PET era, n = 7,817) were studied. Outcomes studied were 60-day coronary angiography, high-grade obstructive CAD, left main/severe 3-vessel disease, revascularization, and 1-year MACE-revascularization (MACE-revasc; death, myocardial infarction [MI], or revascularization >60 days). Patients were 64 ± 13 years old; 54% were male and 90% were of European descent; and 57% represented a screening population (no prior MI, revascularization, or CAD). During the PET era, compared with the SPECT era, a higher percentage of patients underwent coronary angiography (13.2% vs. 9.7%, P < 0.0001), had high-grade obstructive CAD (10.5% vs. 6.9%, P < 0.0001), had left main or severe 3-vessel disease (3.0% vs. 2.3%, P = 0.012), and had coronary revascularization (56.7% vs. 47.1%, P = 0.0001). Similar catheterization outcomes were seen when restricted to the screening population. There was no difference in 1-year MACE-revasc (PET [5.8%] vs. SPECT [5.3%], P = 0.31). The PET-based MPI program resulted in improved identification of patients with high-grade obstructive CAD, as well as a larger percentage of revascularization, thus resulting in fewer patients undergoing coronary angiography without revascularization. This observational study was funded using internal departmental funds.


Simultaneous targeting of XPO1 and BCL2 as an effective treatment strategy for double-hit lymphoma.
Double-hit lymphoma (DHL) is among the most aggressive and chemoresistant lymphoma subtypes. DHLs carry genomic abnormalities in MYC, BCL2, and/or BCL6 oncogenes. Due to the simultaneous overexpression of these driver oncogenes, DHLs are highly resistant to frontline therapies. Most DHLs overexpress both MYC and BCL2 driver oncogenes concurrently. We reasoned that simultaneous suppression of the two driver oncogenes would be more effective in eradicating DHLs than inactivation of single oncogene. XPO1 is a receptor for nuclear cytoplasmic transport of protein and RNA species. Recently, XPO1 inhibition was shown to downregulate MYC expression in several cancer cell lines. We therefore examined the role of XPO1 as a therapeutic target in suppressing MYC function and the potential synergistic effects of simultaneous suppression of XPO1 and BCL2 in the treatment of DHL. Here, we demonstrate that XPO1 inhibition abrogates MYC protein expression and induces massive tumor cell apoptosis. Combined use of XPO1 and BCL2 inhibitors is highly effective in eradicating DHL cells in cell culture. Notably, in a mouse model of DHL bearing primary tumor cells derived from lymphoma patients, combined treatment with XPO1 and BCL2 inhibitors blocks tumor progression, prevents brain metastasis, and extends host survival. Thus, our study confirms the simultaneous targeting of MYC and BCL2 driver oncogenes through the combined use of XPO1 and BCL2 inhibitors as a unique approach for the treatment of DHLs.


Mechanisms of Aging and the Preventive Effects of Resveratrol on Age-Related Diseases.
Aging gradually decreases cellular biological functions and increases the risk of age-related diseases. Cancer, type 2 diabetes mellitus, cardiovascular disease, and neurological disorders are commonly classified as age-related diseases that can affect the lifespan and health of individuals. Aging is a complicated and sophisticated biological process involving damage to biochemical macromolecules including DNA, proteins, and cellular organelles such as mitochondria. Aging causes multiple alterations in biological processes including energy metabolism and nutrient sensing, thus reducing cell proliferation and causing cellular senescence. Among the polyphenolic phytochemicals, resveratrol is believed to reduce the negative effects of the aging process through its multiple biological activities. Resveratrol increases the lifespan of several model organisms by regulating oxidative stress, energy metabolism, nutrient sensing, and epigenetics, primarily by activating sirtuin 1. This review summarizes the most important biological mechanisms of aging, and the ability of resveratrol to prevent age-related diseases.


Vibrational cooling, heating, and instability in molecular conducting junctions: full counting statistics analysis.
We study current-induced vibrational cooling, heating, and instability in a donor-acceptor rectifying molecular junction using a full counting statistics approach. In our model, electron-hole pair excitations are coupled to a given molecular vibrational mode which is either harmonic or highly anharmonic. This mode may be further coupled to a dissipative thermal environment. Adopting a master equation approach, we confirm the charge and heat exchange fluctuation theorem in the steady-state limit, for both harmonic and anharmonic models. Using simple analytical expressions, we calculate the charge current and several measures for the mode effective temperature. At low bias, we observe the effect of bias-induced cooling of the vibrational mode. At higher bias, the mode effective temperature is higher than the environmental temperature, yet the junction is stable. Beyond that, once the vibrational mode (bias-induced) excitation rate overcomes its relaxation rate, instability occurs. We identify regimes of instability as a function of voltage bias and coupling to an additional phononic thermal bath. Interestingly, we observe a reentrant behavior where an unstable junction can properly behave at a high enough bias. The mechanism for this behavior is discussed.


PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.
In the phase III PARAMOUNT trial, pemetrexed continuation maintenance therapy reduced the risk of disease progression versus placebo (hazard ratio [HR], 0.62; 95% CI, 0.49 to 0.79; P < .001). Here we report final overall survival (OS) and updated safety data. In all, 939 patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) received four cycles of pemetrexed-cisplatin induction therapy; then, 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were randomly assigned (2:1) to maintenance pemetrexed (500 mg/m(2) on day 1 of 21-day cycles; n = 359) or placebo (n = 180). Log-rank test compared OS between arms as measured from random assignment (α = .0498). The mean number of maintenance cycles was 7.9 (range, one to 44) for pemetrexed and 5.0 (range, one to 38) for placebo. After 397 deaths (pemetrexed, 71%; placebo, 78%) and a median follow-up of 24.3 months for alive patients (95% CI, 23.2 to 25.1 months), pemetrexed therapy resulted in a statistically significant 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.64 to 0.96; P = .0195; median OS: pemetrexed, 13.9 months; placebo, 11.0 months). Survival on pemetrexed was consistently improved for all patient subgroups, including induction response: complete/partial responders (n = 234) OS HR, 0.81; 95% CI, 0.59 to 1.11 and stable disease (n = 285) OS HR, 0.76; 95% CI, 0.57 to 1.01). Postdiscontinuation therapy use was similar: pemetrexed, 64%; placebo, 72%. No new safety findings emerged. Drug-related grade 3 to 4 anemia, fatigue, and neutropenia were significantly higher in pemetrexed-treated patients. Pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo, further demonstrating that it is an efficacious treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy.


Mental health management of elite athletes during COVID-19: a narrative review and recommendations.
Elite athletes suffer many mental health symptoms and disorders at rates equivalent to or exceeding those of the general population. COVID-19 has created new strains on elite athletes, thus potentially increasing their vulnerability to mental health symptoms. This manuscript serves as a narrative review of the impact of the pandemic on management of those symptoms in elite athletes and ensuing recommendations to guide that management. It specifically addresses psychotherapy, pharmacotherapy and higher levels of care. Within the realm of psychotherapy, crisis counselling might be indicated. Individual, couple/family and group psychotherapy modalities all may be helpful during the pandemic, with novel content and means of delivery. Regarding pharmacotherapy for mental health symptoms and disorders, some important aspects of management have changed during the pandemic, particularly for certain classes of medication including stimulants, medications for bipolar and psychotic disorders, antidepressants and medications for substance use disorders. Providers must consider when in-person management (eg, for physical examination, laboratory testing) or higher levels of care (eg, for crisis stabilisation) is necessary, despite potential risk of viral exposure during the pandemic. Management ultimately should continue to follow general principles of quality health care with some flexibility. Finally, the current pandemic provides an important opportunity for research on new methods of providing mental health care for athletes, and consideration for whether these new methods should extend beyond the pandemic.


Impact of pregnancy-associated plasma protein-a deletion on the adult murine skeleton.
The metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A) functions to enhance local insulin-like growth factor (IGF)-I bioavailability through cleavage of inhibitory IGF binding proteins. Because IGF-I is an important regulator of skeletal growth and remodeling and PAPP-A is highly expressed by osteoblastic cells, we hypothesized that, in the absence of PAPP-A, bone physiology would be compromised because of a blunting of local IGF-I action even in the presence of normal circulating IGF-I levels. pQCT, muCT, histomorphometry, and mechanical strength testing were performed on bones from PAPP-A knockout (KO) mice and wildtype (WT) littermates at 2-12 mo of age. IGF-I levels and bone formation and resorption markers were determined in sera from these animals. Volumetric BMD in PAPP-A KO mice measured by pQCT at the femoral midshaft, which is primarily cortical bone, was 10% less than WT at 2 mo. This difference was maintained at 4, 6, and 12 mo. Cortical thickness at this site was similarly decreased. On the other hand, trabecular bone at the distal femur (pQCT) and in the tibia (muCT) showed age-progressive decreases in bone volume fraction in PAPP-A KO compared with WT mice. Tibial muCT indicated a 46% relative decrease in trabecular bone volume/total volume (BV/TV) and a 28% relative decrease in trabecular thickness in PAPP-A KO compared with WT mice at 6 mo. These trabecular deficiencies in PAPP-A KO mice corresponded to a weakening of the bone. Serum markers and bone histomorphometry indicated that the primary impact of PAPP-A is on skeletal remodeling resulting in a state of low-turnover osteopenia in adult PAPP-A KO mice. Circulating IGF-I levels were not altered in PAPP-A KO mice. PAPP-A is a bone growth regulatory factor in vivo and, in its absence, mice show skeletal insufficiency in mass, density, architecture, and strength. The data suggest a primary role for PAPP-A in modulating local IGF bioavailability for trabecular bone remodeling.


Development and validation of a new tool measuring nurses self-reported professional competence--the nurse professional competence (NPC) Scale.
To develop and validate a new tool intended for measuring self-reported professional competence among both nurse students prior to graduation and among practicing nurses. The new tool is based on formal competence requirements from the Swedish Board of Health and Welfare, which in turn are based on WHO guidelines. A methodological study including construction of a new scale and evaluation of its psychometric properties. 1086 newly graduated nurse students from 11 universities/university colleges. The analyses resulted in a scale named the NPC (Nurse Professional Competence) Scale, consisting of 88 items and covering eight factors: "Nursing care", "Value-based nursing care", "Medical/technical care", "Teaching/learning and support", "Documentation and information technology", "Legislation in nursing and safety planning", "Leadership in and development of nursing care" and "Education and supervision of staff/students". All factors achieved Cronbach's alpha values greater than 0.70. A second-order exploratory analysis resulted in two main themes: "Patient-related nursing" and "Nursing care organisation and development". In addition, evidence of known-group validity for the NPC Scale was obtained. The NPC Scale, which is based on national and international professional competence requirements for nurses, was comprehensively tested and showed satisfactory psychometrical properties. It can e.g. be used to evaluate the outcomes of nursing education programmes, to assess nurses' professional competences in relation to the needs in healthcare organisations, and to tailor introduction programmes for newly employed nurses.


Antifibrotic Effects of Sakuraso-Saponin in Primary Cultured Pterygium Fibroblasts in Comparison With Mitomycin C.
To investigate the antifibrotic effects of sakuraso-saponin on a primary culture of human pterygium fibroblasts (HPFs) and normal human Tenon fibroblasts (HTFs) as compared to the effects of mitomycin C (MMC). Samples of HPFs and HTFs were acquired during primary pterygium surgery. Cell toxicity, cell migration, and expression of α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β) were evaluated in HPFs and HTFs after treatment with sakuraso-saponin and MMC. To determine the possible mechanisms underlying the antifibrotic effects of sakuraso-saponin, the expression of phosphorylated Smad2/3 was evaluated after treatment with sakuraso-saponin and MMC. MMC (≥200 μg/mL) significantly reduced cell viability in both HPFs and HTFs, whereas sakuraso-saponin (1.0 μg/mL) decreased cell viability in HPFs only. Both sakuraso-saponin (1.0 μg/mL) and MMC (200 μg/mL) treatment significantly reduced the expression of α-SMA and TGF-β in HPFs (P < 0.05). It is interesting that the expression of α-SMA and TGF-β after treatment with sakuraso-saponin was significantly lower than that after treatment with MMC (P < 0.05). The expression of phosphorylated Smad2/3 protein was decreased by sakuraso-saponin and MMC in HPFs. Both sakuraso-saponin and MMC inhibited TGF-β1-induced cell migration as compared to the control in HPFs. Sakuraso-saponin could be more effective than MMC for the reduction of fibrosis in HPFs. Our results might present the basis for its use as a promising candidate drug for adjuvant therapy to prevent recurrent pterygium after surgery.


Measurement of multisite oxidation kinetics reveals an active site conformational change in Spo0F as a result of protein oxidation.
When most proteins undergo oxidative damage, they yield a variety of products containing oxidative damage at a large number of sites, most of which are modified substoichiometrically. The resulting complex mixture of products is not amenable to high-resolution structural analyses. The previous methods of structural analysis have relied upon either very generalized structural analyses such as circular dichroism or the creation of a battery of mutants to try to isolate single-residue damage effects. We present a methodology using mass spectrometry to measure the kinetics of oxidation at many sites simultaneously. Previous studies have shown that these kinetics are determined by the chemical nature of the damage site and by the accessibility of that site to the radical. By measuring deviations in the rate of oxidation from the expected pseudo-zero-order kinetics, we can detect and characterize local structural changes due to the oxidative damage. We demonstrate the application of this new technique to the Spo0F protein, a regulator of sporulation in Bacillus subtilis. Circular dichroism studies suggest a partial loss of helical structure of Spo0F as a result of oxidative damage. We report that oxidation causes a three-stage conformational change in Spo0F. Furthermore, we find the dramatic structural changes affect only the region surrounding the active site, while the remainder of the structure remains relatively unperturbed. Finally, we are able to determine that the specific oxidation event that triggers the conformational change at the active site of Spo0F occurs at Met81, a partially conserved methionine in the CheY superfamily.


Influence of surface energy distribution on neuritogenesis.
PC12 cells are a useful model to study neuronal differentiation, as they can undergo terminal differentiation, typically when treated with nerve growth factor (NGF). In this study we investigated the influence of surface energy distribution on PC12 cell differentiation, by atomic force microscopy (AFM) and immunofluorescence. Glass surfaces were modified by chemisorption: an aminosilane, n-[3-(trimethoxysilyl)propyl]ethylendiamine (C(8)H(22)N(2)O(3)Si; EDA), was grafted by polycondensation. AFM analysis of substrate topography showed the presence of aggregates suggesting that the adsorption is heterogeneous, and generates local gradients in energy of adhesion. PC12 cells cultured on these modified glass surfaces developed neurites in absence of NGF treatment. In contrast, PC12 cells did not grow neurites when cultured in the absence of NGF on a relatively smooth surface such as poly-L-lysine substrate, where amine distribution is rather homogeneous. These results suggest that surface energy distribution, through cell-substrate interactions, triggers mechanisms that will drive PC12 cells to differentiate and to initiate neuritogenesis. We were able to create a controlled physical nano-structuration with local variations in surface energy that allowed the study of these parameters on neuritogenesis.


Itraconazole targets cell cycle heterogeneity in colorectal cancer.
Cellular dormancy and heterogeneity in cell cycle length provide important explanations for treatment failure after adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC), yet the molecular control of the dormant versus cycling state remains unknown. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumor cells. Unexpectedly, we demonstrate that dormant CRC cells are differentiated, yet retain clonogenic capacity. Mouse organoid drug screening identifies that itraconazole generates spheroid collapse and loss of dormancy. Human CRC cell dormancy and tumor growth can also be perturbed by itraconazole, which is found to inhibit Wnt signaling through noncanonical hedgehog signaling. Preclinical validation shows itraconazole to be effective in multiple assays through Wnt inhibition, causing both cycling and dormant cells to switch to global senescence. These data provide preclinical evidence to support an early phase trial of itraconazole in CRC.


Utility of the Serum Cystatin C Level for Diagnosis of Osteoporosis among Middle-Aged and Elderly People.
Osteoporosis is a common age-related disorder leading to increased bone fragility and risk of fracture. Early diagnosis of osteoporosis is a vital step in providing early therapeutic intervention. Serum cystatin C is a marker of early renal dysfunction, a predictor of cardiovascular and inflammatory diseases, and an inhibitor of the differentiation of osteoclast precursor cells. The purpose of this study was to evaluate the relationship between serum cystatin C and osteoporosis. We enrolled 46 subjects who attended a health checkup and underwent measurement of bone status by quantitative ultrasound and determination of the level of serum cystatin C. A comparative study was conducted between those with and without osteoporosis for all subjects collectively and in two subgroups aged <65 and ≥65 years. Serum cystatin C levels were strongly correlated with age, creatinine, and bone status data, with significant negative correlations with stiffness, T-score, and percentage of young adult mean. Among patients with osteoporosis, serum cystatin C was significantly higher even after adjustment for age and sex, whereas no significant difference was noted in creatinine. For patients aged ≥ 65 years, serum cystatin C was significantly higher in subjects with osteoporosis, although there was no significant difference in age between normal subjects and those with osteoporosis. To the best of our knowledge, this is the first study to demonstrate an association between serum cystatin C and osteoporosis. Serum cystatin C is significantly higher in osteoporosis and in particular may be a useful marker for osteoporosis among middle and elderly people aged ≥ 65 years. Measurement of serum cystatin C can be carried out easily and may contribute to early diagnosis and treatment of osteoporosis.


A review of economic evaluations of tobacco control programs.
Each year, an estimated 443,000 people die of smoking-related diseases in the United States. Cigarette smoking results in more than $193 billion in medical costs and productivity losses annually. In an effort to reduce this burden, many states, the federal government, and several national organizations fund tobacco control programs and policies. For this report we reviewed existing literature on economic evaluations of tobacco control interventions. We found that smoking cessation therapies, including nicotine replacement therapy (NRT) and self-help are most commonly studied. There are far fewer studies on other important interventions, such as price and tax increases, media campaigns, smoke free air laws and workplace smoking interventions, quitlines, youth access enforcement, school-based programs, and community-based programs. Although there are obvious gaps in the literature, the existing studies show in almost every case that tobacco control programs and policies are either cost-saving or highly cost-effective.


Acute respiratory failure as primary manifestation of antineutrophil cytoplasmic antibodies-associated vasculitis.
The systemic vasculitides are multifocal diseases characterized by the presence of blood vessel inflammation in multiple organ systems. Their clinical presentation is variable extending from self-limited illness to critical complications including diffuse alveolar hemorrhage and glomerulonephritis. Alveolar hemorrhage is a life-threatening manifestation of pulmonary vasculitis that can rapidly progress into acute respiratory failure requiring ventilatory support. We present the case of a 74-year-old patient admitted to the Intensive Care Unit with severe hypoxic respiratory failure and diffuse alveolar infiltrates in chest imaging that was later diagnosed as antineutrophil cytoplasmic antibodies-associated vasculitis. The report highlights the importance of differentiate between alveolar hemorrhage and acute respiratory distress syndrome of other etiology because alveolar hemorrhage is reversible with prompt initiation of treatment.


The role of breast milk in protecting urban Peruvian children against cryptosporidiosis.
To test the hypothesis that breast milk of nursing mothers may afford children protection against cryptosporidiosis, a prospective cohort study was carried out in the young peoples' community of San Juan de Miraflores near Lima, Peru. Mothers and newborn children were sorted into cohort groups based on the mothers' breast milk antibody response to Cryptosporidium sporozoites using an antibody-capture enzyme-linked immunosorbent assay to detect parasite-specific immunoglobulin A. Children were monitored for Cryptosporidium infection using an indirect immunofluorescence assay. Of 211 mothers enrolled in the study, 39 (18.5%) had high breast milk antibody titers, 107 (50.7%) had medium titers, and 65 (30.8%) had low titers. Sixty-one episodes of Cryptosporidium infection were detected in 50 children of these mothers. Eleven (22%) had mothers in the high antibody titer group, 20 (40%) had mothers in the medium titer group, and 19 (38%) had mothers in the low titer group. The prevalence of infection within children of each group was 0.17, 0.19 and 0.38 respectively. There was no significant difference in the prevalence or duration of infection among children of the different groups. The data does not support the notion that there is protection from Cryptosporidium infection afforded children whose mothers have demonstrable breast milk antibodies against the parasite.


A key role for the mRNA leader structure in translational control of ribosomal protein S1 synthesis in gamma-proteobacteria.
The translation initiation region (TIR) of the Escherichia coli rpsA mRNA coding for ribosomal protein S1 is characterized by a remarkable efficiency in driving protein synthesis despite the absence of the canonical Shine-Dalgarno element, and by a strong and specific autogenous repression in the presence of free S1 in trans. The efficient and autoregulated E.coli rpsA TIR comprises not less than 90 nt upstream of the translation start and can be unambiguously folded into three irregular hairpins (HI, HII and HIII) separated by A/U-rich single-stranded regions (ss1 and ss2). Phylogenetic comparison revealed that this specific fold is highly conserved in the gamma-subdivision of proteobacteria (but not in other subdivisions), except for the Pseudomonas group. To test phylogenetic predictions experimentally, we have generated rpsA'-'lacZ translational fusions by inserting the rpsA TIRs from various gamma-proteobacteria in-frame with the E.coli chromosomal lacZ gene. Measurements of their translation efficiency and negative regulation by excess protein S1 in trans have shown that only those rpsA TIRs which share the structural features with that of E.coli can govern efficient and regulated translation. We conclude that the E.coli-like mechanism for controlling the efficiency of protein S1 synthesis evolved after divergence of Pseudomona.


The clinical benefits of long-term supplementation with omega-3 fatty acids in cystic fibrosis patients - A pilot study.
Effectiveness of omega-3 supplementation in cystic fibrosis (CF) remains controversial. This study sought to evaluate clinical status, exercise tolerance, inflammatory parameters, and erythrocyte fatty acid profile after 1 year of oral omega-3 supplementation in CF patients. Fifteen ΔF508-homozygous patients undergoing chronic azithromycin were randomized to receive omega-3 fish oil supplementation at a dose of 60mg/Kg/day or placebo. In comparison with the previous year, in the supplemented group, the number of pulmonary exacerbations decreased at 12 months (1.7 vs. 3.0, p<0.01), as did the duration of antibiotic therapy (26.5 days vs. 60.0 days, p<0.025). Supplementation significantly increased the levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as early as <3 months of administration, with concomitant decreases in arachidonic acid (AA) levels. This pilot study suggests that long-term omega-3 supplementation offers several clinical benefits as to the number of exacerbations and duration of antibiotic therapy in CF patients.


Primary hip and knee replacement surgery: Ontario criteria for case selection and surgical priority.
To develop, from simple clinical factors, criteria to identify appropriate patients for referral to a surgeon for consideration for arthroplasty, and to rank them in the queue once surgery is agreed. Delphi process, with a panel including orthopaedic surgeons, rheumatologists, general practitioners, epidemiologists, and physiotherapists, who rated 120 case scenarios for appropriateness and 42 for waiting list priority. Scenarios incorporated combinations of relevant clinical factors. It was assumed that queues should be organised not simply by chronology but by clinical and social impact of delayed surgery. The panel focused on information obtained from clinical histories, to ensure the utility of the guidelines in practice. Relevant high quality research evidence was limited. Ontario, Canada. Appropriateness ratings on a 7-point scale, and urgency rankings on a 4-point scale keyed to specific waiting times. Despite incomplete evidence panellists agreed on ratings in 92.5% of appropriateness and 73.8% of urgency scenarios versus 15% and 18% agreement expected by chance, respectively. Statistically validated algorithms in decision tree form, which should permit rapid estimation of urgency or appropriateness in practice, were compiled by recursive partitioning. Rating patterns and algorithms were also used to make brief written guidelines on how clinical factors affect appropriateness and urgency of surgery. A summary score was provided for each case scenario; scenarios could then be matched to chart audit results, with scoring for quality management. These algorithms and criteria can be used by managers or practitioners to assess appropriateness of referral for hip or knee replacement and relative rankings of patients in the queue for surgery.


Antisense oligonucleotide therapy for neurodegenerative disease.
Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.


Fluctuations of dissolved organic matter in river used for drinking water and impacts on conventional treatment plant performance.
Natural organic matter (NOM) in drinking water supplies can provide precursors for disinfectant byproducts, molecules that impact taste and odors, compounds that influence the efficacy of treatment, and other compounds that are a source of energy and carbon for the regrowth of microorganisms during distribution. NOM, measured as dissolved organic carbon (DOC), was monitored daily in the White River and the Indiana-American water treatment plant over 22 months. Other parameters were either measured daily (UV-absorbance, alkalinity, color, temperature) or continuously (turbidity, pH, and discharge) and used with stepwise linear regressions to predict DOC concentrations. The predictive models were validated with monthly samples of the river water and treatment plant effluent taken over a 2-year period after the daily monitoring had ended. Biodegradable DOC (BDOC) concentrations were measured in the river water and plant effluent twice monthly for 18 months. The BDOC measurements, along with measurements of humic and carbohydrate constituents within the DOC and BDOC pools, revealed that carbohydrates were the organic fraction with the highest percent removal during treatment, followed by BDOC, humic substances, and refractory DOC.


Characterization of maize genotypes for genetic diversity on the basis of inter simple sequence repeats.
Genetic diversity in crops is essential to make improvements related to superior germplasms. Implementation of molecular markers to identify suitable genotypes speeds up the breeding progress by enhancing selection efficiency. This study was carried out to probe genetic diversity among 21 maize genotypes using 20 inter simple sequence repeat (ISSR) markers. We identified a total of 190 polymorphic bands with an average of 9.5 alleles per primer. The highest number of polymorphic bands (17) was found using ISSR marker UBC-10, whereas the lowest number of polymorphic bands (4) was found using UBC-809. The coefficient of genetic similarity ranged from 0.888 to 0.118%. The highest similarity was found between accessions 12 (015224) and 9 (015114), whereas the lowest similarity was found between genotypes 20 (EV-5098) and 14 (015030). The polymorphism information content ranged from 0.17 to 0.47. A dendrogram was generated based on Jaccard's distance matrix. The genotypes were found to group into two major clusters that could be further partitioned into two sub-clusters. Genotypes located within the same cluster are genetically more closely related to each other. The present study efficiently identified diverse genotypes that may be used for creating new varieties with distinct characteristics. The identified genotypes could be used as parents for future development of diverse populations.


Topography of the submental artery that should be considered in bleeding during dentoalveolar surgery.
The purpose of the present study was to provide precise data regarding the branching pattern of the submental artery, which should be considered in occasions of bleeding during various dentoalveolar surgical procedures of the mandible, such as implant surgeries, tori removal, and iatrogenic injuries. Twenty-six embalmed adult hemifaces from Korean cadavers were used in this study. The vertical distance, horizontal distance, and diameter of the submental artery were measured from the site of the first premolar to the third molar. In cases where there was penetration of the mylohyoid muscle by the main branches of the submental artery, the same items were measured at that point. The vertical distance between the submental artery and the inferior border of the mandible decreased toward the premolar, whereas the horizontal distance from the lingual plate of the mandible increased gradually as it traveled in the anterior direction. The diameter of the artery narrowed slightly toward the premolar. The main branches of the submental artery perforated the mylohyoid muscle in 14 (54%) of the 26 specimens. As a result of this study, the submental artery is located higher from the inferior border and closer to the lingual plate of the mandible in the region of the molar than that of the premolar. Therefore, clinicians should be more careful of bleeding when performing surgery in the molar region compared with the premolar region. Where the mylohyoid muscle is perforated by the main branches of the submental artery, its point of insertion can be observed in diverse locations.


Reduced insulin secretion in offspring of African type 2 diabetic parents.
To determine the early biochemical predictors of increased susceptibility to develop diabetes in offspring of African type 2 diabetic parents. A total of 69 offspring (case subjects) of 26 families in Cameroon with at least one type 2 diabetic parent were studied, and 62 offspring (control subjects) from 25 families in Cameroon with no parent with type 2 diabetes underwent an oral glucose tolerance test. Early insulin secretion was calculated using the ratio of the 0- to 30-min incremental insulin values to the 0- to 30-min incremental glucose. Anthropometric parameters were also measured. Of the case subjects, 23% were glucose intolerant (4% with diabetes and 19% with impaired glucose tolerance [IGT]) compared with 6.5% (all with IGT) of control subjects (P = 0.02). There was also an increasing prevalence of glucose intolerance, especially IGT with increasing number of glucose-intolerant parents. Fasting serum insulin levels were not different in the two groups; however, at 30 min, the case subjects had lower insulin levels than the control subjects (P < 0.006). Case subjects with IGT had lower 30-min insulin concentration, early insulin secretion, and 2-h insulin levels than those with normal glucose tolerance (NGT) (F = 4.1, P < 0.05; F = 4.1, P < 0.04; and F = 5.1, P < 0.03, respectively). Furthermore, case subjects with NGT and IGT had lower early insulin secretion than control subjects (F = 4. 1, P < 0.03). These differences remained after adjustment for BMI and regardless of the status of parental diabetes. Two-hour insulin concentration showed a positive association (odds ratio = 0.95 CI 0.90-0.99, P = 0.039) with IGT in the case subjects. Diabetes and IGT are more prevalent in the offspring of African type 2 diabetic parents, and this may be due to an underlying degree of beta-cell impairment marked by reduced early-phase insulin secretion.


Active Commuting Behaviors in a Nordic Metropolitan Setting in Relation to Modality, Gender, and Health Recommendations.
Active commuting between home and place of work or study is often cited as an interesting source of physical activity in a public health perspective. However, knowledge about these behaviors is meager. This was therefore studied in adult active commuters (n = 1872) in Greater Stockholm, Sweden, a Nordic metropolitan setting. They received questionnaires and individually adjusted maps to draw their normal commuting route. Three different modality groups were identified in men and women: single-mode cyclists and pedestrians (those who only cycle or walk, respectively) and dual-mode commuters (those who alternately walk or cycle). Some gender differences were observed in trip distances, frequencies, and velocities. A large majority of the commuting trip durations met the minimum health recommendation of at least 10-minute-long activity bouts. The median single-mode pedestrians and dual-mode commuters met or were close to the recommended weekly physical activity levels of at least 150 minutes most of the year, whereas the single-mode cyclists did so only during spring-mid-fall. A high total number of trips per year (range of medians: 230-390) adds to the value in a health perspective. To fully grasp active commuting behaviors in future studies, both walking and cycling should be assessed over different seasons and ideally over the whole year.


A Technology-Enabled Adaptation of Face-to-Face Caregiver-Mediated JASPER Intervention: Preliminary Examination of Video Conferenced Caregiver Coaching.
Family-centered practices that involve direct participation of caregivers as part of intervention is critical to effective early intervention. However, regularly scheduled, in person service delivery is not always possible in remote communities, prompting a need for adaptations to the delivery of services, such as the use of live video conferencing to coach caregivers in strategies to promote their children's development. In this study, caregivers and their children ages 2-9 with autism who were living in rural and remote Canadian communities were included. A concurrent multiple baseline design across participants was applied to examine the effects of live video conference caregiver coaching on children's time jointly engaged with caregivers and caregivers' intervention strategy implementation. Results indicated that all children demonstrated greater time jointly engaged and caregivers demonstrated greater use of strategies in comparison to baseline. The results of this study offer preliminary evidence of the effectiveness of real time video conference coaching for caregivers engaging their children with ASD in play.


Rapid bench-top fabrication of poly(dimethylsiloxane)/polystyrene microfluidic devices incorporating high-surface-area sensing electrodes.
The development of widely applicable point-of-care sensing and diagnostic devices can benefit from simple and inexpensive fabrication techniques that expedite the design, testing, and implementation of lab-on-a-chip devices. In particular, electrodes integrated within microfluidic devices enable the use of electrochemical techniques for the label-free detection of relevant analytes. This work presents a novel, simple, and cost-effective bench-top approach for the integration of high surface area three-dimensional structured electrodes fabricated on polystyrene (PS) within poly(dimethylsiloxane) (PDMS)-based microfluidics. Optimization of PS-PDMS bonding results in integrated devices that perform well under pressure and fluidic flow stress. Furthermore, the fabrication and bonding processes are shown to have no effect on sensing electrode performance. Finally, the on-chip sensing capabilities of a three-electrode electrochemical cell are demonstrated with a model redox compound, where the high surface area structured electrodes exhibit ultra-high sensitivity. We propose that the developed approach can significantly expedite and reduce the cost of fabrication of sensing devices where arrays of functionalized electrodes can be used for point-of-care analysis and diagnostics.


High prevalence of triazole resistance in Aspergillus fumigatus, especially mediated by TR/L98H, in a French cohort of patients with cystic fibrosis.
Triazole resistance in Aspergillus fumigatus due to a single azole resistance mechanism (TR/L98H) is increasingly reported in European countries. Data from patients with cystic fibrosis (CF) are limited. Our study aimed to investigate the prevalence and molecular mechanisms of azole resistance in A. fumigatus in a cohort of patients with CF. Eighty-five A. fumigatus isolates from 50 CF patients, collected between January 2010 and April 2011, were retrospectively analysed for azole resistance using agar plates containing 4 mg/L itraconazole. MICs of itraconazole, voriconazole and posaconazole were determined according to EUCAST methodology for each isolate able to grow on this medium. Species identification was performed by sequencing of the β-tubulin gene. Sequencing analysis of the cyp51A gene and its promoter region was conducted. Nine isolates (four patients, 8% prevalence) were able to grow on itraconazole-containing agar plates. Itraconazole resistance was confirmed by EUCAST methodology (MICs >2 mg/L). All isolates had mutations in the cyp51A gene at residues previously involved in azole resistance: L98H (n = 5), M220T (n = 4) and G54R (n = 1). One patient had three genetically distinct azole-resistant isolates identified during the study. The isolates with L98H that were recovered from three patients (6% prevalence) also had the 34 bp tandem repeat in the promoter region of cyp51A (TR/L98H) and displayed multiazole resistance. We report an 8% prevalence of itraconazole resistance in CF patients in our centre, mostly driven by TR/L98H (6%). Our data confirm that TR/L98H occurs in France and can be highly prevalent in CF patients.


Geographical variation in the response of visceral leishmaniasis to paromomycin in East Africa: a multicentre, open-label, randomized trial.
Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India. This was a 3-arm multicentre, open-label, randomized, controlled clinical trial to compare three treatment regimens for VL in East Africa: paromomycin sulphate (PM) at 15 mg/kg/day for 21 days versus sodium stibogluconate (SSG) at 20 mg/kg/day for 30 days; and the combination of both dose regimens for 17 days. The primary efficacy endpoint was cure based on parasite-free tissue aspirates taken 6 months after treatment. Overall, 135 patients per arm were enrolled at five centres in Sudan (2 sites), Kenya (1) and Ethiopia (2), when the PM arm had to be discontinued due to poor efficacy. The trial has continued with the higher dose of PM as well as the combination of PM and SSG arms. These results will be reported later. Baseline patient characteristics were similar among treatment arms. The overall cure with PM was significantly inferior to that with SSG (63.8% versus 92.2%; difference 28.5%, 95%CI 18.8% to 38.8%, p<0.001). The efficacy of PM varied among centres and was significantly lower in Sudan (14.3% and 46.7%) than in Kenya (80.0%) and Ethiopia (75.0% and 96.6%). No major safety issues with PM were identified. The efficacy of PM at 15 mg/kg/day for 21 days was inadequate, particularly in Sudan. The efficacy of higher doses and the combination treatment warrant further studies.


Metformin Use is Associated with Improved Survival for Patients with Advanced Prostate Cancer on Androgen Deprivation Therapy.
Metformin is commonly prescribed for patients with type 2 diabetes mellitus. We hypothesized that metformin plus androgen deprivation therapy may be beneficial in combination. Our objective was to assess this combination in a retrospective cohort of patients with advanced prostate cancer. Using national Veterans Affairs databases we identified all men diagnosed with prostate cancer between 2000 and 2008 who were treated with androgen deprivation therapy with followup through May 2016. Study exclusions included treatment with androgen deprivation therapy for 6 months or longer, or receipt of androgen deprivation therapy concurrently with localized radiation. Three patient cohorts were developed, including no diabetes mellitus, diabetes mellitus with no metformin and diabetes mellitus with metformin. Cox proportional HRs were calculated for overall survival, skeletal related events and cancer specific survival. After exclusions the cohort consisted of 87,344 patients, including 61% with no diabetes mellitus, 22% with diabetes mellitus and no metformin, and 17% with diabetes mellitus on metformin. Cox proportional hazard analysis of overall survival showed improved survival in men with diabetes mellitus on metformin (HR 0.82, 95% CI 0.78-0.86) compared to those with diabetes mellitus who were not on metformin (HR 1.03, 95% CI 0.99-1.08). The reference group was men with no diabetes mellitus. Cox proportional hazard analysis of predictors of skeletal related events revealed a HR of 0.82 (95% CI 0.72-0.93) in men with diabetes mellitus on metformin. Cox proportional hazard analysis of cancer specific survival showed improved survival in men with diabetes mellitus on metformin (HR 0.70, 95% CI 0.64-0.77) vs those with diabetes mellitus without metformin (HR 0.93, 95% CI 0.85- 1.00). The reference group was men with no diabetes mellitus. Metformin use in veterans with prostate cancer who receive androgen deprivation therapy is associated with improved oncologic outcomes. This association should be evaluated in a prospective clinical trial.


Association of obesity and systemic factors with bone marrow lesions at the knee: a systematic review.
The objective of this study was to systematically review the literature to determine whether obesity and systemic factors, including age, gender, heritability, dietary factors, smoking, serum and urine biomarkers of cartilage or bone metabolism, bone-related factors, and medication, are associated with knee bone marrow lesions (BMLs) identified on magnetic resonance imaging in asymptomatic pre-osteoarthritis and osteoarthritis populations. Electronic searches of MEDLINE and EMBASE were performed from January 1, 1996 to September 30, 2012 using the following keywords: bone marrow lesion(s), bone marrow (o)edema, osteoarthritis, and knee. Studies examining obesity and non-biomechanical factors in relation to the presence, incidence, or change in BMLs were included. Two independent reviewers extracted data and assessed methodological quality of selected studies. Due to the heterogeneity of the studies, we performed a best evidence synthesis. Among 30 studies, 17 were considered high quality. The study populations were heterogeneous in terms of symptoms and radiographic knee osteoarthritis. There was strong evidence for an association between serum lipids and BMLs and no association between age and BMLs. There was moderate evidence for a relationship between obesity and BMLs. There was limited evidence for gender, smoking, C-telopeptide of type I collagen, anti-bone-resorptive treatments, licofelone, and chondroitin sulfate. There was a paucity of evidence for heritability and conflicting evidence for dietary fatty acids. There is strong evidence for serum lipids and moderate evidence for obesity as risk factors for knee BMLs. Given the role of BMLs in the pathogenesis of knee osteoarthritis, identification of modifiable risk factors of BMLs and therapeutic interventions targeting BMLs has the potential to reduce the burden of knee osteoarthritis.


Comparison of plasma and leukocyte vitamin C status between asthmatic and healthy subjects.
In a case-control study the vitamin C status of 50 adults with chronic controlled asthma was compared with that of 50 randomly selected healthy controls. Vitamin C intake was assessed by 3-day dietary recall, and plasma and leukocyte vitamin C concentrations were measured colorimetrically. A positive significant correlation was found between plasma vitamin C and dietary vitamin C intake. Plasma and leukocyte vitamin C levels were significantly lower in the asthma group. Plasma vitamin C was deficient (< 0.4 mg/dL) in significantly more patients than controls (38.0% versus 0%) and leukocyte vitamin C (< 20 microg/10(8) leukocytes) was deficient in 92.0% of asthmatics versus 8.0% of controls. A significant association was observed between duration of asthma and plasma vitamin C level.


Human papillomavirus genomics: past, present and future.
Human papillomaviruses (HPV) are a group of divergent DNA viruses, of which a select few evolutionarily related HPVs have emerged to be highly oncogenic and of significant medical importance. Essentially all cases of cervical cancer, as well as a subset of other anogenital and oral cancers are caused by this limited set of HPV types. At present, over 150 HPV types have been identified and may be classified into genera, species and types based upon comparison of the viral genome. Established nucleotide phylogenies sort the highly pathogenic HPV types to the genus Alphapapillomavirus (α-PV). A species group includes viral types with 60-70% genomic nucleotide similarity that share a most-recent common ancestor; for example the species group's alpha-9 (HPV16-related) and alpha-7 (HPV18-related), contain the majority of known oncogenic HPV types. Genomes from the same HPV type with 1-10% nucleotide differences designate HPV variant lineages. The established nucleotide variations observed in extant HPV genomes have been fixed through evolutionary processes prior to human population expansion and global dissemination. To characterize viral types and variants associated with pathology for clinical applications (e.g. screening), molecular epidemiological studies have proven essential for identifying links between HPV natural history and carcinogenicity. This chapter presents a historical account of HPV genomics in the context of major discoveries and advances over the past 2 thousand years.


Enhancing the radiology learning experience with electronic whiteboard technology.
The purpose of this study is to quantitatively evaluate the use of an interactive whiteboard for use in teaching diagnostic radiology and MRI physics. An interactive whiteboard (SMART Board model 3000i) was used during an MRI physics course and diagnostic radiology teaching conferences. A multiquestion instrument was used to quantify responses. Responses are reported as simple percentages of response number and, for ordinal scale questions, the two-tailed Student's t test was used to assess deviation from the neutral response. All of the subjects attended all sessions and completed the assessment questionnaire; 89% of respondents said that image quality of the SMART Board was superior to that of a projector-screen combination, 11% said that the image quality was similar, and none said that it was inferior. Sixty-seven percent of respondents said that the SMART Board's display of diagrams was superior to that of a conventional whiteboard, 33% said it was similar, and none said it was inferior. Participants thought that the smaller SMART Board display compared with the projector screen was an unimportant limitation (p = 0.03). Room lighting did not degrade image quality (p = 0.007), and a trend toward preference for the lighted room (while using the SMART Board) was detected (p = 0.15) but was not significant. The impact of the SMART Board on the visual material and flow of teaching sessions was favorable (p = 0.005). All of the subjects preferred the SMART Board over a traditional projector and screen combination. Learners endorsed that the SMART Board significantly enhanced learning, universally preferring it to the standard projector and screen approach. Major advantages include enhanced engagement of learners; enhanced integration of images and annotations or diagrams, including display of both images and diagrams simultaneously on a single screen; and the ability to review, revise, save, and distribute diagrams and annotated images. Disadvantages include cost and potentially complicated setup in very large auditoriums.


Microfluidic system for high throughput characterisation of echogenic particles.
Echogenic particles, such as microbubbles and volatile liquid micro/nano droplets, have shown considerable potential in a variety of clinical diagnostic and therapeutic applications. The accurate prediction of their response to ultrasound excitation is however extremely challenging, and this has hindered the optimisation of techniques such as quantitative ultrasound imaging and targeted drug delivery. Existing characterisation techniques, such as ultra-high speed microscopy provide important insights, but suffer from a number of limitations; most significantly difficulty in obtaining large data sets suitable for statistical analysis and the need to physically constrain the particles, thereby altering their dynamics. Here a microfluidic system is presented that overcomes these challenges to enable the measurement of single echogenic particle response to ultrasound excitation. A co-axial flow focusing device is used to direct a continuous stream of unconstrained particles through the combined focal region of an ultrasound transducer and a laser. Both the optical and acoustic scatter from individual particles are then simultaneously recorded. Calibration of the device and example results for different types of echogenic particle are presented, demonstrating a high throughput of up to 20 particles per second and the ability to resolve changes in particle radius down to 0.1 μm with an uncertainty of less than 3%.


Assessing the multi-scale predictive ability of ecosystem functional attributes for species distribution modelling.
Global environmental changes are rapidly affecting species' distributions and habitat suitability worldwide, requiring a continuous update of biodiversity status to support effective decisions on conservation policy and management. In this regard, satellite-derived Ecosystem Functional Attributes (EFAs) offer a more integrative and quicker evaluation of ecosystem responses to environmental drivers and changes than climate and structural or compositional landscape attributes. Thus, EFAs may hold advantages as predictors in Species Distribution Models (SDMs) and for implementing multi-scale species monitoring programs. Here we describe a modelling framework to assess the predictive ability of EFAs as Essential Biodiversity Variables (EBVs) against traditional datasets (climate, land-cover) at several scales. We test the framework with a multi-scale assessment of habitat suitability for two plant species of conservation concern, both protected under the EU Habitats Directive, differing in terms of life history, range and distribution pattern (Iris boissieri and Taxus baccata). We fitted four sets of SDMs for the two test species, calibrated with: interpolated climate variables; landscape variables; EFAs; and a combination of climate and landscape variables. EFA-based models performed very well at the several scales (AUCmedian from 0.881±0.072 to 0.983±0.125), and similarly to traditional climate-based models, individually or in combination with land-cover predictors (AUCmedian from 0.882±0.059 to 0.995±0.083). Moreover, EFA-based models identified additional suitable areas and provided valuable information on functional features of habitat suitability for both test species (narrowly vs. widely distributed), for both coarse and fine scales. Our results suggest a relatively small scale-dependence of the predictive ability of satellite-derived EFAs, supporting their use as meaningful EBVs in SDMs from regional and broader scales to more local and finer scales. Since the evaluation of species' conservation status and habitat quality should as far as possible be performed based on scalable indicators linking to meaningful processes, our framework may guide conservation managers in decision-making related to biodiversity monitoring and reporting schemes.


Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis.
Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC. We performed a retrospective, single-center analysis of data collected from a tertiary referral center from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score ≤1, assessed at weeks 10-14, with baseline sub-score ≥2. Infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy by using an enzyme-linked immunosorbent assay we developed. Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 μg/mL (AUROC, 0.781) that associated with STMH at weeks 2, 6, and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ≥15 at week 6 (P = .025; odds ratio, 4.6; 95% confidence interval, 1.2-17.1) and ≥2.1 μg/mL at week 14 (P = .004; odds ratio, 5.6; 95% confidence interval, 1.7-18) as independent factors associated with STMH. In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC.


Face coverings for the public: Laying straw men to rest.
Background This article responds to one by Graham Martin and colleagues, who offered a critique of my previous publications on face coverings for the lay public in the Covid-19 pandemic. Their paper reflects criticisms that have been made of face coverings policies more generally. Method Narrative rebuttal. Results I address charges that my coauthors and I had misapplied the precautionary principle; drawn conclusions that were not supported by empirical research; and failed to take account of potential harms But before that, I remind my critics that the evidence on face coverings goes beyond the contested trials and observational studies they place centre stage. I set out some key findings from basic science, epidemiology, mathematical modelling, case studies, and natural experiments, and use this rich and diverse body of evidence as the backdrop for my rebuttal of their narrowly framed objections. I challenge my critics' apparent assumption that a particular kind of systematic review should be valorised over narrative and real-world evidence, since stories are crucial to both our scientific understanding and our moral imagination. Conclusion I conclude by thanking my academic adversaries for the intellectual sparring match, but exhort them to remember our professional accountability to a society in crisis. It is time to lay straw men to rest and embrace the full range of evidence in the context of the perilous threat the world is now facing.


The role of CTCF in coordinating the expression of single gene loci.
The CCCTC-binding factor (CTCF), which binds insulator elements in vertebrates, also facilitates coordinated gene expression at several gene clusters, including the β-globin, Igf2/H19 (insulin like growth factor 2/H19 noncoding RNA), and major histocompatibility complex (MHC) class II loci. CTCF controls expression of these genes both by enabling insulator function and facilitating higher order chromatin interactions. While the role of CTCF in gene regulation is best studied at these multi-gene loci, there is also evidence that CTCF contributes to the regulated expression of single genes. Here, we discuss how CTCF participates in coordinating gene expression at the CFTR (cystic fibrosis transmembrane conductance regulator) and IFNG (interferon-gamma) loci. We consider the structural similarities between the loci with regard to CTCF-binding elements, the possible interaction between nuclear receptors and CTCF, and the role of CTCF in chromatin looping at these genes. These comparisons reveal a functional model that may be applicable to other single-gene loci that require CTCF for coordinated gene expression.


Potential Predictors of College Women Meeting Strength Training Recommendations: Application of the Integrated Behavioral Model.
Due to numerous health benefits, national recommendations call Americans to participate in muscle-strengthening activities at least 2 days/week. However, college-aged women tend to fall short of recommendations. This study sought to examine correlates of college women meeting strength training recommendations using the Integrated Behavioral Model (IBM). Undergraduate women (n = 421) completed surveys measuring strength training, demographics, and IBM constructs. Descriptive, bivariate, and multivariate analyses were conducted using SPSS 19. Respondents were on average 20.1 years old, 79.3% were white, and 66.3% did not meet strength training recommendations. Bivariate correlations revealed significant relationships (P ≤ .01) between strength training and attitude, descriptive norms, perceived behavioral control, self-efficacy, intention, and moderate-to-vigorous physical activity. A logistic regression model revealed self-efficacy, intention, and moderate-to-vigorous physical activity were predictive of college women meeting U.S. strength training recommendations. This study supports using the IBM to understand strength training behavior among college women. Further research is needed to better understand mediating effects among IBM constructs.


Repertoire enhancement with adoptively transferred female lymphocytes controls the growth of pre-implanted murine prostate cancer.
In prostate cancer, genes encoding androgen-regulated, Y-chromosome-encoded, and tissue-specific antigens may all be overexpressed. In the adult male host, however, most high affinity T cells targeting these potential tumor rejection antigens will be removed during negative selection. In contrast, the female mature T-cell repertoire should contain abundant precursors capable of recognizing these classes of prostate cancer antigens and mediating effective anti-tumor immune responses. We find that syngeneic TRAMP-C2 prostatic adenocarcinoma cells are spontaneously rejected in female hosts. Adoptive transfer of naïve female lymphocytes to irradiated male hosts bearing pre-implanted TRAMP-C2 tumor cells slows tumor growth and mediates tumor rejection in some animals. The success of this adoptive transfer was dependent on the transfer of female CD4 T cells and independent of the presence of CD25-expressing regulatory T cells in the transferred lymphocytes. We identify in female CD4 T cells stimulated with TRAMP-C2 a dominant MHC II-restricted response to the Y-chromosome antigen DBY. Furthermore, CD8 T cell responses in female lymphocytes to the immunodominant MHC I-restricted antigen SPAS-1 are markedly increased compared to male mice. Finally, we find no exacerbation of graft-versus-host disease in either syngeneic or minor-antigen mismatched allogeneic lymphocyte adoptive transfer models by using female into male versus male into male cells. This study shows that adoptively transferred female lymphocytes, particularly CD4 T cells, can control the outgrowth of pre-implanted prostatic adenocarcinoma cells. This approach does not significantly worsen graft-versus-host responses suggesting it may be viable in the clinic. Further, enhancing the available immune repertoire with female-derived T cells may provide an excellent pool of prostate cancer reactive T cells for further augmentation by combination with either vaccination or immune regulatory blockade strategies.


Altered manganese homeostasis and manganese toxicity in a Huntington's disease striatal cell model are not explained by defects in the iron transport system.
Expansion of a polyglutamine tract in Huntingtin (Htt) leads to the degeneration of medium spiny neurons in Huntington's disease (HD). Furthermore, the HTT gene has been functionally linked to iron (Fe) metabolism, and HD patients show alterations in brain and peripheral Fe homeostasis. Recently, we discovered that expression of mutant HTT is associated with impaired manganese (Mn) uptake following overexposure in a striatal neuronal cell line and mouse model of HD. Here we test the hypothesis that the transferrin receptor (TfR)-mediated Fe uptake pathway is responsible for the HD-associated defects in Mn uptake. Western blot analysis showed that TfR levels are reduced in the mutant STHdh(Q111/Q111) striatal cell line, whereas levels of the Fe and Mn transporter, divalent metal transporter 1 (DMT1), are unchanged. To stress the Fe transport system, we exposed mutant and wild-type cells to elevated Fe(III), which revealed a subtle impairment in net Fe uptake only at the highest Fe exposures. In contrast, the HD mutant line exhibited substantial deficits in net Mn uptake, even under basal conditions. Finally, to functionally evaluate a role for Fe transporters in the Mn uptake deficit, we examined Mn toxicity in the presence of saturating Fe(III) levels. Although Fe(III) exposure decreased Mn neurotoxicity, it did so equally for wild-type and mutant cells. Therefore, although Fe transporters contribute to Mn uptake and toxicity in the striatal cell lines, functional alterations in this pathway are insufficient to explain the strong Mn resistance phenotype of this HD cell model.


The role of cancer antigen 125 (CA 125) in the management of ovarian epithelial carcinomas.
From June 1, 1984, to May 31, 1985, 98 cases of epithelial ovarian carcinomas were assessed and followed prospectively using a new murine monoclonal antibody OC 125 which detects the antigen CA 125. Serous tumors comprised 43.7% of cases, mucinous tumors 20.4%, endometrioid tumors 16%, and other epithelial tumors 19.4%. Tumors of low malignant potential and benign epithelial cystadenomas were not included. For this study the upper limit of normal for CA 125 was 20 U/ml. Thirty-six were new cases. In this group the initial CA 125 levels greater than 20 U/ml, greater than 35 U/ml, and greater than 65 U/ml were 97.2, 94.4, and 86.1%, respectively. When mucinous types were excluded the specificity rate did not change significantly. There was no significant difference in initial CA 125 levels between early stages I and II and late stages III and IV. No correlation between tumor bulk and the serum level of antigen was observed. The remaining 62 patients were being followed and in this group 50 were considered to be in remission. Six cases in the remission group had elevated CA 125 levels greater than 20 U/ml and 5 of these developed clinical recurrence. The correlation between the clinical status and concordant fluctuations in the serum levels of CA 125 in all histological types was 87.8 and 93.5% when 10 cases of mucinous tumors were excluded. The contingency coefficient was 0.746. Seven SLOs were performed. All had CA 125 levels less than 20 U/ml and the mean was 6.9 U/ml. Only 1 case was positive with microscopic disease. In our experience CA 125 was invaluable in the management and follow-up of patients with ovarian carcinoma especially for the early detection of recurrent disease and for the monitoring of patients on therapy.


Myofibroblast development is characterized by specific cell-cell adherens junctions.
Myofibroblasts of wound granulation tissue, in contrast to dermal fibroblasts, join stress fibers at sites of cadherin-type intercellular adherens junctions (AJs). However, the function of myofibroblast AJs, their molecular composition, and the mechanisms of their formation are largely unknown. We demonstrate that fibroblasts change cadherin expression from N-cadherin in early wounds to OB-cadherin in contractile wounds, populated with alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts. A similar shift occurs during myofibroblast differentiation in culture and seems to be responsible for the homotypic segregation of alpha-SMA-positive and -negative fibroblasts in suspension. AJs of plated myofibroblasts are reinforced by alpha-SMA-mediated contractile activity, resulting in high mechanical resistance as demonstrated by subjecting cell pairs to hydrodynamic forces in a flow chamber. A peptide that inhibits alpha-SMA-mediated contractile force causes the reorganization of large stripe-like AJs to belt-like contacts as shown for enhanced green fluorescent protein-alpha-catenin-transfected cells and is associated with a reduced mechanical resistance. Anti-OB-cadherin but not anti-N-cadherin peptides reduce the contraction of myofibroblast-populated collagen gels, suggesting that AJs are instrumental for myofibroblast contractile activity.


Implementing the DICOM Standard for Digital Pathology.
Digital Imaging and Communications in Medicine (DICOM®) is the standard for the representation, storage, and communication of medical images and related information. A DICOM file format and communication protocol for pathology have been defined; however, adoption by vendors and in the field is pending. Here, we implemented the essential aspects of the standard and assessed its capabilities and limitations in a multisite, multivendor healthcare network. We selected relevant DICOM attributes, developed a program that extracts pixel data and pixel-related metadata, integrated patient and specimen-related metadata, populated and encoded DICOM attributes, and stored DICOM files. We generated the files using image data from four vendor-specific image file formats and clinical metadata from two departments with different laboratory information systems. We validated the generated DICOM files using recognized DICOM validation tools and measured encoding, storage, and access efficiency for three image compression methods. Finally, we evaluated storing, querying, and retrieving data over the web using existing DICOM archive software. Whole slide image data can be encoded together with relevant patient and specimen-related metadata as DICOM objects. These objects can be accessed efficiently from files or through RESTful web services using existing software implementations. Performance measurements show that the choice of image compression method has a major impact on data access efficiency. For lossy compression, JPEG achieves the fastest compression/decompression rates. For lossless compression, JPEG-LS significantly outperforms JPEG 2000 with respect to data encoding and decoding speed. Implementation of DICOM allows efficient access to image data as well as associated metadata. By leveraging a wealth of existing infrastructure solutions, the use of DICOM facilitates enterprise integration and data exchange for digital pathology.


Differential expression of two different homeobox gene families during mouse tegument morphogenesis.
The expression of six genes belonging to two different homeobox gene families was studied during the embryonic and postnatal morphogenesis of head and body regions of the mouse integument. The first family included the Otx1 and Otx2 genes, both related to the orthodenticle Drosophila gene and the second was represented by four members of the Antennapedia class HOX genes: Hoxc8 and three Hoxd genes, d9, d11 and d13. In situ hybridizations with 35S labeled antisense RNA probes were performed on head serial frontonasal sections, as well as entire embryo and postnatal tail longitudinal sections. The expression of these genes shows a differential spatiotemporal pattern along the cephalo-caudal axis. In 12.5-day and 15.5-day embryos, the Otx2 gene expression is restricted to the nasal epithelium and its associated glands, while the Otx1 transcripts are present in both nasal and facial integuments, including nasal glands and hair vibrissa follicles. The Hoxc8 expression first appears in skin at 14.5 days of gestation in the sternal region and is extended at 16.5 days to the thoracic ventral and lumbar dorsal regions. The Hoxd9 and Hoxd11 genes are only expressed in the caudal skin from 14.5 days of gestation. The Hoxd13 transcripts are the last to appear, 2 days after birth, and are limited to the last epidermal cells to differentiate, i.e. those of the hair matrix of the caudal pelage hair follicles. Taken together, these observations strengthen the hypothesis that different homeobox gene families specify the regional identity of the skin in the cephalic and body regions.


Inappropriate nonsteroidal anti-inflammatory drug use: prevalence and predictors.
Inappropriate nonsteroidal anti-inflammatory drug (NSAID) use can occur by using more than one prescription or over-the-counter NSAID or exceeding the manufacturer's recommended dosage. There are risks associated with inappropriate NSAID use; however, the prevalence and predictors of inappropriate NSAID use are unknown. The study objectives are to estimate the prevalence of inappropriate NSAID use and identify characteristics associated with inappropriate use. We identified 6877 patients at 2 Veterans Affairs Medical Centers through pharmacy records who filled 3 or more NSAID prescriptions in 6 months. We randomly selected 2535 patients and mailed them a survey about NSAIDs, gastroprotective medications, gastrointestinal (GI) symptoms, and pain. Inappropriate NSAID users either took 2 or more NSAIDs for 3 days or more or exceeded the maximum daily recommended dosage of 1 or more NSAID in the past week. Data were also collected from medical records. Approximately 1572 patients (62%) returned the survey, and 1250 reported NSAID use in the past week. Approximately 32% (n = 400) used NSAIDs inappropriately, including taking 2 or more NSAIDs (n = 173), exceeding the highest daily recommended dosage (n = 161) or both (n = 66). Being a minority (odds ratio = 1.62, P < 0.001) and having an income of $20,000 (odds ratio = 1.70, P < 0.001) or lesser both predicted inappropriate NSAID use. Inappropriate NSAID use was associated with more GI symptoms (β = 0.57, P < 0.001) and higher levels of pain (β = 0.85, P < 0.001). Inappropriate NSAID use is prevalent. Providers should consider counseling all patients about NSAID use, especially patients with GI problems or pain problems.


A single-chamber microbial fuel cell without an air cathode.
Microbial fuel cells (MFCs) represent a novel technology for wastewater treatment with electricity production. Electricity generation with simultaneous nitrate reduction in a single-chamber MFC without air cathode was studied, using glucose (1 mM) as the carbon source and nitrate (1 mM) as the final electron acceptor employed by Bacillus subtilis under anaerobic conditions. Increasing current as a function of decreased nitrate concentration and an increase in biomass were observed with a maximum current of 0.4 mA obtained at an external resistance (R(ext)) of 1 KΩ without a platinum catalyst of air cathode. A decreased current with complete nitrate reduction, with further recovery of the current immediately after nitrate addition, indicated the dependence of B. subtilis on nitrate as an electron acceptor to efficiently produce electricity. A power density of 0.0019 mW/cm(2) was achieved at an R(ext) of 220 Ω. Cyclic voltammograms (CV) showed direct electron transfer with the involvement of mediators in the MFC. The low coulombic efficiency (CE) of 11% was mainly attributed to glucose fermentation. These results demonstrated that electricity generation is possible from wastewater containing nitrate, and this represents an alternative technology for the cost-effective and environmentally benign treatment of wastewater.


Single nucleotide polymorphisms and disease gene mapping.
Single nucleotide polymorphisms are the most important and basic form of variation in the genome, and they are responsible for genetic effects that produce susceptibility to most autoimmune diseases. The rapid development of databases containing very large numbers of single nucleotide polymorphisms, and the characterization of haplotypes and patterns of linkage disequilibrium throughout the genome, provide a unique opportunity to advance association strategies in common disease rapidly over the next few years. Only the careful use of these strategies and a clear understanding of their statistical limits will allow novel genetic determinants for many of the common autoimmune diseases to be determined.


Evolution of branch points for a laser beam propagating through an uplink turbulent atmosphere.
Evolution of branch points in the distorted optical field is studied when a laser beam propagates through turbulent atmosphere along an uplink path. Two categories of propagation events are mainly explored for the same propagation height: fixed wavelength with change of the turbulence strength and fixed turbulence strength with change of the wavelength. It is shown that, when the beam propagates to a certain height, the density of the branch-points reaches its maximum and such a height changes with the turbulence strength but nearly remains constant with different wavelengths. The relationship between the density of branch-points and the Rytov number is also given. A fitted formula describing the relationship between the density of branch-points and propagation height with different turbulence strength and wavelength is found out. Interestingly, this formula is very similar to the formula used for describing the Blackbody radiation in physics. The results obtained may be helpful for atmospheric optics, astronomy and optical communication.


Automatically Diagnosing Skin Cancers From Multimodality Images Using Two-Stage Genetic Programming.
Developing a computer-aided diagnostic system for detecting various skin malignancies from images has attracted many researchers. Unlike many machine-learning approaches, such as artificial neural networks, genetic programming (GP) automatically evolves models with flexible representation. GP successfully provides effective solutions using its intrinsic ability to select prominent features (i.e., feature selection) and build new features (i.e., feature construction). Existing approaches have utilized GP to construct new features from the complete set of original features and the set of operators. However, the complete set of features may contain redundant or irrelevant features that do not provide useful information for classification. This study aims to develop a two-stage GP method, where the first stage selects prominent features, and the second stage constructs new features from these selected features and operators, such as multiplication in a wrapper approach to improve the classification performance. To include local, global, texture, color, and multiscale image properties of skin images, GP selects and constructs features extracted from local binary patterns and pyramid-structured wavelet decomposition. The accuracy of this GP method is assessed using two real-world skin image datasets captured from the standard camera and specialized instruments, and compared with commonly used classification algorithms, three state of the art, and an existing embedded GP method. The results reveal that this new approach of feature selection and feature construction effectively helps improve the performance of the machine-learning classification algorithms. Unlike other black-box models, the evolved models by GP are interpretable; therefore, the proposed method can assist dermatologists to identify prominent features, which has been shown by further analysis on the evolved models.


Breathing Rate Estimation From the Electrocardiogram and Photoplethysmogram: A Review.
Breathing rate (BR) is a key physiological parameter used in a range of clinical settings. Despite its diagnostic and prognostic value, it is still widely measured by counting breaths manually. A plethora of algorithms have been proposed to estimate BR from the electrocardiogram (ECG) and pulse oximetry (photoplethysmogram, PPG) signals. These BR algorithms provide opportunity for automated, electronic, and unobtrusive measurement of BR in both healthcare and fitness monitoring. This paper presents a review of the literature on BR estimation from the ECG and PPG. First, the structure of BR algorithms and the mathematical techniques used at each stage are described. Second, the experimental methodologies that have been used to assess the performance of BR algorithms are reviewed, and a methodological framework for the assessment of BR algorithms is presented. Third, we outline the most pressing directions for future research, including the steps required to use BR algorithms in wearable sensors, remote video monitoring, and clinical practice.


Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement.
Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.


Which obstacle attributes place additional demands on higher-level cognitive function in patients with Parkinson's disease?
Previous reports show that patients with Parkinson's disease (PD) rely on prefrontal activation to compensate for impaired motor function during complex activities such as obstacle negotiation. However, the influence of the properties of the obstacles on prefrontal activation has not been systematically evaluated. Here, we examined the effects of obstacle height and anticipation time on prefrontal activation in patients with PD and older adults. 34 patients with PD (age: 67.4 ± 5.7 years; 14 women) and 26 older adults (age: 71.3 ± 8.9 years; 11 women) walked in an obstacle course while negotiating anticipated and unanticipated obstacles (long/short available time response, ART) at heights of 50 mm and 100 mm. Prefrontal activation was measured using functional Near-Infrared Spectroscopy (fNIRS); obstacle negotiation performance was measured using Kinect cameras. PD patients showed greater increases in prefrontal activation during and after obstacle crossing compared to the older adults (p < 0.001). Obstacle height affected prefrontal activity only when crossing anticipated obstacles (ARTxheight interaction, p = 0.011), in which case higher obstacles were accompanied by higher prefrontal activity. PD patients showed higher levels of activation during unanticipated obstacles, compared to older adults (groupXART: p = 0.015). Different correlations between prefrontal activation and obstacle negotiation strategies were observed in patients and controls. These results point to the use of prefrontal activation as a compensatory mechanism in PD. Moreover, the higher activation observed when negotiating more challenging obstacles suggests that there is greater reliance on cognitive resources in these demanding situations that may contribute to the higher risk of falls in PD patients.


Cryogenic optical measurements of 12-segment-bonded carbon-fiber-reinforced silicon carbide composite mirror with support mechanism.
A 720 mm diameter 12-segment-bonded carbon-fiber-reinforced silicon carbide (C/SiC) composite mirror has been fabricated and tested at cryogenic temperatures. Interferometric measurements show significant cryogenic deformation of the C/SiC composite mirror, which is well reproduced by a model analysis with measured properties of the bonded segments. It is concluded that the deformation is due mostly to variation in coefficients of thermal expansion among segments. In parallel, a 4-degree-of-freedom ball-bearing support mechanism has been developed for cryogenic applications. The C/SiC composite mirror was mounted on an aluminum base plate with the support mechanism and tested again. Cryogenic deformation of the mirror attributed to thermal contraction of the aluminum base plate via the support mechanism is highly reduced by the support, confirming that the newly developed support mechanism is promising for its future application to large-aperture cooled space telescopes.


Recent insights into upconverting nanoparticles: spectroscopy, modeling, and routes to improved luminescence.
The development of reliable and reproducible synthetic routes that produce monodisperse lanthanide-doped upconverting nanoparticles has resulted in an appreciable need to determine the mechanisms which govern upconversion luminescence at the nanoscale. New experimental and theoretical evidence explicates the quenching phenomena involved in the low luminescence efficiencies. A deeper understanding of the role of surfaces and defects in the quenching mechanisms and the properties of upconverting nanoparticles are of fundamental importance to develop nanomaterials with enhanced luminescence properties. Herein, we summarize the most recent spectroscopic investigations, which have enabled the scientific community to ascertain that the predominant source of quenching involved in the luminescence of lanthanide-doped upconverting nanoparticles can be attributed to surface-defects. Modeling of these mechanisms in nanomaterials supports the experimental findings and yields further insights into the surface phenomena, providing a predictive tool to improve the luminescent efficiencies in nanomaterials.


Six-year-old boy with a slow-onset persistent back pain.
A 6-year-old boy was evaluated for a 6-week history of low back pain. Initially, the pain was exacerbated by movements, eventually showing a milder and fluctuating trend. History was unremarkable for previous traumatic events, fever or nocturnal pain. Physical examination revealed localised pain at palpation of the spinous processes at the lumbosacral level. Blood tests showed a normal blood count, negative C reactive protein (CRP) and erythrocyte sedimentation rate, normal lactic acid dehydrogenase (LDH) and creatine phosphokinase. A posterior-anterior radiograph of the lumbar spine resulted normal. An MRI scan revealed a lumbosacral transitional vertebra with bone oedema of the posterior arch until the spinous process. For better bone definition, a CT scan was performed ( figure 1 ).


Analysis of secondary modifications of mouse mammary tumor virus proteins by two-dimensional gel electrophoresis.
The structural proteins of mouse mammary tumor virus (MMTV) were analyzed by two-dimensional electrophoresis on isoelectric focusing and sodium dodecyl sulfate gels. Many of the viral proteins displayed heterogeneity in charge due to variable contents of carbohydrates (in particular, sialic acid) and phosphate residues. Neuraminidase treatment of the virions influenced the isoelectric pattern of the envelope glycoproteins. The glycoproteins of an MMTV variant which was attenuated by replication in feline kidney cells had different isoelectric points. This suggested that the acquisition of an altered carbohydrate configuration had changed the host range of the virus. The major MMTV structural core protein, p27, consisted of two species, which had identical iodinated tryptic peptide compositions but differed in phosphate contents. Another MMTV phosphoprotein, p21, was separated into four different phosphorylated species. Phosphorylation of p21 could be performed in vitro by the MMTV virion-associated protein kinase. This enzyme also has a high affinity for MMTV p30 as a substrate. Possible functions of this enzyme are discussed.


Normal stages of cardiac organogenesis in the mouse: II. Development of the internal relief of the heart.
Normal stages of intracardiac development of the mouse heart are illustrated by a collection and analysis of two complementary SEM views, the septal and parietal halves of the right ventricle and conotruncus. These views are particularly suitable for understanding the septation of the outflow tract of the heart. They represent references for the studies of the pathogenesis of conotruncal malformations. The analysis is based on 90 hearts between 11ed and 15ed at intervals of 8 hours with an additional stage at 16ed. They were prepared by perfusion fixation, microdissection, and critical point drying and were examined in SEM. The following main features of the intracardiac morphogenesis were observed: 1) the presence of two spirally positioned conotruncal ridges, their disto-proximal fusion, and the formation of the semilunar valves at their distal part; 2) the trabecular transformation of the conotruncal wall; and 3) the presence of two different interventricular foramina (FIV II and FIV III), with the final closure of FIV III at 14ed16h-15ed. As a result of these observations, our description of the outflow tract septation and its interpretation are different from other conceptions based on mechanisms such as bulbar shift, bulbar absorption, torsions, or transfer of the aorta into the left ventricle.


Building a Medicaid Ambulatory Complex Care Program Within an Urban Medical Home.
Five percent of Medicaid patients account for 50% of total costs. Preventable costs are often incurred by patients with complex medical, behavioral, and social needs who disproportionately utilize acute care services. Evidence for design, implementation, and evaluation of complex care programs in the urban Medicaid population is lacking. The article provides a description of a complex care program (CCP), challenges, and early outcomes based on a pre-post evaluation. The CCP was located within an existing urban medical home. Patients were eligible if they lived within 10 miles of the clinic and had at least 2 inpatient visits and/or 3 emergency room visits within the prior 6 months. Ambulatory Care Groups® were used to predict estimated total costs of patients, who were included if potential cost savings exceeded $5000. Patient experience and quality of care were assessed using validated measures and costs. Return on investment was calculated based on investment and cost savings. Costs include visits (clinic, specialty, and emergency room), hospital admissions, medications, tests and services, as well as salary and benefits of clinical staff. Eighty-six of 211 eligible patients (41%) were enrolled during the first 18 months of the pilot program. There were positive trends in quality metrics and patient satisfaction. The pre-post evaluation demonstrated a reduction in emergency room visits and hospitalizations (67% and 65%, respectively), which resulted in a 2.2:1 return on investment. This article offers lessons learned to colleagues considering population health approaches in the care of high-risk Medicaid patients.


Education modulates brain maintenance in presymptomatic frontotemporal dementia.
Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time. Two-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling. Highly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers. This longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.